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PMC6662528_01

Female

A 25-year-old right-handed woman was admitted to our hospital with a 3-week history of intermittent non-throbbing bilateral headache involving frontal and temporal lobes, accompanied by nausea, vomiting, left upper extremity numbness and weakness, left-sided tongue and perioral numbness, and involuntary movements of the left upper extremity. There were five episodes with complete recovery in the last 3 weeks, of which two episodes were without any neurologic deficit and three episodes were preceded by transient symptoms. The numbness and weakness lasted for about 10 to 20 mins and were ensued by headache and involuntary movements of the left upper extremity. The headache lasted approximately 2-9 hrs and was graded as 8/10 in the VAS (with 0 indicating no headache and 10 the most severe headache). The involuntary movements of the left upper extremity occurred in two episodes and lasted for about 1 to 2 hrs. The involuntary movements of the left upper extremity and headache occurred simultaneously after numbness and weakness of the left upper extremity, and the duration of involuntary movement was shorter than that of the headache. She was conscious during the episodes. The involuntary movements were chorea of the left upper extremity, which presented as irregular, arrhythmic and brief movements of the left hand and forearm. The chorea of the left hand was more obvious than the forearm, and the movement was remarkable during the voluntary movements. Cough, yellow sputum and snot were also reported, but no fever. She had no history or relevant family history of migraine. She had a regular menstrual cycle and no history of previous pregnancy. She did not take oral contraceptives or any other medication before the headache. She was Han Chinese and worked as an office clerk. Upon admission, she had no symptom and the neurological examinations were unremarkable. Fundus examination revealed no papilledema or any other abnormalities. The routine blood tests and autoimmune tests were both normal. Also, the cerebral magnetic resonance imaging (with contrast medium) and angiography did not show any abnormality (Figure 1). The first lumbar puncture at an external hospital showed intrathecal cerebrospinal fluid (CSF) opening pressure of 20cmH2O and prominent lymphocytic (90%) pleocytosis with the cell count of 114/microL. The second lumbar puncture conducted in our hospital revealed slightly increased CSF opening pressure of 30cmH2O, and confirmed the pleocytosis with cell count of 54/microL (lymphocytes 81%). There was also increased level of protein with 5.04 g/L, but normal glucose level. Serological tests were positive for lgG coxsackie virus and lgG varicella-zoster, and CSF tests of IgM/G virus were negative. Mycobacterium tuberculosis and parasites were not detected in CSF, and oligoclonal bands were not detected as well. Electroencephalogram of asymptomatic period showed no abnormality. Initial treatment with non-steroidal anti-inflammatory drugs, ganciclovir, mannitol and anti-epileptic medications at an external hospital did not halt the recurrence of the symptoms. During admission at our hospital, she was given ganciclovir initially, but she developed two new episodes of headache (VAS 7/10) with focal neurological symptoms, including numbness, weakness and involuntary movements of the left upper extremity. Chorea of the left hand lasted for 30-45 mins and headache for about 2 hrs. The left upper extremity weakness was graded as 4/5 using the Medical Research Council grading system. The characteristics of the episodes were similar to that described above. Meningeal irritation sign was absent during the attack. The third lumbar puncture showed 30cmH2O of CSF opening pressure and lymphocytosis (74%). She was treated with intravenous methylprednisolone with initial dose of 120 mg/day which was tapered to 40 mg/day within 7 days. The fourth CSF examination after the administration of methylprednisolone for 7 days showed CSF opening pressure of 23cmH2O and cell number of 24/microL with 74% of lymphocytes. She did not experience any recurrence of the symptoms, and the oral methylprednisolone was discontinued gradually within 1 month. After about 1 month, she was discharged from our hospital. The final and fifth CSF examination showed CSF opening pressure of 17cmH2O and cell count of 12/microL with 79% of lymphocytes. The five CSF examinations are summarized in Table 1. At 1-year follow-up, she denied any recurrence of the symptoms. Written informed consent from the patient was obtained to perform invasive procedures and publish data. The ethics committee of our institute approved the publication of the case details.

intracranial hypertension, involuntary movement, steroids, syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (handl)

PMC6066802_01

Male

A 21-year-old man presented with upper abdominal pain since 3 months associated with intermittent vomiting, melena, and 7 kg weight loss. Clinical examination revealed pallor with lump in epigastric region approximately 2 cm x1.5 cm in size. The lump was nontender, moving with respiration, with normal overlying skin and temperature. Routine blood investigations are summarized in Table 1. There was microcytic hypochromic anemia. Upper GI endoscopy revealed a large deep excavated ulcer in the esophagus at about 25 cm from the incisors and associated ulcer of size 2 cmx1.5 cm with a suspicious fistulous opening seen in the antropyloric region. Computed tomography (CT) of abdomen revealed diffuse circumferential thickening involving the antrum and pylorus together with thickening involving the proximal transverse colon for a length 7 cm, with multiple necrotic perigastric and periportal lymph nodes. Colonoscopy showed nodular mucosa with superficial ulceration in proximal transverse colon. Histopathology from esophageal, antral, and transverse colon ulcer biopsies showed prominent lymphoid aggregate with occasional caseating granuloma and Langerhans giant cell (Figure 2A). Tuberculosis culture using Mycobacteria Growth Indicator Tube (MGIT) was positive from the antral and transverse colon biopsy specimens. Patient was started on antituberculous treatment regimen consisting of isoniazid 5 mg/kg, rifampicin 10 mg/kg, ethambutol 15 mg/kg, and pyrazinamide 25 mg/kg body weight for initial 2 months followed by isoniazid and rifampicin in same dose for another 7 months. Repeat upper GI endoscopy after 4 months of treatment showed healed esophageal and gastric ulcer with healed fistula (Figure 3A). He is asymptomatic and under regular follow-up.

gastroduodenal, fistula, gastric outlet, malignancy, tuberculosis

PMC6066802_02

Female

A 24-year-old woman presented with nonbilious, nonprojectile vomiting, 1 to 2 hours after meals, with low-grade fever for 1 month. There was loss of appetite with significant loss of weight. Clinical examination showed pallor. Routine investigations are summarized in Table 1. There was microcytic hypochromic anemia. Upper GI endoscopy revealed nodularity with ulceration at the junction of the first and second parts of duodenum with a suspicious fistulous opening (Figure 1A). Asymmetric mucosal thickening involving the junction of first and second parts of duodenum with multiple necrotic perigastric and retroperitoneal lymph nodes was noted on CT abdomen. There was also evidence of a suspicious fistulous communication between proximal transverse colon and jejunum along with clumping of bowel loops on contrast-enhanced CT (CECT). Colonoscopy showed long segment ulceronodular lesion in the transverse colon. Biopsy from the duodenal and colonic lesions showed lymphoid aggregate with multiple noncaseating granuloma (Figure 2B). The TB MGIT culture from duodenal biopsy showed growth of Mycobacterium tuberculosis. Patient was given antitubercular drugs for 9 months. She had complete resolution of clinical symptoms with weight gain. Repeat endoscopy after 6 months of antitubercular therapy showed decreased nodularity with healed fistulous opening in the duodenum (Figure 3B).

gastroduodenal, fistula, gastric outlet, malignancy, tuberculosis

PMC6066802_03

Female

A 22-year-old woman presented with history of upper abdominal pain, mild in intensity, dull aching, nonradiating, associated with occasional nonbilious vomiting since 1 month. There was no clinical evidence of abdominal lump or lymphadenopathy. Routine investigations are summarized in Table 1. There was mild microcytic hypochromic anemia. Upper GI endoscopy revealed multiple small nodules with erosions in the duodenum (Figure 1B). Multiple conglomerated lymph nodes at porta hepatis together with thickening of antropyloric region were seen on CECT. Biopsy from duodenal erosions showed mixed inflammation with multiple noncaseating granulomas (Figure 2C). Duodenal biopsies were positive for TB GeneXpert and TB MGIT culture. Patient has completed 9 months of antitubercular drug therapy. Repeat upper GI endoscopy at the end of 5 months revealed healed duodenal lesions.

gastroduodenal, fistula, gastric outlet, malignancy, tuberculosis

PMC5303562_01

Male

The patient was a 69 year-old male with a history of waxing and waning cognitive decline. In addition, the patient had visual hallucinations, and significant balance problems with numerous reported falls and a history of a Parkinsonian disorder. He had a limited response to L-Dopa, but had an early good response to Exelon. Past medical history included spinal stenosis, gastroparesis, possible REM sleep disorder, autonomic dysfunction (increased sweating), and kidney stones with numerous kidney infections. Other diseases included myocardial infarction and aspiration pneumonia in 2007. Past social history included playing football in junior high and high school with a history of multiple diagnosed concussions. He also was involved and participated in other contact sports including karate, kick boxing, and was a Golden Gloves boxing coach. In his boxing coach role, he would spar without a helmet, increasing his risk for concussive injury. Finally, the patient was in an automotive accident in 1988 with possible head injury. On post-mortem examination, the fixed brain weight was 1130 grams. A portion of cerebral dura was available for examination and showed no dural fibrosis and no significant epidural or subdural hemorrhages. There were no old or new subarachnoid hemorrhages. The cerebral gyral pattern was of normal anatomic configuration with moderate cerebral edema, but without masses, vascular abnormalities, or palpable lesions. The left occipital lobe was mildly dusky. There was no evidence of orbital or temporal tip contusions. The cerebral vasculature was ectatic but without atherosclerosis. The circle of Willis had a normal anatomical configuration. The brainstem and cerebellum had a normal external appearance. The spinal dura showed no evidence of epidural hemorrhages and the spinal cord was not distorted by any contained masses or other lesions. Serial coronal sections of the cerebral hemispheres revealed the cortical gray and white matter structures to be without hemorrhages, infarcts, or mass lesions. There was mild atrophy of the anterior hippocampus with moderate atrophy of the posterior hippocampi bilaterally. There was also mild atrophy of the posterior cerebral white matter, which followed the corpus callosum trajectory. The corpus callosum demonstrated mild atrophy as well. The basal ganglia, thalamus, amygdalae, and mamillary bodies bilaterally were of normal size, color and consistency. The ventricular system was moderately dilated with no gradient and was otherwise symmetrical. Serial sections of the brainstem and cerebellum revealed mild superior cerebellar vermal atrophy and mild to moderate cerebellar dentate nucleus atrophy with a dusky gray discoloration. The substantia nigra was thin but did not demonstrate pallor. The locus ceruleus was well pigmented. Serial sections of the spinal cord were symmetrical without discoloration or lesions. The H&E and Bielschowsky silver stains revealed numerous amyloid plaques of both the diffuse as well as neuritic type in all neocortical areas in laminar arrangement. In addition, there were numerous neurofibrillary tangles, particularly in the pyramidal neurons of layers 3 and 5, but no cortical Lewy bodies were present measured by alpha-synuclein staining (Figure 1). There was marked pallor of the white matter with numerous vessels that were hyalinized. The caudate nucleus and putamen contained diffuse plaques, gliosis, and numerous vessels that were hyalinized. The hippocampus and amygdala contained numerous plaques and neurofibrillary tangles in a laminar distribution. The thalamus contained tangles in the midline nuclei. The substantia nigra was focally gliotic with some neuronal dropout but without evidence of Lewy or pale bodies determined by negative staining for alpha-synuclein. The pons contained tangles in the locus ceruleus and raphe nuclei. The cerebellum contained no diffuse plaques in the molecular layer. Throughout the brain there was retraction artifact surrounding neurons and blood vessels. Immunoperoxidase staining for PHF1/tau revealed numerous neurofibrillary tangles in the cerebral cortex including the temporal lobe, cingulate gyrus, and superior frontal cortex. The overall score for tau changes was at a B3 level (NIA criteria). The PHF/tau also significantly stained the neuritic component of the amyloid plaques and the amyloid plaque score was at a C3 level (NIA criteria). Tau positive tangles were also noted in the raphe and the locus ceruleus. No tau positive tangles were found in the substantia nigra, periaqueductal grey, or in the basis pontis. Ubiquitin stains for Lewy bodies and TDP-43 staining were also negative in the midbrain and pons. The neuropathological findings were consistent with AD Braak stage VI, by the NIA Consensus Criteria. Therefore, because no brainstem or cortical Lewy bodies were indentified with alpha-synuclein staining, the diagnoses of typical idiopathetic Parkinson's disease or diffuse Lewy body disease were ruled out. In addition, no neurofibrillary tangles or tufted astrocytes were found in areas that are usually associated with progressive supranuclear palsy (PSP).

alzheimer’s disease, chronic traumatic encephalopathy, dementia, neurotrauma, traumatic brain injury

PMC5303562_02

Male

The patient was a 41 year-old male with a history of participation in the National Football League for multiple seasons over the course of years. Upon retirement, the patient began to exhibit forgetfulness that was subsequently followed by progressive agitation, depression, anxiety, and agoraphobia in the years prior to his death. The fixed brain weighed 1554 grams. A portion of the dura was not available for examination. The leptomeninges were thin and translucent over the convexities but over the base of the brain were fibrotic. There was no cerebral edema, and no evidence of contusions at the base of the brain. There was no evidence of cortical atrophy, infarctions or mass lesions. There was mild cerebral edema. The arteries of the circle of Willis demonstrated no atherosclerosis. There were no aneurysmal dilatations of the cerebral vasculature. Subfalcine, transtentorial, uncal, or tonsillar herniation was not appreciated. The brainstem and cerebellum had a normal external appearance. Serial coronal sectioning through the fixed brain revealed the usual internal architectural features without infarcts or mass lesions. The subcortical nuclei including the basal ganglia and thalamus, as well as mammillary bodies bilaterally were of normal size, color, and consistency. There was no evidence of hippocampal or amygdalae atrophy. The posterior corpus callosum showed mild thinning. The ventricular system was mildly dilated. Serial sections of the brainstem and cerebellum revealed no lesions, but the substantia nigra and the pontine locus ceruleus showed moderate pallor. The H&E and Bielschowsky silver stains revealed no amyloid plaques of either the diffuse or neuritic type in any of neocortical or subcortical areas examined. However, there were neurofibrillary tangles, particularly in the neurons of the superficial temporal neocortex. No cortical Lewy bodies were identified with alpha-synuclein staining. Neurofibrillary tangles were also noted in entorhinal cortex particularly in the origin of the perforant pathway. The hippocampus and amygdala contained neurofibrillary tangles in a diffuse distribution in the latter. Most of the hippocampal CA fields contained diffuse neurofibrillary tangles. The substantia nigra showed no significant neuronal drop out. Lewy bodies were not readily identified in the substantia nigra. The pons contained tangles in the locus ceruleus. PHF-1 tau staining revealed numerous positive tangles and neuritic neuropil changes in the entorhinal cortex including the neurons in the origin of the perforant pathway. In addition, there was PHF-1 tau positive tangles in the superficial neocortical regions (temporal>mid-frontal>>occipital). The amygdala, hippocampus and thalamus contained PHF-tau positive tangles. The substantia nigra contained a single neuron with surrounding neuritic change, but the locus ceruleus (LC) was severely affected with numerous PHF-tau positive tangles and neuritic change in the neuropil. The raphe and the surrounding pontine tegmentum contained a few scattered phosphorylated tau positive cells (Figure 2).

alzheimer’s disease, chronic traumatic encephalopathy, dementia, neurotrauma, traumatic brain injury

PMC5303562_03

Male

The patient was a 74 year-old man at the time of death with a past medical history positive for atrial fibrillation and AD (clinically diagnosed at age 67). His initial symptoms included an inability to compute simple percentage discounts at his furniture store, followed by a gradual progression with variable response to Aricept/memantine, eventually becoming aphasic. Additional neurological history is significant for head trauma in the following instances: breech delivery (as an infant), diving accident (as a child), bicycle accident, warehouse fall (age 60), high school and college football starter with numerous concussions sustained while participating, and two falls while in the nursing home. The brain weighed 1336 grams. The leptomeninges were fibrotic, including at the base of the brain; there were no exudates. There was no cerebral edema, and no evidence of contusions at the base of the brain. The brain demonstrated evidence of diffuse cerebral cortical atrophy involving the frontal and temporal lobes as well as the cingulate gyrus. The arteries of the circle of Willis demonstrated mild atherosclerosis. The brainstem and cerebellum had a normal external appearance. Serial coronal sectioning revealed the usual internal architectural features without infarcts or mass lesions. The caudate nuclei, however, were flattened bilaterally. The remainder of the basal ganglia and thalamus, and mammillary bodies bilaterally were of normal size, color, and consistency. There was, however, bilateral hippocampal and amygdalae atrophy. The ventricular system was moderately dilated (posteriorly > anteriorly). In addition, a cavum septum pellucidum was found and was most prominent ventrally. Serial sections of the brainstem and cerebellum revealed no lesions with the substantia nigra being well pigmented. However, the pontine locus ceruleus was pale. There was mild superior vermal atrophy in the cerebellum. The H&E and Bielschowsky silver stains revealed numerous amyloid plaques of both the diffuse as well as neuritic type in all neocortical areas (Figure 3). In addition, there were numerous neurofibrillary tangles seen, particularly in the neocortical pyramidal neurons of layers 3 and 5, but no cortical Lewy bodies were found. The tangles were both laminar in distribution with some punctate perivascular positive staining. The sensory motor-strip and temporal tip showed Congo red positive cortical blood vessels for cerebral amyloid angiopathy. There was pallor of the white matter with numerous hyalinized barrel-shaped small blood vessels. The caudate and putamen contain diffuse plaques, evidence of gliosis, and numerous hyalinized barrel-shaped small blood vessels. Neurofibrillary tangles were also noted in the ventral striatum. The hippocampus and amygdala contained numerous amyloid plaques and neurofibrillary tangles, particularly in the CA1 field. In addition, the amygdala contained Lewy bodies evidenced by positive alpha-synuclein. The thalamus contained neurofibrillary tangles in the midline nuclei. The substantia nigra was gliotic with neuronal drop out with some remaining neurons containing neurofibrillary tangles, but no Lewy bodies were indentified. The pons contained tangles in the locus ceruleus and raphe nuclei. The cerebellum contained diffuse plaques in the molecular layer. PHF-1 tau staining revealed numerous positive neurofibrillary tangles and neuritic plaques as well as a laminar distribution of neuritic neuropil changes consistent with typical AD as described above. However, there were significant PHF-1 tau tangles and neuritic changes in the following areas: the pontine tegmentum outside the locus ceruleus and raphe, the substantia nigra both laterally and medially, and the lateral thalamic nuclei and pulvinar. Additionally, characteristic of CTE, perivascular PHF was seen at the depths of the sulci in cortical white matter and the indusium griseum (Figures 4 and 5). The neuropathologic findings were consistent with AD neuropathologic change (high level) by the NIA Consensus Criteria . Each category of scoring - Abetaplaque distribution (A score-3), neurofibrillary tangles extent (B score-3), and number of neuritic plaques (C score-3) - received a high grade (A3 B3 C3). When cognitive impairment and behavioral change is apparent clinically, an intermediate or high grade of neuropathologic change strongly substantiates AD as the main disease. The finding of cerebral amyloid angiopathy was typical, as it is rather common in cases with a significant degree of Abeta plaques. The finding of Lewy bodies in the amygdala (Lewy body disease, amygdala-predominant) is also typical for AD, as Lewy body disease in the amygdala typically occurs along with high grade AD neuropathologic change. There was both small and large vessel disease present. Cerebrovascular disease is thought to be a comorbid factor. Additional abnormal tau findings in the reticular activating system of the pons, the entire substantia nigra, lateral thalamic nuclei, the pulvinar, and in the perivascular subcortical white matter, suggest a concomitant diagnosis of CTE. CTE has a clinical picture of mood, personality, cognitive change, behavioral change, and motor symptomatology, as described above. Associated histopathologic changes are considered due to an extensive accumulation of phosphorylated tau protein, seen as neurofibrillary and astrocytic tangles. With or without the specific label of CTE, football players with a history of TBI have a higher risk of chronic mood, behavioral, and cognitive issues. AD clearly played a significant role in the neurological morbidity but may have been exacerbated by CTE. The deceased patient competed in contact sports at a high level for many years, experiencing multiple concussive events, along with head injuries acquired outside of athletics. Therefore, it is important to consider CTE, in addition to AD, as a separate and/or concomitant contributor in his neurological decline.

alzheimer’s disease, chronic traumatic encephalopathy, dementia, neurotrauma, traumatic brain injury

PMC4272956_01

Male

A strain of S. marcescens, designated GN1384, was isolated from the urine of a 81-yr-old male patient who suffered from urinary tract infections in September 2009 and was admitted to the second hospital of Hefei, China. Species identification was performed with the Vitek2 system (bioMerieux, Marcy l'Etoile, France) and confirmed with API 20E (bioMerieux). The minimum inhibitory concentrations (MICs) of various antibiotics were determined by using the agar dilution method, and susceptibility data were interpreted by using the Clinical and Laboratory Standards Institute guidelines. The isolate showed a multiple drug resistant pattern, including some beta-lactams, all the aminoglycosides, and fluoroquinolones (Table 1). Then, genomic and plasmid DNA of strain GN1384 was extracted. Using primers described previously, we identified the resistance genotype of this strain by detecting the following resistance determinants through PCR, based on the above resistance phenotypes: 16S rRNA methyltransferase genes (armA, rmtA, rmtB, rmtC, rmtD, rmtE, and npmA); plasmid-mediated quinolone resistance determinants (qnrA, qnrB, qnrS, qnrC, qnrD, aac (6')-Ib-cr, and qepA); chromosome mutations associated with fluoroquinolone resistance (gyrA, parC, and parE); and genes coding for beta-lactamases (TEM, CTX-M, SHV, OXA-1). The positive amplicons were subsequently sequenced, and the results indicated the presence of rmtB, aac(6')-Ib-cr, blaCTX-M-14, blaTEM-1, and blaOXA-1. In addition, two amino acid changes (Ser83Leu and Asp87Asn) in GyrA and five amino acid changes (Thr57Ser, Ser80Ile, Ala129Ser, Val131Leu, and Gly134Ser) in ParC were observed. Conjugation experiments were performed with Escherichia coli J53 as the recipient, as previously described. The transconjugants were selected on agar plates containing sodium azide (100 mg/L) supplemented with amikacin (128 mg/L). Conjugation experiments showed that aac(6')-Ib-cr, blaTEM-1, blaCTX-M-14, and blaOXA-1 were cotransferred with rmtB to the recipient. The MIC results revealed that it simultaneously exhibited an elevated level of resistance to beta-lactams, aminoglycosides, and fluoroquinolones (Table 1). The extremely high MICs of all aminoglycosides tested against the multidrug-resistant S. marcescens were likely due to the presence of the rmtB gene. In contrast to the rmtB plasmid isolated by Doi et al., the plasmid bearing rmtB in our study was self-transferable, as observed by Bogaerts et al.. In accordance with a previous study, the close linkage between 16S rRNA methyltransferase and beta-lactamase as well as plasmid-mediated quinolone resistance determinants revealed the significant relationship of these genes amongst Enterobacteriaceae. It was also observed that the plasmid-mediated quinolone resistance gene together with the mutations in gyrA and parC contributed to the high-level quinolone resistance in S. marcescens GN1384. Further studies are required to assess the genetic environment of these genes and the role of these new substitutions in resistance to fluoroquinolones. The continuous and widespread use of aminoglycosides, fluoroquinolones, and beta-lactams in human or animal infection is the major driving force leading to these sophisticated resistance gene linkages. The dissemination of these linked genes by horizontal transfer simultaneously is very worrisome, and continuous monitoring should be reinforced.

PMC9868274_01

Male

An 18-year-old adult, Hispanic male was presented to the Emergency Department (ED) by his family via personal automobile. According to the family, the patient was unconscious for approximately 10 minutes during which time he did not receive cardiopulmonary resuscitation (CPR). Upon arrival, he was found to be in cardiac arrest; the patient was not alert or oriented to person, place, or time, cool to the touch, had no agonal respirations, no radial pulse on palpation, no activity on cardiac monitor, no heartbeat on auscultation, pupils that were equal, and 4 mm dilated but non-reactive. The patient's Glasgow Coma Scale score was 3. A CPR protocol was initiated immediately. Spontaneous circulation was achieved after three rounds of epinephrine administration. The patient was admitted to an isolated room in the Intensive Care Unit (ICU), intubated, and placed on a ventilator with a sedation regimen. A 12-lead EKG was obtained following stabilization of the patient demonstrating ST changes consistent with lateral wall ischemia (Figure 1). Vital signs, laboratory values, including a toxicology screen, and urinalysis (Table 1) were all unremarkable; urine culture had no growth (Table 2). COVID-19 and Rapid Viral Panel testing, including for influenza were returned as negative. Preliminary treatment for sepsis and leukocytosis included intravenous 3.375 g combination piperacillin-tazobactam q.8.h. and 1,000 mg vancomycin q.d. Blood samples from two access sites for culture and gram stain were collected. Draws from both sites grew C. diphtheriae (anaerobic bottles) and Klebsiella pneumoniae (both aerobic and anaerobic bottles) as identified with polymerase chain reaction (PCR) analysis (Table 2). The New York State Department of Health (NYDOH) and the U.S.'s Center for Disease Control's (CDC) Emergency Operations Center were contacted promptly. Patient samples were shipped overnight for confirmatory testing. Per that NYDOH laboratory, again real time PCR amplified C. diphtheriae DNA, but not toxin A or toxin B DNA fragments. The patient's social and vaccination history was accertained. The patient was reported to have immigrated to the U.S. from Honduras 3 years prior at the age of 15. At the time of admission, he did not have citizenship, but had attended public high school, which requires by New York State Public Health law, documentation of his vaccination and medical history by a U.S.-based primary care physician. The patient's family denied history of substance abuse disorders, smoking history, high risk sexual behavior, or recent travel. He was taking no medications and had no known complaints. The patient's primary care pediatrician was contacted who verified this medical and social history and confirmed full and timely vaccination status including for hepatitis A and B, human papillomavirus, meningococcal B, pneumococcal conjugate, varicella and influenza. Documentation was obtained from that source, and per those records he received 4 out of 5 recommended DTaP vaccinations- at ages 3 months, 5 months, 8 months, and 2 years:in Honduras, a country that successfully converted from a toxoid-based to DTaP vaccination system in 1998 as recommended by the World Health Organization and United Nations International Children's Emergency Fund, based on the similarity of side-effect profiles, marginal cost increase, and more sustained immunity. Honduras has reported rates of DTaP vaccination comparable to the U.S. since 2009. Further, the patient received a TDaP booster in the U.S. at age 15; therefore, by all accounts our patient had an up-to-date vaccination series. Review of the patient's medical charts revealed one other admission nearly 1 year prior to the current presentation. At that time, the patient also presented in a state of unresponsiveness after he was found reportedly "sleeping" in his room by his sibling who described labored breathing. The patient presented to the hospital in a state of shock. He received atropine 0.5 mg IV bolus and fluids. The patient was sedated, intubated, and transferred to the ICU. Naloxone (Narcan) 0.4 mg IV was administered empirically, and Psychiatry Services were consulted for possible toxin ingestion. Urine and blood toxicology analysis were unremarkable (Table 1) and urine culture had no growth (Table 2). COVID-19 PCR testing from nasal swab sample collection was negative. Initial, two-draw blood cultures grew K. pneumoniae after 36 h in one bottle, and a subsequent second draw 48 h later had no growth. The patient's antibiotic treatment included four 1 g doses of third-generation cephalosporin (Ceftriaxone) b.i.d. for empiric, broad-spectrum coverage as recommended by the Infectious Disease team which also prescribed a 10-day course with 875/125 mg Amoxicillin/Clavulanate potassium (Augmentin) b.i.d. by mouth outpatient. As the patient could not be directly interviewed during his acute presentations we cannot be sure whether the patient was experiencing symptoms prior to his presentation. This is in part why the Pediatric Infectious Disease services empirically treated the patient for K. pneumo at the time of his first admission. Further workup included a computerized tomography scan of the cranium, cervical spine, abdomen, thorax; no significant findings were reported. Cardiac electrocardiography (ECG) showed sinus tachycardia and a prolonged QTc interval of 572 ms (Figure 2). Repeat cardiac ECG showed a QTc duration of 579 ms (Figure 3). No medications associated with medication-induced QT syndrome were given during his hospitalization. A limited cardiac echocardiogram study was performed during which coronary arteries were not visualized. The patient was extubated and discharged 4 days following his admission. He was scheduled for outpatient follow up with Pediatric Cardiology Services. A stress test performed in that setting was normal with one premature ventricular contraction. Repeat cardiac echocardiogram and CT angiogram of coronary arteries were performed showing non-structural cardiac disease. He was referred for genetic testing for further work-up of a suspected genetic cardiac abnormality due to a family-reported (but unconfirmed) paternal uncle who passed away suddenly from a heart attack at the age of 40 in Honduras. The patient did not follow up for this genetic testing, likely due to financial limitations. Presently, testing confirmed the strain to be non-toxigenic. As per the CDC's Investigational New Drug protocol, antitoxin is only in cases of early detection of toxin-producing strains. As per official guidance, the patient was placed on droplet precaution isolation and contact-tracing of household members was conducted. All family members and close contacts were confirmed to be asymptomatic. Nasal swabs of four of the patient's nine immediate household members came back positive for C. diphtheriae, indicating carrier status. In addition to Tdap boosters, IM Penicillin G for adult, family household and close contacts were chosen for treatment after discussion between Suffolk County Department of Health and the in house Infectious Disease team. The patient's antibiotic course of piperacillin-tazobactam was extended, and cefepime 2,000 mg q.d. was added to the regime. Subsequent two-draw blood cultures on days 2 and 5 had no growth. The patient's progress was poor; due to the extended period without protected airway and circulation, the patient suffered irreversible anoxic brain injury. His family asked that "everything be done for him" and that the Chaplain's Office, wherein representatives provide spiritual or religious support at the bedside, be involved in his case. Palliative Care Services were also consulted. Given the patient's prior cardiac history and workup, and current presentation of cardiac arrest with pulseless electrical activity, Electrophysiology (EP) Services was consulted, and the patient was kept on telemetry monitoring as part of his ICU care. That team confirmed the likelihood of a prolonged QTc and recommended continued avoidance of exacerbating medications for which review of concomitant medications was performed. A 2D echocardiogram demonstrated left ejection fraction (LVEF) of 50-55%. The patient was not considered a candidate for any EP intervention given his poor functional status and prognosis. On day 2 of admission, the patient deteriorated into status epilepticus and was started on 1,000 mg IV levetiracetam q.12.h. Overnight on day 2, he was noted to have a fever and continued to spike fevers daily (maximum temperature of 39.0 C) for a period of 4 days. A suprapubic catheter and feeding tube were placed. On day 9 of the patient's admission, his ventilatory status improved and a tracheostomy was performed, but he continued to produce oropharyngeal secretions requiring suctioning every few hours. Two bronchoscopies were performed; cultures of which grew ventilator-associated species- Staphylococcus aureus and Stenotrophomonas maltophilia (Table 2), for which he received 4 doses of 1,000 mg vancomycin q.d. and 12 doses of 160/800 mg trimethoprim-sulfamethoxazole q.12.h. Over 34 days he sustained a 20 lb weight loss, reaching a clinically underweight BMI of 16 despite supplementation with enteral nutrition. The patient's condition ultimately stabilized; he was discharged to a long-term care facility 45 days following his admission as per his family's wishes.

c diphtheria, corynebacterium diphtheriae, corynebacterium diphtheriae infection, critical care medicine, non-toxigenic corynebacterium diphtheriae, prolonged qt syndrome

PMC7908333_01

Male

A 61-year-old man with no preceding history of genitourinary infections, surgery or trauma and no risk factors for testicular cancer, he denied any contact with tuberculosis patients. He was referred with a 6-month history of right-sided testicular pain and scrotal enlargement witch was progressive, without extra genital signs, notably no respiratory, skin or eye symptoms and no fever. Clinical examination revealed painful and non-tender right testicular mass on palpation with no signs of inflammation at this level. Scrotal ultrasonography showed that the volume of the right testicle is 23ml (25 * 40 * 44mm), with irregular contours, with the presence of hypoechogenic and heterogeneous foci. Color-Doppler showed only subtle intralesional vascularisation (Figure 1). Laboratory examination revealed a white blood cell count of 5,780/mm3, lymphocytes of 620/mm3, a hemoglobin level of 13.3g/dL; an erythrocyte sedimentation rate (ESR) of 41 mm/h; a C-reactive protein (CRP) level of 9mg/dl (normal, <0.8mg/dl); serum electrolyte levels and renal, liver function test results, were in the normal reference ranges. The 24-h urinary calcium excretion was 5.2mmol/24h (normal, 0-7.5mmol/24h). Tumor markers (serum alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [beta-HCG]) were negative, whereas lactate dehydrogenase (LDH) was at 220IU/L (normal, 135-225IU/L). The tuberculin skin test (TST) was also negative. For three consecutive days, mycobacteria in the sputum and urine were negative. As malignancy could not still be ruled out, the patient underwent a radical right orchidectomy. Histological examination of the orchidectomy patch showed that the pulp of the testes as well as the siminiferous tubes are partially destroyed and replaced by granulomatous folicular foci of which some areas consist mainly of lymphoplasmocytes, polynuclear neutrophils and eosinophils accompanied by many giant multinucleated cells without casous necrosis, this lesion does not invade the epididymis (Figure 2). Chest CT showed traction bronchiectasis with peripheral reticulations, especially in the upper lobes without visible mediastinal lymphadenopathy (Figure 3). A bronchoscopy was performed to eliminate multifocal tuberculosis (testicular and pulmonary) since tuberculosis is a very common disease in the Moroccan epidemiological context. The histological examination of the bronchial biopsy found non-caseating epitheloid granulomas with the presence of the giant cells containing the shaumann bodies (Figure 4). Bronchoalveolar lavage showed lymphocytic alveolitis (lymphocytes at 47%), GeneXpert MTB/RIF in bronchial aspiration with culture of bronchial fragment in search of tuberculosis mycobacteria were negative. Minor salivary gland biopsy revealed no abnormalities, ophthalmic examination is normal. Further pulmonary work up was consistent with the diagnosis of sarcoidosis: pulmonary function tests showed a slightly decreased total lung capacity suggesting a restrictive lung pattern with normal diffusion capacity. No other vital organs were involved and the patient is in follow up every 4 months. The evolution was favorable after 4 months, the patient was asymptomatic on the respiratory and urinary planes, with a testicular echograhy did not show lesions on the left testicle.

sarcoidosis, scrotal mass, testis

PMC9712710_01

Male

A 50-year-old man sought treatment in several hospitals because of a severe dry cough. The cough first appeared in December 2020 without obvious inducement, accompanied by a small amount of white foam sputum and sticky sputum. During 1 month, the patient's cough gradually worsened, with dyspnea after activities and paroxysmal dyspnea at night. Cough symptoms were associated with postural changes, such as standing up from sitting, bending over, or turning over during sleep, which could trigger severe coughs, and the patient even had transient amaurosis (self-reported syncope three times). The patient was hospitalized at Xinqiao Hospital of Army Military Medical University (Chongqing, China) on 11 January 2021, and discharged on 21 January 2021. Computed tomography (CT) of the chest showed bilateral pleural effusion (Figure 1A), which was later tested to be chylous fluid (Table 1). The cough was relieved after extracting the pleural fluid. However, the relief could only last for 1 day until the pleural effusion reappeared. The patient had to have pleural effusion extracted every other day to relieve his cough, and the amount of pleural effusion was very large (800-1,000 mL each time). It was suspected that the severe cough was related to recurrent pleural effusion. To determine the cause of such a serious pleural effusion, the patient received enhanced CT, which found an occlusion in the superior vena cava. Because the patient had a long history of dialysis because of uremia, he was recommended to go to the nephrology department to treat his superior vena cava occlusion. The patient then visited the Department of Nephrology of our hospital. The patient was diagnosed with chronic kidney disease stage 5 in 2003 and received kidney transplantations in 2003 and 2017. The second transplantation failed. He had undergone dialysis for 8 years. In the first 6 months, a right internal jugular vein long-term catheter was used for dialysis, which was later changed to a left brachiocephalic arteriovenous fistula. Physical examination showed that the patient had erythema and edema on the face and neck, diffuse varicosities across the anterior chest, and distended jugular veins. Subsequent CT venography and digital subtraction angiography showed occlusion of the superior vena cava (Figure 1B) and extensive venous collateral vessels within the lower neck and superior mediastinum. The patient was admitted for hospitalization on 20 February 2021. To determine the cause of pleural effusion, 40 mL of pleural fluid was drawn from the right thoracic drainage tube and sent for pleural effusion analysis, exfoliated cell examination (thoracic tumor), and bacterial culture (tuberculosis infection). The results of the pleural effusion analysis returned on 21st February, showing chyle positivity with elevated lymphocytes (Table 1). No abnormality was found in exfoliated cell examination. Ward rounds showed that the patient's temperature was normal, superficial lymph nodes were not palpable, the breath sounds were low and clear, and no rales were heard. Routine blood tests showed that leukocytes (7.77 x 109/L) and neutrophils (86.5%) were elevated. Because the inflammatory indicators increased in the pleural effusion and blood samples, the patient was given piperacillin-tazobactam (4.5 g q12 h) as treatment. At 1:00 p.m. that day, the patient experienced transient syncope. Sudden loss of consciousness occurred after coughing induced by positional changes from lying to sitting. The patient fell to the ground, without limb twitching, incontinence, or foaming at the mouth. The patient improved spontaneously after 5 s and did not complain of dizziness, headache, palpitations, chest tightness, or dyspnea. His blood pressure was 105/63 mmHg, and his heart rate was 88 times/min. No special treatment was carried out for this syncope. On 22 February, several tests, including the detection of anti-tuberculosis antibody, sputum smear, sputum culture, and detection of acid-fast bacilli in sputum, were performed. The patient had been taking immunosuppressants since renal transplantation, which might increase the susceptibility to tuberculosis infection. Tuberculosis infection is a possible cause of chylothorax, so we decided to further search for evidence of tuberculosis infection. The bacterial culture of the pleural effusion showed positive results for Staphylococcus lugdunensis, so the antibiotic treatment was continued. On 23 February, 1,000 mL of effusion was extracted from both lungs through thoracentesis. The pleural fluid analysis showed that the total cell counts decreased, suggesting that the antibiotic treatment was effective. Antibody tests for tuberculosis (gold labeled immunoassay) were weakly positive (+/-), but no Mycobacterium tuberculosis was detected in sputum specimens (sandwich cup method). According to the current examination results, the possibility of tuberculosis infection could be ruled out. Therefore, we speculated that superior vena cava occlusion was the most likely cause of recurrent chylothorax. On 24th February, percutaneous balloon dilatation was performed to recanalize the superior vena cava (Figure 1C). The superior vena cava was clearly visualized and unobstructed. The collateral circulation mostly disappeared, and the stenosis was relieved. The patient recovered well in the following days. Physical examination showed that the swelling of the face and neck obviously subsided. Three days after the operation (March 1), the patient received an ultrasound examination for the detection of pleural effusion. The results showed a flaky anechoic area in the bilateral chest, with a maximum depth of 46 mm in the right chest and 40 mm in the left chest. The location of the pleural fluid was not determined due to the small amount. On 3rd March, the patient received a chest CT again. Only a small amount of pleural effusion was found, and most of the lungs were dilated. The patient was discharged on the same day. Follow-up was conducted after 4 months and 12 months. Chest CT showed no pleural effusion (Figure 1D). The patient reported that cough symptoms were eliminated. Based on the results, we can confirm that the obstruction of the superior vena cava caused the patient to develop recurrent chylothorax, and further stimulated severe postural change-related cough.

case report, chylothorax, dry cough, enhanced computed tomography, superior vena cava syndrome

PMC9389152_01

Male

A 65-year-old male patient was admitted to the hospital because of fever and headache lasting for 5 days. The patient long had poor oral hygiene and 4 years ago, the patient underwent implantation of mandibular dentures. Fever usually occurred at noon and was generally under 38 C. In addition, the patient was presented with persistent heartburn, anorexia, asthenia, and night sweats. Blood routine examination revealed that the white blood cell (WBC) count was 12.08 x 109/L (normal range, 4-10 x 109/L) with neutrophil leukocytosis of 71.1%. No significant abnormality was found in the heart or lungs of the patient. Then the patient was admitted to the Department of Infectious Diseases. On admission, physical examination showed poor mental status and subtle abduction limitation in the left eye without other neurological signs or symptoms. The patient underwent a lumbar puncture on the day of admission. Cerebrovascular fluid (CSF) showed a normal WBC count (4/mul, reference range 0-8/mul), mildly increased protein level (0.6 g/L, reference range 0.15-0.45 g/L), reduced chloride levels (114.6 mmol/L, reference range 118-132 mmol/L), and normal glucose levels (3.97 mmol/L, reference range 2.5-4.2 mmol/L; Table 1). Pre-antibiotic blood culture was taken with a negative result. Additional laboratory examinations, such as serology testing for HIV, hepatitis B/C, syphilis, rheumatic diseases, and tumor markers, were normal. Cranial magnetic resonance imaging (MRI) was normal (Figure 1A), and there was no evidence of intracranial aneurysm on brain magnetic resonance angiography (MRA; Figure 1B). The diagnosis of viral encephalitis was considered and treatment with intravenous acyclovir (10 mg/kg) was initiated and continued every 8 h. However, with frequent low fever, the illness was not well-controlled. Considering the likelihood of bacterial infections, ceftazidime (2 g every 12 h) was given on the third day of admission. On hospital day 7, the patient developed significant diplopia and weakness in the right upper extremity with a brain MRI showing acute multiple cerebral infarcts in the left cerebral hemisphere (Figures 1C,D). On the same day, the patient underwent a lumbar puncture once more, and the macroscopic appearance of the CSF was slightly yellow with a pressure of 190 mmH2O (normal range, 80-180 mmH2O). CSF results are shown in Table 1. The patient was diagnosed with intracranial infection and transferred to the Department of Neurology. Neurological examination showed drowsiness, left abducens nerve palsy, degree 4 muscle strength in right upper limb, and neck rigidity (+). The culture of bacteria and mycobacterium tuberculosis and the detection of viral nucleic acid for retrovirus, herpes virus 1 and 2, rhinovirus, Epstein-Barr (EB) virus, and cytomegalovirus in CSF were negative. Additionally, the brucellosis agglutination test, Japanese encephalitis virus antibodies detection, T cell spot test for tuberculosis (T-SPOT), tuberculin test, and mycobacterium tuberculosis/rifampicin resistance test (X-pert) were also negative. Since our patient had such signs, the diagnosis of tuberculous meningitis was considered. The patient was administered an anti-tuberculous therapy that included isoniazid (0.6 g once daily), rifampicin (0.45 g once daily), ethambutol (0.75 g once daily), and pyrazinamide (0.5 g three times daily). In the following days, the body temperature returned to normal, but the patient still had intermittent headache. Compound codeine phosphate and ibuprofen sustained release tablet (0.2 g/13 mg two times daily) were added to control the headache. On hospital day 16, the patient developed frequent nausea and vomiting. The mental state of the patient also became very poor yet no fever, abdominal pain, or blurred vision were observed. Physical examinations, laboratory tests, and abdominal computed tomography (CT) scans could not reveal the cause of the patient's deterioration. We suggested that it might be the side effects of anti-tuberculosis drugs. Ondansetron (8 mg) and metoclopramide (10 mg) were intravenously utilized for anti-emesis. His gastrointestinal symptoms were improved. However, the mental state was getting even worse. On hospital day 25, the patient was presented with near-complete left oculomotor nerve palsy with blepharoptosis and dilated pupils on the left side. CSF results showed an increased WBC count (300 x 106/L) with 63% mononuclear cells (Table 1). Cranial CT revealed significantly increased low-density shadow in the left frontal, temporal, and parietal lobes (Figures 1E-G). As a result of the disease progression, the patient was transferred to a superior hospital. Detailed neurological examinations and evaluations were performed on this patient again. The MRI (Figures 1H,I) and MRA (Figure 1J) re-examination demonstrated that the lesions in the left cerebral hemisphere were increased significantly, and a cerebral aneurysm was formed in the intracavernous segment of the left internal carotid artery (ICA). In addition, the sphenoid sinus mucosa was thickened. Taking the possibility of bacterial infection into consideration, the patient was treated with ceftriaxone (2 g every 12 h). On hospital day 28, the patient underwent a lumbar puncture examination again. CSF results are shown in Table 1. Metagenomic sequencing of viral and bacterial genomes from this patient's CSF sample was performed with a negative result. Unfortunately, the patient fell into a coma the following day and was admitted to the intensive care unit (ICU). Head MRI showed a markedly enlarged size of the left temporal lesions with abscess formation and bleeding, accompanied by peripheral ring-shaped enhancement (Figures 1K,L). Due to the patient's poor condition, the anti-infection regimen was adjusted to an intravenous drip of biapenem (0.3 g every 12 h) and vancomycin (1 g every 12 h). The patient was gradually recovered consciousness within the next 7 days. On hospital day 37, brain MRI showed a decreased size of the left temporal lesions but with perifocal evident edema (Figure 1M). To further clarify the nature of the intracranial lesions, the patient was transferred to the Neurosurgical Department to perform the needle biopsy with the assistance of real-time neuro-navigation on hospital day 38. The next day, this patient underwent the procedure, and the surgical specimen was sent for smear, culture, and deoxyribonucleic acid sequencing. According to the sequencing results, the patient was diagnosed with bacterial meningitis caused by a mixed infection of oral microflora dominated by anaerobes, such as Fusobacterium nucleatum (69.79% relative abundance), Prevotella intermedia (20.77% relative abundance), Bacteroides uniformis (1.35% relative abundance), Campylobacter rectus (1.26% relative abundance), Oral peptostreptococcus (0.08% relative abundance), Streptococcus constellatus (0.02% relative abundance), Torque teno virus 15, and Treponema socranskii. The anti-microbial regimen (biapenem combined with vancomycin), which could sufficiently cover anaerobe, was used continuously. For the poor oral hygiene, the patient received a detailed oral examination and nursing intervention. In the following days, the overall condition of the patient was significantly improved, but there was still a loss of appetite. However, the clinical symptoms worsened from the hospital day 53. The patient was presented with severe lethargy, headache, nausea, and vomiting. Repeat brain MRI showed that the lesions and edema of the left temporal lobe were improved, but hydrocephalus became even worse (Figures 1N,O). The patient was transferred to the Department of Neurosurgery of our hospital at the insistence of family of the patient on hospital day 58. Neurological examination revealed consciousness disturbance with a Glasgow Coma Scale (GCS) of 9 (E2V2M5), right hemiplegia, left eyeball fixation, pupil dilation with ptosis on the left side, and stiffness in the neck. Cranial CT showed intraventricular extension and hydrocephalus (Figure 1P). We considered that the aggravation of this patient's disease might be related to the progressive hydrocephalus. Then, the patient underwent ventriculostomy on hospital day 59. The anti-infection therapy regimen previously described was changed to the combination of meropenem (2 g every 8 h) and linezolid (0.6 g every 12 h). The clinical symptoms of the patient were improved significantly, and the patient gradually regain consciousness. On hospital day 85, this patient underwent a ventriculoperitoneal shunt operation, and then the mental state of the patient improved further. On hospital day 97, when the patient was discharged, patient was able to walk with assistance and engage in simple conversation but showed a loss of appetite and significant weight loss. In the 1-month follow-up, the patient could walk without the assistance of a cane or brace. However, severe neurological deficits, such as diplopia and right hemiplegia, still existed. To prevent disease recurrence, we suggested that the patient should maintain good oral hygiene and regular follow-up at the stomatology clinic. Because of the high risk of rupture and mortality of the patient's intracranial aneurysm, surgical treatment was advised. However, the patient refused further examination and treatment for financial reasons. Regular follow-ups will be carried out for our patients. The clinical course is summarized in Figure 2.

anaerobes, case report, intracranial aneurysm, meningitis, oral microflora

PMC10242072_01

Female

Despite vaccination (Moderna, booster 6 months earlier), a 34-year-old patient affected by B-lymphoblastic leukemia t(9;22)(q34;q11.2) BCR-ABL1 developed Omicron BA.5 infection while waiting for her scheduled transplant from a matched unrelated donor (MUD). She was referred to our center for allo-HSCT after treatment with Imatinib, which was withdrawn after one week for intolerance in favor of Dasatinib obtaining a first hematological complete remission with minimal residual disease (MRD) positivity. Subsequently, the patient received Ponatinib due to increased MRD levels according to GIMEMA LAL2620 (NCT04475731), but the disease relapsed. After achieving second complete morphological remission with detectable MRD after two cycles of Inotuzumab ozogamicin (IO), an allo-HSCT was scheduled. Figure 1 displays the Next-Generation Sequencing (NGS) analysis of the virus. The patient received prompt preventive antiviral therapy with nirmatrelvir/ritonavir, obtaining fever resolution within 72 hours and a consistent viral load reduction at nasopharyngeal swabs. Twenty-three days after COVID-19 diagnosis, based on increasing MRD values in the context of high-risk disease refractory to third generation tyrosine kinase inhibitor and clinical resolution of SARS-CoV-2 infection, it was decided not to delay further allo-HSCT. During conditioning chemotherapy [fludarabin, 12 Gy total body irradiation (TBI)], nasopharyngeal viral load increased (virus confirmed viable in cell culture), while the patient remained asymptomatic. Two days before PBSC reinfusion in July 2022, tixagevimab/cilgavimab 300/300 mg and a 3-day course of remdesivir were administered. The donor was a female 10/10 HLA-MUD, vaccinated for SARS-CoV-2. The graft-versus host disease (GVHD) prophylaxis was based on post-transplant cyclophosphamide (PT-Cy), mycophenolate mofetil, and cyclosporine A (CsA). Neutrophil engraftment was reached at +20 days after the transplant. The pre-engraftment phase was characterized by uncomplicated febrile neutropenia without documented infections. Despite trying to minimize the risk factors for veno-occlusive disease (VOD) in the context of IO exposure and a TBI-based myeloablative-preparing regimen, administering ursodeoxycholic acid prophylaxis and using CsA rather than sirolimus as GVHD prophylaxis, VOD occurred at day +13 (thinning of hepatic veins, thickening of gallbladder, ascites, bilirubin peak 2.3 mg/dL, Fibroscan peak 75kPa), requiring defibrotide treatment to obtain a slow but complete resolution of this complication. The post-engraftment phase was characterized by mild COVID-19 at day +23 (cough, rhino-conjunctivitis, fever). A spontaneous symptom resolution was observed, enabling the patient to achieve a definitive viral clearance at day +28 after transplant. At day +32, the patient experienced grade I acute GVHD (skin grade II) treated with methylprednisolone 0.5 mg/kg/daily and three cycles of weekly extracorporeal photo-apheresis as a steroid-sparing approach due to concomitant SARS-2-CoV infection, without side-effects. At day +40 after transplant with a full donor chimerism of myeloid and T-cells and in complete remission with negative MRD, the patient was discharged home. Then, a steroid dose increase was required to obtain GVHD remission, without further complications or adverse events during follow-up until day +180. Bone marrow evaluation performed at six months confirmed complete hematological remission with negative MRD, without requiring additional treatments. Figure 2 summarizes the comprehensive clinical course of SARS-CoV-2 nasopharyngeal viral load trends by PCR cycles, C-reactive protein, D-dimer values, COVID-19 treatments in pre and post-transplant phases, veno-occlusive disease, and acute GVHD treatments. SARS-CoV-2-specific cellular and humoral responses were also analyzed in detail and detailed methods are reported in the Supplementary Materials of this case study. IgGs against the SARS-CoV-2 RBD were present before transplant although the omicron RBD antibody binding was 7 and 4-fold lower compared with that of the Wuhan-Hu-1 and delta RBDs, respectively. Post tixagevimab-cilgavimab administration, anti-RBD IgG levels against Wuhan and delta increased and followed a similar kinetic over time, while an omicron IgG rise lagged until day +30, which is consistent with the reduced binding by tixagevimab-cilgavimab to this VOC ( Figure 3A ). Binding IgGs against the SARS-CoV-2 nucleocapsid protein were initially negative and developed by day +37 after the positive swab. Neutralizing Ab (NAb) against delta and omicron VOC were at low titers (1/82 and 1/66 respectively) twenty-one days after the positive swab, a time point which was, however, two days after chemotherapy ( Figure 3B ). NAb against both VOCs showed increased titers when tested at twelve days after administration of tixagevimab-cilgavimab and had similar kinetics thereafter. Overall, the neutralizing response to omicron was persistently lower than that of delta (fold range: 2-90). None of the serum samples neutralized the LV-Luc/VSV.G pseudo-viral vector, indicating that the detected neutralizing responses were specific for SARS-CoV2 (data not shown). Both polyclonal ( Figure 3C ) and SARS-CoV-2 specific T-cell reconstitution ( Figure 3D ) were longitudinally evaluated before (-4 days) and at day +30, +60 and +90 after HSCT. Before the transplant, the patient showed a limited but detectable level of specific responses toward the Spike (6 SFC/400'000 PBMC) and the Nucleocapsid protein (5 SFC/400'000 PBMC). Early after transplant (+30 days), the frequency of both polyclonal and SARS-CoV-2 specific T-cell responses were below the limit of detection of the assay due to the low CD3+ T-cell counts (59 CD3+ T cells/microl, 48 CD4+ T cells/microl, and 11 CD8+ T cells/microl). At the following time points, the absolute counts of CD3+ T cells increased (379 and 353 CD3+ T cells/microl at day +60 and +90, respectively). Accordingly, the polyclonal T-cell response rose to 1'664 SFC/400'000 PBMC at day +90 after HSCT. However, the specific response to the Nucleocapsid protein remained negative after transplant, and the frequency of Spike-specific T-cells was assessed to be at very low levels (3 SFC/400'000 PBMC at both days +60 and +90). A progressive decrease of the viral load was observed within a few weeks after transplant and the molecular SARS-CoV-2 nasopharyngeal swab test was negative by day +28 after transplant, before the reconstitution of an adequate number of T-cells that could elicit a specific response.

covid – 19, sars – cov – 2, acute b-lymphoblastic leukemia, allogeneic transplant, veno-occlusive disease

PMC5847294_02

Female

The third patient is a 58-year-old female with a single kidney and nephrotic syndrome. She complained of feeling weak, dry skin, alopecia, and severe fatigue, clinically consistent with hypothyroidism. Her 24-hour urinary protein was approximately 1 g/day. Her low serum thyroxine-binding globulin (TBG, 5.6 microg/mL, reference range 13 - 39 microg/mL), the main thyroid hormone binding protein, suggests that she is losing TBG and thyroid hormones in her urine. Free and total thyroid hormones were all low as measured by mass spectrometry (Table 1), indicating that she was biochemically hypothyroid, despite her normal TSH concentration at 1.33 microIU/mL. She will shortly begin thyroid hormone therapy. Our studies on the effect of ACTH administration on serum TSH concentration were conducted in the morning between 8AM and 9AM. Sixty minutes post ACTH simulation, TSH showed a mean decrease of 17% compared to baseline with minimum and maximum decreases of 6.9% and 42.9% (Figure 1). This effect is presumably caused by the increased steroid concentrations as a result of the ACTH stimulation. This further supports our contention that TSH measurement is interfered with by many compounds which could affect the diagnosis of hypothyroidism.

hypothyroidism, mass spectrometry, tsh, thyroid, thyroid hormones

PMC3307457_01

Male

A 63-year-old male presented with swelling in the right inguinal region for the past 10 years with a sudden increase in size since two months. On examination, a single, firm three cm swelling was felt in the right inguinal region. No abnormality was detected in the left inguinal region. No other lesion such as an ulcer or swelling was noted in the right leg or thigh. There was no history of fever, rigors and loss of weight or appetite in the recent past. Patient gave no history of exposure to tuberculosis. On general examination, patient was well built and nourished. There was no pallor or generalized lymphadenopathy. No abnormality was detected on systemic examination. Base line blood investigations were found to be within normal limits. An ultrasonogram of the right inguinal mass showed circumscribed hypoechoic mass suggestive of a lymph node shadow. An ultrasound guided aspiration was done and the smears were submitted for cytological examination. Ultrasonogram of the abdomen was unremarkable. Cytosmears examined were moderately cellular with dual cell population, composed predominantly of oval to polygonal cells with abundant cytoplasm and round bland nuclei resembling histiocytes [Figure 1]. These cells were arranged in loose clusters and as isolated forms. The background showed few discrete round cells with round nuclei and scanty cytoplasm suggestive of mature lymphocytes [Figure 1]. No precursor lymphoid cells were seen on cytosmears. In correlation with clinical and image findings, an impression of reactive lymph node was suggested on cytology. A clinical follow-up and excision was advised if clinically suspicious or lesion further increased in size. An excision biopsy was performed which showed skin with a neoplasm located in lower dermis and subcutis. Tumor cells were arranged in nests with focal diffuse pattern. Individual cells appeared round to oval with abundant granular eosinophilic cytoplasm and centrally placed bland nuclei [Figure 2]. Focal collections of lymphocytes were also seen [Figure 2]. Tumor cells were seen surrounding the adnexal structures and nerve fibres. Immunohistochemistry showed S100 positivity in nucleus and cytoplasm ([Figure 2] inset). Immunostains for CD68 and inhibin showed cytoplasmic positivity. A final diagnosis of granular cell tumor was given based on histology and immunoprofiling.

granular cell tumor, histiocytes, inguinal, lymphocytes

PMC3262522_01

Female

We describe the case of a 23-year-old girl with unknown HCM, that has syncope after a basketball game. In the medical evaluation Cardiac auscultation in left lateral decubitus and orthostatic position revealed no systolic murmur, and she did an echocardiogram that reveals HCM. She has septal hypertrophy (Figure 1 and see VIDEO 1 in Supplementary Material available online at doi10.5402/2011/346797), and she does not have systolic anterior movement of mitral valve (SAM) or intraventricular gradient (VIDEO 1 and VIDEO 2). Treadmill exercise echocardiogram was performed, using the standard Bruce protocol, and the patient did not develop LVOT gradient at peak exercise (Figure 2). After finishing the exercise we maintained the patient in orthostatic position and SAM of mitral valve and LVOT gradient greater than 100 mmHg (Figure 3 and VIDEO 3) developed. With evidence of falling systolic arterial pressure from 130 to 110 mmHg in that moment we put the girl in supine position. Previously considered a nonobstructive HCM, after the exercise echocardiography, the patient was considered to have an obstructive pattern with probable influence in clinical symptoms. Therefore, she was medicated with bisoprolol 5 mg a day.

PMC7666697_01

Male

A 43-year-old non-diabetic Indian male reported to our outpatient department with chief complaints of cough with expectoration, chest pain, reduced appetite, fever with chills, and night sweats for two weeks. He also complained of breathlessness on exertion and had two episodes of blood in his sputum. The patient explained that the cough was continuous and was relieved after taking cough syrup. He also mentioned that the episodes of fever were initially intermittent and then daily for the last two weeks and were relieved after taking Paracetamol. The chest pain was localized to the middle of the chest and was aggravated on exertion. He was a businessman by profession with no history of smoking, alcoholism, or any other substance abuse. Also, there was no history of any contact of TB or COVID-19 in the family or close contacts. And there was no history of foreign travel in the recent past. But he had reported having traveled by a domestic airline about twenty days back. There was no history of weight loss or any other major illness in the past. On examination his vitals were- pulse-108/minute, arterial BP-130/80 mm of Hg, respiratory rate of 30 breaths/minute, Sp02-89% on room air, temperature- 101-degree centigrade. His Sp02 fell by 70% on room air after waking. On auscultation, there was crepitation on the bilateral middle lobes of the lungs. Also, dyspnea on exertion was noted. The rest of the systemic examination was within normal limits. Considering this as a probable case of TB with COVID-19 he was advised a chest radiograph with sputum microscopy (Ziehl Neelsen (ZN) staining for acid-fast bacilli), Cartridge-based nucleic acid amplification test (CBNAAT) of the sputum and other routine investigations. To check for the COVID-19 he was advised qualitative polymerase chain reaction (PCR) test from the oropharyngeal swab. The results were surprising with Mycobacterium tuberculosis detected on sputum fluorescent microscopy and were also confirmed by the CBNAAT. However, there was no resistance to Rifampicin. The results of the PCR were positive for RNA specific to SARS-CoV-2. Besides, the chest radiograph PA-view was suggestive of bilateral consolidations on the middle lobes of lungs with ill-defined borders. The other investigations revealed a low lymphocyte count (1x 109/L) and increased levels of C-reactive protein (CRP) (57 mg/L), lactate dehydrogenase (LDH) (580 U/L), and erythrocyte sedimentation rate (ESR) (70 mm in the 1st hour). Also, a sample for liquid culture (MGIT BACTEC) was sent to the Intermediate Reference Laboratory (IRL) which revealed the growth of Mycobacterium tuberculosis. Computed tomography was not performed as the diagnosis was established by other cheaper and faster methods and also the patient was unwilling for the same. All the other routine investigations were within normal limits. He was referred to the nearest designated COVID-19 management center, where he was managed as per national guidelines. Besides, he was also started on an antitubercular treatment of four drugs as per the National Tuberculosis Elimination Program (NTEP) guidelines. He was advised follow-up post completion of his stay at the designated COVID-19 center, but he has not yet reported back for follow-up. Written informed consent was obtained from the patient for using clinical data and images for publication in this study.

covid-19, sars-cov-2, tuberculosis

PMC6873422_01

Female

Our patient is a 3-year-old Pakistani female born to first-degree cousins. She presented at the age of 10 months with enlarged cervical lymph nodes and diarrhea. She had multiple admissions for recurrent diarrheal illnesses. The diarrhea started at the age of 7 days, with a frequency of more than 10 times per day of watery consistency but no blood or mucus. She was started on an elemental amino acid-based formula because of a diagnosis of food protein-induced enterocolitis syndrome based on a presentation of severe bloody diarrhea, acidosis and hypotension. She had a sister who had a similar presentation of chronic diarrhea and fever and died at the age of 1 year due to septic shock. Immune deficiency was not suspected and the underlying cause was not investigated. Also, no genetic tests were obtained and the family did not receive any prenatal genetic counseling. After removing cow's milk from our patient's diet and initiating the special formula, her diarrhea settled, but at the age of 1 year, she had a recurrence of diarrhea described as bloody and associated with multiple perianal abscesses. The abscesses were treated with intravenous antibiotics and surgically drained. The culture from the drained pus repeatedly grew extended spectrum beta-lactamase-producing E. coli and Klebsiella species. At the age of 2 years, she developed arthritis involving large joints of the lower limb (knees and ankle) and wrist associated with morning stiffness and an inability to walk. On examination, the patient had severe failure to thrive. Multiple enlarged cervical lymph nodes were noted. The scar of the Bacillus Calmette-Guerin (BCG) vaccine was normal, and no axillary lymph nodes were detected. The liver was palpable 3 cm below the costal margins. She had swelling of the left knee joints with a reduced range of movement. Perineal examination revealed inflammation, multiple scars of drained perianal abscesses and a perianal fistula opening (Fig. 1). Laboratory investigation revealed leukocytosis (29.1 x 109/L), anemia (hemoglobin 8.4 g/dL), elevated inflammatory markers (C-reactive protein 12.0 mg/dL, and ESR 80 mm/h) and elevated immunoglobulin levels. A rheumatological workup was positive for serological markers of autoimmunity, including antinuclear antibodies (ANA) (titer 1:80, speckled pattern), rheumatoid factor (25.1 IU/mL; normal < 15), anti-cyclic citrullinate peptide (anti-CCP) antibody titer (216.7 u/mL; normal < 20) and anti-double-stranded DNA (anti-dsDNA) antibodies (83.6 IU/mL; normal < 35). In addition, these markers were positive on repeated testing. Other markers, including anti-RNP, anti-SSA, anti-SSB, and anti-Sm, remained negative, while C3 and C4 complement levels were not suppressed. Joint fluid sampling was obtained, and an infectious etiology for joint involvement was excluded by culture obtained from the knee joint. Based on the clinical presentation and laboratory workup, a diagnosis of oligoarticular juvenile idiopathic arthritis (JIA) was provided. Furthermore, microbiological testing for infectious diarrhea, including stool culture and sensitivity tests, a stool ova and parasite examination, Clostridium difficile toxin test, and Giardia lamblia and Cryptosporidium stool antigen tests, were negative. The celiac panel was also negative, and malabsorption tests, including fecal fat and fecal elastase tests, were normal. Stool examination was positive for fecal occult blood, and fecal calprotectin, an indicator of intestinal inflammation, was elevated at 580 mcg/g (normal < 50.0). Workup for TB was negative, including bone marrow and lymph node examination, using polymerase chain reaction (PCR) assay, cultures, and the TB gold test. In addition, a purified protein derivative (PPD) skin test was performed on the patient and showed no reaction. In view of her presentation and the early colitis symptoms, she was further evaluated, and a diagnosis of CGD was made based on the oxidative burst assay [dihydrorhodamine-1,2,3 (DHR) flow cytometry test], which revealed an absence of NADPH oxidase activity in the patient's neutrophils upon phorbol myristate acetate (PMA) stimulation (Fig. 2). The neutrophil oxidative index (NOI) of the patient was < 5. NOI measures the oxidative ability of phagocytes and their overall integrity and is calculated from the ratio of the fluorescence in stimulated phagocytic cells to the fluorescence expressed in unstimulated phagocytic cells. The normal value in control specimens is usually > 73. The diagnosis of CGD was confirmed by targeted next-generation sequencing using Ion AmpliSeq Designer software (Life Technologies, Carlsbad, CA, USA). The gene panel used analyzed over 200 genes associated with immune deficiency and immune dysregulation, including auto-Inflammatory and Autoimmunity syndromes. The test was performed on venous blood samples collected in EDTA tubes for DNA extraction after obtaining written consent from the parents to perform the genetic diagnostic assay. The test revealed a deletion mutation in exon 10 as a homozygous loss-of-function variant of NCF2 (NCF2: NM_001190789, nucleotide change: c.855_856del:p.T285fs). Both parents were heterozygous for the mutation. We believe this to be a novel variant that has not been previously reported. To prevent serious and life-threatening infections, the patient was started on an antibacterial and antifungal prophylactic regimen consisting of trimethoprim-sulfamethoxazole (trimethoprim 6 mg/kg/day) and itraconazole (5 mg/kg/day), respectively. She remained free of infection. Her arthritis symptoms were initially managed with naproxen followed by oral prednisolone at a dose of 1 mg/kg/day for 4 weeks followed by gradual tapering and then discontinued after 4 months. In addition, hydroxychloroquine was initiated and continued throughout the observation period, which lasted for 18 months following the onset of arthritis. She showed improvement and started to walk with no pain and had no relapse of symptoms during subsequent follow-up visits. However, we failed to establish long-term follow-up. In addition, further endoscopic, histological and imaging studies were planned but not performed because the patient and family traveled to their home country and were lost to follow-up.

chronic granulomatous disease, early-onset colitis, inflammatory bowel disease, juvenile idiopathic arthritis, primary immunodeficiency

PMC8302404_02

Male

A 53-year-old man was referred to our hospital because of fever and cytopenia for 2 months. He went to a local hospital initially. Laboratory tests showed Hb 83 g/L, PLT count 53 x 109/L, and serum globulin 68.8 g/L. The T-SPOT test was positive. Ultrasound examination revealed right pleural effusion, abdominal effusion, and generalized lymphadenopathy. No acid-fast bacilli or malignant tumor cells were found in ascites. Fine-needle aspiration (FNA) biopsy of left cervical LN was negative. He received a diagnostic antituberculosis therapy, which suspended in the fifth day due to sudden high fever, and pleural effusion was increased. Thereafter, he went to the tuberculosis specialist hospital, and no acid-fast bacilli were found in the pleural and ascites effusion. Finally, two months later, after clinical symptoms appear, he was referred to our hospital. Laboratory tests showed WBC 6.8 x 109/L, Hb 53 g/L, and PLT count 42 x 109/L. Serum globulin was more than 100 g/L. SPEP and IFE demonstrated polyclonal hypergammaglobulinemia (IgA 14.7 g/L, IgG 89.4 g/L, IgM 6.73 g/L, and IgG4 4.96 g/L) and Coomb's test was positive. Human immunodeficiency virus, sera cytomegalovirus, hepatitis B serology, and hepatitis C serology were negative. Plasma EBV DNA was 1.19 x 103 copies/ml, and seven days later, it was quantified by qRT-PCR as 3.768 x 106 copies/2.0 x 105 cells, EBV-infected B cells. Symptomatic treatment of anti-infection, red blood cell transfusion, and plasma exchange was failed to prevent disease progression. LN immunohistochemistry revealed tumor cells with CD3, CD5, PD1, and BCL2 positive and CD10 negative, suggesting AITL, which was verified by ancillary examinations results. The results of this patient's examination are shown in Table 1 and Figure 2. A diagnosis of AITL was established, and the patient received a cycle of R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Serum globulin was decreased to 84.8 g/L on the fourth day of chemotherapy. However, polyserous effusions and serum globulin levels had not been improved. The blood coagulation disorder is worse than before, and the performance of disseminated intravascular coagulation (DIC) appears. Ultimately, the patient abandoned treatment and discharged.

PMC4307963_01

Male

Presented here is a case of a twenty-six-year-old young male who was brought to the emergency room in a state of unconsciousness following by massive drug intake. He was diagnosed with complex partial seizures with secondary generalization 14 years earlier and was on antiepileptic treatment with 300-mg/day phenytoin sodium and 60-mg/day phenobarbitone. His seizures were never controlled, and he had 5-6 episodes of complex partial seizures/month. Precipitating his emergency room presentation, he deliberately consumed a massive dose of antiepileptic drugs (approx. 25 tablets of phenobarbitone and 45 tablets of phenytoin) on account of a sudden emotional outbreak following a dispute with his relatives. As stated by his family members, there was a significant change in his behavior in the form of irritability, impulsivity, obstinacy, decreased frustration tolerance, and assertiveness. His academic performance also deteriorated. He had poor communication with family members. Before starting antiepileptic medication, he was performing well in his studies. On physical examination, the patient was of an average build with a poor general condition. Vital signs revealed the following: a temperature of 99.6 F, a pulse rate of 120 beats/min, a blood pressure of 110/68 mm Hg, a respiratory rate of 32 breaths/min, and an SPO2 of 86%. On systemic examination, the patient was comatose (GCS: E1V2M2) with bilateral crepitation on chest examination. The rest of the physical examination findings was insignificant. The patient had been resuscitated, gastric lavage was done, and blood and urine samples were taken. He was put on a ventilator and given supportive and symptomatic treatment. Relevant blood parameters were also monitored. His serum drug concentrations were measured by immunoassay and were 36 mug/ml for phenytoin and 105.67 mug/ml for phenobarbitone. With meticulous symptomatic management, the drug level came down to 22.40 mug/ml for phenytoin and 52 mug/ml for phenobarbitone on the 9th day. Gradually, his symptoms resolved, and on the 8th day, there was complete recovery. The patient was subjected to EEG and brain MRI. Brain MRI revealed right mesial temporal sclerosis, and EEG revealed epileptiform discharges arising from the right temporal area. His psychiatric evaluation revealed interictal affective-somatoform (dysphoric) disorder, but no further suicidal ideations/intention were elicited. The patient was put on 600-mg/day oxcarbazepine which was gradually built up to 1200 mg/day, while for the psychiatric symptoms, 10-mg/day olanzapine and 50-mg/day sertraline were started. In the follow-up period of six months, he had three complex partial seizures, but he had a marked improvement in depressive mood, impulsivity, and suicidality.

drug toxicity, psychiatric disorders, suicide, temporal lobe epilepsy

PMC7772466_02

Male

A 71 year old man with a history of recent onset hypertension presented to the hospital for evaluation of moderate renal failure (eGFR = 37 ml/min per 1.72 m2) and proteinuria (1.5 g/d) discovered 4 months earlier. On presentation, he was mildly tachypneic (oxygen saturation 90% while breathing ambient air) and had moderate lower limb edema. Laboratory investigations showed (Table 1): severely reduced eGFR (10 ml/min per 1.73 m2), nephrotic proteinuria (7.0 g/d) and microscopic hematuria with red blood cell casts in the urine sediment; mild hypocalcemia; normal complement levels; negative cryoglobulins; moderately reduced total protein and immunoglobulin G levels; normocytic anemia (hemoglobin, 10.5 g/dl); a small amount (<10%) of lambda monoclonal immunoglobulin on serum immunofixation (k/lambda ratio = 2.1), with negative urine immunofixation. Real-time ultrasound-guided percutaneous renal biopsy was performed, followed by bone marrow aspirate and biopsy. Renal tissue specimens were examined by light microscopy, immunofluorescence, and electron microscopy. Light microscopy showed membranoproliferative glomerulonephritis with nodular mesangial expansion, occasional protein thrombi and numerous endocapillary infiltrating mononuclear and polymorphonuclear leukocytes (Figures 4A-C). Immunofluorescence demonstrated positive, coarsely granular, staining for C3 (3+), IgG (2+), C1q (1+) and lambda-light chain (3+) involving glomerular capillary walls and, occasionally, the mesangium, with negative staining for k-light chain (Figures 5A-C). Ultrastructural evaluation showed large subendothelial, intramembranous, and mesangial electron dense deposits composed of microtubules (27-30 nm) with hollow centers, organized in parallel arrays (Figures 6A-C) consistent with immunotactoid glomerulonephritis. Bone marrow aspirate and biopsy were examined by light microscopy, immunohistochemistry, and flow cytometry, and only showed 6% lambda-restricted plasma cells. The patient was treated with four cycles (cycle length = 28 days) of cyclophosphamide-bortezomib-dexamethasone regimen and received: cyclophosphamide 200 mg per os on days 1, 8, 15 + bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 15, 22 + dexamethasone 20 mg per os on days 1, 8, 15. Then, he received 5 cycles (cycle length = 28 days) of bortezomib-dexamethasone regimen: bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 15, 22 + dexamethasone 20 mg per os on days 1, 8, 15. He also received isoniazid prophylaxis for 6 months due to a positive QuantiFERON-TB Gold test result and acyclovir prophylaxis for 12 months. No adverse effects related to the cytotoxic therapy were observed. Renal biopsy was repeated after 12 months and showed a significant reduction of the membranoproliferative lesions, disappearance of the capillary leukocyte infiltration and of the protein thrombi, and persistent but less evident nodular mesangial expansion (Figures 4D-F). On immunofluorescence there was less evident glomerular capillary wall and mesangial staining for C3 (2+) with complete disappearance of lambda-light chain deposition (Figures 5D,E). Electron microscopy demonstrated nearly complete disappearance of the subendothelial, intramembranous and mesangial electron dense, microtubular deposits (Figures 6D-F). The laboratory investigations at 12 and 24 months showed substantial renal function improvement, and normalization of proteinuria, serum k/lambda free light chain concentration, and calcium levels (Table 1).

c3 glomerulonephritis (c3gn), immunotactoid glomerulonephritis, bortezomib, glomerulonephritis, monoclonal gammopathy of renal significance (mgrs)

PMC5458696_01

Female

A 62-year-old female diabetic patient presented in our outpatient department with complaints of pain in the right shoulder and inability to raise arm of 2 weeks duration. The medical history revealed generalized malaise and weight loss although no history of fever in the last 3 months. There is no history of trauma. Local examination revealed rise of temperature, tenderness over right shoulder and proximal arm and restricted range of movements in all plane. There was no external wound, sinus or discharge from any skin sites. Systemic examination was normal. Neurologically, the patient was normal. Laboratory tests showed hemoglobin - 10 g/dl, total leukocyte count - 9500/cumm, neutrophils - 65%, lymphocytes - 30%, erythrocyte sedimentation rate (ESR) was raised - 40 mm/h. Plain radiograph (Fig. 1 and 2) followed by MRI (Fig. 3 and 4) of the right shoulder with humerus showed transverse fracture of proximal shaft of the right humerus, 5 cm distal to surgical neck. Articular surface was not involved. We suspected tumor or infection and planned computed tomography (CT) chest to look for any pulmonary foci or metastasis. CT chest showed small areas of consolidation in the left upper lobe, pointing toward the infective etiology. Mantaoux test was negative. Bronchoalveolar lavage was done and sample sent for culture and sensitivity came out to be negative for acid-fast bacilli. Considering tumor and tuberculosis as differential diagnosis, J-needle biopsy was done from anterolateral aspect of proximal humerus at the fracture site. The tissue material obtained from biopsy was sent for histopathological examination which confirmed granuloma with epithelioid and Langhan's giant cells. Culture for acid-fast bacilli of biopsy tissue sample was non-conclusive. Based on the histopathology report, we concluded this to be tuberculosis osteomyelitis of humerus and our patient was started on category 1 antitubercular drugs, under Revised National Tuberculosis Control Programme (RNTCP) as per revised WHO guidelines. After 3 days of starting antitubercular drugs, debridement of lesion and fracture fixation using rush nail was done. Standard deltopectoral approach was used to explore the lesion. Both intra- and extra-medullary debridement were done. We used reamers for intramedullary debridement. From the edges of lesion, 1 cm of bone was removed. Debridement was done till all necrotic tissue was removed and bleeding was seen from the edges of bone. Fracture ends were approximated and using greater trochanter as entry point, rush nails were inserted (Fig. 5). We did not use any local antibiotic drug delivery method. Procedure was uneventful, stitches were removed on day 14th and incision healed well. Post-operatively, our patient was continued on category 1 antitubercular drugs. Initial follow-up 4 months postoperative and plain radiography after 7 months (Fig. 6) showed overall improvement in general condition of patient, weight gain, and good fracture healing. After 1 year following index surgery, patient complained of pain at nail insertion site at the tip of greater trochanter and shoulder abduction was restricted beyond 40 . The patient did not have pain at fracture site. Rush nails were removed (Fig. 7). Pain subsided following nail removal and shoulder abduction improved with restriction only in terminal 30 . Fracture healed completely, and patient was pain free. Compared to opposite shoulder, abduction and forward flexion were restricted in terminal 30 . Internal and external rotations and adduction were full.

tuberculosis, humerus, osteomyelitis, spontaneous fracture

PMC6487276_01

Male

A 62-year-old male presented with a cutaneous tumor on the left arm and lymphadenopathy in the left axilla. Skin biopsy showed a diffuse infiltration of tumor cells with immunoblastoid cytomorphology. The cells were positive for CD4, CD123, TCL1, and MYC and partly positive for CD56 (Fig. 1A-G); but negative for CD3, CD20, CD79a, terminal deoxynucleotidyl transferase (TdT), myeloperoxidase (MPO), CD34, and the Epstein-Barr encoding region. In split fluorescence in situ hybridization (FISH) assay, tumor cells were positive for 8q24 (MYC locus) rearrangement but negative for SUPT3H and MYB rearrangements (Fig. 2). The present patient was diagnosed with BPDCN according to the diagnostic criteria proposed by Julia et al.. Peripheral blood yielded a hemoglobin level of 14.4 g/dL, a leukocyte count of 6.6 x 103/muL and a platelet count of 13.5 x 104/muL. Bone marrow examination showed 92% blast cells (Fig. 1H), of which MPO activity was not detected by the diaminobenzidine method. Flow cytometry analysis revealed that the leukemic cells were positive for CD4, CD33, CD123, interleukin-3 receptor, human leukocyte antigen (HLA)-DR, and CD45RA, partly positive for CD56 and negative for TdT and cytoplasmic MPO. G-banding analysis showed del(13)(q12q22) in 7 out of 16 metaphase cells. Rearrangements of the T cell receptor gamma-chain gene by polymerase chain reaction (PCR) analysis and immunoglobulin heavy-chain genes by Southern blotting analysis were not detected. These findings confirmed bone marrow involvement of BPDCN. The induction chemotherapy was initiated with daunorubicin 50 mg/m2 daily for 5 days and cytarabine 100 mg/m2 daily for 7 days, resulting in complete hematological remission (CR). Subsequently, he received 2 courses of consolidation chemotherapy. The patient did not have a related donor who was serologically HLA-matched. Thus, he was transplanted with unrelated bone marrow from a male donor (total nucleated cell dose, 3.4 x 108 cells/kg; genotypically matched for HLA-A, -B, -Cw, and -DR1) from the Japan Marrow Donor Program using a RIC regimen with total body irradiation (TBI) 2 Gy / 1 fraction, fludarabine (Flu) 125 mg/m2, and melphalan (Mel) 80 mg/m2. A combination of tacrolimus (Tac) and short-term methotrexate (sMTX) was used as graft-versus-host disease (GVHD) prophylaxis. Neutrophil engraftment (absolute neutrophil count of at least >0.5 x 109/L for 3 consecutive points) and platelet recovery (platelet count of >50 x 109/l without transfusion for 3 consecutive points) were obtained on days +15 and +30 after transplantation, respectively. He maintained CR without any symptoms of GVHD. Four months after the initial transplantation, he developed two cutaneous tumors on his legs. Skin biopsy showed the infiltration of tumor cells but bone marrow aspiration showed no evidence of relapse, which confirmed extramedullary relapse of BPDCN. Despite the cessation of Tac, lymphadenopathy in the left inguinal was noted. At day 180 after allo-HSCT, bone marrow examination revealed 10% leukemic cells, and short tandem repeat DNA analysis showed 5.5% recipient-type cells at day 180, indicating a progression to hematological relapse of BPDCN. He achieved partial remission after 1 course of re-induction chemotherapy with daily cyclophosphamide 600 mg/m2 on day 1, vincristine 1.3 mg/m2 on days 1, 8, 15, 22, doxorubicin 20 mg/m2 on days 1 to 3, prednisolone 60 mg/body po on days 1 to 7 (then tapered for 28 days) and L-asparaginase 2000 IU/m2 div on days 11, 13, 18, 21. The patient was transplanted with HLA-matched unrelated male bone marrow (total nucleated cell dose, 2.3 x 108 cells/kg; genotypically matched for HLA-A, -B, -Cw and -DR1) followed by a RIC regimen with Flu 30 mg/m2 daily for 5 days, intravenous busulfan (BU) 3.2 mg/kg daily for 2 days, and TBI 2 Gy / 1 fraction. Tac and sMTX were administered as prophylaxis against GVHD. Ten days after the second transplantation (before neutrophil engraftment), he presented with stridor due to severe laryngeal irritation, and underwent mechanical ventilation. Neutrophil engraftment and platelet recovery were achieved on days +21 and +127 after the second transplantation, respectively. He achieved the second CR of BPDCN with complete second-donor chimerism. He developed grade II acute GVHD with stage 2 skin involvement 48 days after transplantation, but did not require additional immunosuppressive treatment, such as systemic administration of corticosteroid. He presented lichen planus-like features in the skin and oral mucosa due to moderate chronic GVHD. He started anti-androgen therapy for localized prostate cancer at day +1525. During anti-androgen therapy, he did not experience any symptom of relapse disease of BPDCN. Furthermore, chronic GVHD in oral mucosa and skin persisted without progression in any other organ, and a lymphocyte count was maintained between 3.01 and 4.41 x 109/L. The withdrawal of immunosuppressants was performed on day +1748. He was alive without any symptom of relapse more than 71 months after the second allo-HSCT.

allogeneic hematopoietic stem cell transplantation, blastic plasmacytoid dendritic cell neoplasm, donor change, myc rearrangement

PMC6676783_01

Male

A 9-year-old male patient with a history of backache was referred from a district hospital to the Dr George Mukhari Academic Hospital, Gauteng province, South Africa, due to severe upper back pain and gibbus (kyphosis) deformity that emerged over 8 months prior to admission. He had no history of tuberculosis contact or constitutional symptoms (cough or fever, loss of weight or loss of appetite). Upon physical examination at admission, the patient was ambulatory but limping, had tenderness at the gibbus area, with pain in the waist. He was cooperative and appeared to have a normal skin condition. There was no Bacillus Calmette-Guerin scar observed. The neurological examination was normal and intact. X-rays revealed kyphosis at the bottom of the thoracic spine (T12 vertebra) and the first vertebra of the lumbar spine (L1 vertebra). His T12 had vertebral destruction with preserved posterior elements. The L1 upper end plate and T12 lower end plate destruction with a peri-vertebral shadow were indicative of an abscess (Figure 1). Plain radiography of the chest was unremarkable (Figure 2). Furthermore, the haemoglobin was low (11.5 g/dL), with a normal-range white blood cell count and an elevated C-reactive protein level of 18 mg/L. The erythrocyte sedimentation rate was a bit high at 20 mm/hour; alkaline phosphatase was 211 U/L. The alanine aminotransferase (19 U/L) and aspartate aminotransferase (31 U/L) were within the normal ranges. A serology test for HIV enzyme linked immunosorbent assay was negative. A superficial pus swab microscope analysis was acid-fast bacilli-negative when stained with auramine-O. An MGIT 960 culture was also negative after 42 days. Magnetic resonance imaging of the entire spine revealed features suggestive of tuberculosis infection (Figure 3). There was kyphotic deformity and pre-vertebral fluid collection at T12/L1 extending to the epidural space. The fluid collection was low on T1, high on T2 and became enhanced post-contrast. There was also an abnormal signal of L1 and T12, as well as associated involvement of the superior end plate of L1. The T12/L1 intervertebral disc was not clearly delineated with the distortion of normal anatomy. Spinal canal stenosis was observed at the level of kyphotic deformity with cord compression, although there was spinal cord edema. Posterior elements were preserved and facet joints were normal (Figure 3). A second set of the magnetic resonance images of the entire spine, which was done eight months later, revealed progression of the disease (infective process), increased kyphosis, and a paravertebral abscess, as well as complete destruction of lower and upper end plates of T12 and L1 with cord compression (Figure 4). The patient was admitted and subsequently started on empirical first-line anti-tuberculosis treatment as recommended by the World Health Organization, as well as other supportive treatment, including thoracic lumber spinal orthosis. The patient did not improve clinically after 1 month of administering the empirical treatment. Non-operative treatment included a thoracic lumber spinal orthosis brace, analgesia and first-line tuberculosis treatment to prevent further collapse and back care. The patient's mother consented to operative management, which included spinal decompression and posterior instrumentation, with rods and screws, as well as a biopsy. The patient was neurologically intact post-surgery (Figure 5). The operation was successful. The pathological diagnosis of the spine (T12/L1) on the vertebral lesion biopsy revealed the presence of chronic necrotising granulomas with multinucleated Langhans-type giant cells. Ziehl-Neelsen staining, used to confirm acid-fast bacilli, was negative. The patient's first-line anti-tuberculosis treatment, included pyrazinamide, rifampin, isoniazid and ethambutol. The patient's condition deteriorated despite a total of 6 months of first-line anti-tuberculosis treatment, and the surgical wound started to open leaving space between the sides of the incision (gaping). X-rays showed failed implants; therefore, the pedicular screws were backed off from the distal part of the vertebra (T12/L1) with increased kyphotic deformity of the spine (Figure 6). When the patient was on rehabilitation, he developed an abscess on the forehead, which was later drained in the ward, and sent to the National Health Laboratory Services - Dr George Mukhari Academic Hospital tertiary laboratory for further mycobacteriological tests. Fluorescent microscopy of the smear stained with auramine-O was negative for fluorescing acid-fast bacilli. The MGIT 960 (Becton Dickinson Diagnostics, Sparks, Maryland, United States) culture was also negative after 42 days. The patient was sent to surgery for incision and drainage of the abscess on the gibbus area, where from thick pus was drained and sent for tuberculosis microscopy, culture, line-probe assay (MTBDRplus assay, Hain Life Sciences, Nehren, Germany) and phenotypic MGIT 960 drug susceptibility testing. The auramine-O smear results were negative, whereas the MGIT culture was positive after 35 days. The line-probe assay result showed rifampin monoresistance, which was later confirmed by the phenotypic MGIT 960 drug susceptibility testing as rifampin monoresistant, ethambutol resistant and isoniazid sensitive after 9 months of first-line anti-tuberculosis treatment. The second-line MGIT 960 drug susceptibility testing showed that the isolate was susceptible to moxifloxacin and kanamycin. This led to an MDR tuberculosis diagnosis, since tuberculosis caused by rifampin-resistant strains is presumed to be MDR tuberculosis and treated as such (95% of rifampin-resistant strains are MDR). The patient was started on the MDR tuberculosis treatment, including moxifloxacin, ethionamide, amikacin, pyrazinamide, terizidone and pyridoxine; he started improving remarkably on the treatment and rehabilitation. At 15 months, the patient fully recovered and the implants were later removed.

extrapulmonary tuberculosis, laboratory diagnosis, multidrug-resistant tuberculosis, radiological improvement, spinal tuberculosis

PMC8032958_01

Male

An 8-year-old boy presents with increasing fatigue (past 2 weeks) and new acute-onset symptoms of aphasia, ataxia, headaches, and progressive vertigo for the past 24 h. He has no personal of family history of clotting disorders, strokes or autoimmune/inflammatory disease. He has had no infections in the past year and no travel history (other than a "sore throat or sniffles here and there"), no pets, and no other symptoms. When asked about diagnostic approaches to this specific case (Q7, N = 74 responses), respondents ranked emergency MRI of the brain including angio-MRI (90.5%) and blood tests including full blood counts, inflammatory markers and clotting tests (90.5%) as most important. These were followed by lumbar puncture to analyze the CSF (82.4%), and brain CT scan including CT angiography (23.0%). Of the respondents who considered blood tests essential (Q8, N = 74 responses), 98.6% would order full blood count including complete white cell count, 97.3% would order clotting tests including PTT, INR, fibrinogen and D dimers, and 94.6% would order immunology tests including ANA, ENA, complement factors, cardiolipin antibodies and ANCA. When asked which blood immunology tests they would order, 97.3% answered anti-phospholipid antibody testing, followed by antinuclear antibody testing (93.2%), requested anti-neutrophil cytoplasmic antibodies (89.2%), anti-dsDNA antibodies (87.8%), complement factors and activation of the complement cascade (83.8%), and anti-NMDA (N-methyl-D-aspartate) receptor and aquaporin antibodies (67.6%) (Q9, N = 74 responses). Of 74 respondents who considered performing a lumbar puncture (Q10, N = 74 responses), most (98.6%) would request cell counts, differentiation and protein quantification, followed by microbial culture (93.2%), glucose levels (90.5%), oligoclonal bands (89.1%), CSF opening pressure (86.5%), lactate (74.3%) and anti-NDMA and aquaporin antibodies (68.9%). When asked about helpful MRI techniques (Q11, N = 71 responses), 87.3% of responders requested MRI angiography, followed by fluid-attenuated inversion recovery (FLAIR; 55/71; 77.5%), diffusion-weighted MRI sequences (53/71, 74.7%), T1 with fat saturation (FS; 30/71; 42.3%), T1FS with contrast medium (38/71, 53.5%), T2FS (37/71, 52.1%), Turbo inversion recovery magnitude (TIRM)/Short tau inversion recovery (STIR; 28/71; 39.4%). Detailed results are summarized in Table 2. Next, respondents were informed that the patient exhibited elevated ESR (30mm/h) and CRP (4mg/L). Approximately 30 h after the onset of ataxia and aphasia, Magnetic Resonance Imaging (MRI) shows alterations in proton diffusion capacity in the Cerebellum and a significant and long ranging stenosis of the distal Basilar artery in MRI angiography (Supplementary Material 1). Based on new information provided, respondents were asked to select 5 most likely differential diagnoses (Q12, N = 73 responses). Most respondents selected progressive p-cPACNS (80.8%), followed by transient p-cPACNS (69.9%), ischaemic stoke (64.4%), congenital anatomical deformity (39.7%) and infections (38.4%). Asking indicators of likely progressive p-cPACNS (Q13, N = 73 responses), the majority of respondents suggested imaging results (87.7%), followed by clinical course with disease progression over 3 months or more (69.9%), laboratory findings suggesting systemic inflammation (46.6%), acute presentation with "systemic signs" (43.8%), and response to immune modulation (41.1%). Detailed results are summarized in Table 3. Next, the following information was provided: Autoantibodies in CSF and blood come back negative, there's no evidence for clotting disorders or infection, including TB. Systemic inflammatory parameters remain normal. Based on the involvement of posterior arteries, the diagnosis of (likely) progressive p-cPACNS (Childhood Primary Angiitis of Central Nervous System) is made. Participants were asked to decide which medication they consider for the induction of remission (Q14, N = 73 responses). Sixty-eight of 73 respondents would start treatment with intravenous Methylprednisolone (IVMP) over 5 days, followed by oral prednisolone (93.2%), 47/73 (64.3%) consider treatment with intravenous Cyclophosphamide every month for 4-6 months, 9/73 (12.3%) would start treatment with mycophenolate mofetil (MMF), and 3/73 (4.1%) would treat with oral prednisolone. None of the respondents chose oral cyclophosphamide or azathioprine for induction treatment. Considering prophylaxis of thromboembolic events (Q15, N = 70 responses), most responders agreed on administering IV heparin initially (65.7%), followed by acetyl salicylic acid (ASA), and a combination of ASA and clopidogrel. Considering post-acute phase thrombosis prophylaxis (Q16, N = 70 responses), the majority of respondents would prescribe aspirin (47.1%), followed by subcutaneous heparin (22.9%), a combination of ASA and clopidogrel (14.3%), warfarin (11.4%), clopidogrel alone (5.7%), or DOACs (2.9%). Opinions on when to discontinue anticoagulation treatments (Q20, N = 70 responses) were divided and ranged between 3 and 36 months. One respondent would not administer anticoagulation treatment (1.4%) (Table 4). Considering immune modulating maintenance treatment (Q17, N = 73 responses), the majority of respondents (72.6%) would prescribe MMF, followed by azathioprine (20.5%), oral prednisolone (17.8%), intravenous cyclophosphamide (13.7%), rituximab (9.6%), methotrexate (5.5%), oral cyclophosphamide (following Fauci scheme) or TNF inhibitors (1.4% each). Opinions on the required duration of treatment were divided (Q18, N = 73 responses) and ranged between 3 and 36 months. When asked how long to include oral corticosteroid treatment in the regimen, including slow taper (Q19, N = 72 responses), respondents responded: 3 months (20.8%), 6 months (41.7%), 12 months (15.3%), 18 months (4.2%), 24 months (5.6%), 36 months (1.4%), and 1.4% indicated no corticosteroid treatment (Table 4). Monitoring disease activity and damage using MRI (Q21, N = 72 responses), 56/72 (77.8%) respondents suggested to repeat MRI after 3 months, 36/72 after 6 months (50.0%), 25/72 after 12 months (34.7%), 11/72 after 18 months (15.3%), 21/72 after 24 months (29.1%), and 10/72 after 36 months (13.9%) and 11/72 answered other (15.3%). When asked when to schedule clinical follow up (Q22, N = 73 responses), 59/73 respondents indicated within 3 months (80.8%), 23/73 after 6 months (31.5%), 22/73 after 12 months (30.1%), 19/73 after 18 months (26.0%), 21/73 after 24 months (28.8%) and 15/73 after 36 months (20.6%).

cns, cns inflammation, childhood, diagnosis, inflammation, pediatric, treatment, vasculitis

PMC8032958_02

Female

A 4-year-old girl presents with headaches and symptoms suggestive of a cerebrovascular stroke (vomiting with some language and speech delays). She has a past medical history of a clinically diagnosed Varicella Zoster Virus (VZV) infection 6 months ago. There's no history of strokes or clotting disorders in her personal or family history. Similarly to case 1 (Q24, N = 70 responses), the majority of respondents suggested that initial investigations should include blood test (94.3%), emergency MRI of the brain including an MRI angiography (92.9%), lumbar puncture and CSF analysis (88.6%), and brain CT scan including CT angiography (31.4%). Of the participants who considered blood tests essential (Q25, N = 70 responses), 98.6% would request full blood count including complete white cell count; 97.1% clotting tests including PTT, INR, fibrinogen and D dimers, and 90.0% would order immunology tests including ANA, ENA, complement factors, cardiolipin antibodies and ANCA; 42.9% suggested blood tests for adenosine deaminase 2 activity (ADA2) and 41.4% for interferon gamma release assay (IGRA) to exclude tuberculosis (Table 5). When asked about blood immunology (Q26, N = 70 responses), 94.3% considered anti-phospholipid antibodies as required, followed by antinuclear antibodies, ANCA, anti-dsDNA antibodies, complement factors and activation of the complement cascade, and anti-NMDA and aquaporin antibodies. Of the 70 participants requesting a lumbar puncture (Q27, N = 70 responses), 98.6% considered cell counts and differentiation, followed by protein (95.7%), glucose (92.9%), microbial cultures (90.0%), opening pressure (84.3%), oligoclonal bands (81.4%), lactate (78.5%), and anti-NMDA and aquaporin antibodies (54.3%). Of 68 participants who considered emergency MRI (Q28, N = 68 responses), 88.2% requested MRI angiography, followed by FLAIR (73.5%), diffusion-weighted sequences (73.5%), T1FS with contrast medium (54.4%), T2FS (50.0%), T1 with FS (41.2%), and TIRM/STIR (39.7%) (Table 5). Next, the participants were informed that autoantibodies in CSF and blood come back negative, there's no evidence for clotting disorders or infection (including negative for TB and VZV PCR in CSF, serum VZV IgG positive, IgM borderline positive). Blood and CSF inflammatory markers remain within normal limits. DWI sequences unveiled altered diffusion capacity in the left hemisphere; Time of flight MR Angiography (TOF-MRA-)sequences demonstrate narrow caliber of left distal internal carotid artery and proximal anterior and medial cerebral artery. Post-gadolinium MRI sequences reveal contrast enhancement of the thickened vascular wall in the affected segments. Conventional angiography showed incomplete occlusion of the left A. cerebri media (Supplementary Material 1). Respondents were then asked to choose the 5 most important differential diagnoses to consider (Q29, N = 70 responses). Most respondents (81.4%) considered p-cPACNS, likely transient related to VZV, followed by ischaemic stroke (70.0%), transient p-cPACNS not related to VZV (62.9%), CNS tuberculosis (61.4%) and infections e.g., meningitis (32.9%) (Table 6). When asked which medication to administer for induction treatment (Q30, N = 69 responses), 53/69 (76.8%) respondents suggested IVMP over 5 days, followed by 18/69 who considered intravenous Cyclophosphamide every month for 4-6 months (26.1%), 12/69 MMF (17.4%), 9/69 (13.0%) oral Prednisolone, and 2/69 Azathioprine (2.9%). None of the participants chose oral Cyclophosphamide for induction treatment. Respondents were asked how long to continue oral corticosteroid treatment including slow taper for (Q34, N = 66 responses), they answered: 3 months (25/66, 37.9%), 6 months (23/66, 34.9%), 12 months (7/66, 10.6%), 18 months (0/66, 0.0%), 24 months (2/66, 3.0%) and 36 months (1/66, 1.5%). Five of 66 respondents answered no to prescribing oral corticosteroid treatment (7.6%). Considering prophylaxis of thromboembolic events (Q31, N = 67 responses), most responders agreed on administering IV Heparin initially as anticoagulation treatment (52.2%) in the acute phase, followed by ASA (29.9%), a combination of ASA and clopidogrel (6.0%) and warfarin (4.5%). Considering post-acute phase prophylaxis (Q32, N = 66 responses), a majority of responders would prescribe Aspirin (53.0%), followed by subcutaneous Heparin (18.2%), a combination of Aspirin and Clopidogrel (9.1%), warfarin (7.6%), clopidogrel or DOACs (4.6% each). Regarding discontinuation of anticoagulation treatments (Q35, N = 63 responses), respondents answered after 3 months (11.1%), 6 months (17.5%), 12 months (20.6%), 18 months (3.2%), 24 months (12.7%) and 35 months (6.4%). Five of 63 respondents answered they would not administer anticoagulation treatment (7.9%) (Table 7). Monitoring of disease activity and damage using MRI (Q36, N = 69 responses) was suggested after 3 months by 60/69 (87.0%) respondents, after 6 months by 32/69 (46.4%) and after 12 months by 25/69 (36.2%). Eight of 69 respondents would repeat MRI after 18 months (11.6%), 17/69 after 24 months (24.6%) and 6/69 after 36 months (8.7%). Clinical follow up (Q37, N = 70 responses) was considered reasonable at 3 months by 58/70 respondents (82.9%), at 6 months by 24/70 (34.3%), 12 months by 24/70 (34.3%), 18 months by 16/70 (22.9%), 24 months by 18/70 (25.7%), and after 36 months by 14/70 (20.0%). To assess how participants would alter their approach based on evidence of VZV infections temporally associated with p-cPACNS, they were provided with alternative test results: After the first line investigations, suppose the autoantibodies in CSF and blood come back negative, there's no evidence for clotting disorders, but the VZV PCR in the CSF comes back as positive. As a result of positive testing for VZV (Q38, N = 68 responses), the majority of the respondents indicated they would treat the patients with IV Acyclovir treatment over 14 days (58/68, 85.3%), 32/68 (47.1%) of responders indicated initially treating with IVMP over 5 days followed by oral Prednisolone. Less common answers indicated by participants were induction with oral Prednisolone, followed by oral Prednisolone taper (10/68, 14.7%), IV Cyclophosphamide (2/68, 2.9%), MMF induction treatment (2/68, 2.9%), Azathioprine (1/68, 1.5%). None of the participants indicated they would treat the patient with oral Cyclophosphamide (Fauci scheme).

cns, cns inflammation, childhood, diagnosis, inflammation, pediatric, treatment, vasculitis

PMC10251288_02

Female

A 1-year-old female child, firstborn of second-degree consanguineous marriage, with global developmental delay, presented with three episodes of seizures. History of seizures at 2 months of age was not evaluated. No history was suggestive of infection and immunodeficiency. Dermatological examination revealed hypopigmentation of skin, silver gray hair over the scalp, eyebrows, and eyelashes, and a normal iris pigmentation [Figure 3]. Blood investigations, imaging studies, and peripheral smear were normal. Scalp hair microscopy revealed multiple irregular large clumps of melanin in the medulla of the hair shaft [Figure 3]. She was diagnosed as a case of Type 1 GS. She was treated conservatively and discharged.

chediak higashi, griscelli, light microscopy, silver hair

PMC6147960_01

Female

The first patient, a 33-year-old Kuwaiti (Middle Eastern) female was referred to the TB Control Unit of the Chest Diseases Hospital in January 2003 with the diagnosis of cold abscess of the right gluteus medius muscle with adjacent trocentric involvement. Both the hip joints and psoas muscles were normal. Ultrasonic guided aspiration from the abscess yielded thin pus that was positive for acid-fast bacilli. The culture was grown from the aspirate (isolate Kw 176) and identified as M. tuberculosis. The drug susceptibility performed with BACTEC 460 TB system showed that the bacilli were sensitive to isoniazid (INH), streptomycin (SM), pyrazinamide (PZA) and ethambutol (EMB) but resistant to rifampin (RMP). She was treated with a regimen of INH, SM, PZA and EMB for seven months and fully recovered.

PMC6147960_02

Male

The second patient, a 63-year-old diabetic Kuwaiti (Middle Eastern) male was the father of the first patient and lived with his daughter. He was diagnosed with pulmonary TB nearly two years earlier (June 2000). The M. tuberculosis isolate recovered from this patient in the year 2000 was susceptible to INH, SM, EMB and PZA but resistant to RMP. He was treated with a four-drug regimen of INH, SM, PZA and EMB for six months. This patient was admitted to the Chest Diseases Hospital in February 2003 with relapsing pulmonary tuberculosis with cough, fever, loss of appetite and loss of weight. The chest radiogram showed pulmonary infiltrates. The sputum was positive for acid-fast bacilli. The drug susceptibility performed with BACTEC 460 TB system on the M. tuberculosis strain (isolate Kw 180) grown from sputum exhibited sensitivity to INH, SM, EMB and PZA but resistance to RMP. A repeat isolate recovered 15 days later (isolate Kw 181) yielded the same profile. The patient was started on daily therapy with INH, SM, PZA, EMB and ciprofloxacin (CIP). However, he could not tolerate PZA, so the treatment was continued with the regimen of SM, INH, EMB and CIP for 75 days after which the sputum was negative for acid-fast bacilli. The treatment was continued with the regimen of INH, EMB and CIP for four months. The patient was successfully treated and the last culture result at the end of therapy was negative. Most (>95%) rifampin-resistant strains of M. tuberculosis contain mutations within an 81-base pair rifampin-resistance-determining region (RRDR) of the rpoB gene encoding the beta-subunit of RNA polymerase. The presence of rifampin resistance conferring mutations in the rpoB gene in clinical M. tuberculosis isolates (Kw 176, Kw 180 and Kw 181) was determined by direct DNA sequencing of the PCR amplified DNA fragments containing RRDR as described previously. The fingerprinting of the isolates was carried out by the modified double repetitive element (DRE)-PCR as described in detail elsewhere. The isolates were assigned to one of four genetic groups on the basis of the polymorphisms at katG codon 463 and gyrA codon 95. The presence of R463/L463 in the katG gene and S95/T95 in the gyrA gene were determined by amplification of the corresponding katG and gyrA gene DNA regions by PCR followed by restriction endonuclease digestion of the PCR amplified fragments with Nci I and Ale I, respectively, to generate restriction fragment length polymorphism as described previously.

PMC3794623_01

Female

In February, 2012, a 36-year-old woman visited our outpatient department due to the progression of a skin disease for several months. Eight months before visiting, she found a pruritic, noduloplaque skin rash over her trunk and extremities. Concurrently, a growing, fungating lesion 15 cm in diameter was in the left lateral chest wall. She visited one of medical center in Taiwan for help. The Ga-67 study showed intense uptake in the lateral left chest wall that was corroborated by the clinical appearance. A whole abdominal computer tomography (CT) showed several subcentimeter lymph nodes in the bilateral inguinal areas, and a biopsy was done. The pathology reports showed cutaneous CD4+ T-cell lymphoma, T3N0M0B0, and stage IIB without lymph node metastasis. Many medium- to large-sized atypical lymphoid cells infiltrated diffusely into the superficial and deep dermis (Figure 1(a)). Most of the atypical lymphoid cells were positive for CD3 (Figure 1(b)) and CD4 (Figure 1(c)). Only a small portion of them were positive for CD8 (Figure 1(d)), CD79a (Figure 1(e)), and CD56 (Figure 1(f)). They were all negative for CD30 (Figure 1(g)). The prescriptions were interferon alpha, psoralen plus ultraviolet A photochemotherapy, and Accutane (Isotretinoin). In addition, local electron radiotherapy was delivered to the left chest wall and right axillary area with 50 Gray (Gy) in 25 fractions, respectively. After local radiotherapy, the producing newly-formed plaques over the trunk and buttock outside the radiation field were noted. Oral methotrexate (2.5 mg) 5 mg twice per day was prescribed immediately but disease progressed. The patient was referred to our hospital for total skin irradiation. HITS with dose painting techniques were applied from head to toe and avoided the previously treated areas. (Figures 2(a) and 2(b)) The patient was dressed with the diving suit (3 mm thick) to increase the superficial dose. The Polyflex II tissue equivalent material (Sammons Preston, Warrenville, IL, USA) was used as bolus for lesions over ears, fingers, and toes. The conformal bolus (R.P.D., Albertville, MN, USA) was used to cover the lesions in trunk. BlueBag immobilization system (Medical Intelligence, Germany) and thermoplastic fixation were used to fix head and neck, main trunk, and extremities. For tomotherapy treatment planning, a computed tomography (CT) image set of the whole body was required. The patients were scanned in a large bore (75 cm) CT scanner (GE, Discovery VCT PET/CT Imaging System) from head to toe. The level at 15 cm above knee was used as a reference point to separate the upper and lower set. The geometric edges of both fields were abutted at the HT treatment's 50% isodose plane. Both image sets were using the Philips Pinnacle3 treatment planning system for contouring. After that, the plan was transferred to the Tomotherapy Hi Art Planning system (v. 4.0.4. Tomotherapy, Inc., Madison, Wisconsin, USA). The clinical target volume (CTV) included the entire body surface system with subcutaneous 0.5 cm. To account for setup variability and respiratory motion, a planning target volume (PTV) was generated with a 0.5 cm margin at first. After 4 days treatment, the data of MVCT showed 0.5 cm for PTV was insufficient for some parts of body, such as shoulder, chest, abdomen, and pelvis. Therefore, the margins for PTV in these areas were changed accordingly. The anterior margin of the chest and abdomen was 1.0 cm with two-dimensional expansion and the shoulder was 0.8 cm with three-dimensional expansion, respectively. The CTV and PTV were sepacrated into five parts of head, chest, abdomen, pelvis, and upper extremities for the body plan. The hypothetical bolus was 1.0-1.5 cm in thickness from skin surface. Five mm was setting on the outer layer of PTV as hypothetical boluses during HITS plan to avoid the overhit of the inverse planning. Due to the different PTV margin used in the different part of body, the thicknesses of hypothetical boluses were variable. A central core complete block (CCCB) 2.5 cm away from PTV in HT planning system was used to restrict the photon beams to be an oblique incidence for increasing the superficial dose and reducing the internal organ dose (Figure 2(c)). Thirty Gy with 40 fractions interrupted at 20 fractions with one week resting, 4 times per week were prescribed. Total doses of 30 Gy to 95% of the PTV were delivered to the total skin area and tumor part, respectively. The normal tissue dose constraints utilized were based on the results of the survey of the clinical outcome of the target dose and dose limits to various organs at risk (OARs). The field width, pitch, and modulation factor (MF) used for the treatment planning optimization were 2.5, 0.287 cm, and 3.5, respectively. The dose volume histograms (DVHs) were calculated for the target and individual OARs. Toxicity of treatment was scored according to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). Daily check of patient positioning was performed by the megavoltage CT (MVCT) system integrated in the tomotherapy machine. MVCT scan from head to thigh were performed to check the patient's whole body alignment. Image fusions were evaluated by the attending physician and physicist. Any translational shifts suggested by the image fusion results were applied to the final patient setup before treatment delivery. The tolerance of setup error allowed only a 5 mm difference in any of the three translation directions and 1 of difference in roll. Additional selected MVCT scans were performed after treatment to verify patient immobilization. Radiochromic EBT2 film (International Specialty Products Inc. Wayne, NJ, USA) with thickness of 0.234 mm and effective measurement depth of 0.153 mm in a layer was used for dose measurements during HITS. Each film sheet was cut into smaller pieces as 5 x 5 cm that were placed on the lesions, head, chest, abdomen, pelvis, back, and extremities for calibration and measurement. The starting day in first period, 128 EBT2 films were measured (Figure 2(d)). In the starting day of second period, only 69 EBT2 films were putting on the important area of body to confirm the previous data. An Epson Perfection V700 flatbed scanner (Epson Seiko Corporation, Epson Seiko Corporation, Nagano, Japan) with the software of ImageJ Version 1.43 (National Institute of Health, Bethesda, MD, http://rsb.info.nih.gov/ij/) was used to scan all of the films at least 24 hours after film exposure. Films were scanned at a central scanner location and with the same orientation. The settings used were 48 bit color and 150 dpi (0.017 cm per pixel). Calibration was performed by irradiating each calibration film individually in a plastic water phantom perpendicularly to a 6 MV beam at dose levels from 0 to 150 cGy. The calibration curve was fitted using a polynomial function with the pixel value (PV) for each measurement film converted to dose accordingly (Figure 3). According to the calibration curve, the dose of the exposued EBT2 films can be measured.

PMC6201338_01

Male

A 58-year-old male was referred to the rheumatology clinic for evaluation of arthralgia of the hands, wrists, and elbows. The patient's symptoms started six months prior and gradually worsened. The patient endorsed swelling of the hands and wrists, difficulty making fists, as well as morning stiffness lasting more than thirty minutes. He denied any constitutional symptoms such as fevers, chills, weight loss, decreased appetite, or night sweats. Review of systems was negative for alopecia, dry eyes, dry mouth, mouth sores, and skin rash. The patient also denied any recent travel, tick bites, or sick contacts. He never smoked and consumed alcohol on an occasional basis. The patient had a past medical history of osteoarthritis, with a surgical history significant for multiple procedures, including bilateral shoulder replacement for severe osteoarthritic changes, carpal tunnel repair of the right side, and laminectomy of the cervical and lumbar spine. Clinical exam revealed normal vitals, with benign head, eye, ear, nose, throat, cardiopulmonary, and abdominal exams. No lymphadenopathy or bruises were observed. Musculoskeletal exam revealed synovitis of the second through fifth metacarpophalangeal (MCP) and proximal interphalangeal regions bilaterally, with swelling and tenderness of the wrists with warmth to touch. In addition, there were 30-degree fixed contractions of the elbows. As per the patient, there was no history of psoriasis or nail changes, which was confirmed on physical exam as well. Laboratory data showed white blood cells of 12,000/mm, hemoglobin of 9.7 g/dl, hematocrit of 30.9%, C-reactive protein of 40 mg per liter (reference value <8), and erythrocyte sedimentation rate of 50 mm per hour (reference range 0 to 15). Laboratory testing of liver function, calcium, thyroid function, uric acid, renal function, and urinalysis was normal. Other normal or negative tests included antinuclear antibody, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, hepatitis B panel, hepatitis C antibody, QuantiFERON-TB Gold test, and angiotensin-converting enzyme. The patient was seen by an outside rheumatologist and treated initially with prednisone 20 mg/d and methotrexate, which was quickly escalated to a dose of 20 mg/weekly, with no response after three months of treatment. He was subsequently started on antitumor necrosis factor inhibitors. Six months later, a follow-up visit showed persistent symptoms. Alternative anti-TNF inhibitors were tried with no improvement. Further workup included X-rays of the hands and wrists, which showed mild degenerative changes only. Chest X-ray revealed no pathology. The patient underwent MRI of the right hand, which showed synovial thickening of the radiocarpal joint and MCP joints with flexor tendon tenosynovitis, compatible with inflammatory arthropathy (Figure 1). Further questioning of the patient revealed a family history of primary amyloidosis in his mother. Serum calcium, uric acid, and creatinine remained normal during the time of RA treatment. As a result, serum protein electrophoresis (SPEP) and urine protein electrophoresis were sent. Interestingly, SPEP was positive for M-band. The patient was then referred to hematology for further evaluation and underwent a bone marrow biopsy, which was positive for more than 40% plasma cells, as well as being Congo red stain negative, findings consistent with MM. FISH analysis was positive for monosomy 13 in 88% of the cells. The patient then started treatment for MM with bortezomib and dexamethasone. Six-month follow-up showed complete resolution of joint swelling, with significant improvement in pain of the hands, wrists, and elbows. His MM remained quiescent with chemotherapy, and the patient did not require bone marrow transplant.

PMC8100432_01

Female

The first case of an Italian contracting COVID-19 was documented on February 21, 2020. "Patient 1" is a 38-year-old man from a small town near Milan whose wife was pregnant. In the turmoil of the breaking news, this detail was often repeated. Our thoughts:as a medical anthropologist and an activist mother engaged in the field of birth:ran to this mother-to-be, who was abruptly separated from her husband when he was confined to intensive care. We felt frightened and powerless, thinking about the health risk to her and their baby. Very little was then known about SARS-CoV-2, let alone about its effects during pregnancy. At that time, we could not imagine that separation, isolation, and loneliness would become trademarks of how we give birth:and die:during a pandemic. This was also when the national hunt for the "culprit" began. Attempts were made to trace the chain of contagion, in the hope of exorcising the growing fear that it was too late to stop it. Before February 21, the only two confirmed cases of the novel coronavirus in Italy dated back to January 30 and were related to two Chinese tourists on holiday in Rome. Until then, the media portrayed the virus as something lethal but exotic, still distant enough to leave all of us living in privileged old Europe substantially safe. A lethal mix of ethnocentric shortsightedness, structural issues in some parts of the Italian National Health Service, and the imponderability of nature created the perfect environment for the virus to proliferate in the country. "Patient 1" and his pregnant wife were the tip of an iceberg that would soon reveal its magnitude. At the end of February, a frightening scenario was emerging: thousands of people were exposed to the risk of being infected, including hundreds of women who were soon to become mothers. Hospitals:where 99.9% of births occur in Italy :were quickly identified as dangerous contagion hotbeds. Health services, including the entire birth carepath, required urgent reorganization. Protocols had to be rewritten and interpersonal relationships reshaped in light of the sudden need for social distancing. Drastic measures were to be implemented, as births could not be stopped. This study looks at maternity care in Bologna, Italy, during the Italian COVID-19 lockdown. To describe this lockdown, an early op-ed in the New York Times was provocatively titled: "Even Mass Is Canceled". From March 9 to May 18, 2020, all citizens not involved in primary activities (such as health care, food production and distribution, vital logistics, law enforcement and security) had to follow one simple rule: stay at home. From our own domestic quarantines, we observed the turmoil that was swirling around maternity care in Bologna through texts, calls, photos, and accounts coming from "outside." These were the voices of soon-to-be parents and birth providers:hospital midwives in particular:confronting this new Covidian world and enduring its immediate effects. On April 17:a full month into the total lockdown:the association Voci di Nascita sent a formal letter to the local political and healthcare authorities in representation of parents, birth professionals, and birth activists 1 . The goal was to denounce the temporary suspension of women's right to be accompanied by a person of choice during labor and childbirth in the city hospitals. Dozens of parents followed suit, enclosing a copy of the letter in their inquiries to the public relations departments of the hospitals where they were planning to give birth. The authorities responded, opening up a dialogue with the association and its members. Shortly after that, along with the gradual decrease in the emergency and the progressive systematization of the scientific evidence, the most restrictive measures were modified. This article, like our engagements in the field of birth, is driven by our shared desire to contribute to fostering positive cultural change and social impact. Such an aspiration proves more urgent than ever in times of social distancing and temporary restriction of reproductive rights: timely and informed critique is vital to the constant maintenance process that public health deserves in a democratic setting. This was also the primary driving factor for the social campaign empowered by Voci di Nascita and the reason why we decided to analyze that campaign and its repercussions on the community and on maternity care. Anthropological work normally requires prolonged participation in the research field and direct engagement in relationships with interlocutors and research collaborators. Given social distancing measures, this was not possible for us. Therefore, we designed a short-term ethnographic research plan, which included two online questionnaires, in-depth conversations between we two authors, informal exchanges with local birth providers, participation in relevant webinars, and a review of the latest literature on the topic. Our study combines the analysis of data derived from such sources and unfolds on the basis of previous engagements in the field:both Daniela's as an activist mother and Brenda's as an anthropologist.

covid-19, italy, birth, covidian, maternity care, midwifery, public health, reproductive rights

PMC7755560_01

Female

A 33-year-old female gravida 2 para 0110 presented to the obstetric and gynecologic clinic to establish prenatal care. Her estimated gestational age determined by last menstrual period was 10 weeks 6 days. A diagnosis of missed abortion was made after ultrasound revealed a crown rump length of 9.2 mm, consistent with a gestational age of 7 weeks 0 days, with no fetal heartbeat identified. The patient had a history of normal 28-day menstrual cycles and used a combined oral contraceptive pill prior to this pregnancy. She reported a history of polycystic ovary syndrome, human papillomavirus infection, and CIN grade 3 (CIN 3) diagnosed 3 years prior. Two years prior to the current visit, the patient received cryotherapy treatment for CIN 3 that failed to resolve her cervical dysplasia as evidenced by a repeat Pap smear. She was offered CKC but declined, and instead opted for homeopathic treatment with topical black salve. She reported that her cervical dysplasia was confirmed as resolved by Pap smear after one treatment with black salve; however, she applied another treatment that resulted in significant vaginal pain. Pelvic examination at presentation revealed normal external genitalia without lesions and normal hair distribution. The vagina was moist and well rugated without lesions or discharge. The vaginal canal appeared shortened, and the cervix appeared pink and flush with the vaginal cuff. The uterus was of normal size, mobile, without tenderness, and with no evidence of adnexal masses or tenderness. She was prescribed oral misoprostol 800 mug for management of missed abortion, and she passed fetal tissue without complication. Three months after her initial presentation, the patient returned to the clinic with complaints of oligomenorrhea, with her last menstrual period occurring 38 days prior to this visit. She denied any fevers or pelvic pain. The patient was afebrile, and vital signs were normal. Pelvic examination findings were identical to those from the previous examination. A uterine sound was placed through the external cervical os, and purulent material with a small amount of red blood was passed through the cervix. Human chorionic gonadotropin level was <1.2 mIU/mL. Transabdominal ultrasound revealed no sonographic abnormality of the uterus. Aerobic cultures were collected at the time of examination. Three days later, the cultures grew Klebsiella pneumoniae sensitive to ciprofloxacin. The patient was treated with ciprofloxacin 500 mg orally twice daily for 10 days and instructed to return if signs or symptoms of pelvic abscess developed. The patient returned to clinic 6 weeks later with continuing oligomenorrhea to discuss a management plan. Hysteroscopy was scheduled 5 days later for evaluation and management of cervical stenosis. On the day of the procedure, visual examination revealed a shortened vaginal canal measuring approximately 5 cm in length and a cervix that appeared flush against the vagina. The cervix was serially dilated to accommodate a 5-mm rigid hysteroscope. Once through the dilated os, the hysteroscope entered a blind pouch measuring approximately 3.5 cm in length, and the true cervix was visible on the right anterior vaginal wall (Figure). Two attempts to advance the hysteroscope through the cervical os failed because of the distorted anatomy. The procedure was terminated after the second attempt, and the hysteroscope was withdrawn without complication. The patient was referred to the urogynecology service to discuss management of her newly diagnosed vaginal stenosis. Vaginoscopy and hysteroscopy were scheduled for 3 months later. Vaginoscopy findings were consistent with the prior attempted hysteroscopy. Hysteroscopy revealed a normal cervix leading to an arcuate uterus with normal-appearing ostia. Postoperatively, the patient was recommended to use a cervical dilator daily for 5 to 10 minutes. Future plans were to perform a vaginal adhesiolysis and to place an indwelling vaginal stent to relieve the stenosis.

administration–intravaginal, cervical intraepithelial neoplasia, sanguinarine

PMC10214961_04

Transgender

The annual incidence of LYH may be estimated at one case per 9 million. Data from 4 large patient analyses (905-2500 people) indicate that LYH is seen in less than 1% (0.88-0.24%) of all surgical pituitary specimens. In 2012, Kalra et al. indicated that the number of children under 18 years old with LYH was greater than 96 in the literature. The incidence in children was much lower compared to approximately 460 adults with autoimmune hypophysitis. In contrast to adults (more female patients were identified with a female-to-male ratio of 8:1) no significant sex predilection was seen among children. Concurrent autoimmune conditions were reported in 20-50% of cases of LYH in adults. The most common association was observed with autoimmune thyroid disease, reported in 15-25% of LYH cases, i.e. 70-80% of cases with an associated autoimmune disease. Chronic autoimmune thyroiditis constituted about 75%, while Graves' disease and subacute thyroiditis were reported less frequently. Autoimmune adrenalitis was reported in 5-7% of cases (15-25% of patients with an associated autoimmune condition), while pernicious anaemia and type 1 diabetes were seen in 2% of cases. Associated autoimmune disorders occurred in 7 out of 96 children, with an incidence of 7% as compared to 20-50% in adults. The clinical presentation of LYH is variable and comprises 4 categories of symptoms: sellar compression, hypopituitarism, CDI, and hyperprolactinaemia. In adults with LYH, 96% have PST and 72% have CDI. The symptoms of sellar compression, represented by headache and visual disturbances, are the most common and usually the initial complaints in LAH. Headache is the result of the distortion of the dura mater and diaphragma sellae by the expanding pituitary mass. However, a recent study showed that pituitary volume did not correlate with its severity. Headache is observed more often in patients with LAH (53%) than in those with LINH (13%). Visual abnormalities include visual field defects, decreased acuity, and diplopia, which are secondary to the compression of the optic chiasm by a pituitary mass expanding upward or laterally to the cavernous sinus. Visual disturbances are described in 43% of LAH and seldom in LINH, i.e. only in 3%. The other most common symptoms are due to a partial or complete deficit of the anterior pituitary hormones. CDI is another of the most common problems, which may be attributed either to direct immune destruction or to the compression of the posterior lobe and infundibular stem. CDI is the cardinal feature of LINH (98%) and may be very rare in LAH (1%). CDI may be masked in the presence of a coexisting glucocorticoid deficit because it opposes the action of antidiuretic hormone (ADH) at several levels. Glucocorticoids inhibit the secretion of ADH from the neurons of the paraventricular nucleus and suppress the synthesis of aquaporin 2, an ADH-dependent water channel expressed in the renal collecting tubules. The manifestations of hyperprolactinaemia, mainly represented by amenorrhoea and galactorrhoea, are the least common. Hyperprolactinaemia results from stalk compression, with the resulting decrease in dopamine delivery to the anterior pituitary. The inflammatory process may directly destroy the lactotrophs, inducing the release of prolactin (PRL) into the general circulation. Headache, visual disturbances, hypocortisolism, and hypothyroidism are more common in LAH than in LINH or LPH. In contrast, CDI suggests LINH, a condition in which other presenting symptoms, such as visual disturbances, hypocortisolism, hypogonadism, and hyperprolactinaemia are rare. A presumptive diagnosis of LYH may be made based on clinical, laboratory, and imaging studies, but the definitive confirmation requires a pituitary biopsy. Antibodies against pituitary protein and vasopressin-secreting hypothalamic cells may be found in patients with LYH. They may be measured with indirect immunofluorescence, immunoblotting, or enzyme-linked immunosorbent assay (ELISA). However, the specificity and sensitivity of pituitary antibodies is poor, as they were found in various pituitary diseases such as Cushing's disease, pituitary adenoma, empty sella syndrome, as well as in other autoimmune diseases, such as type 1 diabetes mellitus, Hashimoto's thyroiditis, and Graves' disease. A retrospective analysis of 379 patients with LYH conducted by Caturegli et al. revealed that antibodies against pituitary protein were detected in 10-80% of patients depending on the form of LYH and the method used (they were more often confirmed in immunoblotting). The authors of a case series presenting LAH reported that MRI studies showed an enlarging pituitary mass in 75-90% of patients. Even in cases with CDI, in which the initial scan was normal, repeated imaging evaluations performed months later might reveal a mass-like image. Heinze and Bercu published a review of 63 patients in which they reported a post-contrast enhancement of the lesion in 70%. Honegger et al. reported a tongue-like extension toward the hypothalamus as a characteristic finding of LAH. A diffuse thickening of the pituitary stalk is a very characteristic MRI feature in patients with LINH. Its greater diameter was found to exceed 3.5 mm at the level of the median eminence of the hypothalamus. The normal smooth tapering of the infundibular stalk is lost, and a varying degree of asymmetry may exist. Marked gadolinium enhancement of the stalk is quite common, extending even into the lower hypothalamus. The loss of the usual neurohypophyseal "bright spot" was also commonly reported. However, it should be kept in mind that this MRI sign may be absent in 10% of normal subjects. Extensive pituitary inflammatory changes were reported in LINH, extending upwards to the suprasellar area and affecting the optic pathway, or laterally to the cavernous sinuses, with thickening of the pituitary stalk, enlargement of the neurohypophysis, or lack of the neurohypophyseal bright spot on the normal neurohypophysis on MRI. Histopathology remains the gold standard for the diagnosis of LYH. The infiltration of the pituitary gland with lymphocytes, with the predominance of T cells and particular CD4 cells is the defining pathological feature of LYH. Plasma cells, eosinophils, macrophages, histiocytes, and neutrophils are also present. Fibrosis and rare necrosis may be reported in pathological specimens. LINH should be suspected as a cause of PST when we observe: an acute onset of CDI with headache and mass-effect symptoms; isolated, early or disproportionate disruption of ACTH or TSH secretion, disproportionate disruption of anterior pituitary function for the magnitude of the changes on MRI; the presence of other autoimmune conditions and/or positive autoantibodies, including thyroid peroxidase antibodies, antinuclear antibodies, antiparietal cells, adrenal antibodies, and anti-smooth muscle antibodies; the presence of antipituitary antibodies in the serum; lymphocytic pleocytosis in the CSF; and characteristic MRI findings (diffuse thickening of the pituitary stalk with or without enhancement after gadolinium, loss of the normal posterior "bright spot" on T1-weighted images). Currently, the treatment of LYH is only symptomatic. It includes reducing the size of the pituitary/stalk mass and/or replacing the defective endocrine function. Mass reduction may be achieved via pituitary surgery, immunosuppressive drugs, or radiotherapy. Glucocorticoids should be used as the first line of treatment, rather than surgery. Glucocorticoids may be effective for treating LYH, both as anti-inflammatory agents to reduce the size of the pituitary mass or the thickened stalk, and as the replacement of defective adrenal function. Prednisone, hydrocortisone, and methylprednisolone were the most commonly used glucocorticoids. In the case of patients with poor response to glucocorticoids, other immunosuppressive drugs, such as azathioprine, methotrexate, or cyclosporine A, may be used. Surgery should be performed only in the presence of serious and progressive deficits of visual field, visual acuity, ocular movements, or increased intracranial pressure, not responsive to pharmacological treatment. Radiotherapy (conventional fractionated external-beam radiotherapy, Gamma Knife radiosurgery) should be limited to cases with severe mass-effect symptoms, those who show poor response, or those who are poor candidates for high doses of glucocorticosteroids and/or surgery. However, it is important to mention the findings of some authors, e.g. Caturegli et al., who reported that LYH resolved spontaneously without any treatment in 11 patients (3%). Sarcoidosis is an auto-inflammatory, granulomatous disorder of unknown aetiology, with multi-organ involvement, hilar lymphadenopathy, and pulmonary interstitial infiltrations being the most common manifestations. Furthermore, it affects the eyes, skin, liver, and spleen. Sarcoidosis may also involve any area of the CNS: the meninges, ventricles, cerebellar hemisphere, white matter of the frontal lobe, adjacent brain or spinal cord parenchyma, pituitary stalk, pituitary, hypothalamus, thalamus, optic nerve and chiasm, cranial nerves such as the facial, auditory, and vestibulocochlear nerve. The incidence of clinically recognized sarcoidosis in children is 0.22-0.29/100,000 children per year, and gradually increases with age to a small peak in teenagers at 13-15 years of age. However, adults aged 45-55 years are most often affected, with half of them being older than 55 years of age at the time of diagnosis. Neurosarcoidosis was reported in 5-10% of adults with systemic sarcoidosis and was seldom recognized in children. Isolated neurosarcoidosis is very rarely diagnosed. According to the English sources, a total of 54 children and adolescents were diagnosed with neurosarcoidosis, and only 9 children with isolated neurosarcoidosis. The average age of onset was 12 years (3 months - 18 years). General symptoms of sarcoidosis are fatigue, weight loss, fever, persistent cough, skin changes (subcutaneous infiltrates, erythema nodosum, lupus pernio), eye lesions (uveitis, retinal changes, conjunctival nodules), and peripheral lymphadenopathy. The manifestations of neurosarcoidosis include seizures, headache, vomiting, somnolence, cranial neuropathies (common: VII, II, infrequent: III, IV, VI, V, VIII), pituitary and hypothalamic dysfunction, cerebellar signs, neuropsychological deficits, myelopathy, and peripheral neuropathy. Granulomatous masses that involve the hypothalamus and pituitary gland cause the following: diabetes insipidus, growth and sexual maturation failure, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hypothalamic-pituitary involvement accounts for 6-9% of all neurosarcoidosis cases. Endocrine investigations mostly identify GH, gonadotropin and thyrotropin deficiency, CDI in over half of cases, and - the least frequently - corticoadrenal insufficiency. Convulsions are the most common symptom of neurosarcoidosis in children, while cranial neuropathies, especially in nerve VII, are the most common after puberty and in adults. Neurosarcoidosis is a diagnosis of exclusion. There is no single diagnostic test for sarcoidosis. Diagnosis is achieved by the combination of history, examination, CNS MRI, CSF analysis, gallium-67 scintigraphy, 18F-FDG PET/CT, and biopsy. The MRI features of neurosarcoidosis include diffuse leptomeningeal thickening and enhancement, focal dural or brain parenchymal enhancement with or without mass effect, periventricular radial vascular enhancement, and enhancement, enlargement, or atrophy of the cranial nerves or enlargement of the pituitary stalk. Criteria for the paediatric diagnosis of neurosarcoidosis have not been established, although most clinicians use the classification scheme (definitive-probable-possible) by Zajicek et al.. Anaemia, leukopaenia, and eosinophilia are commonly seen on blood counts. Hypercalcaemia and/or hypercalciuria occur in up to 10% and 40% of children, respectively, because a sarcoid macrophage is able to synthesize 1,25-dihydroxyvitamin D. Angiotensin-converting enzyme (ACE) is a biomarker of sarcoidosis. ACE levels are elevated in sarcoidosis because of the activation of monocytes, which are the precursors to the epithelioid cells that form granulomas. ACE is not specific for sarcoidosis. However, it is elevated in the serum of 68-88% of patients with systemic disease and in the CSF of 24-55% of patients with neurosarcoidosis. It should be noted that other disease processes that have also shown elevated serum ACE levels include tuberculosis, lung cancer, Hodgkin lymphoma, and cirrhosis of the liver. Normal serum/CSF ACE level cannot exclude the diagnosis of sarcoidosis. However, an elevated CSF ACE level should prompt further neurosarcoidosis evaluation. The analysis of the CSF may show pleocytosis (> 5 white blood cells) with slight lymphocytosis (10-100 cells per microl), slightly elevated protein (> 50 mg/dl) in 76% of samples, slightly decreased glucose (< 50 mg/dl) in 51% of samples and increased immunoglobulins with oligoclonal banding. However, CSF abnormalities are not specific to neurosarcoidosis, and normal CSF results were obtained in more than a third of cases. A retrospective review of the Mayo Clinic record system revealed that oligoclonal banding was present in the spinal fluid of 18% of patients. Kidd et al. presented 6 patients with hypothalamic involvement of neurosarcoidosis in MR imaging. Stalk enlargement was reported in 2 of those patients. In a case of HPR involvement, a whole-body gallium or FDG-PET scan can show other lesions that are more accessible for biopsy. Biopsy still provides the strongest evidence for this disease. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. No established treatment guidelines exist for neurosarcoidosis. High-dose corticosteroids, particularly oral prednisone, are widely used and are often effective in the treatment of sarcoidosis. If corticosteroid therapy is unsuccessful, second-line immunosuppressants are administered, e.g. methotrexate, azathioprine, mycophenolate mofetil, and leflunomide. More recently, third-line agents, including tumour necrosis factor inhibitors, i.e. infliximab or adalimumab, have been indicated in the treatment. Infliximab was dentified as an effective treatment option for patients, including those who had previously been refractory to other immunosuppressants. Pituitary tuberculosis should also be considered in the differential diagnosis of PST. The incidence of tubercular hypophysitis is 0.5-4% of all intracranial lesions. 25-30% of tubercular hypophysitis cases reported in the literature had previous or active tuberculosis. Primary pituitary tuberculosis caused by Mycobacterium tuberculosis is a sporadic condition, and only 106 cases were reported from 1924 to 2019. It mainly affects young adults with the median age being 35 years (from 5 to 60). Several cases of children with pituitary tuberculosis were also reported, especially in endemic countries. Headache (85.2%), somnolence, visual disturbances (48.1%), low-grade fever (14.8%), and vomiting are common clinical symptoms. Anterior pituitary insufficiency (51.9%), hyperprolactinaemia (27.6%), and CDI are common endocrine dysfunctions in pituitary tuberculosis. The presence of CDI is one of the key features in distinguishing pituitary tuberculoma from pituitary adenoma. It is difficult to differentiate inflammatory lesions from those of pituitary adenoma clinically and radiologically. In MRI, pituitary tuberculosis usually presents the features suggestive of a sellar and suprasellar mass, and it may be very difficult to differentiate between pituitary tuberculoma and adenoma. The thickening and nodularity of the pituitary stalk are also considered to be signs of pituitary tuberculoma. However, this finding is non-specific; it is also seen in other inflammatory conditions like sarcoidosis or lymphocytic hypophysitis. The following tests should be performed in patients with a suspected tuberculous aetiology of PST: tuberculin skin test, QuantiFERON-TB test (sensitivity 92.6%), and chest X-ray/computed tomography (CT). CSF examination may reveal moderate pleocytosis (100-300 mm3), increased protein level (100-400 mg/dl), and decreased glucose level (< 40 mg/dl). The samples do not always stain for acid-fast bacilli and Mycobacterium spp. when tested with polymerase chain reaction (PCR) method. The definitive confirmation of the diagnosis requires a histopathological examination, which reveals necrotizing granulomatous inflammation, staining for acid-fast bacilli (not usually demonstrable from pathological tissue), and the PCR of Mycobacterium spp. in DNA extracted from the tissue. Surgery is not indicated in tuberculous hypophysitis except for obtaining biopsies to confirm the diagnosis. Antitubercular drugs that cross the blood-brain barrier are administered to patients for 9-24 months depending on the clinical and imaging outcome. A significant reduction in size was reported as early as 2 months after treatment, usually with a complete resolution of sellar mass at the end of the regimen. The improvement of endocrinological status and even eliminated panhypopituitarism were reported in some patients. In cases such as tubercular hypophysitis, early diagnosis is very important given that panhypopituitarism may be eliminated in clinical terms following an effective anti-tuberculosis treatment. A delayed diagnosis may lead to permanent endocrine dysfunction. Considering the causes of PST described above, Table 1 presents tests used in the diagnostic process of PST in children. After PST imaging in MRI, diagnostic tests should be planned, taking into account the history and physical examination data. First- and second-line tests may be distinguished. The first-line tests used in the diagnosis of patients with PST include: complete blood count, ESR, ALAT, ASPAT, GGTP, urea level, creatinine, INR, APTT, blood electrolytes; 1,25-dihydroxyvitamin D; serum ACE, QuantiFERON, tuberculin test; antipituitary antibodies, anti-vasopressin antibodies, systemic autoantibodies; endocrine tests assessing the function of the anterior and posterior pituitary gland, serum tumour markers ( beta-hCG, alpha-FP); imaging tests (chest X-ray, skeletal radiograph, abdominal ultrasound), and neurological and ophthalmic examination. If first-line tests are inconclusive, it is possible to use the so-called second-line tests in selected cases, depending on the clinical presentation. These tests include the following: tumour markers in CSF, ACE in CSF, the detection of Mycobacterium spp. by PCR in CSF, and immunoglobulin G4 (IgG4) in the serum. Imaging tests of the second line are whole-body imaging with MRI, gallium 67-scintigraphy, 18F-FDG PET/MRI, or PET/CT. It is crucial when LCH or sarcoidosis is suspected because it might detect extracranial lesions not otherwise identified, which may be biopsied. In 2021, the British national recommendations for diagnosing children and adolescents with PST, CDI, or both, developed by specialists under the auspices of paediatric endocrinology and oncology societies, were published. According to the recommendation mentioned above, a routine CSF examination for acid-fast bacilli is not recommended due to the sporadic occurrence of pituitary tuberculosis in children. Nonetheless, it should be considered in exposed patients or those at a high risk. Likewise, due to the sporadic diagnosis of neurosarcoidosis as the cause of PST in children and adolescents, the authors do not recommend routine ACE in the CSF, unless neurosarcoidosis is strongly suspected. Because IgG4-related hypophysitis seldom affects a child or young person, routine measurement of IgG4 concentrations is not currently advisable. The indications for and timing of endoscopic pituitary biopsy in children and young people are controversial. Biopsy should be performed in a specialist pituitary neurosurgical unit with perioperative endocrine support on-site to reduce the risk of complications. According to the British recommendations of 2021, pituitary biopsy should be considered only in markedly thickened (>= 6.5-7 mm) or enlarging stalk with additional visual or endocrine deficits, which continue to pose a worrying diagnostic dilemma after repeated tests. Histopathological examination is conclusive in most cases. However, it is important to remember that histological findings compatible with a lymphocytic inflammatory process may represent the first sign of a host reaction to occult germinoma, which requires a repeated biopsy. In the case of CDI, a repeated brain MRI and investigation of beta-hCG tumour marker in the serum and CSF should be performed every 3-6 months during the first 3 years after the onset of CDI (the frequency depending on the presence of a progressively enlarging pituitary stalk), to rapidly establish a diagnosis before the developed large tumour triggers visual and neurological symptoms. Subsequently, MRI should be performed every year for the following 2 years and every 2-5 years thereafter, depending on the size and evolution of the lesion. Therefore, the follow-up strategy should be individually adapted.

diabetes insipidus, germinoma, histiocytosis, pituitary stalk thickening, children

PMC9898808_01

Female

A 46-year-old healthy woman of Turkish ancestry was referred to our clinic for a second opinion. She had a history of seeking emergency assistance in another hospital 1 month before with redness, purulent discharge, and discomfort in her OS, with contralateral involvement after 4 days. At this time, she was diagnosed with bilateral bacterial conjunctivitis, being aggressively treated with topical 0.5% moxifloxacin/0.1% dexamethasone every 2 h, for a week. Three weeks later, she developed ocular hypertension, ocular pain, severe photophobia, mild hyperemia, and decreased vision in her OS, being diagnosed with autoimmune hypertensive uveitis in both eyes. For this reason, treatment with topical prednisolone acetate 1% every 2 h, atropine 1% twice-daily, topical carbonic anhydrase inhibitor/beta-blocker combination, and oral steroids (1 mg/kg/day, tapered during 3 weeks) was prescribed, with no improvement of the symptoms. Past family and personal ocular history were negative, including for glaucoma. During our initial examination, her best correct visual acuity was 20/25 in the right eye (OD) and 20/200 in OS, with normal color vision. Slit-lamp revealed severe pigment dispersion in the anterior chamber, iris transillumination defect, and mydriatic atonic pupils OU (Fig. 1). There were no inflammatory keratic precipitates and no inflammatory cells in the anterior chamber. Corneal sensibility was normal, with no hypoesthesia. Gonioscopy revealed wide-open angles (Shaffer IV), heavy pigment deposition in the trabecular meshwork, and no appearance of posterior iris bowing and/or peripheral anterior synechiae in OU (Fig. 2). Even though she was not using steroids anymore, her IOP was 30 mm Hg in OD and 45 mm Hg in OS, despite the use of topical and oral antiglaucomatous medications described above. Fundus examination revealed tilted discs and increased cup-disc ratio in OU. In the OS, an edematous optic nerve, associated with peripapillary retinal hemorrhage, suggestive of nonarteritic optic neuropathy (NAION) was noticed (Fig. 3), and confirmed by optical coherence tomography, and high-frequency B-scan-ultrasonography. Fluorescein angiography did not show any signs of inflammation. A routine laboratory workup was performed including complete blood cell count, erythrocyte sedimentation rate (11 mm/h), infectious - including VDRL, FTA-ABS, herpes simplex virus and cytomegalovirus serology - and inflammatory tests, quantiFERON-TB gold test, homocysteine, anticardiolipin antibody, lupus anticoagulant, antinuclear antibody, human leukocyte antigen-B27 (HLA-B27), all with negative results. Chest, orbit, and brain magnetic resonance imaging, as well as magnetic resonance angiography were unremarkable. Since ocular hypertension persisted despite maximal medical therapy, and as the patient was not using any more steroids, a tube shunt was implanted in OU 3 weeks after her first appointment with us. After the procedure, the IOP gradually decreased, hence, topical hypotensive medications were reduced. Anterior chamber pigment was also significantly reduced in the second postoperative week. After 6 months of follow-up, best correct visual acuity was still 20/25 in OD and 20/200 in OS. IOP was 12 mm Hg OU with topical use of carbonic anhydrase inhibitor/beta-blocker twice a day. Pigment dispersion in the anterior chamber resolved in OU, and optical coherence tomography of retinal nerve fiber layer showed a localized temporal inferior defect in the OD and a diffuse loss in the OS (Fig. 4). Visual field tests revealed a superior paracentral scotoma in the OD and a diffuse reduction in sensitivity in the OS. The presence of bilateral iris atrophy, heavy pigment dispersion in the anterior chamber and trabecular meshwork, in the absence of inflammatory cells and keratic precipitates, associated with high IOP, with no improvement with maximum medical therapy, in a patient with history of using topical moxifloxacin/dexamethasone drops led us to the diagnosis of BAIT syndrome.

atonic pupil, bilateral cute iris transillumination syndrome, iris transillumination, moxifloxacin/dexamethasone, pigment dispersion

PMC6589305_01

Female

A 38-year-old nonsmoking female presented with left-sided chest pain and dyspnea for three consecutive days. The patient was admitted to Masih Daneshvari Hospital on September 19, 2016. She had no history of fever, weight loss, and arthralgia or skin rash. Her blood pressure was 110/70 mmHg, pulse rate was 85, temperature was 37.5 C, and respiratory rate was 28. The breath sound was decreased in the left lower zone of the lung, and other physical examinations were unremarkable. Chest radiograph manifested two pulmonary nodules and basal atelectasis in the left lower lobe with pneumothorax (Figure 1). Chest CT scan exhibited collapsed consolidation of the left lower lobe with pneumothorax and the presence of relatively two separated small-sized cystic lesions within the collapsed segment (Figure 2). The laboratory tests revealed the increase in WBC count with predominantly neutrophils; the erythrocyte sedimentation rate and C-reactive protein were elevated. The nitroblue tetrazolium (NTB) blood test was at the 99% accuracy level. Anti-nuclear antibodies (ANAs), anti-neutrophil cytoplasmic antibodies (C-ANCA and P-ANCA), and anti-double-stranded DNA (anti-dsDNA) were negative; in addition, the anti-HIV antibody test was negative. Transparently, the pulmonary function tests showed moderately restriction. Lung lesion resection for two intraparenchymal pulmonary nodules and cavitary lung lesion in the left lower lobe was performed; furthermore, the histological examination showed some epithelioid and giant cell granulomas with necrotizing arteritis in conjunction of a large area of necrosis (Figures 3 and 4). Acid-fast staining, periodic acid-Schiff (PAS) staining, and Gomori methenamine-silver (GMS) staining were negative; therefore, the ultimate diagnosis was necrotizing sarcoid granulomatosis. The prognosis of NSG is favorable, and medical treatment is usually not required. As a matter of fact, in our case report, the patient recovery conspicuously occurred; nevertheless, in some cases, treatment with corticosteroids is quite essential.

PMC9286925_01

Male

A 34-year-old Caucasian male was in his usual state of good health until July 2020 when he presented with a 1-week history of fever up to 39.3 C, sore throat, headaches, cough, and malaise. Having developed this during the SARS-CoV-2 pandemic, he presented to a COVID-19 testing site where jaundice was noted. He was triaged to the emergency room and then hospitalized. He tested negative for SARS-CoV-2 infection by polymerase chain reaction (PCR). A review of the system was negative for oral ulcers, change in vision, enlarged lymph nodes, chest or abdominal discomfort, dyspnea, nausea, vomiting, diarrhea, genital lesions, dysuria, hematuria, arthralgia, myalgia, neurological change, memory deficit, or rash. He had a cholecystectomy two years ago. He reported no illicit drug use, recent travel, or exposure to sick contacts, tuberculosis, ticks, animals, vaping, herbs, or supplements. He had two young children, both in daycare, and his wife was pregnant. The family medical history was unremarkable; no immunodeficiency, malignancy, autoimmunity, or severe infections. He had used over-the-counter acetaminophen and ibuprofen at the recommended doses. Laboratory tests revealed white blood cell count (WBC) 4.6 k/mm3 (range, 4.5-11 k/mm3) with neutrophils 55.6%, lymphocytes 24.2%, and monocytes 13.8%; hemoglobin (Hgb) 13.6 g/dL (range, 13.5-17.5 g/dL); platelets 155 k/mm3 (range, 150-450 k/mm3); peripheral smear with reactive lymphocytes; alkaline phosphatase 94 IU/L (range, 20-140 IU/L); alanine transaminase (ALT) 219 IU/L (range, 5-55 IU/L); aspartate aminotransaminase (AST) 99 IU/L (range, 5-45 IU/L); total bilirubin 8 mg/dL (range, 0.2-1.5 mg/dL); indirect bilirubin 7.1 mg/dL (range, 0.1-1.4 mg/dL); and normal serum creatinine. Urine analysis showed clear orange urine at pH 6.0 (range, 4.5-7) with specific gravity 1.205 (range, 1.010-1.030), protein 20 mg/dL (negative), ketones 20 mg/dL (negative), urobilinogen >20 (range, 0.1-1.8 mg/dL) and negative values for bilirubin, blood, glucose, nitrite, and leukocyte esterase. Serological testing was negative for hepatitis A virus IgM, hepatitis B virus surface antigen, hepatitis B virus core IgM, hepatitis C virus antibody (Ab), human immunodeficiency virus (HIV) p24 antigen (Ag), HIV-1 and HIV-2 Abs, antinuclear antigen Ab, liver-kidney microsomal Ab, mitochondrial Ab, and antismooth muscle Ab. Ceruloplasmin was normal. Iron level was 219 mcg/dL (range, 35-160 mcg/dL), normal TIBC, elevated iron saturation at 83% (range, 30-50%), and low transferrin at 161 mg/dL (range 200-430 mg/dL). IgG level was normal at 957 mg/dL (range, 650-1600 mg/dL). Blood cultures were negative. Abdominal ultrasound showed moderate hepatomegaly and changes consistent with fatty liver disease. Abdominal MRI showed similar changes plus splenomegaly (16 cm). The patient was discharged home on hospital day 3. On the following day, he was readmitted because of worsening symptoms and normocytic anemia. The Hgb of 12.5 g/dL on the day of entry steadily decreased to 8.7 g/dL on day 8 of this hospitalization. Other remarkable blood count results included WBC 4.2 k/mm3 (range, 4.5-11 k/mm3), neutrophils 1.9 k/mm3 (range, 1.8-7.7 k/mm3), and platelets 155 k/mm3. Peripheral smear revealed an increase in reactive lymphocytes but a normal lymphocyte count and no schistocytes. Other remarkable laboratory findings included AST 56 IU/L, ALT 120 IU/L, total bilirubin 7.7 mg/dL, indirect bilirubin 6.7 mg/dL, ferritin 1570 ng/mL (range, 24-336 ng/mL), fibrinogen 488 mg/dL (range, 200-450 mg/dL), triglycerides 173 mg/dL (range, <149 mg/dL), LDH 341 IU/L (range, 135-220 IU/L), haptoglobin 1 mg/dL (range, 40-280), absolute reticulocyte count 0.1947 million/mm3 (range, 0.62-1.88 million/mm3), plasma free Hgb 60 mg/L (range, 0-9 mg/dL), no urinary hemosiderin, and negative Coomb's test. Computed tomography of the chest, abdomen, and pelvis showed hepatosplenomegaly without lymphadenopathy. To investigate the cause of the liver abnormalities, a percutaneous liver biopsy was performed on day 2 of hospitalization. This showed portal triad inflammation involving lymphocytes, eosinophils, and granulomatous inflammation (Figure 1), as well as rare lobular microgranulomata (Figure 2). Liver sinusoids had excessive numbers of Kupffer cells (Figure 3) and T-lymphocytes (Figure 4). Occasional benign appearing histiocytes/Kupffer cells had findings of hemophagocytosis of red blood cells and probable leukocytes (Figure 5). Immunohistochemical stains for CMV, HSV-1, and HSV-2 Ags were negative. In situ hybridization for EBV EBER RNA was negative. Special stains for acid-fast bacilli and fungi were negative. Additional testing performed on blood for the HLH possibility included a soluble CD25 (IL-2 receptor) level that was elevated at 1200.3 pg/mL (range, 175.3-858.2). Natural killer cell activity was not assessed. The infectious disease workup revealed CMV IgM and IgG in serum and CMV DNA in plasma at 41 IU/mL (reference value, undetected; quantification range, 35-106 IU/mL). Primary CMV infection was later confirmed by evidence of a low CMV IgG avidity index of 0.18 (cut off >0.7 for past infection). EBV viral capsid antigen (VCA) IgG and IgM were positive, EBV nuclear antigen IgG >8 (EBNA antibody), and plasma EBV DNA was absent. The blood was negative by PCR for HHV8, ehrlichia, anaplasma, and Coxiella burnetii DNA. Also negative in the blood were brucella IgG and IgM, ehrlichia and anaplasma Abs, parvovirus B19 IgM, Rickettsia rickettsii Abs, and tuberculosis interferon gamma release assay. Histoplasma Ag in blood and urine; blastomyces Ag in urine, CSF, and blood were negative. Flow cytometry applied to the blood was negative for blasts and atypical lymphoid proliferation. Bone marrow biopsy performed on day 6 of the hospitalization (blood count Hgb 9.8 g/dL), showed normocellular marrow for age with 1+ polychromasia, normal trilineage hematopoiesis, increased storage iron, and no hemophagocytosis, malignancy, CMV Ag, EBV EBER RNA, or stainable acid-fast bacilli and fungi. The patient's condition was improving before he was given oral valganciclovir for 5 days and discharged home. He received no corticosteroids, immune globulin, or other immunomodulatory therapy. After discharge from the hospital, he had four face-to-face follow-up visits over 10 months. At 5 weeks after the onset of illness, the patient had returned to his usual activity level and had no symptoms of CMV DNAemia. At four months, the cytopenia had resolved (WBC 4.0 k/mm3, Hgb 14.3 g/dL, and platelets 210 k/mm3), liver transaminases had normalized, and total bilirubin had improved. At 10 months, the labs showed Hgb 14.5 g/dL, total bilirubin 3.7 mg/dL, direct bilirubin 1 mg/dL, ferritin 280 ng/mL, and haptoglobin 49 mg/dL. The persistent elevation in indirect bilirubin levels could be from residual compensated hemolysis or previously unrecognized Gilbert syndrome. The patient elected to not return for further follow-up.

PMC4555937_01

Male

In January 2007, the patient, a 21-year-old male with tooth fracture sustained during a football game was referred to Center for Dental Specialties Visioli, Cascavel, Parana, Brazil. This study followed the Declaration of Helsinki on medical protocol and ethics. During the interview, the patient reported no history suggestive of presence of a tumor in the maxillary sinus. The affected tooth was the maxillary left central incisor. After clinical and periapical radiographic examination, a vertical fracture of the tooth root was diagnosed. The proposed treatment was the atraumatic removal of the root and the immediate installation of a dental implant with an immediate temporary prosthesis. At physical examination, the absence of maxillary left second and third molars and a swelling of the alveolar process with a firm consistency and obliteration of the vestibular sulcus were noted. The soft tissue had normal color and patient denied pain. Panoramic radiographs revealed a solid radiopaque mass involving the left alveolar ridge, maxillary sinus, and orbit [Figure 1]. Axial and multiplanar reconstructed computed tomography images [Figures 2-4] revealed a hyperdense mass extending from the alveolar ridge to the middle third of the maxillary sinus with extension to the orbital roof. The differential diagnosis for the lesion includes calcifying odontogenic cyst, calcifying odontogenic tumor, ameloblastic fibroma, fibro-odontoma, and fibro-osseous lesion. Excisional biopsy of the lesion was performed. One hour prior to surgery patient was given decadron 40 mg intravenous (IV), 1 g kefazol IV, plasil 20 mg IV, nalbuphine hydrochloride IV, and 750 mg acetaminophen (Tylenol ; Cilag Farmaceutica Ltda., Sao Paulo, SP, Brazil) for pain management. Extraoral and intraoral antisepsis was performed with polyvinylpyrrolidone-iodine 10-2.0% chlorhexidine solution and 0.12% chlorhexidine rinse for 1 min, respectively. The operation was performed with the patient under hypotensive general anesthesia. The surgical procedure was initiated with an intrasulcular incision, from the maxillary left first premolar until the first molar and continued on the tuberosity. A relaxing incision was performed on the mesial of the premolar to allow a mucoperiosteal flap raise to expose the very superficially located mass [Figure 5]. Surgical approach was performed using a spherical drill and a #702 tapered stem, and several blocks of the lesion were removed [Figure 6] and submitted for histopathological examination. During surgery, it was observed that the impacted teeth (second and third molars) exhibited an apparent change in shape and size. Surgical cavity was totally smoothened and no complementary treatment was necessary. The flap was repositioned and closed with interrupted stitches. Subjects were prescribed analgesics LISADOR 3 days + AMOXI 500, 7 days + FLAGYL 400, 5 days + omeprazol 40, 7 days, periogard 12 days. For 3 days and antibiotics (amoxicillin 500 mg, 3 times a day) for 1-week and instructed to use 0.12% chlorhexidine rinse twice daily for 1-week. The area healed uneventfully. Histopathological examination of the excised mass showed irregularly arranged dental hard tissues with areas of cell rich pulpal tissue. Clear spaces and clefts representing the mature enamel that is lost in the process of decalcification are often seen confirming the diagnosis of a complex odontoma [Figure 7]. Two years after lesion removal, panoramic radiographic demonstrated occurrence of bone repair in the treated area and did not reveal any signs of recurrence [Figure 8].

computed tomography, diagnostic imaging, odontogenic tumors, odontoma

PMC5457763_01

Female

A 53-year-old female patient consulted physical medicine, rehabilitation and rheumatology department due to the pain radiating from the right inguinal region and the right hip to knee while she was being followed by general surgery clinic because of solid mass in the liver. During the assessment, patient complained of having an intermittent backache for a long time; she described a constant pain in her right hip and groin spreading to right knee that started 1 week ago and was increasing with rest. Patient also reported there was pain and slight swelling in the right ankle 10 days before that lasted for 3 days. In her background no previous illness is noted. Patient had an abdominal pain lasting for the last 6 months and abdominal ultrasound was performed; a solid mass was detected in the liver. We learned that the patient had no history of arthritis, gastroenteritis, urinary tract infection, psoriasis, or previous operation. She has not been using any medication except for analgesic. The patient had no relatives with history of inflammatory disease or malignancy in her family history. In the physical examination loss of lumbar lordosis was detected. Waist movement was slightly restricted to all directions due to pain, hand fingertip-to-floor distance was 10 cm, sacroiliac compression test was positive on the right, FABERE test was positive on the right, her right knee was warm and tender, there was no rash on the skin, local sensitivity was detected in the right upper quadrant with palpation, and other system evaluations were normal. Sacroiliac MRI was seen because of the suspicion of sacroiliitis. The sacroiliac MRI, which was assessed independently by radiology department, showed a signal enhancement consistent with the right iliac focal bone marrow edema adjacent to the right sacroiliac junction (Figure 1) and there were 2 cystic lesions at iliac front adjacent to the right hip joint. Abdomen tomography of our patient, which was requested by general surgery department, showed a well-defined 55 x 48 mm hypodense lesion with a superior calcification (lily symptom) in segment 3 (Figure 2). Hydatid cyst hemagglutination titer test was 1/320 and the patient was diagnosed as hydatid cyst disease. The patient was taken to our clinic because of development of right ankle arthritis and right knee arthritis. In our clinic, the laboratory tests required for sacroiliitis and arthritis etiology were done. The results of these tests showed that RF was negative, anti-CCP was negative, anti-cardiolipin antibodies were negative, ds DNA was negative, ANA was negative, c-ANCA and p-ANCA were negative, sedimentation was 38 m/h, CRP was 23 mg/L, WBC was 7,31 (103/12.7 g/dL), PLT was 364 (103/muL), tumor markers were negative. In addition, Brucella Wright and Coombs agglutination tests were negative. EBV VCA Ig M, EBV VCA Ig G, and Anti-CMV Ig G were detected as positive; EBV EA, Anti-CMV IG m were detected as negative. The right knee joint was punctured and 60 cc yellow clear liquid aspirated. At the examination of knee joint fluid Tbc DNA, tbc real time PCR, mycobacterial culture were detected as negative and there was no reproduction in cell culture; 8000 leucocytes (30% MNL, 70% PMNL) and 20 erythrocytes were detected in the cell analysis of aspiration fluid. Microscopic examination of the joint fluid showed no protoscolex and hook structures of the Echinococcus parasite. There was no reproduction in the blood culture. Anti-HCV, HBsAg, and Anti-HIV tests were negative. There was no evidence in the ECO for infective endocarditis. The patient consulted pulmonary medicine department. In the assessment PPD test was 5 mm and sputum culture and microscopic examination showed no Tbc Bacillus. HLA-B27 genetic assay was negative for spondyloarthropathy. The patient is diagnosed as reactive arthritis secondary to echinococcal infestation after all tests and no history of other diseases which can cause sacroiliitis and peripheral arthritis like SPA (spondyloarthropathy), familial Mediterranean fever, Behcet's disease, sarcoidosis, inflammatory bowel disease, and malignancy. Symptomatic treatment as 4 x 1 cold pack and TENS treatment were applied to the right knee of the patient. Acemetacin 60 mg capsule 2 x 1 was given as medical treatment. On the 5th day of treatment, right knee and ankle arthritis were clinically regressed and then patient was directed to the general surgery department for surgical treatment of hydatid cysts.

PMC4496644_01

Female

A 53-year-old woman with no significant past medical history presented with slowly progressive weakness in the lower extremities, new-onset numbness below the midthoracic area, urinary incontinence, and slurred speech. One year prior to presentation, she experienced left-sided transitory weakness involving the face and extremities. She was evaluated by multiple neurologists and her brain imaging studies were unrevealing. She later developed tremor in the upper extremities and she was suspected to have central tremor or Parkinson's disease. The patient never had fever, chills, or sweating; however, she had lost 30 pounds during the three-month period preceding her presentation. The patient grew up on a dairy farm and played in silos. She is married; she lives and works in a farm in rural Kansas, where they grow corn and soy. She has no significant travel history. She denied having sick contacts or significant animal exposure. And she had no history of drug use, incarceration, or exposure to tuberculosis. The patient first presented to an outside hospital. MRI of the brain and spine, as well as lumbar puncture (LP), was obtained. The MRI images showed leptomeningeal enhancement, predominantly linear, involving the basal cisterns, the brainstem, and spinal cord. Cerebrospinal fluid (CSF) analysis showed 4 rbc/mm3, 157 wbc/mm3 (55% lymphocytes, 35% neutrophils, and 10% monocytes), protein 362 mg/dL, and glucose 24 mg/dL. CSF Gram stain showed no organisms and AFB smear was negative. Bacterial culture was negative. CSF studies including cryptococcal antigen, human herpes simplex virus PCR, West Nile virus PCR, Lyme antibodies, M. tuberculosis (TB) PCR, and cytology were all negative. HIV screen, RPR, and QuantiFERON-TB Gold were negative as well. A CT of the chest, abdomen, and pelvis was unremarkable. The patient was treated with antibiotics and steroids and transferred to our hospital 8 days after her initial admission for further evaluation and treatment. At that time, her CSF fungal and mycobacterial cultures were pending. After transfer to our facility, a second LP was performed, three days after the initial one. CSF analysis revealed 248 wbc/mm3 (77% lymphocytes, 6% neutrophils, and 17% monocytes), protein 340 mg/dL, and glucose 51 mg/dL. Routine bacterial culture was again negative. C-reactive protein and procalcitonin levels were normal. Repeat brain and spine MRI at our facility showed mild improvement of the meningeal enhancement (Figures 1, 2, and 3). Repeat CSF analysis two days later revealed 25 rbc/mm3, 150 wbc/mm3 (61% neutrophils, 23% lymphocytes, and 16% monocytes), glucose 14 mg/dL, and protein 587 mg/dL. The shift from lymphocytes to neutrophils was felt to be due to steroid therapy. The CD4 lymphocyte count was 372 (58.5%), despite treatment with steroids. The work-up at this point focused on ruling out a fungal infection since TB seemed unlikely. Fungitell was negative. Serum Histoplasma antibody was positive by EIA; however, complement fixation and immunodiffusion assays were negative. Histoplasma urine antigen was 0.68 ng/mL. Blastomyces antibody was negative (immunodiffusion assay). Blastomyces urine antigen was 0.55 ng/dL. Sporothrix antibody was negative. CSF Histoplasma and Blastomyces antibodies were both negative. At this time, fluconazole, which was given initially for empiric antifungal therapy, was changed to liposomal amphotericin B. Repeat Histoplasma urine antigen was 0.71 ng/mL and Blastomyces urine antigen was 0.56 ng/dL. CSF Histoplasma and Blastomyces antigens were both positive, above the limits of quantification. Last LP, two weeks later, showed further improvement of pleocytosis and protein level (60 wbc: 58% lymphocytes, 33% neutrophils, and 9% monocytes; glucose 54 mg/dL; protein 173 mg/dL). Repeat CSF Histoplasma and Blastomyces antibodies were again negative, while repeat CSF Histoplasma and Blastomyces antigens were both positive, above limits of quantification. Serum Histoplasma antigen was measured as well and came back positive, below limit of quantification (<0.4 ng/dL). Two CSF fungal and mycobacterial cultures done at the outside hospital remained negative. One of two CSF fungal cultures, obtained two days after admission to our facility, eventually grew Histoplasma capsulatum one month later. Four weeks after admission to our facility, the patient was discharged to a long-term acute care hospital to continue treatment. She received 6 weeks of treatment with liposomal amphotericin B followed by oral voriconazole with minimal improvement of her weakness during the first two months of treatment. Patient was lost to follow-up afterwards.

PMC4862986_01

Female

A 21-year-old girl, while attending college, was referred to our outpatient department with a 12-day history of gradual onset of quadriparesis. Weakness was present both proximally and distally, was initially asymmetric to start with but reached its nadir and became almost symmetric within 2 days. Along with her weakness she also experienced decreased sensation up to her lower chest and developed incontinence of urine. There was no history of any convulsions, loss of consciousness/altered sensorium, decreased vision, diplopia, facial weakness, or dysphagia. After review of the initial MRI and cerebrospinal fluid (CSF) profile, the patient had been prescribed anti-tubercular drugs along with steroids 1 week earlier by a local practitioner and associated with mild improvement in her symptoms. On examination, she had a temperature of 37.2 C; no palpable lymph nodes were detected. The remainder of her general examination was unremarkable. On neurological examination, she was conscious, well-oriented but apprehensive. Tone was increased in both lower limbs; however, it was normal in the upper limbs. Strength was decreased in all four limbs (2/5 in both upper limbs and 1/5 in lower limbs), and muscle stretch reflexes were increased with Babinski sign bilaterally. On sensory examination, superficial and deep sensation to all modalities was diminished below the C7 dermatome. Routine blood investigations, including complete blood count, erythrocyte sedimentation rate, blood sugar (BS), serum electrolytes, and liver and kidney function tests were normal. Serologies for human immunodeficiency virus, hepatitis C virus, hepatitis B surface antigen, and tuberculosis skin test were negative. Collagen vascular disease work up was also non-contributory. Chest X-ray and ultrasonography of the abdomen were also normal. MRI of the cervical spine, done prior to admission, had revealed long segment lesions with T2 hyperintensity in cervical and dorsal cord favoring demyelination (Figure 1). CSF study done prior to presentation at our hospital had shown 350 cells out of which 62% were neutrophils and 38% were mononuclear cells, protein was 180 mg/dL and sugar was 50 mg/dL (BS: 82). On presentation at our center, we performed a MRI of the brain that revealed a single well-circumscribed T2 hyperintense lesion in the right subcortical frontal region (at gray white interface) (Figure 2) without any diffusion restriction or contrast enhancement. Accordingly, we repeated the CSF study in view of these lesions that showed 300 cells out of which 58% were neutrophils and 42% were mononuclear cells; however, there were no red blood cells. Protein was 203 mg/dL, sugar was 60 mg/dL (BS: 82), tuberculosis polymerase chain reaction was negative, and adenosine deaminase came out to be 3.2 U/L. Furthermore, oligoclonal band (OCB) was positive in the CSF. In view of the longitudinally extensive myelitis and a high CSF count, AQP4-Ab was also ordered. Although visual-evoked potentials (VEP) test was normal bilaterally, somatosensory evoked potentials (SSEPs) were suggestive of prolonged latency of N13 and N17 waveforms. We made the provisional diagnosis of NMO spectrum disorder (NMOSD) in light of overall picture. She received a 5-day course of 500 mg daily intravenous methyl-prednisolone (IVMP) followed by oral prednisolone (OPN) at a dose of 1 mg/kg/day (60 mg). Significant improvement in power was noted (4/5 in upper limbs and 2/5 in lower limbs) at the seventh day from initiation of therapy. Meanwhile AQP4-Ab (done by indirect immunofluorescence) was positive (1:500 titer), so azathioprine therapy was initiated at a dose of 50 mg daily and subsequently increased to 100 mg/day over the next 4 weeks with monitoring of blood counts and liver function tests. Meanwhile, OPN was continued at the same dose. The patient's neurological status remained unchanged over for next 5 weeks when she developed a left focal motor seizure, neck weakness, and bilateral facial and bulbar palsy along with increased weakness in all four limbs. A repeat MRI of the brain revealed bilateral frontal-parietal hyperintensities on T2 sequence with central hypointensity on FLAIR (Figures 3A,B). Furthermore, on contrast injection incomplete ring enhancement was noted (Figures 3C,D). Cervical MRI showed patchy enhancing long TR hyperintensities in cervical and dorsal cord favoring demyelination (Figures 4A,B). We decided to treat the patient with five cycles of therapeutic plasma exchange (TPE) along with IVMP. On the fourth day of TPE, she again started recovering with regard to extremity strength and with significant improvement in facial and bulbar weakness as well. She was discharged on azathioprine and continued physiotherapy at home. At her 4 months follow-up, she was ambulatory, had re-joined her college, and was doing fine otherwise. Subsequently, OPN was tapered off and azathioprine maintained at a dose of 125 mg/day.

aquaporin-4, longitudinally extensive transverse myelitis, neuromyelitis optica spectrum disorder, therapeutic plasma exchange, tumefactive multiple sclerosis

PMC5835301_01

Male

A 54-year-old male with past medical history of degenerative joint disease, major depressive disorder, polysubstance dependence, and history of childhood burn presented to the Emergency Department (ED) complaining of imbalance, irritability, outburst of temper, fatigue, and weakness for the last five days after he ingested five ounces (oz) (148 cc) of mercury as a suicidal attempt. In the ED, the patient denied any changes in vision, hearing impairment, or tremors. He also denied shortness of breath, abdominal pain, nausea, vomiting, or diarrhea. On physical examination, the patient appeared to be in no obvious distress. He seemed well developed, alert, and oriented to time, place, and person. Vital signs (BP 144/96, HR 74, RR 16, and temperature 96.3). A neurological examination yielded intact cranial nerves, with normal motor function and no sensory deficits. Abdominal examination showed a distended and nontender abdomen with normoactive bowel sounds. The rest of the physical examination showed no abnormalities. On admission, laboratory workup was done and showed hemoglobin of 13.9 gm/dl (normal range 13.5-17.5), platelet of 309 k/ul (normal range is 40-440), WBC of 8 k/ul (normal range 4-12), a mildly elevated creatinine at 1.4 mg/dl (eGFR 56) (reference range 0.6-1.3 mg/dl), and a low potassium at 3.5 (reference range 3.7-5.1 mg/dl). A urine drug screen was done which was positive for amphetamine, benzodiazepine, and cannabinoid. A mercury toxicology workup was initiated and showed an elevation in serum mercury level at 110 microg/l (reference range < 10 microg/l), urine mercury level at 37 microg/l (reference range < 10 microg/l), and 24-hour urinary mercury level at 248 microg (no exposure < 20 microg/24, inconclusive 20-150 microg/24h, and potentially toxic > 150 microg/24h). Initial abdominal X-ray (Figure 1) showed diffuse radiopaque material visualized throughout the colon. Due to the patient's toxic mercury levels and worrying neurological signs and symptoms, the patient was admitted to the intensive care unit with a one on one sitter available at his bedside. Vital signs, neurological checks, and electrolytes were measured on regular basis. The poison-control team was consulted upon admission and recommended starting the patient on succimer, as a chelating agent, to be given in a dose of 500 mg every eight hours for the first 5 days then every twelve hours for the 14 days. The patient was also started on polyethylene glycol 17 gm twice a day and magnesium citrate to enhance GI motility along with intravenous fluids and continuous replacement of electrolytes. The neurology team was consulted for further evaluation of the patient neurological complaints. They agreed with the current plan of care; head computed tomography (CT) was performed and showed no intracranial abnormalities. The psychiatry team was asked to assess the patient for his suicidal attempt and was evaluated as nonsuicidal at that time and was started on escitalopram 10 mg. Bedside sitter was discontinued. The patient was showing slow progress in term of feeling weak, fatigue, and imbalance during his stay but remained hemodynamically stable. The patient was transferred out of the ICU to the floor, and serial abdomen X-rays were done. The patient was having recurrent bowel movements on daily basis, and X-rays showed continued decrease in the amount of mercury in the descending colon with interval increase in the hyperdense materiel in the cecum and ascending colon. Mercury levels were trended during the patient's hospitalization, and results are shown in Table 1. The gastroenterology team was consulted and recommended placing a nasogastric tube and to give 4 liters of polyethylene glycol through the tube and magnesium citrate every 8 hours in an attempt to enhance gastrointestinal motility and hasten mercury clearance. Repeated X-rays showed no advancement of the hyperdense material which remained in the cecum and ascending colon. The decision was made to do a colonoscopy for an attempt of colonoscopic decompression (Figure 2). The colon was evacuated with copious amount of washing, and a repeat abdominal X-ray showed decreased hyperdense material in the colon with a nonobstructive gas pattern (Figure 3). The patient was discharged in a good condition after a 10-day hospital stay and followed up after 3 months; at that time, he had a mercury level of 33, and an abdominal X-ray showed no hyperdense material in the colon (Figures 4 and 5). The patient followed up again 1 month later. His neurological symptoms resolved, and kidney function preserved. Also, his mercury level was trending down at 18.

PMC8329552_01

Female

The 64 years-old female, born in Campania region, is affected by arterial hypertension, potential occult HBV infection under prophylaxis with lamivudine and follicular variant of non-Hodgkin lymphoma, diagnosed in January 2018 and treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. She was under maintenance therapy with subcutaneous rituximab 14 mg every two months, with last dose administered in June 2020. She started complaining low-grade fever and dysgeusia on the 31st of August 2020. A nasopharyngeal swab (NFS) resulted positive for SARS-CoV-2 RNA on the 5th of September 2020. She was admitted to a peripheral hospital of the metropolitan area of Naples on the 26th of September for development of dyspnea and low peripheral oxygen saturation. At the admission, the high-resolution chest CT-scan (HRCT) showed bilateral ground-glass opacities (GGO) and peripheral bilateral consolidation. She was treated with intravenous methylprednisolone 20 mg BID, ceftriaxone 2 g i.v. QD and enoxaparin 4000 IU BID. A second HRCT evaluation was performed on the 14th of October, resulting in a significant reduction of the previously descripted parenchymal lesions. Nonetheless, at the beginning of December 2020, she started complaining low-grade fever and she showed a three-fold increase of C-reactive protein (CRP) level. Therefore, the third HRCT achieved, showed again bilateral increase of GGO. Since NFS continued to be positive for SARS-CoV-2 RNA, the patient was then transferred to Federico II University Hospital within the Infectious disease Department on date 11th of December 2020, for both the infectious disease and hematologic assessment. On admission she was in good clinical conditions, good hemodynamic values, oxygen saturation of 93% on room-air, with PaO2 of 68 mmHg, low grade fever (Tmax 37.8 C). Omeprazole 20 mg QD, atorvastatin 10 mg QD, folic acid 14 mg QD, lamivudine 100 mg QD, olmesartan/hydrochlorothiazide 20/12.5 mg were administered. Blood tests at the admission showed high glucose level (150 mg/dL), blood ferritin (860 ng/mL), LDH (319 U/L), PCR (1.43 mg/dL), WBC (4.230/mm3), with absolute lymphocyte count of 423/mm3, CD4+: 28% (absolute count: 118/mm3), CD8+: 50% (absolute count: 211/mm3) and CD56+ 10% (absolute count: 42/mm3); hemoglobin (10 g/dL) and normal neutrophil count. Blood, urine, and sputum cultures, as well as serological test for intracellular bacteria, resulted negative for Legionella pneumophila and molecular assay for respiratory viruses. Due to the concomitant IgG hypogammaglobulinemia (IgG level 2.6 g/L), she received 20 g of intravenous immunoglobulins for two consecutive days. The superficial and deep ultrasound on lymph nodes resulted normal: moreover, the hematologic consultation confirmed the complete remission from the disease and withheld further administration of rituximab until the resolution of COVID-19. The patient was therefore scored as class four following the WHO clinical progression scale. She was treated from the 11th to 17th of December with ceftaroline 600 mg BID and levofloxacine 750 mg QD, in a suspicion of bacterial superinfection, with no improvement. Two consecutive Beta-D-Glucan assays resulted negative. On the 26th of December, another HRCT was performed, that showed bilateral GGOs with a severity score of 11/20. A bronchoalveolar lavage fluid (BALF) was then collected two days later: galactomannan antigen, CMV-DNA, VZV-DNA, PCR for respiratory viruses, microscopic and bacteria, fungi and mycobacteria cultures were performed. GeneXpert assay for Mycobacterium tuberculosis resulted negative, while P. jiroveci direct immunofluorescence was positive. SARS-CoV-2 RNA was detected on BALF with a cycle threshold of 24. Trimethoprim-sulfamethoxazole (CTX) 20 mg/kg p.o. daily together with prednisone 20 mg BID were started, with improvement of blood gas exchanges and CRP reduction. Therapy with CTX was stopped after 21 days, with prednisone tapering. A HRCT performed on the 26th of January 2021 showed improvement of GGOs, with a score of 6/20. Nonetheless, despite the clinical and radiologic improvement following the therapy for Pneumocystis pneumonia, our patient started to have low-grade fever, increased CRP, leukopenia and persistence of hypogammaglobulinemia, with IgG level of 4,4 g/dL. Thus, she received a further i.v. immunoglobulin administration 30 days apart from the previous. CMV DNA, beta-D-glucan, galactomannan resulted as negative on new repeated samples, with blood, sputum and urine cultures negative. On date 5th of February 2021, she was still recovered in the isolation hospital unit, in discrete respiratory conditions, still febrile, with increased CRP (last determination 2.3 mg/dL), negative procalcitonin, leukopenia (WBC 1790/mm3, Neu 870/mm3, lymphocytes 570/mm3) with confirmed positivity for SARS-CoV-2 RNA on NFS after 150 days from the first detection. The WBC cytometry typing on the peripheral blood, one week after the admission to our Medical School resulted in: absolute lymphocyte count (1043/mm3), with the absence of B-cells (i.e., 0/mm3), CD4+: 27% (absolute count: 282/mm3); CD8+: 58% (absolute count: 605/mm3) and CD56+: 7% (absolute count: 73/mm3). She never developed anti-nuclear and anti-spike SARS-CoV-2 antibodies. The hematologic consultation for bone marrow examination was requested, together with SARS-CoV-2 RNA sequencing, to evaluate the presence of potential viral mutations associated to the persistence of detectable viral load. She could not yet be treated with rituximab, according to a board of hematologist from our hospital. On date 26th of February she was administered with hyperimmune serum-based therapy: two weeks later she finally became negative at NFS molecular assay.

orf3a, sars-cov-2, long-term infection, non-hodgkin lymphoma, novel variant, whole genome sequencing

PMC6515148_01

Female

A 30 year old female on a routine antiretroviral clinic visit presented with diarrhea, abdominal discomfort, painful swallowing, epigastric pain and a facial rash spread on the forehead, nose, cheeks and chin. The rash on the face was pruritic (Fig. 1A) especially when the patient was exposed to sunlight. There were also rashes on both fore arms, both hands and both feet (Fig. 1B-D) respectively. The patient reported to be weak and not able to perform her usual chores. At the time of presentation of these symptoms, she was on antiretroviral therapy (lamivudine, tenofovir, and efavirenz) for several years from 2015 and trimethoprim/sulfamethoxazole prophylactic therapy. Isoniazid prophylactic therapy (IPT) (300 mg) and pyridoxine (50 mg) from 4th January 2018. The patient did not have signs/symptoms of tuberculosis and had no history of tuberculosis treatment in the past. There was no history of alcoholism or cigarette smoking. She lived with her five children. A dietary history data collected revealed that the 30 year old female relied on maize as the main staple food that was often consumed with kale (green leafy vegetables locally referred to as sukuma wiki). She rarely consumed beans and meat. The woman was a farmer and did not engage in poultry keeping. Clinical examination revealed that the patient was distressed and had hyperpigmented rashes on the forehead, nose, zygomatic and just below zygomatic regions, upper lip, lower lip, and chin. Some parts of the rashes had acne-like appearance; when squeezed gently a white substance (sebum) came out. The facial rash had a butterfly-like appearance. There were rashes on both feet and hands with no definite margins, all hyperpigmented. There were two separate rashes with definite margins on the lateral side of the right forearm just below the elbow joint. The rash closer to the elbow joint had its margins only with hyperpigmentation. The rash below was entirely hyperpigmented. Tests done include complete blood count (Table 1) which had all parameters normal including a negative VDRL. Viral load result done earlier indicated the patient was virally suppressed. An impression of pellagra (isoniazid induced) was made with differentials as sebaceous hyperplasia, acne, auto immune disorder and Systemic Lupus Erythromatosus. The management plan included withdrawal of isoniazid and trimethoprim/sulfamethoxazole, nutritional review (dietary counseling and niacin supplements), dermatological review, nicotinamide capsules and prednisolone tablets. A review by a dermatologist confirmed pellagra. Prednisolone was stopped after one week. Nicotinamide capsules of 90 mg three times a day for 8 weeks were recommended. Pyridoxine dose increased to 50 mg twice a day for 8 weeks. The nutritionist recommended increased dietary proteins intake, preferably animal-source protein foods. Niacin supplements- Replace with 5 mg/100 g of niacin was given two level scoops per serving twice a day for 3 weeks and Ensure with 5 mg /100 g of niacin given six level scoops per serving twice a day for 5 weeks. The patient was reviewed weekly for the first 3 weeks then twice weekly. After the second week on treatment the sebum secreting rash on the face disappeared and diarrhea stopped. There was no fatigue. On the fourth week of treatment there was marked improvement on the facial rash. The facial rash was completely gone by the sixth week of treatment. All rashes had cleared by the seventh week. Treatment was extended for a week then stopped.

hiv, isoniazid, niacin, nicotinamide, pellagra, supplements

PMC7393322_01

Male

A 66-year-old gentleman presented acutely to secondary care with acutely worsening, progressive shortness of breath. His past medical history includes congestive cardiac failure, hypertension, wheelchair bound due to previous polio and chronic obstructive pulmonary disease (ex-smoker with a 40-pack year smoking history). His chest x-ray on admission showed a left upper lobe mass lesion (Fig. 1). A CT thorax, abdomen and pelvis was reported as showing a large lobulated soft tissue mass in the left upper lobe measuring 7.2 cm x 6.9 cm x 7.5cm which was contiguous with the soft tissue extending from the anterior left main bronchus, suggestive of a lymph node, measuring 1.4 cm x 2.9 cm. There was evidence of direct tumour extension into the left pulmonary vein, almost into the left atrium (Fig. 2). Following discussion in the Lung Cancer Multi-Disciplinary meeting the patient underwent an EBUS. Sampling from station 4R and 7 lymph nodes showed benign lymphoid material and pigmented macrophages on ROSE, therefore the procedure continued to the area of the 10L node. Ultrasound evaluation of this area were consistent with either tumour or solid material (thought likely tumour thrombus) within the left pulmonary vein, as there was a circumferential rim of fluid that was well visualised. TBNA was performed (Fig. 3). Direct probe contact with the endobronchial wall was maintained for several minutes looking for biopsy complications (including extravasation). There were no immediate complications as a result of the TBNA. ROSE showed blood cells only with subsequent cell block material containing scanty material suggestive of non-small cell carcinoma. During the procedure, therefore, further material was obtained from the primary left upper lobe mass which ROSE revealed to be non-small cell carcinoma. A subsequent cell block was morphologically like that obtained from the tumour thrombus, but of greater quantity, allowing immunocytochemistry. This demonstrated strong p40 and TTF1 positivity and the tumour was classified as non-small cell carcinoma, not otherwise specified (Fig. 4). Following further discussion in the Lung Cancer Multi-Disciplinary Meeting this patient was staged as T4N0M0 non-small cell lung cancer, not otherwise specified with the plan for surgical resection.

ct, computerised tomography, ebus, endobronchial ultrasound, endobronchial ultrasound, endobronchial ultrasound-guided transbronchial needle aspiration (ebus-tbna), lung cancer, rose, rapid on-site evaluation, tbna, transbronchial needle aspiration, ttf-1, thyroid transcription factor 1, tumour thrombus

Labelled computerised tomography showing left upper lobe lung tumour contiguous with station 10 left lymph node and left pulmonary vein.

PMC7481734_01

Female

In 2017, a 60-year-old female presented to her General Practitioner (GP) in Scotland with a slow-healing 1 cm wound on her right finger. She had sustained a minor burn to the finger 9 days prior to her attendance. A swab was taken by the attending clinician. This swab subsequently grew toxigenic C. ulcerans . This result was telephoned to the out-of-hours local health protection team, 8 days after the case presented to her GP. The case lived with her partner and owned two German Shepherd dogs. One dog had a history of a long-standing skin complaint, which had been documented as quiescent. The case worked in retail and had no recent travel history. She had not eaten unpasteurized dairy food nor visited any farms within the last 2 weeks. Her most recent diphtheria vaccination was in 2009. A nose and throat swab were collected from the patient and she was treated with diphtheria vaccine and a 2 week course of clarithromycin. She was excluded from work under the Public Health Act Scotland (2009) until completion of antibiotics and clearance swabs, one from each site (nose, throat and wound) were negative. Four close contacts were identified who required nose and throat swabs to assess for carriage of C. ulcerans , of whom two were healthcare professionals who had dressed the wound. Contacts were all given diphtheria vaccine and a 1 week course of erythromycin. The two healthcare workers were excluded from work until nose and throat swabs were culture negative. One contact (husband) was identified as carrying C. ulcerans in his nose and required a repeat swab following completion of antibiotics to check for clearance. His repeat swab was culture negative. Initial swabs for the fourth contact (a close friend) were negative. A local veterinary practitioner examined the dogs, which revealed one had an infected skin lesion, which was swabbed. Throat swabs were also collected from both dogs. Toxigenic C. ulcerans was recovered in culture from the skin lesion and throat swabs of both dogs. They were commenced on antibiotic therapy and antimicrobial skin wash. Repeat swabs for the dogs were negative following completion of treatment. The dogs were identified as the most likely source of infection, however, it is possible human-human transmission may have occurred. Wound swab was submitted for routine culture and was inoculated on Columbia blood agar (Thermo-Fisher, Perth, UK). Large numbers of C. ulcerans were cultured and identified using MALDI-TOF (MALDI Biotyper, Bruker, Massachusetts, USA). MALDI-TOF generates unique mass spectrometry profiles, which are compared to a known database of micro-organism profiles, identifying the organism to genus and species levels. The MALDI-TOF score was >2.0, which is an acceptable score for species identification. Susceptibility testing was performed by E-test (bioMerieux) using European Society of Clinical Microbiology and Infectious Disease (EUCAST) interpretative criteria. The isolate was sent to the Diphtheria National Reference Laboratory, Public Health England (PHE), Colindale, London, where the isolates were characterized by genotypic and phenotypic methods. In April 2014, a real-time PCR (qPCR) assay was formally introduced as the front-line test for putative toxigenic corynebacteria to inform public health action. This assay provides confirmation of both identification of C. diphtheriae and C. ulcerans / C. pseudotuberculosis and detection of the diphtheria toxin gene. Phenotypic characterization was perfomed by culture on Columbia horse blood, Hoyle's tellurite and Tinsdale agar plates (PHE Media Services, Colindale); API Coryne (bioMerieux) and additional differential biochemical tests (e.g. nitrate reduction, glycogen hydrolysis as required. The modified Elek immunodiffusion test was used to confirm toxin expression. Further genotypic characterization of isolates was performed by MLST as previously described. The clinical isolate from the index case was identified as C. ulcerans /C.diphtheriae, diphtheria toxin gene positive by qPCR. The species was confirmed as C. ulcerans phenotypically and toxin expression was confirmed by the Elek test. Antimicrobial susceptibility testing results were also confirmed at the reference laboratory and it showed resistance to penicillin and clindamycin but sensitivity to vancomycin, erythromycin, linezolid, ciprofloxacin, doxycycline and rifampicin. S. aureus was isolated along with C. ulcerans. S aureus. could be colonizing the skin but was also likely contributing to any skin and soft tissue infection. C. ulcerans was also isolated from a nose swab from the close contact of the index case and this was confirmed as toxigenic C. ulcerans as above. Throat swabs from the two dogs and the skin lesion were collected by their veterinary practitioner and submitted to SAC Consulting Veterinary Services laboratory in Inverness where they were cultured on Columbia sheep blood agar and Hoyles tellurite medium (Thermo-Fisher, Perth, UK). C. ulcerans was obtained in moderate growth from the throat swabs collected from each dog and in heavy growth from the wound. The wound also contained a heavy growth of Staphylococcus schleiferi subsp. coagulans, and an unidentified Gram-positive coccus. Suspect C. ulcerans were identified with the API Coryne system. Follow-up samples were collected from the throats of both dogs after treatment was completed and C. ulcerans was not detected. Furthermore, the skin lesion had resolved and neither C. ulcerans , S. schleiferi subsp. coagulans nor the unidentified Gram-positive coccus were detected. The three canine isolates from the two dogs were also confirmed as toxigenic C. ulcerans . The six isolates (three human, three canine) were subjected to MLST analysis. Full profiles were not obtained, most likely due to variation in primer binding sites. However, of the partial alleleic profiles obtained (range 2 to 5 out of 7 alleles); all alleles occurring in >1 isolate matched and there were no mismatches, supporting an epidemiological link. All partial allelic profiles obtained (0, 41, 79, 49, 0, 45, 39) were consistent with sequence type 349 (42, 41, 79, 49, 49, 45, 39), which is present in the MLST database (https://pubmlst.org/cdiphtheriae/), from C. ulcerans isolated from a cutaneous clinical case in 2005, from Toulouse, France.

corynebacterium, public health, vaccination, wound infection, zoonoses

PMC6165620_01

Female

A 46-year-old previously healthy female developed an insidious onset severe persistent headache, most prominent in the occipital region lasting for 10 days. Six days after the onset, she experienced dysarthria and a difficulty in moving her tongue within the mouth with a difficulty in eating and drinking. She did not complain of nasal regurgitation of food or nasal quality of speech. After admission, she was found to have a high-grade fever. She was otherwise healthy and denied symptoms of cough, decreased appetite, weight loss, or past history of tuberculosis. On admission, she was found to be ill with elicitable neck stiffness. Neurological examination revealed bilateral hypoglossal nerve palsy with marked tongue atrophy, more prominent in the left side (Figure 1) with tongue fasciculations and without other cranial nerve palsies or pyramidal weakness. Her eye movements were saccadic with a broad-based ataxic gait without other signs of cerebellar involvement. Her blood tests revealed a haemoglobin of 12.5g/dl with a neutrophil leukocytosis (19,000/microL; 92.2% of neutrophils) with elevated ESR (100 1st Hr) and CRP (195 u/L). Her blood cultures were negative. Noncontrast CT brain did not reveal any abnormality. Cerebrospinal fluid (CSF) biochemistry revealed significant elevation of protein (111 mg/dL) with 59 polymorphs and 8 lymphocytes per cubic millimetre with reduced CSF glucose (29 mg/dL). CSF for GeneXpert for tuberculosis and staining for acid-fast bacillus (AFB) and fungal and atypical cells were negative. Pyogenic, mycobacterial, and fungal CSF cultures were negative and CSF for Meningococcus, Haemophilus, and Pneumococcus antigens were also negative. Her chest radiograph did not reveal any changes suggestive of pulmonary tuberculosis or sarcoidosis. Syphilis (VDRL & THPA), HIV serology, and autoimmune markers for vasculitis (rheumatoid factor, ANA (IF), and p & c-ANCA) were negative. We initiated her on empirical treatment as for pyogenic meningitis with ceftriaxone and vancomycin for which she had a gradual improvement of general status with improvement of fever, meningism, gaze, and gait abnormalities while tongue weakness and atrophy persisted. Since we considered tuberculous meningitis as a possibility, we deferred treatment with steroids. Her rapid recovery in the absence of steroids or antituberculous drugs further supported our presumed diagnosis of pyogenic meningitis. Subsequently, she underwent MRI of brain and brainstem, which revealed a posteromedial infarction in the lower part of the medulla oblongata without leptomeningeal enhancement and did not show a significant cerebral oedema (Figure 2). At the end of three weeks of antibiotics, inflammatory markers and repeat CSF analysis reached normal levels. After discharge, we reviewed her at one month and three & six months and she was free of fever with good general condition and had normal inflammatory markers. However, she had persistent tongue atrophy with difficult speech from which she was gradually recovering with the help of physiotherapy.

PMC4532108_01

Female

A 39-year old woman was admitted to Severance Hospital via the emergency room with symptoms of palpitation, dyspnea on exertion and tarry stool for 20 days. There was no history of pulmonary tuberculosis, hypertension and diabetes mellitus. There was no family history of neurofibromatosis. Five years prior to admission, she visited a private clinic for multiple skin nodules, which she had had since birth, and biopsy from the lesion of the thigh revealed neurofibromatosis. Three years before admission, she had palpitation and dizziness and was hospitalized in another general hospital, where she was discharged with the diagnosis of anemia of unknown origin, in spite of all kinds of examinations. Later she had experienced the above events three times for two years before admission. Laboratory findings showed iron deficiency anemia at the first admission (October 1988). Simultaneously, UGI series showed no abnormality. Abdominal ultrasonography showed gall bladder dilatation with cystic duct stone and splenomegaly. Endoscopic retrograde cholangiopancreatography showed cystic duct stone. On sigmoidoscopy, internal hemorrhoid with some blood was noticed. After hemorrhoidectomy, she had taken iron pills. For twenty days before readmission, she had had tarry stool with pale face. On admission, the temperature was 36.9 C, the pulse 70/min and the respirations 14/min. The blood pressure was 100/70 mmHg. The height was 151 cm and the body weight 53 kg. She had a chronically ill-looking appearance. The conjunctivae were pale and the sclerae were not icteric. There were multiple 1-2 cm sized neurofibromas on the whole body, especially on the back (Fig. 1). The chest, heart and abdomen were normal. The hemoglobin was 5.1 g/dl, the hematocrit 17.4 percent, the white cell was 6,200/mm3 with 66 percent neutrophil. The platelet was 339,000/mm3. The reticulocyte count was 1.6 percent. The corrected erythrocyte sedimentation rate was 0 mm/hr. The urine was normal. The prothrombin time was 12.3 seconds. The calcium was 8.5 mg/dl, the phosphorus 3.1 mg/dl, the glucose 95 mg/dl, the blood urea nitrogen 9.0 mg/dl, the creatinine 0.7 mg/dl, the uric acid 4.4 mg/dl, the total bilirubin 1.2 mg/dl, the alkaline phosphatase 53 IU/l, the SGOT 13 IU/l and the SGPT was 5 IU/L. The electrolyte was within normal limit. The serum iron was 12 mg/dl, the total iron binding capacity was 355 mg/dl and the iron saturation 3.4 percent. The occult blood examination of stool was negative. The antinuclear antibody titration was 1:20 positive and 1:80 negative, and the anti-DNA was 1:10 negative. The electrocardiography was normal. After transfusion of 5 units of packed red cell, the hemoglobin was 9.9 g/dl, the hematocrit 31.1 percent. The fiberoptic gastroscopy showed mild diffuse chronic superficial gastritis. The UGI series and small bowel series (Fig. 2) revealed no specific abnormal findings. The radionuclide scanning, using 99mTc pertechnate-labelled RBC, revealed abnormal radioactivity in the right lower abdomen and increased activity by the time sequence, which was suggestive of lower gastrointestinal bleeding from the right hypogastric arterial branch (Fig. 3). On the flexible sigmoidoscopy, internal hemorrhoid without evidence of recent active bleeding was found. The superior mesenteric and ileal arteriogram showed bleeding from the left ileal arterial branches (Fig. 4). On the 15th hospital day, operation was performed under the diagnosis of small bowel tumor. There were two masses on jejunum located 60 and 120 cm from the ligament of Treitz, respectively. The distal mass was irregulary lobulated with some ulcerations on its surface, and tumor bleeding into the lumen was noted. Segmental resection of jejunum with end to end anastomosis and cholecystectomy were performed. Also the skin biopsy on the left breast was performed during the operation. The pathologic diagnosis was neurofibromas of the jejunum (Fig. 5-, 8) and the skin (Fig. 9). The patient has been in good health without intestinal bleeding until now.

PMC2698174_01

Female

A 42-year-old woman had presented to the local clinic with jaundice of two months duration and she was suspected of having periampullary cancer; she was then referred to us and admitted to our hospital for further evaluation. The physical examination revealed no abnormality. The serum total bilirubin level was 3.1 mg/dl and the aspartate aminotransferase/alanine aminotransferase levels were 80/180 U/L. Abdominal CT showed a cystic dilatation of the common hepatic duct and a marked dilatation of the intrahepatic bile duct (Figs. 1A, B). Abdominal ultrasonography also revealed these lesions, but there was a partial thin septum-like structure within the upper aspect of the cystic dilated common hepatic duct (Fig. 1C). However, neither definite septation nor an enhancing portion within the dilated duct was noted, and so this was considered to be a choledochal cyst. Percutaneous transhepatic biliary drainage (PTBD) was done through the left hepatic duct, and the subsequent tubogram showed obstruction of the left hepatic duct by a large filling defect. On endoscopic retrograde cholangiopancreatography (ERCP), a well-demarcated filling defect was seen in the common hepatic duct and this did not communicate with the bile duct. The distal portion of the common hepatic duct showed a beaking appearance near this mass and the left hepatic duct was not opacified (Fig. 1D). Any anomalous pancreaticobiliary ductal union was not found. Before surgery, magnetic resonance cholangiopancreatography (MRCP) was performed, and it showed a well-defined cystic mass extending from the left hepatic duct to the common hepatic duct with a definite thin wall displaying a dark signal intensity. Magnetic resonance cholangiopancreatography also showed a bile duct variation; the right posterior segmental duct drained into the left hepatic duct (Fig. 1E). The patient underwent resection of the extrahepatic biliary tract including the cystic mass, and hepaticojejunostomy was next performed. During surgery, the cystic mass was noted to arise from the common hepatic duct, yet it had no communication with this duct. Pathologically, this unilocular cystic mass arose from the serosal surface of the common hepatic duct, which was bulging into the common hepatic duct (Fig. 1F). It was lined by a single layer of tall columnar mucin-secreting cells with focal evidence of mucinous secretion (Fig. 1G). Our case was diagnosed as a biliary mucinous cystadenoma in the common hepatic duct. The patient has been alive with no tumor recurrence for one year after surgery.

PMC8447091_01

Male

A 33-year-old man with a reported history of sickle cell anemia and a penicillin allergy presented to the emergency department (ED) with an extensive ulcerative rash involving his face, extremities, trunk, genitals, and back with sparing of the mucous membranes, eyes, palms, and feet (Figure 1). The rash initially began 5 days prior to presenting at our hospital as painful, small ulcerations localized to the left arm. The patient originally sought care at an outside ED where he was diagnosed with severe dermatitis with suspected bacterial superinfection, but the patient declined admission and was subsequently discharged with a prescription of cephalexin. The rash progressively worsened and disseminated despite antibiotic treatment, prompting the patient to present to our ED. He denied a history of eczema, asthma, allergic rhinitis, recent exposure to a new environmental allergen, shortness of breath, headaches, and visual disturbances. Cardiovascular, pulmonary, and neurologic examinations were normal. The patient's social history is remarkable for a monogamous relationship with 1 male partner. He endorsed consistent use of barrier contraception during intercourse. He denied a history of sexually transmitted infections, prior blood transfusions, and intravenous (IV) drug use. Given the severity of the rash, recent antibiotic exposure, and history of serious penicillin allergy, initial differential diagnoses were drug allergy and a disease on the Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) spectrum. However, the latter was ruled out by the burn team and dermatology (virtually) due to the absence of mucosal involvement, negative nikolsky sign, and absence of skin sloughing. Laboratory studies in the ED revealed a reactive HIV antigen/antibody screen with a subsequently positive HIV-1 antibody and negative HIV-2 antibody. In addition, his labs were significant for CD4 count of 259, white blood cell count (WBC) of 7.4 k/microL with 54% neutrophils, 9% lymphocytes, 0% eosinophils, 0% basophils, and creatinine and sodium of 3.05 mg/dL and 119 mEq/L, respectively. These findings suggested an immune deficiency cause rather than an allergic reaction, and dermatology subsequently recommended starting IV acyclovir for possible disseminated HSV-1 infection. Infectious disease (ID) was consulted, and he was admitted for further workup of the skin lesions. Screening for hepatitis, syphilis, gonorrhea and chlamydia was negative. Further tests for opportunistic infections, including coccidiomycosis antigen/antibody, cryptococcal antigen, tuberculosis, varicella zoster virus (VZV), and cytomegalovirus (CMV) were also negative. In addition, autoimmune disease screening with antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), and serum complements were unremarkable. However, HSV polymerase chain reaction (PCR) from the skin lesions was positive for HSV-1 and negative for HSV-2. A positive repeat test further suggested a diagnosis of disseminated HSV-1, and subsequent HSV antibody testing showed elevated IgM. A skin punch biopsy of the left upper extremity revealed irregular psoriasiform hyperplasia with epidermal hypergranulosis, hyperkeratosis, and superficial pigmentary incontinence. There was superficial perivascular inflammation consisting of lymphocytes and histiocytes. No spongiosis and intraepidermal vesicles were present. There was no evidence of viral morphologic changes. The patient was continued on IV acyclovir and emollients with gradual improvement in the lesion throughout the admission (Figure 2). He was discharged with 2 weeks of oral valganciclovir followed by lifelong daily acyclovir prophylaxis. He was scheduled to follow up with ID outpatient for initiation of highly active antiretroviral therapy (HAART).

acyclovir, cutaneous, dermatology, disseminated, herpes simplex virus, human immunodeficiency virus

PMC5828564_01

Female

A 21-year-old female of mixed heritage (Caucasian and African American), with a history of provoked deep venous thrombosis diagnosed six months before, currently treated with warfarin, presented with complaints of acute chest pain. The pain was midsternal, severe, sharp, and worse with inspiration but improved by sitting upright. Vital signs revealed tachycardia (154 beats per minute), tachypnea (30 breaths per minute), and normal blood pressure (136/73 mmHg). The INR was 5.4 on admission. The chest X-ray showed cardiomegaly with a bottle neck sign. The echocardiogram showed a large pericardial effusion, with evidence of right-sided collapse during diastole. Chest, abdomen, and pelvis CT demonstrated a large pericardial effusion, consistent with hemorrhage. There were no pulmonary emboli or signs of pulmonary hemorrhage. The patient was transfused plasma and blood with improvement of the INR to 2.1. Pericardiocentesis was performed with a return of 500 cc of bloody fluid, and a drain was placed. Her vital signs improved and symptoms diminished immediately after the procedure. She was diagnosed with underlying pericarditis with effusion that converted to a hemorrhage from the anticoagulation. The etiology of her pericarditis was sought. She denied any recent viral illnesses, tuberculosis exposure, malignancy, or fungal infections. She denied any arthritis, oral ulcers, fever, weight loss, night sweats, rash, or family history of autoimmune disease. Pericardial fluid was sent for cytology as well as viral, fungal, aerobic, anaerobic, and AFB cultures that were all negative. No autoimmune testing was performed on the pericardial fluid. Initial laboratory work revealed normal electrolyte panel and renal function and BNP 59 pg/ml (0-100). She had mildly elevated liver function tests with AST 69 U/L (10-37) and ALT 52 U/L (8-37). She was also found to have normocytic anemia. The hemoglobin was 9 g/dl (baseline was 11.1) with a normal white blood cell and platelet count. Inflammatory markers were elevated: erythrocyte sedimentation rate was 35 mm/hr (0-18), C-reactive protein was 10.4 mg/dl (0-0.8), and ferritin was 314 ng/ml (12-207). Autoimmune evaluation showed an ANA titer of 1 : 1280 with speckled pattern and markedly elevated anti-double-stranded DNA 195 IU/ml (<100). SSA Ab and SSB Ab were also elevated at 187 and 538 AU/ml (<100), respectively. The patient did not have any clinical symptoms to suggest sicca syndrome (no dry eyes or mouth). TSH on admission was 0.60 (0.5-5.20 mcIU/ml) with repeat serial TSH remaining in normal limits. Clinically, she was never symptomatic with thyroiditis. Complement C4 was low at 7 mg/dl (12-43). Rheumatoid factor was 27 IU/ml (0-14). ANCA, SPEP, CCP, anti-Smith Ab, RNP Ab, and complement C3 were normal. Initial antiphospholipid screen (APS) was positive; however, repeat testing approximately 12 weeks later was negative. Initial APS enzyme-linked immunosorbent assay (ELISA) showed anti-cardiolipin Ab IgA < 9.5 (<12 APL), IgG 21.6 (<15 GPL), IgM 19.7 (<12.5 MPL), beta-2 glycoprotein 1 IgG 12.1 (<20 SUG), and beta-2 glycoprotein I IgM 24.5 (<20 SMU). Repeat APS panel was negative with all results at <9.5. DRVVT screen was 50 (0-52 seconds). The patient was determined to not have antiphospholipid syndrome due to lack of positive repeat APS Ab blood work. Infectious work-up including VDRL, HIV, pericardial fluid Gram-stain, culture, AFB stain and culture, and virus culture was negative. Pericardial fluid cytology was negative for malignancy and revealed increased neutrophils and lymphocytes. The patient was diagnosed with systemic lupus erythematosus and was started on intravenous (IV) methylprednisolone 100 mg for 3 days with transition to prednisone 40 mg daily, hydroxychloroquine 200 mg twice daily, and colchicine 0.6 mg twice daily. She was also treated with ibuprofen 400 mg every 6 hours and opioids for pain control. Over the next 48 hours, an additional 120 cc bloody fluid was drained after repositioning the pericardial drain, which was then successfully removed. In hospital day 3, troponin peaked at 3.09 ng/dl (0-0.05) and lupus myocarditis was considered. A cardiac MRI showed normal LV function and no evidence of myocarditis. However, it did reveal severe diffuse, circumferential pericardial contrast uptake involving both the visceral and parietal pericardium with trivial pericardial effusion. She continued to improve and was discharged after 8 days from the hospital with colchicine 0.6 mg twice daily, hydroxychloroquine 200 mg daily, and prednisone 40 mg daily. Colchicine was used to treat the patient for inflammatory pericarditis as imaging revealed inflammation, and she remained symptomatic despite evacuation of pericardial fluid. Three weeks later, she presented with recurrent chest pain despite compliance with her medications. ECG showed new T-wave inversions in multiple leads and troponin peaked at 4 ng/dl (0-0.05). BNP was elevated at 742 pg/ml (0-100). A transesophageal echocardiogram showed an ejection fraction of 45% with mild-moderate mitral regurgitation. A cardiac MRI showed midmyocardial and epicardial hyperenhancement in the midlateral and inferolateral walls, suggestive of myocarditis. It also revealed persistent pericarditis similar to prior cardiac MRI but no pericardial effusion or constriction. Myocardial perfusion imaging showed fixed radiotracer defect in the mid-distal inferior and inferolateral walls concerning for myocardial scar. PET Myocardial Perfusion and Viability study showed resting hypoperfusion in the midinferior lateral region, which was matched on FDG suspected to be scar formation and flow-metabolic mismatch in the basal inferior and basal inferolateral regions, approximating 12% of the left ventricle. The myocardial scar was estimated to be 6% of the left ventricle myocardium. She was started on aspirin and carvedilol 3.125 mg twice daily. She was again treated with IV steroids and started on azathioprine 50 mg twice daily. Repeat anti-double-stranded DNA had decreased to 130 IU/ml (<100); however, complements C3 and C4 remained low at 76 mg/dl (80-200) and <6 mg/dl (12-43), respectively. Her symptoms improved, and she was discharged home after 6 days from the hospital. Six weeks later, she presented to the hospital again with recurring chest pain that was associated with bilateral leg swelling, dyspnea with exertion, and orthopnea. BNP was markedly elevated at 1098 pg/ml (0-100). Transesophageal echocardiogram also revealed EF 35% with left ventricular global hypokinesis and moderate-severe mitral regurgitation. Infectious endocarditis was ruled out with serial blood cultures, and no vegetations were found on imaging. A third cardiac MRI was performed which showed a severely depressed ejection fraction 29% and midinferolateral wall akinesis with full thickness hyperenhancement. When compared to the prior MRI, it also showed progression of her myopericarditis. Cardiac catheterization showed normal coronary arteries, ejection fraction 25%, global hypokinesis, and severe +4 mitral regurgitation with severely enlarged left atrium. Cardiovascular surgery was consulted regarding evaluation for mitral valve repair; however, recommendations were made to pursue surgery only if she were to fail maximum medical treatment. Given no recommendations for surgery, invasive myocardial biopsy was deferred as well. She was treated for acute decompensated congestive heart failure with IV furosemide, and later adequate diuresis was transitioned to oral furosemide 20 mg daily. She was also started on spironolactone 25 mg daily, carvedilol 6.25 mg twice daily, and lisinopril 5 mg daily. Interestingly, a repeat anti-double-stranded DNA was normal at 83 IU/ml (<100); however, complement C4 remained low at 6 mg/dl (12-43). Given progression of her disease despite medication compliance, she was treated with 1 gram IV methylprednisolone for 3 days along with IVIG for 2 days. She was continued on hydroxychloroquine sulfate 200 mg twice daily and colchicine. Azathioprine was eventually discontinued and changed to mycophenolate mofetil 500 mg twice daily with plans to increase to 1000 mg twice daily. She was monitored by serial echocardiograms which showed stabilization and mild improvement in her valve function. She was then discharged home after 12 days from the hospital. Repeat PET Myocardial Perfusion and Viability study performed 3 weeks later (and 4 months after initial presentation) showed similar findings to a prior study with active inflammation of the basal inferior, and basal inferior lateral regions were estimated to be 12% of the left ventricle myocardium. Myocardial scar/fibrosis was estimated to be 8% of the left ventricle myocardium. She was then started on cyclophosphamide with repeat echocardiogram showing improvement in ejection fraction to 36% and mild-moderate mitral regurgitation and complement levels improving. Fortunately, her most recent echocardiogram (2.5 years after initial diagnosis) reveals an EF of 55%, mild mitral regurgitation, and no hypokinesis appreciated. Her complement levels and anti-double-stranded DNA remain within normal range and no other manifestations of SLE. Unfortunately, due to prolonged, high-dose steroid use for over 1 year, she developed avascular necrosis of her bilateral femoral heads and condyles necessitating surgery on her bilateral knees and hip. Currently, her only immunosuppressive medication remains hydroxychloroquine.

PMC3518091_01

Male

A 28-year-old man presented with recurrent outbreaks of herpes simplex virus (HSV) type 2 in the form of ulcers on the glans penis associated with the onset of red-to-brown maculopapules located predominantly in trunk in each recurrence. The patient had four recurrences on a two-year followup (Figure 1(a)). Positive serologies to HSV type 2 were detected in each outbreak (IgM and IgG). He received acyclovir 400 mg five times a day for 5 days, then a prophylactic dose of 400 mg twice a day; however, after discontinuation of antiviral drug, lesions reappeared. Histopathological examination of one of the lesions showed epidermal acanthosis, scanty lymphocytic exocytosis, without spongiosis, or focal necrosis. Perivascular infiltrates of lymphocytes with occasional eosinophils and erythrocytic extravasation were seen in the dermis (Figure 1(b)). HSV DNA was not detected in the epidermal keratinocytes or lymphocytes in the biopsy specimen. These findings were consistent with a diagnosis of pityriasis lichenoides chronica.

PMC4712423_01

Female

A 76-year-old female presented with New York Heart Association class IV dyspnea. She had a history of hypertension and atrial fibrillation and was taking diuretics, angiotensin receptor blockers, amiodarone, and warfarin. On physical examination, an irregular heartbeat with a pansystolic murmur was auscultated, and pitting edema was observed. Initial arterial blood gas analysis results showed hypoxemia. Cardiomegaly was noted on a chest radiograph. Echocardiography revealed dilation of the right atrium, right ventricle, and left atrium, as well as severe tricuspid regurgitation (Fig. 1A) with pulmonary hypertension (the right ventricular systolic pressure was 75 mmHg and the tricuspid valve showed poor coaptation with a D-shaped left ventricle; the tricuspid annular plane systolic excursion [TAPSE] was 1.6 cm). Doppler echocardiography showed a turbulent shunt flow near the inferior vena cava (IVC). To clarify the anatomical features of the shunt, transesophageal echocardiography was performed. The results showed an inter-ASD near the IVC with a size of approximately 1.74 cm (Fig. 2A). Chest computed tomography revealed an approximately 1.7 cm-sized inferior venosus ASD (Fig. 2B). Although elective surgical repair of the defect is normally the treatment of choice, the patient's general condition and her age were not suitable for general anesthesia, and she did not want to receive surgery. Typical inferior sinus venosus ASD is a contraindication for transcatheter closure, but we decided to repair the septal defect using the transcatheter technique because of the atypical features of the septal defect; it was located away from the tricuspid valve, and there was a small ridge on the posterior side of the defect. Using the transcatheter approach, a 20 mm-sized Amplatzer occluder device (St. Jude Medical, St. Paul, MN, USA) was successfully applied in the defect. There were no acute complications after the procedure, and the surgery was well tolerated. After the closure, the patient's dyspnea improved dramatically and her hypoxemia recovered. On follow-up echocardiography, there was no abnormal shunt flow, the occlusion device was well placed (Fig. 3A), and the tricuspid regurgitation (Fig. 1B) and pulmonary hypertension were improved (the right ventricular systolic pressure was 41 mmHg, moderate tricuspid regurgitation was noted, and the TAPSE was 1.92 cm). A follow-up exam 1 year after surgery showed that the patient was in good condition and did not suffer from dyspnea when performing daily activities. Six months following the procedure, warfarin was switched to dabigatran because of the patient's non-compliance and difficulty achieving the target international normalized ratio; the patient showed good compliance with dabigatran. Follow-up echocardiography 9 months after the procedure showed that the occluder device was well placed, without abnormal shunt flow (Fig. 3B). Surgical repair is the standard therapeutic option for ASD patients of all ages. However, transcatheter closure has recently received increased acceptance in ASD patients. Transcatheter closure guarantees fewer complications and a shorter hospital stay than surgical repair, and both procedures have similar success rates. However, transcatheter closure is indicated only in ostium secundum ASD patients because of its anatomical features. In this case report, we described the catheter-based repair of an inferior sinus venosus ASD. To the best of our knowledge, this is the first successful case of transcatheter sinus venosus ASD closure. Typical sinus venosus ASD remains a contraindication for transcatheter closure of the defect. However, this case suggests that if a sinus venosus ASD patient cannot undergo surgery due to several causes (e.g., combined comorbidities, general condition, and old age) and the patient's septal defect has anatomical features suitable for device closure (e.g., a rim or small ridge toward the caval vein), transcatheter closure might be an alternative therapeutic option. While it may not be generally applied, transcatheter closure could be considered a secondary option for carefully selected patients.

heart septal defects, atrial, septal occluder device

PMC5409999_01

Female

A 20 years old female patient, the sixth of a family of 8 children is treated since 2010 for edematous-ascitic syndrome related to a primary intestinal lymphangiectasia (or Wildmann's disease) suspected by hypoalbuminemia, lymphopenia and hypogammmaglobulinemia. The disease was confirmed by an intestinal biopsy indicating dilated lymphatic ducts Figure 1, Figure 2. The patient followed a low-fat diet associated with medium-chain triglycerides, vit A and K supplementations. The evolution was good with effusions resorption. However, 6 months ago, the patient presented MRC grade 3 dyspnea with alternated fever and apyrexia. It appeared after she chose to stop, 8 months ago, the low fat diet that was prescribed by her pediatrician. The physical exam revealed a cachectic, apyretic patient with BMI of 17kg / m2, WHO performance index of 1, a minor Conjunctivial discoloration and a RR of 22 B/min. The lung exam showed a bilateral fluid effusion syndrome. The cardiovascular exam indicated a pericardial rub with a systolic murmur at the mitral area. The abdominal exam found a shifting dullness with a smoothed umbilicus. The skin exam showed a thin skin with no dehydration signs, skin lesions or edema. Suspected diagnoses were: Tuberculosis, type B Lymphoma, Disseminated Lupus erythematosus. Paraclinical tests showed a moderate inflammatory syndrome. The AFB sputum examination by direct microscopy, the tuberculin skin test, the 24h proteinuria and the immunological tests were negative. The thoracentesis revealed a lymphocytic exudative fluid with no MTB in the pleural fluid (direct microscopy) and a negative ADA level. The abdominal ultrasound showed medium-abundance ascites associated with an abundant pleurisy and a renal cyst. Heart ultrasound reveals a pericardial effusion with a normal ejection fraction. However, no causal factor has been found in either thoracoabdominal CT scan, bronchoscopy or thoracoscopy.

waldmann’s disease, intestinal, malabsorption, primary intestinal lymphangiectasia

PMC9584768_01

Male

The patient was a 69-year-old male farmer who presented to a local hospital with right-sided chest pain, cough, sputum production, and fever for one week. Chest computed tomography (CT) at the local hospital showed multiple right pleural effusions and pneumothorax with right lung atelectasis. This patient had a cerebral infarction a year prior to this visit, with a slight decrease in right-sided muscle strength. He had a history of hypertension for several years and was receiving amlodipine benzoate with poor blood pressure control. The patient denied any history of other chronic diseases such as coronary heart disease, diabetes mellitus and malignancy. He had a 30-year history of smoking, 1 pack/day, had quit smoking for a year, and denied alcoholism. The patient was transferred to our hospital on October 17 after ineffective treatment with anti-infection (details unknown) and oxygen therapy. The patient's vital signs on admission were as follows: temperature, 37.4 C; heart rate, 81 beats/min; breathing rate, 24 beats/min; and blood pressure, 165/85 mmHg. His consciousness was clear, and oxygen saturation was 85% (air). Reduced respiratory motility, decreased breathing sounds, and wet rales were observed on the right side. Both the lower extremities were moderately edematous. His right limb muscle strength was of grade V. Routine blood test showed leukocytes 13.5x109/L (normal range 3.5-9.5x109/L), neutrophils 12.4x109/L (normal range 1.4-7.12x109/L), hemoglobin 82 g/L (normal range 130-175 g/L) and normal eosinophils. Blood biochemistry showed only 18.1 g/L of albumin (normal range 40-55 g/L) and mildly elevated liver and kidney function parameters. PCT 4.88 ng/mL (normal range 0-0.05 ng/mL) and CRP 456 mg/l (normal range 0-8 mg/L) were observed. Serum GM and BDG levels were normal. T-SPOT. TB and ANA profiles were negative. T cell subsets and serum immunoglobulins were within normal limits. The chest CT on admission is shown in Figure 1. On day 2 of hospitalization, 700 mL of celiac fluid was extracted via closed chest drainage. Pleural fluid tests showed 19.6 g/L total protein, 4.9 g/L albumin, LDH 4700 IU/L (serum normal range 109-245 U/L), and ADA 183.4 U/L (serum normal range 2-17 U/L). The pleural fluid celiac characterization test results were negative. Pleural fluid CEA was within normal limit. Levantine tests were positive, with a nucleated cell count of 273.6x109/L (pleural fluid normal range <500x106/L) and 92% neutrophilic. A protozoan slightly larger in size than leukocytes, oval in shape, with rotational movement, was microscopically observed on a wet smear of pleural fluid. Suspected T. tenax was observed (Figure 2). On day 3 of hospitalization, intravenous infusion of metronidazole (0.5 g, q8h) combined with piperacillin tazobactam (4.5 g, q8h) was started. Thoracoscopy was performed on day 4 of hospitalization. Yellow flocculent pus was seen and aspirated. Adhesions on the pleural surface and granulation tissue were also visible. The adhesions were partly released and a biopsy of the mural pleura was performed. Pathological examination suggested fibrous connective tissue and many inflammatory fibrin-like exudates. After the operation, the patient felt relieved with chest pain and cough, and continued with closed thoracic drainage. Bronchoscopy was performed on day 5 of hospitalization, and mucous secretions were seen in the right lower lobe, where they were suctioned and lavaged. On day 6 of hospitalization, the patient agreed to complete mNGS, and pleural fluid was sent for mNGS. The following day, the results were reported as 387 sequences of T. tenax, and 2,139,183 sequences of Porphyromonas endodontalis with a relative abundance of 70.73%. At this time, the diagnosis was clear of right-sided encapsulated pyopneumothorax, T. tenax and Porphyromonas endodontalis coinfection, type I respiratory failure, hypertension, and sequelae of cerebral infarction. On day 8 of hospitalization, the patient experienced nausea and vomiting during the intravenous infusion of metronidazole, which was considered an adverse drug reaction. Symptomatic treatment was administered, and metronidazole was replaced to levonidazole intravenous infusion (0.5g, q12h). No further gastrointestinal reactions occurred after medication adjustment. The daily chest drainage fluid gradually became clearer and the volume decreased. Ultrasound examination of the pleural fluid showed that the right pleural fluid was separated. Multiple intrapleural injections of urokinase were administered. Subsequently, the pleural fluid was rechecked several times and no more Trichomonas was detected. The blood culture results were negative. On day 24 of hospitalization, the patient was discharged after significant resolution of the chest lesion (Figure 3) and improvement of the inflammatory indicators. The patient was followed-up for 6 months without any chest infections.

porphyromonas endodontalis, trichomonas tenax, vats, aspiration, pyopneumothorax

PMC5502507_01

Female

A 55-year-old female patient came to surgical outpatient clinic with complaint of gradual increasing painless swelling of the floor of the mouth and submental region under the tongue and beneath the chin with difficulty in speech and swallowing for 6 months of duration. No history of trauma, operation, or prolonged fever was present. She was nondiabetic, nonhypertensive and had no history of tuberculosis or chronic illness. On clinical examination, her vitals were within normal limit. Central nervous system, cardiovascular, and chest and abdominal examination revealed no abnormality. Local examination revealed cystic, nonpulsatile, noncompressible, nontender, and nontranslucent sublingual and submental swellings [Figure 1a and b]. The submental swelling was not moving with tongue protrusion. No sign of inflammation was present. No transmitted pulsation over the sublingual swelling was felt during compression of submental swelling and vice versa. Clinical diagnosis was plunging ranula or dermoid/epidermoid cyst. Ultrasound examination of the sublingual swelling showed cystic swelling with uniform low-level echogenicity, internal particulate content with no internal vascularity on the color Doppler study [Figure 1d]. The submental lesion revealed particulate internal content with multiple floating echogenic lobules (like stalk of marble) inside the cystic swelling with no posterior acoustic shadow and no evidence of internal vascularity on color Doppler study [Figure 1c]. Noncontrast-enhanced computed tomography (CT) of the face shows hypodense cystic lesion in the sublingual and submental region [Figure 2a]. Magnetic resonance imaging of the face revealed two separate sublingual and submental cystic lesions showing T1-weighted hyperintense, T2-weighted/short tau inversion recovery (STIR) hyperintense signal and diffusion restriction in diffusion weighted image (DWI), and apparent diffusion coefficient (ADC) sequences [Figure 2b-f]. The submental swelling shows T1-/T2-weighted hypointense discrete nodular structures within the fluid content. No fat signal was seen within the both swellings. Radiological diagnosis was sublingual and submental epidermoid cysts. She was operated under general anesthesia. Both cystic lesions were enucleated by intraoral sublingual dissection with intact capsules, and the opening in the floor of the mouth was marsupialized [Figure 3a-c]. The sublingual cyst was below the floor of mouth mucosa and the submental cyst was between genioglossus muscles. The cystic lesions were pearly white and revealed epidermoid cyst on histopathological examination [Figure 4a and b]. The echogenic nodules of submental lesion in ultrasonography (USG) study were keratin accumulation. Her postoperative period was uneventful. She was advised for 6 monthly follow-up for 2 years. No recurrence was seen during 18 months of postoperative follow-up.

dermoid cyst, epidermoid cyst, sublingual, submandibular

PMC6159108_01

Female

A Caucasian 68-year-old non-smoker female, without a significant medical history except for hypertension and family history of pancreatic cancer, underwent total splenopancreatectomy for ductal adenocarcinoma associated with branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) of the neck of the pancreas. Since May to September 2014 she received adjuvant treatment in another hospital: 3 cycles of weekly gemcitabine (1000 mg m-2) followed by chemoradiation with gemcitabine (50.4 Gy in 28 fr). A thoracoabdominopelvic computer-assisted tomography (TAP-CT) performed in March 2015 showed the presence of cancer recurrence locally, in retroperitoneal lymph nodes and in lungs. A positron emission tomography with 18-fluoro-deoxyglucose was also performed in order to confirm the diagnosis of relapse. Since April 2015 the patient received first-line chemotherapy at our oncology department. We administered gemcitabine plus nab-paclitaxel combination (gemcitabine 1000 mg m-2 and nab-paclitaxel 125 mg m-2 on days 1, 8 and 15 every 4 weeks) for 12 cycles. The CT scans performed every two cycles showed stable disease, while a metabolic response was seen on positron emission tomography with 18-fluoro-deoxyglucose. Following the administration of cycle 12, day 15 of gemcitabine plus nab-paclitaxel, the patient experienced low-grade pyrexia, effort dyspnoea, persistent non-productive cough and malaise. She was empirically treated with a 5-day course of levofloxacin as outpatient, without any beneficial effects, and for the worsening of the symptoms she was eventually hospitalized. On admission, blood examination revealed moderate anaemia (haemoglobin 9.3 g dl-1) and an increased level of C-reactive protein (8.2 mg dl-1), whereas white cell differential count, electrolytes and glucose levels and renal and liver function were within normal limits. A chest X-ray showed diffuse reduction of normal lung lucency, both perihilar and peripherical. High-resolution computed tomography (HRCT) scan showed new-onset bilateral peripheral ground-glass opacities, smooth interlobular septal thickening and patchy subpleural consolidation areas. These findings were consistent with OP (Figure 1). Blood cultures were negative, as well as urine was negative for Legionella and Pneumococcal antigens. Serology tests for Mycoplasma, Legionella, cytomegalovirus, Epstein-Barr virus, adenovirus, influenza, parainfluenza and respiratory syncitial virus were negative, as was the Quantiferon-TB gold In-tube. The patient underwent bronchoscopy for bronchoalveolar lavage, and cytopathological and microbiological analyses were negative for infectious causes; the cell findings in bronchoalveolar lavage fluid were total cell count 271,000 ml-1; macrophages 60%; lymphocytes 30%; neutrophils 10%; eosinophils 0%; no neoplastic cells. Chronic medications at diagnosis consisted in pancreatic enzyme supplements, insulin, amlodipine, pantoprazole and furosemide. Suspecting chemotherapy-induced pneumonitis, nab-paclitaxel and gemcitabine were discontinued; the patient was started on treatment with prednisone 1 mg kg-1 day-1, which led to rapid clinical improvement. HRCT scan performed after 2 months showed disappearance of alveolar infiltrates and complete resolution of consolidation (Figure 2).

PMC8443791_01

Male

A 16-year-old boy was admitted to our hospital with a 10-day history of abdominal distension and epigastric pain, accompanied by anorexia, nausea, vomiting, dyspnea, palpitations, as well as low fever and night sweating. He had always been in good health with no significant medical or malignant family history. On physical examination, the patient showed tachycardia, abdominal tension, tenderness, rebound tenderness in the upper quadrant, and shifting dullness. No palpable masses and no extremity edema were noted. Neither lymphadenopathy nor hepatosplenomegaly was detected. Peripheral blood counts elevated in white blood cell 10.71x109/L (reference range: 3.50-9.50x109/L), neutrophils 8.03x109/L (reference range: 1.80-6.30x109/L), and monocytes 1.10x109/L (reference range: 0.10-0.60x109/L). The values of lymphocytes, hemoglobin, and platelets were normal. Fecal occult blood test was positive. The laboratory tests revealed a high uric acid level of 1,240.2 mumol/L (reference range: 208.0-506.0 mumol/L), aspartate aminotransferase value of 57 U/L (reference range: 15-46 U/L), and the serum carbohydrate antigen 125 value of 758 U/ml (reference range, <35 U/ml). Other values of blood urea nitrogen, creatinine, electrolytes, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), as well as other tumor markers (Carcinoembryonic antigen, Carbohydrate antigen 19-9, and Alpha fetoprotein), and hepatitis markers were negative. Assistant examinations associated with tuberculosis (Tuberculin skin test, T-SPOT test, and IgG antibody for tuberculosis) were negative. Additionally, abdominocentesis and ascitic fluid examination were performed as well. Orange-yellow turbid fluid with predominance of mononuclear cell indicated exudate. Cervicothoracic and whole abdominal computed tomography (CT) scan without any intestinal involvement, tumor formation, or enlarged lymph nodes revealed diffuse thickening of peritoneum and omentum, thoracic, abdominal, and pelvic effusion (Figure 1), inflammation in the inferior lobe of the right lung, strip shadow of hepatic hilum and hepatogastric space, dilatation of intrahepatic bile duct, as well as edema and thickening of gallbladder wall. During the coronavirus disease 2019 (COVID-19) pandemic, since the patient's condition deteriorated progressively, we failed to take any gastrointestinal endoscopies. The result of bone marrow biopsy was negative for malignancy. Finally, the patient underwent a surgical laparoscopy to determine the cause. A biopsy of the greater omentum showed diffuse peritoneal thickening and nodular omental infiltration, consistent with an aggressive type of non-Hodgkin's B-cell lymphoma. Immunohistochemical stain subsequently showed positivity for CD10, CD20, PAX-5, and c-myc with proliferative fraction of 90% (Figure 2), negativity for CD3, CD56, CD138, and Mum-1, which was in favor of the diagnosis of diffuse large B-cell lymphoma, germinal center B-cell type, stage IV. Considering the possibility of a diagnosis of peritoneal carcinomatosis, the patient firstly received three courses of hyperthermic intraperitoneal chemotherapy, followed by five cycles of cyclophosphamide, doxorubicin, vincristine, and Prednisone (CHOP) regimen with rituximab. During the first course of chemotherapy, the patient experienced signs and symptoms concerning for tumor lysis syndrome, including oliguria, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Follow-up CT reexamination demonstrated remission of his condition (Figure 3). Later autologous peripheral blood stem cell transplantation was completed 4 months after the chemotherapy. Unfortunately, the patient suffered a relapse 4 months after the blood stem cell transplantation and was given cisplatin, dexamethasone, and high-dose cytarabine (DHAP) regimen with rituximab, administered concurrently with intrathecal chemotherapy (methotrexate, cytarabine, dexamethasone). In the end, the patient suffered severe marrow suppression and gave up all the treatments for financial difficulty and died 10 months after initial diagnosis.

case report, diagnosis, non-hodgkin’s lymphoma, peritoneal carcinomatosis, peritoneal lymphomatosis

PMC8197667_01

Female

A 3-year and 6-month-old girl presented in December 2019, with fever, cough, rhinorrhea, and watery stools (a few times) for four days. Two weeks before that, she had a brief hospital stay for acute viral gastroenteritis. She was healthy and had been immunized appropriately for her age, including with BCG. The parents were nonconsanguineous and healthy. She had a high temperature (40 C) and was tachypneic, with rales predominantly on the right lung field. In addition, she had moderate dehydration on admission. After initial stabilization, oral clarithromycin and intravenous co-amoxiclav were started empirically with a presumptive diagnosis of community-acquired pneumonia. Laboratory evaluation indicated neutropenia and thrombocytopenia (white blood cells (WBCs) = 2.78 x 103/mm3, neutrophils = 0.83 x 103/mm3, and platelets = 76 x 103/mm3). The erythrocyte sedimentation rate and C-reactive protein (CRP) were 56 mm/1st h and 7.4 mg/dL. Liver enzyme levels were elevated (aspartate transaminase = 472 U/L; alanine transaminase = 194 U/L). Renal function test results were within the normal range. Antidengue IgM and IgG were negative. Chest radiography revealed peribronchial thickening, mainly in the right upper and middle zones. Polymerase chain reaction (PCR) of the nasopharyngeal aspirate was positive for adenovirus and negative for influenza and parainfluenza viruses. Clinical improvement remained poor after 48 h of treatment. Tachypnea fluctuated between 48 and 60 breaths/min. The lowest oxygen saturation was 91%. Blood gas analysis revealed normal levels of carbon dioxide. Repeat investigations on day 8 of illness revealed reduced platelets (49 x 103/mm3) and neutrophils (0.65 x 103/mm3) and increased CRP levels (43 mg/dL). Repeat chest radiography revealed worsening lung condition, with interstitial infiltrates in both lung fields. No effusion was detected by ultrasound of the chest. The antibiotics were changed to intravenous cefotaxime and amikacin. The blood culture (sampled on day 7 of illness) showed Candida infection. Two sputa (induced) cultures tested negative for bacteria and fungi. Cerebrospinal fluid (CSF) analysis revealed no cells and a protein concentration of 24.7 mg/dL. The CSF fungal culture was negative. Candida species were not isolated in urine and stool cultures. Mycobacterium tuberculosis was not detected in the induced sputum or gastric aspirate using the Xpert MTB/RIF assay. Echocardiography and eye assessments were normal. Abdominal ultrasound was normal. Fluconazole was administered intravenously; however, blood cultures on illness days 9 and 11 remained positive for Candida. Fungal identification, which was performed using manual biochemical methods, revealed the presence of Candida famata. Molecular tests or gene sequencing for identification were not performed because of nonavailability of resources. With the sensitivity pattern, intravenous fluconazole was continued for an additional ten days after the first negative culture on day 13 of illness. Upon clinical recovery, complete blood count returned to normal (WBCs = 14.75 x 103/mm3, neutrophils = 5.16 x 103/mm3, and platelets = 896 x 103/mm3). The levels of liver enzymes had normalized, and chest radiography on day 18 indicated recovery. The subsequent immunological workup revealed parameters within the normal range (immunoglobulin levels, lymphocyte subsets, and neutrophil function tests). The serum tested negative for HIV antigen and antibody. The patient remained well, without signs of relapse during the subsequent follow-up.

PMC5173513_01

Male

A 63-year-old man with a history of MS was referred to our hospital for a detailed investigation of an erythematous nodular lesion with ulceration present on his left mandible. Three months prior to referral, he developed a papular lesion on his left lower jaw, low-grade fever, lethargy, and muscle weakness. The cutaneous lesion had gradually increased in size and eventually developed into an ulcer. One month prior to this referral, lower-extremity muscle weakness and cognitive impairment worsened and he could not read or write correctly. He was referred to our dermatology department for an investigation of the cutaneous lesion. The case had a 30-year history of MS with poor responses to disease-modifying therapy, and two years prior to referral, treatment with fingolimod had been started. Nifedipine, valsartan, clopidogrel, aspirin, and atorvastatin had also been administered for hypertension and coronary heart disease in his past medical history. Since the start of fingolimod treatment, his lymphocyte counts were approximately 500 /muL. He denied any recent travel or close contact with birds. On examination, he was not in acute distress, but his speech was slow and his accent was flat. He had no fever. He had a normal blood pressure (122/64 mmHg) and heart rate (60 bpm). His respiratory rate and oxygen saturation were 16 per minute and 99% in room air, respectively. There was an erythematous multilocular lesion with ulceration that measured 5x3 cm on his left mandible (Fig. 1). There was slight neck stiffness. Cardiovascular, pulmonary, and abdominal examinations were normal. A neurological examination revealed left lateral gaze palsy, left central facial paralysis, slight dysarthria, and limb-kinetic apraxia. His muscle strength and tendon reflex of the upper extremities were normal and his bilateral lower-extremity muscle strength was 2/5 (an inability to overcome gravity). Positive findings for Babinski's reflex and foot clonus were seen bilaterally. These neurological findings, except for lower-extremity muscle weakness, were the same as they had been before referral. To investigate the cause of the skin lesion, a skin biopsy was performed. The histopathology of the skin biopsy revealed no malignant cells. However, many yeast-like organisms with thick capsules were observed in the skin specimens and periodic acid-Schiff and Grocott staining were positive for these organisms (Fig. 2). C. neoformans was isolated and identified from a tissue culture. Both a tissue culture and polymerase chain reaction for Mycobacterium tuberculosis were negative. Computed tomography (CT) of the chest revealed multinodular lesions in the left lung. Both staining and a culture of his sputum showed no pathogen growth. Bronchoscopy for lung nodular lesions was not performed. Fluid attenuated inversion recovery images of brain magnetic resonance imaging (MRI) showed multiple hyperintense oval lesions in the white matter. The same oval lesions observed by brain MRI performed one year prior to this episode were present. Therefore, these lesions were most likely due to MS. A cerebrospinal fluid (CSF) examination yielded elevated white blood cell numbers (74 /muL) and protein (323 mg/dL), and the titer of cryptococcal antigen by latex agglutination of CSF was 1:1,024. The opening pressure of a lumbar puncture was 16 cm H2O. Mononuclear and polynuclear white cells in the CSF were present at 90% and 10% of overall white blood cells, respectively. However, gram staining, India ink staining and a culture of CSF showed no bacterial or fungal pathogens. Repeated blood cultures were all negative for bacterial and fungal pathogens. Laboratory investigations, including liver enzyme levels, renal function and electrolytes, were all within the normal limits, but the titer of serum cryptococcal antigen was 1:256. White blood cell counts were 5,000 /muL (neutrophils 82%, lymphocytes 6%, monocytes 8%). Absolute lymphocyte counts were 300 /muL (CD4+ lymphocytes 145 /muL, CD8+ lymphocytes 113 /muL). Antigen and antibody tests for HIV were negative. We reached a diagnosis of disseminated cryptococcal infection based on a tissue culture of the skin biopsy, and positive findings for CSF and the serum cryptococcal antigen test. After admission, the administration of fingolimod was stopped because of lymphocytopenia, which might have led to an immunocompromised state. Liposomal amphotericin B 300 mg/day (5 mg/kg/day) and flucytosine 4,000 mg/day (64 mg/kg/day) were administered for 6 weeks as induction therapy. Thereafter, consolidation therapy for 8 weeks with fluconazole 400 mg orally daily was administered. Two weeks after the initiation of induction therapy, we repeated a CSF examination and observed a decrease in the number of white blood cells (49 /muL) and protein (177 mg/dL). After 4 weeks of induction therapy, the absolute lymphocyte counts returned to normal levels (1,239 /muL) and a follow-up study with chest CT showed diminished nodular lesions in the left lung. After 6 weeks of induction therapy, his cutaneous lesion had almost completely healed. However, the lower-extremity muscle weakness and cognitive impairment had only slightly improved, though no obvious exacerbation of MS was seen. He was transferred to a regional hospital for continuous care and rehabilitation.

PMC3710997_02

Male

The patient was a 67-year-old man with chronic glomerulonephritis. He received a heminephrectomy due to renal tuberculosis in 1955. His renal function progressively deteriorated, and albuminuria and hematuria had been present since his 30s. He first visited our hospital in 1999, and over the years his blood urea nitrogen and serum Cr levels gradually increased. In 2008, his estimated glomerular filtration rate and 24-hour Cr clearance reached 7.1 ml/min/1.73 m2 (CKD stage 5) and 11.2-15.4 ml/min, respectively. He was hospitalized for the preparation for hemodialysis. The patient began to complain about forgetfulness and stumbling about 4 months before hospitalization. Plain cranial MRI showed prominent hippocampal and cerebrocortical atrophy, and he was diagnosed with AD. Administration of DPZ was started at a low dose of 1.5 mg/day in consideration of his deteriorated renal function. As the serum Cr level was elevated after 2 weeks of treatment, the dose was changed to 3 mg twice a week, and then finally to 5 mg twice a week. His renal function has been stable since then. Figure 3 shows changes in the renal function, MMSE, and HDR-S over time. Overall, MMSE and HDR-S scores remained almost unchanged 7 months after DPZ administration. The plasma concentration was measured at 0, 1, 2, 3, 4, 6, 9, 12, 24, 48, and 72 h after the administration of 5 mg of DPZ following about 4 months of treatment with DPZ (fig. 4). The trough level (9.1 ng/ml) with this dose was the same as or slightly lower than the trough level in healthy male adults with the 5-mg daily dose (10-15 ng/ml). The change in the plasma concentration in the initial 24 h was similar to that in healthy male adults with 5 mg/day. However, since this patient received DPZ twice a week, it was not reasonable to compare the Cmax in this patient with the Cmax in the DI according to which volunteers received daily administration. The AUC for 7 days was 3,681.09 ng h/ml in healthy male adults with the 5-mg daily dose, while the AUC was 2,096.3 ng h/ml in this patient with the 5-mg dose twice a week. As the plasma concentration in this patient had only two peaks a week, the AUC per week was expected to be lower than that under daily administration. The tmax was 1-2 h for this patient, which was almost the same as the tmax in healthy male adults with single-dose administration (table 1). No side effects were observed in this patient throughout the observed period.

alzheimer's disease, chronic kidney disease, donepezil hydrochloride

PMC8650667_01

Female

A 51-year-old patient was admitted to the outpatient department with swelling to the right shoulder and surrounding area, a skin wound, restriction in shoulder movement, and pain. The patient received rotator cuff repair surgery four years prior at an external clinic. Following the initial repair, she was operated on a total of 13 more times to address the infection, based on persistent pain and wound discharge, finally resulting in a final bone resection. The patient reported that the erythema, swelling, and tenderness in her right shoulder reappeared one month before admission to this current clinic. Her medical history revealed that she was under follow-up by the rheumatology department at another hospital for Behcet's disease and that she did not receive anti- tumor necrosis factor (anti-TNF) drug therapy at the time of admission; however, she received oral steroids for a significant period of time. The patient was also being treated for hypertension. A physical examination revealed a yellow-brown swollen nodular lesion with a necrotic surface and lobular contour, located on the anterior part of the shoulder joint, approximately 7.5 cm in size (Figure 1). The circumference of the shoulder was oedematous, and shoulder movements were painful and limited in all directions. There were no palpable lymph nodes around the shoulder. During radiographic examination, contrast-enhanced magnetic resonance imaging (MRI) was performed, following the inspection of previous direct radiographs provided by the patient herself. Contrast-enhanced MRI assessment revealed a complete resorption appearance in the right humeral head, extending to proximal diaphysis; soft tissue appearances in the resorption zone, which were thought to belong to severe hypertrophic synovial tissues; full-thickness defect in the subcutaneous adipose tissue at shoulder level and in the deltoid muscle, extending to humeral head level; and condensed liquid collection and continuity of this collection within the proximal resorbed humerus zone. The supraspinatus, infraspinatus, and subscapularis muscles all presented with a highly fatty atrophy appearance. However, MRI was inadequate to clearly identify whether the fluids were infected (Figure 2). In her routine blood tests, leukocyte was 8.2 Tu/L, erythrocyte sedimentation rate was 77 mm/h, and C-reactive protein was 19.14 mg/L. A culture sample was taken from the wound discharge on the patient's shoulder; however, it showed no reproduction during culture sample monitoring. After clinical evaluation, septic arthritis was considered. To make a microbiological diagnosis and to obtain pathology and culture samples for differential diagnosis of other possible pathologies, such as neoplasms, an excision of the sinus tract, extending into the joint, and skin lesion and joint debridement were planned. A written informed consent was obtained from the patient. The patient was operated on under general anesthesia. To avoid affecting the culture samples taken during surgery, intravenous cefazolin sodium (1 g) (Cezol; Deva Holding AS, Istanbul, Turkey) was administered for surgical prophylaxis, after the samples were taken. During surgery, the patient was in a beach chair position with an arm board to support her right elbow and forearm. Prior to surgery, a Z-plasty incision was planned to allow for closure of the skin after the mass was removed. Following the incision around the mass, dissection was carried out and advanced through the deltopectoral space. Preserving the axillary vessel-nerve package, the mass, including the joint capsule, was excised extensively along with the anterior fibers of the deltoid muscle. Subsequently, the shoulder joint was explored. Dead bone residues and infected synovial tissues were debrided, until bleeding was observed. At this stage, culture samples were taken for microbiological examination, followed by irrigation of the surgical field with approximately six liters of saline solution. A suction drain was inserted after bleeding was under control, and the wound was closed. Following surgery, the patient's shoulder was dressed using a Velpeau bandage. Physical therapy for the patient's elbow and wrist commenced on the first postoperative day. The suction drain was removed on the third postoperative day, and the patient was discharged. The remaining bone stock after surgery was evaluated on postoperative Day 15 by direct radiography (Figure 3). Macroscopic pathological examination revealed a 14.5x5.8x3.5-cm mass with papillary infoldings. On the cut surface, irregularly delineated white confluent foci were visible (Figure 4). Microscopically, granulomas with Langhans giant cells and caseous necrosis could be seen. Some granulomas were cuffed by lymphocytes (Figures 5 and 6). Acid-fast bacillus (AFB) stain showed TB bacilli in the necrotic areas and histiocytes (Figure 7); however, there was no reproduction in the joint fluid culture. The TB treatment was initiated by consulting with the Department of Infectious Diseases and Clinical Microbiology. At six months after surgery, TB treatment using a combination of drugs was ongoing, while the patient no longer experienced symptoms and pain related to the infection. Direct radiographic evaluation of the shoulder joint was made (Figure 8), and joint reconstruction was planned for the end of the medication treatment.

PMC8111671_01

Male

A 29-year-old man with Philadelphia chromosome-negative B-ALL had been treated in another hospital. He achieved CR after induction chemotherapy and continued consolidation chemotherapy. Although he had been in CR after the third course of consolidation chemotherapy, he had a relapse during the fourth. For reinduction therapy, he was treated with INO (0.8 mg/m2 on day 1, 0.5 mg/m2 on days 8 and 15). The percentage of lymphoblasts after the first course of INO was 15%. However, he finally achieved a second CR (0.1% lymphoblasts) after the second course of INO. He was transferred to our hospital for allogeneic HSCT. At the time of admission, laboratory tests showed white blood cell count 1.56 x 109/l, blasts 0%, red blood cell count 429 x 1010/l, hemoglobin concentration 13.0 g/dl, and platelet count 53.0 x 109/l. Although the serum level of aspartate transaminase (AST) was slightly increased (34 U/l; normal range, 13-30 U/l), alanine aminotransferase (ALT) (30 U/l; normal range, 10-42 U/l) and total bilirubin (0.81 mg/dl; normal range, 0.40-1.50 mg/dl) were within the normal range. Hepatitis B surface antigen, anti-hepatitis B surface and core antibodies, and anti-hepatitis C virus antibody were negative. Contrast-enhanced computed tomography did not detect any extramedullary lesions. Bone marrow aspiration showed no lymphoblasts in the smear, and flow cytometric analysis detected <1.0% blasts. Minimal residual disease analysis by measuring immunoglobulin heavy chain rearrangement was not performed. The conditioning regimen for HSCT comprised fludarabine 30 mg/m2/day from days -7 to -5 and total body irradiation (TBI) of 12 Gy delivered in six fractions from days -4 to -2, followed by peripheral blood stem cell transplantation (PBSCT) from a haploidentical sibling donor. He received posttransplant cyclophosphamide (PT-CY) 40 mg/kg on days +3 and +4. Posttransplantation immunosuppression was initiated on day +5 with intravenous tacrolimus (target level, 10-12 ng/ml) and oral mycophenolate mofetil (MMF; 15 mg/kg body weight twice daily) for graft-versus-host disease (GVHD) prophylaxis. The total infused dose of CD34-positive cells was 4.64 x 106 cells/kg body weight. Ursodeoxycholic acid (200 mg/body, thrice daily) for veno-occlusive disease (VOD)/SOS prevention was initiated on day -7. The disease status before initiation of the conditioning regimen was CR. However, swelling of the left submandibular mass appeared on day -2. Bone marrow examination on day -1 showed blast-like cells, approximately 7% of total nuclear cells. A needle biopsy of the mass lesion on day 0 showed that the lymph node was infiltrated by lymphoblasts later. He received PBSCT on day 0, 39 days after the last INO administration. The left submandibular mass gradually improved and disappeared around day +7. On day +17, we performed bone marrow examination because his peripheral blood did not show any recovery of neutrophils. The bone marrow examination showed a hypocellular marrow with no blasts; however, there were 39% macrophages, suggesting hemophagocytosis. On days +17 and +18, we administered dexamethasone palmitate 5 mg/day, and neutrophil engraftment was finally observed on day +22. Administration of MMF was gradually decreased from day +30 and terminated after 7 days. Bone marrow examination on day +31 showed normocellular marrow without lymphoblasts, suggesting CR. Fluorescence in situ hybridization of the bone marrow fluid indicated complete donor chimerism. On day + 34, 18F-fluorodeoxyglucose positron emission tomography/computed tomography found no extramedullary infiltration of ALL. He developed a skin rash and was diagnosed with acute GVHD on day +35; however, no other acute GVHD features were observed in the liver and intestine. Grade I skin acute GVHD was improved by treatment with topical steroids. He was discharged on day +52. During the hospitalization period, we did not observe any laboratory results or signs suggesting SOS. Fig. 1 shows the clinical course of the patient. Unfortunately, his ALL recurred in the bone marrow on day +89, and he died on day +158.

acute lymphoblastic leukemia, hematopoietic stem cell transplantation, inotuzumab ozogamicin, posttransplant cyclophosphamide, sinusoidal obstruction syndrome

PMC4016732_01

Male

A 41-year-old Caucasian man presented to the emergency department with left eye pain and loss of vision after complicated cataract surgery 2 days prior. His past ocular history was significant for blunt trauma to the left eye with a stick while riding an all-terrain vehicle 8 months ago; over the following 3 months, the eye became painful with deterioration of vision for which he sought ophthalmic care. At that initial examination, outside records indicated that his vision was light perception, and there was significant conjunctival injection, corneal edema, and anterior chamber reaction precluding a view of the fundus. There was no recorded sign of previous ocular trauma, keratic precipitates, hypopyon, or afferent pupillary defect, and his poor vision was attributed to the inflammation from initial injury. He was treated for non-granulomatous anterior uveitis with topical and subtenon's corticosteroid injection for several months. The lens developed progressive cataract changes with corticosteroid treatment, and he underwent cataract surgery that was complicated and unsuccessful due to significant sequela from uveitic changes. An intraocular lens was not placed due to questionable lens capsule integrity. Our examination revealed a visual acuity of 20/30 right eye (OD) and no light perception of the left eye (OS). The right pupil was reactive to light, but the left pupil was fixed and non-reactive, with a left relative afferent pupillary defect. He had marked restriction of ocular motility of the left eye due to pain. The left upper eyelid was ptotic and edematous. The orbit was slightly tense to retropulsion, but no proptosis was appreciated. The intraocular pressures were 19 mmHg OD and 27 mmHg OS. Slit-lamp biomicroscopy of the left eye revealed injected and chemotic conjunctiva. The cornea was hazy with diffuse fluorescein staining of the epithelium. The cataract wound incision was intact, and Siedel test was negative. The anterior chamber was without hypopyon, but moderate cells and flare were seen. A pupillary membrane precluded view to the fundus of the left eye. The patient's vital signs were normal. Complete blood count revealed an elevated white blood cell count (11,300 cells per dL) without a left shift. B-scan ultrasonography of the left eye revealed diffuse vitritis and choroidal thickening. No retinal detachment was seen. The patient was admitted to the hospital for anterior chamber washout with removal of pupillary membrane, diagnostic vitrectomy, and intravitreal injection of vancomycin (1 mg/0.1 ml), ceftazidime (2.5 mg/0.1 ml), dexamethasone (0.4 mg/0.1 ml), and amphotericin B (0.4 mg/0.1 ml). Intraoperative findings included significant fibrin anterior chamber reaction, purulent material filling the vitreous cavity, funnel retinal detachment, and multiple choroidal infiltrates. Retinal detachment repair was not attempted due to the poor status of the retinal tissue. Initial gram stain revealed several polymorphonuclear cells with rare budding yeast and very rare pseudohyphae. Fungal culture subsequently revealed C. dubliniensis sensitive to amphotericin, caspofungin, and fluconazole (Figure 1). Serologic work-up for infection and inflammation included blood culture, rapid plasma reagin, fluorescent treponemal antibody-absorption, tuberculosis quantiferon gold, chest X-ray, angiotensin-converting enzyme, tick-borne disease panel, sedimentation rate, C-reactive protein, and human leukocyte antigen B27 which all were within normal limits. The patient was treated with fluconazole 800 mg daily and evaluated by the infectious disease service who found no signs of extra-ocular infection. He had a normal cardiac exam, and additional cardiac imaging was not recommended by the infectious disease service. He adamantly denied intravenous drug use but was found to be hepatitis B and C positive without prior history of vaccination. Human immunodeficiency virus testing was negative, and hemoglobin A1c was 5.6. The patient did not recover his vision and continued to experience severe pain for which enucleation surgery was offered. He underwent enucleation surgery with placement of a porous implant without complication. He was treated for 4 weeks with fluconazole and had an uneventful recovery at 3-month follow-up.

candida dubliniensis, enucleation, exogenous endophthalmitis, ocular trauma

PMC6354651_01

Male

A 17-year-old immunocompetent male visited our emergency department with a high fever, cough for four days previous, and abdominal pain, vomiting, and diarrhea (5-6 times per day) for two days previous to admission. He also complained of a sore throat, purulent sputum, and rhinorrhea, as well as a headache and dizziness at admission. He had a history of meningitis at the age of seven, and his 12-year-old brother had also complained of an upper respiratory infection for the previous three days. He was a senior in high school, and as an athlete (Taekwondo), he had been staying in an athlete's village for the previous two months with other student athletes training for an upcoming competition. He denied a history of smoking or alcohol. His initial vital signs included blood pressure of 141/56 mmHg, heart rate of 114 beats/min, respiration rate of 22 breaths/minute, and a temperature of 40.7 C. On physical examination, bilateral tonsillar hypertrophy with pharyngeal injection was identified. Coarse crackles were auscultated in the left lung field, and tenderness was revealed in left lower quadrant of the abdomen. There was no evidence of nuchal rigidity or impaired neurologic signs. Laboratory exams showed a normal total white blood cell (WBC) count (5.01 x 109/L) with increased neutrophil proportion (84.0%) and decreased lymphocyte proportion (9.4%). Hemoglobin was within the normal range (14.0 g/dL), but mild thrombocytopenia was revealed (126 x 109/L). Hypochloremia (96 mEq/L) and hyponatremia (133 mEq/L) were observed with elevated C-reactive protein (CRP, 8.65 mg/dL; reference range: 0-0.3 mg/dL) and procalcitonin (0.88 ng/mL; reference range: 0-0.05 ng/mL). His community-acquired Pneumonia Severity Index (PSI) and CURB-65 scores were 31 and 1, respectively. An initial chest X-ray and computed tomography (CT) confirmed dense consolidation and centrilobular nodules in the left upper and lower lungs (Fig. 1-A, Fig. 2-A, B). An abdomen X-ray and CT showed diffuse bowel wall swelling, mucosal enhancement of the rectosigmoid colon, and mild hepatosplenomegaly (Fig. 2-C, D). The patient underwent blood, urine, and sputum Gram stain/culture tests and began empirical antibiotic treatment with a third-generation cephalosporin and a macrolide under an initial diagnosis of community-acquired pneumonia combined with severe extrapulmonary symptoms. On the third hospital day, the patient still showed a high fever and complained of a cough, vomiting, and diarrhea. His chest radiography showed infiltration and rapid progression in the left upper and lower lung fields and a newly developed consolidation in the right upper lung field (Fig. 1-B). Although his total WBC counts were still in the normal range (4.43 x 109/L), neutrophilia (84.7%), lymphopenia (9.5%), and thrombocytopenia (121 x 109/L) were sustained, and his CRP increased from 8.65 to 10.90 mg/dL. Multiplex real-time reverse transcription polymerase chain reaction (RT-PCR) for respiratory viruses in his initial sputum specimen was positive for adenovirus, whereas other microbiological tests, including mycoplasma antibody-PCR, acid-fast bacilli, fungus, and mycobacterium tuberculosis-PCR, were all negative. After observing the overall clinical findings, we diagnosed him with combined pneumonia and gastroenteritis caused by systemic adenovirus infection and administered Cidofovir (5 mg/kg per week) with probenecid for a progressive clinical course. His fever subsided after 24 h of Cidofovir administration, and his other clinical symptoms also improved rapidly (Fig. 3); however, his radiologic and laboratory findings, including CRP (13.05 mg/dL) and platelet (139 x 109/L) levels, did not improve until hospital day five. On hospital day nine, he complained of only a mild cough and showed significant improvement in the chest X-ray (Fig. 1-C) and normalization of laboratory markers such as CRP (1.0 mg/dL), platelets (478 x 109/L), neutrophil (55.9%), and lymphocyte (29.5%) fraction (55.9%). In addition, abnormal renal function was not identified in follow-up laboratory tests after Cidofovir. He was discharged at hospital day 10, and an outpatient visit was scheduled to monitor further complications. After discharge, we confirmed that adenovirus was cultured in his sputum sample from the initial visit. The patient showed complete improvement of residual pneumonic consolidation in follow-up chest X-rays taken two weeks after discharge (Fig. 1-D).

adenovirus, crp, c-reactive protein, ct, computed tomography, cidofovir, gi, gastrointestinal, healthy, immunocompetent, psi, pneumonia severity index, pneumonia, rt-pcr, real-time reverse transcriptase polymerase chain reaction, wbc, white blood cell, young adult

PMC8632214_01

Male

A 48-year-old man was referred to our hospital for the study of cushingoid phenotype. Medical history included allergy to penicillin and dyslipidemia. He presented an ACTH of 152 pg/ml (range, 4.7-48.8 pg/ml) cortisol of 47 mug/dl (range, 5.27-22.45 mug/dl), dynamic endocrine laboratory tests were suggestive of CD, and the magnetic resonance imaging (MRI) revealed a macroadenoma. Therefore, initial treatment with a transsphenoidal resection was performed. The morphological changes were consistent with a pituitary adenoma, with a loss of reticulin network ( Figure 1B ). The cells displayed a pathological appearance with a glassy pale eosinophilic cytoplasm, with intranuclear or perinuclear vacuoles, consistent with Crooke's hyaline change ( Figure 1A ). ACTH cytoplasmic immunoreactivity was found at the periphery of the cell ( Figure 1C ); PAS positivity was found, stronger at the periphery ( Figure 1D ). The proliferation index (Ki-67) reached 2% to 4% of cells. Pituitary surgery was unsuccessful, and the follow-up pituitary MRI showed an 8-mm lesion on the right margin of the sella turcica. With this finding, a second surgical intervention was performed and the histology reported a pituitary adenoma with mild and diffuse expression of ACTH, absence of p53 overexpression, and a Ki-67 of 2%-3%. Despite surgical rescue, the patient remained with active Cushing and an increasing tumor volume in follow-up. Thus, a third surgical intervention was performed with adjuvant stereotaxic radiotherapy at a dose of 54 Gy in 27 fractions to prevent NS but was not expected to be curative. The last histological study showed again a pituitary adenoma with ACTH expression, absence of p53 overexpression, and a Ki-67 of 2%. The patient failed to control hypercortisolism with ketoconazole (200 mg/8 h) and pasireotide (40 mg/month). Therefore, the case was presented to the endocrine tumors committee, and treatment with TBA was indicated. After TBA, the cortisol levels became undetectable and steroid replacement was initiated with hydrocortisone 300 mg iv during the first 24 h. After the initial treatment, the corticosteroid dose was gradually decreased until an oral dose of hydrocortisone at 30 mg/day was reached. Moreover, oral fludrocortisone at 0.1 mg/day was initiated. The pathological anatomy report of the adrenal glands showed diffuse corticoadrenal hyperplasia with an absence of malignancy. During postsurgical TBA follow-up, the annual pituitary MRIs showed tumor stability for 2 years. Two years and eleven months after the TBA, the patient presented to the emergency room with an intermittent bilateral diplopia of 3 weeks of evolution. He denied ocular symptoms like exudate, chemosis, or ecchymosis. He also denied fever, bulbar symptoms, nausea, vomiting, headache, or head trauma. On physical examination, he presented generalized skin and mucosa hyperpigmentation, horizontal diplopia to dextroversion, without ptosis or clear restrictions in the oculomotor muscles, and no peripheral sensory or motor neurological alterations were present. The ophthalmic funduscopy and ultrasound biomicroscopy were unremarkable. The presentation of diplopia to dextroversion as the main clinical sign suggested differential diagnoses such as lens ectopias, cataracts, and corneal opiates. The ocular fundus examination without pathological findings helped to dismiss these possible diagnoses. The diplopia was not accompanied by ocular exudate, chemosis, or ecchymosis, which made it unlikely to relate the symptom to an infectious process. The neurological evaluation with an absence of peripheral sensory or motor alterations made diagnoses such as multiple sclerosis or Eaton-lambert syndrome very unlikely. Diplopia was not associated with systemic symptoms such as fever or chills, which could suggest an orbital or brain abscess or cavernous sinus thrombosis. An emergency CT scan was requested and did not show growth of the lesion or signs of compression. However, during follow-up, the patient persisted with intermittent diplopia and subsequently presented ACTH levels at 1,838 pg/ml and chromogranin A of 41.5 ng/ml (range, 0-101.9 ng/ml). A pituitary MRI ( Figures 2A, C ) reported an increase in the size of the pituitary tumor that invaded the clivus, a subacute bleeding component that affected the right margin of the tumor (9 x 14 mm), and an invasion of both cavernous sinuses extending to the lateral carotid line (Knosp grade III). With the three criteria of plasma ACTH level increase, imaging evidence of pituitary mass enlargement, and hyperpigmentation, the patient was diagnosed with NS. No other surgery was performed due to the low probability of success and no clear clinical benefit. Prior to the committee, a thoracic and abdominal CT scan was performed and was negative for extracranial disease. The case was presented to the endocrine tumors committee and the patient started treatment with CAP 2,500 mg daily on days 1 to 14 every 28 days for 14 days and TMZ 140 mg/m2 once daily on days 10 to 14 every 28 days. After two cycles of CAP-TMZ, the diplopia disappeared, hyperpigmentation improved, and ACTH levels decreased to 80% (from 1,838 to 414 pg/ml). The patient reported asthenia and diarrhea grade one during the first two cycles, which disappeared after four cycles. The patient completed four cycles of CAP-TMZ and started maintenance treatment with TMZ 140 mg/m2 once daily on days 10 to 14 every 28 days. After 14 months of initial CAP-TMZ treatment, the last pituitary MRI showed a 65% shrinkage of the tumor ( Figures 2 and 3B, D ) compared with the prior brain MRI ( Figures 3A, C ). At the time of this article's publication, after 18 months of the first dose of CAP-TMZ, the patient continues treatment with hormone replacement therapy and TMZ with excellent tolerance, maintaining a PS ECOG of 0 without new neurological focality in the last follow-up visit ( Table 1 ).

nelson’s syndrome, aggressive pituitary tumors, capecitabine, case report, temozolomide

PMC419374_01

Male

A 42-year-old Nigerian male was referred to the outpatient clinic of the Oral and Maxillofacial Surgery Department of the Lagos University Teaching Hospital in May 2002 with a painless, slow growing recurrent left neck mass of 20 years, duration without any associated constitutional symptoms. There was no history of difficulty in swallowing. He had undergone surgical resection for the similar neck mass earlier in 1972 and 1982, which was diagnosed as pleomorphic adenoma. The patient gave a history of tuberculosis in 1973 and regular visit to the psychiatrist. Clinical examination revealed a firm non-tender multilobulated mass in the left submandibular region. The overlying skin appeared clinically normal with the incision scar of previous surgeries. Intra-oral examination revealed a firm non-tender bulge on the left parapharyngeal/tonsilar fossa. Bimanual palpation of the left parotid gland revealed no abnormalities. A provisional clinical diagnosis of pleomorphic adenoma or Warthin's tumor involving the left parapharyngeal space and submandibular gland was made. Incision biopsy of the submandibular discrete lobule confirmed the diagnosis pleomorphic adenoma. Computed tomographic (CT) scan could not be done, as the patient could not afford the cost, while magnetic resonance imaging (MRI) facilities are not available at our centre. The patient was subsequently admitted for surgical excision of the submandibular and parapharyngeal tumor. The submandibular lesion was approached through a left submandibular incision. The mass was found to be completely distinct from the parapharyngeal tumor, which was enucleated by blunt dissection. Recovery and immediate post-operative period were uneventful. On gross examination, the submandibular tumor consisted of multiple nodules of solid, well encapsulated masses ranging from 1 to 4 cm (figure 1). While the parapharyngeal mass measured 8 cm x 4 cm x 2 cm and was well encapsulated (figure 2). Histological examination confirmed the diagnosis of pleomorphic adenoma (figure 3 and figure 4). Both lesions exhibited dense fibrous connective tissue stroma in which sheets and nests of neoplastic epithelium and epithelial lined ductal structures containing eosinophilic coagulum were seen. Myoepithelial cells were seen in a myxochondroid area. These were more prominent in the parapharyngeal tumor. Both lesions also contained squamous metaplasia and keratin pearl formation. Myxoid areas were predominant in the submandibular tumor. The stroma of the submandibular tumor showed hyalinization. There was no evidence of malignancy in any of the sections examined.

PMC7807103_01

Male

A 49-year-old man presented at our hospital complaining of palpitation and shortness of breath upon exertion. Palpitation and shortness of breath had begun approximately 3 years prior to presentation, but had become exacerbated over the past several weeks. The patient did not experience either palpitation or shortness of breath prior to the onset of CEAS 3 years previously. Esophagogastroduodenoscopy (EGD) and colonoscopy showed no abnormality, whereas intestinal capsule endoscopy demonstrated scattered round ulcers throughout the entire ileum. He had undergone treatment for the eradication of Helicobacter pylori infection because of a gastric ulcer. No disease-related family history was reported. Physical examination revealed anemia, tachycardia, functional systolic murmur, and spoon nails. A blood examination showed severe refractory anemia (hemoglobin: Hb, 2.5 g/dL), hypoproteinemia (total protein: TP, 5.8 g/dL), hypoalbuminemia (albumin: alb, 3.3 g/dL), and normal C-reactive protein (CRP: 0.2 mg/dL) before treatment. The fecal occult blood test was positive. Laboratory parameters improved approximately one month after treatment with iron tablets and mesalazine (Hb, 13.9 g/dL; TP, 7.6 g/dL, alb 4.1 g/dL, CRP, 0.48 mg/dL). Data at the most-effective time point with treatment were Hb, 13.6 g/dL; TP, 7.4 g/dL, alb 4.1 g/dL, CRP, 0.26 mg/dL, and at the time of relapse were Hb, 9.9 g/dL; TP, 6.5 g/dL, alb 3.6 g/dL, CRP, 2.3 mg/dL. The time-course changes of hemoglobin and albumin are demonstrated in Fig. 1. EGD showed atrophic gastritis, whereas colonoscopy showed no abnormal findings. Video capsule endoscopy (VCE) revealed multiple nonspecific ileal ulcers of various sizes and shapes (Fig. 2). Double balloon enteroscopy (DBE) and VCE showed multiple longitudinal and spiral ulcers in the ileum except in the terminal ileum (Fig. 3a, b). NSAID use was excluded. However, cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) or CD could not be excluded based only on the features of ileal ulcers. Although the multiple longitudinal and spiral ulcers in the ileum remained, those ulcers showed improvement, with evidence of granulation, after treatment with mesalazine 3,000 mg/day per oral (p.o.) (Fig. 3c, d). Bone radiography indicated periostosis of the fingers and long bones in the limb (Fig. 4a). Brain-CT revealed skin hypertrophy (Fig. 4b). A pathological examination of the ileal ulcers showed non-specific inflammation (Fig. 5a, b). Follow-up DBE showed longitudinal or irregular-shaped ulcers and erosions. Immunohistochemistry demonstrated CD68-positive histiocytes of a small granuloma (Fig. 5c). The patient was suspected to have CD. However, the terminal ileum lacked longitudinal ulcers or a cobblestone appearance, which are typical findings in CD. The patient exhibited digital clubbing (Fig. 6a), a deeply wrinkled forehead, and a chiseled face (Fig. 6b). Immunohistochemical studies of SLCO2A1 expression in the vascular endothelial cells of ileal ulcers showed that the patient did not express normal SLCO2A1 protein (Fig. 7). In addition, next-generation sequencing revealed a point mutation of the 1807C>T homo-mutation in the 13 exon allele of SLCO2A1 (Fig. 8). CD, BD, NSAID-induced ulcers, and tuberculosis should be considered in the differential diagnosis. The patient was diagnosed with pachydermoperiostosis, which is also known as primary hypertrophic osteoarthropathy (PHO). Since the SLCO2A1 mutation has been reported in pachydermoperiostosis, the present patient was diagnosed with CEAS with ileal ulcers and pachydermoperiostosis. The patient was treated with an RBC transfusion for severe anemia at hospitalization in 201X/10. The administration of oral Fe tablets (100 mg/day) was commenced a few weeks later, which took 3 months to achieve an improvement in anemia, and he continues to take this medication at the time of writing this report. Additionally, oral mesalazine (3,000 mg/day) has been administered from 201X+1/1 until now. The TP and albumin were improved at 201X+1/2; therefore, improvement in TP and albumin by mesalazine took approximately 4 weeks in the initial phase. However, as shown in Fig. 1, the effect of oral mesalazine for albumin and Hb fluctuated during the time course. The inflammation improved 2 years later after the commencement of mesalazine. The combination of Fe tablets and oral mesalazine was continued without other treatments even in the relapsing periods, because anemia and inflammation were within the acceptable range. The albumin, Hb as shown in Fig. 1, and inflammation fluctuated during the time course, and the patient occasionally has diarrhea. We continue to follow this patient on an out-patient basis while continuing to administer Fe tablets and mesalazine.

ceas, slco2a1, pachydermoperiostosis

PMC8571293_01

Male

An 18-year-old male was admitted to the department of neurosurgery on March 14, 2016, with headache, nausea, and vomiting for 2 days. The patient denied a history of head trauma, operation, or any other infectious or systemic diseases, and he was not taking any medication. On examination, the patient's consciousness level according to the Glasgow Coma Scale was E4V4M6, and the patient exhibited confusion, lethargy, and disorientation. There were no meningeal signs or any other neurological deficits. The temperature on admission was 36.8 C, and the blood pressure and laboratory tests were within the normal range. A noncontrast computed tomography (CT) scan of the head showed a mixed density lenticular mass with some air collection in the left frontal region [Figure 1a], which is associated with compression of the left lateral ventricle, and a 10 mm midline shift to the right and effacement of the left ambient cistern were observed [Figure 1b]. The bone window revealed thickening of the left frontal bone [Figure 1c]. The axial sinus CT image demonstrated opacification of the left frontal, ethmoid, and maxillary sinuses [Figure 2a], and the corresponding image in the bone window revealed diffuse thickening and sclerosis of the right maxillary sinus wall [Figure 2b], suggesting paranasal sinusitis and osteomyelitis of the maxillary wall. After obtaining informed consent for surgery, an emergency operation was performed. Under general anesthesia, the patient was placed in a supine position, and a left frontotemporal craniotomy was performed. When the first burr hole was made, approximately 50 mL of odorous, thick, yellow pus was removed from the epidural space and bone edge. After elevation of the bone flap, bone was further removed until the normal bone edge was encountered. The infected bone was hypertrophic and soft, and its surface was irregular with some small pores. A fresh EDH beneath the abscess was also found after removal of the EDA, which was carefully evacuated. After abundant irrigation, subdural exploration was deemed unnecessary. The bone flap was discarded. Before closure, the wound was thoroughly washed with povidone-iodine and hydrogen peroxide, and an epidural drainage tube was placed. On the 1st day after the operation, a CT scan revealed that the left frontal EDA was removed, with return of the midline and enlargement of the ambient cistern [Figure 3]. The epidural drainage tube was removed 48 h after surgery. The pus was examined for fungi, Mycobacterium tuberculosis, and aerobic and anaerobic bacteria, but no organisms were identified. Histopathological examination of the bone flap revealed findings consistent with chronic osteomyelitis, including inflammatory granuloma, massive bone necrosis, and pus formation, but no neoplastic process was identified. The blood culture was also negative. Echocardiography did not show any signs suggestive of endocarditis. Empiric antibiotic therapy (vancomycin 1 g bid combined with metronidazole 500 mg bid) was initiated intravenously for 4 weeks. Postoperatively, the patient's condition improved with the resolution of symptoms, and he was discharged home 4 weeks later with an indication for 4 more weeks of oral antibiotic therapy (cefixime capsule 100 mg bid). A subsequent CT scan 3 months after surgery showed no signs of infection [Figure 4a-c]. Cranioplasty with titanium mesh was performed nine months after surgery [Figure 4d], and the patient recovered uneventfully. At the 3-year follow-up after cranioplasty, the patient was doing well.

cranial osteomyelitis, epidural abscess, sinusitis, spontaneous epidural hematoma

PMC4718472_01

Female

A 33-year-old female recreational runner underwent hip arthroscopy for cam FAI. Diagnostic arthroscopic evaluation of the central compartment revealed an anterior labral tear at the 1-2 o'clock position. Labral repair was performed utilizing two 2.3-mm suture anchors (Osteoraptor, Smith and Nephew, Andover, MA, USA) placed via the mid-anterior portal. After placement of the suture anchors, inspection of the acetabular cartilage revealed focal ballooning of the articular chondral surface adjacent to the labral repair (Fig. 1). Post-operative rehabilitation was uneventful with protective weightbearing for 2 weeks. She returned to normal activities after 6 months without symptoms. Two-year follow-up revealed improvement of modified Harris Hip Score Hip (mHHS) (from 67 to 96), Hip Outcome Score Daily Activity Part 1 (from 88 to 100) and Sport Specific Part 2 (from 33 to 86) and post-operative radiographs revealed joint space preservation (Fig. 2).

PMC4718472_02

Male

A 16-year-old male high-school swimmer with mixed FAI which was treated with elective arthroscopic rim trimming and femoroplasty. During suture anchor placement via mid-anterior portal for anterosuperior labral refixation, the acetabular articular cartilage was elevated but not penetrated by a 3.5-mm knotless anchor (Push-lock, Arthrex, Naples, FL, USA). The anchor was not removed. The patient had an uneventful post-operative course and eventually resumed asymptomatic competitive swimming and intramural collegiate basketball. His pre-operative non-arthritic hip score (NAHS) was 34 and his latest post-operative NAHS was 89 at 6 years following surgery and radiographs show no joint deterioration or narrowing.

PMC4718472_03

Male

A 30-year-old semi-professional bowler with symptomatic cam-pincer FAI underwent elective arthroscopic acetabuloplasty and femoroplasty. Labral refixation was performed via the modified mid-anterior portal with 3.5-mm suture anchors (Pushlock, Arthrex, Naples, FL, USA) was performed at the 1 and 2 o'clock positions. During suture anchor placement, mild elevation of adjacent acetabular articular cartilage without implant penetration was seen. Sixteen months later, because of recurrent groin pain and index of suspicion, revision hip arthroscopy was performed at that time the suture anchor was partly visible under a 'veil' of thin translucent articular cartilage. Probing revealed no gross motion of the seated implant. A 4-mm unhooded burr was used to remove the encroaching longitudinal side of the anchor, initially at chondral surface level, to a subchondral level 2 mm below the articular surface. After an initial 6 weeks of protected weightbearing, he felt initial subjective improvement. But by 10 months, his pain had returned. He underwent a second revision arthroscopy. Intra-operatively, the previously burr-resected side of the anchor was exposed at the level of the adjacent chondral surfaces (Fig. 3) but not loose. Outerbridge grade 2 changes were observed at the anterior apex of the femoral head. Conservative 'unroofing' of marginal cartilage was done with a shaver. The anchor was dislodged using a microfracture awl and subsequently removed with a grasper through an 8-mm arthroscopic cannula without incident (Fig. 4). The remaining trough was treated with microfracture chondroplasty (Fig. 5). Pain and mechanical symptoms gradually resolved. Pre-operative NAHS of 36 decreased to a nadir of 18 at 10 months post-first revision, and increased to 88 at 2.4 years post-second revision surgery. Post-operative radiographs showed no joint narrowing. He has resumed competitive bowling and limits impact sports.

PMC4978199_01

Female

A 71-year old immunocompetent female, with past medical history of osteoarthrosis, chronic obstructive lung disease, chronic kidney disease, hypertension, and nephrolithiasis, presented with postoperative left arthroplasty knee pain. The patient was 40 days post-operative from an uncomplicated left total knee arthroplasty. Approximately, one week prior to admission, she was treated outpatient with oral sulfamethoxazole/trimethoprim DS as a superficial incisional stitch abscess, which involved the proximal aspect of the linear arthroplasty incision. Clinical follow-up demonstrated persistence and increasing peri-incisional soft tissues edema and erythema, progressively extending along the incisional line, and peri-incisional soft tissues. This, in spite of the oral antimicrobials, raised concern for an associated septic bursitis. Upon hospital admission, empiric intravenous vancomycin and ampicillin-sulbactam were initiated for broad antibacterial coverage of gram negative and positive bacteria, including potential methicillin sensitive and methicillin resistant pathogens, targeting a pre-patellar septic bursal infection. Laboratory analysis revealed normocytic normochromic anemia (Hemoglobin 10.2 g/dL); normal White count (10,000 per cubic millimeter); thrombocytosis (716,000 per cubic millimeter); elevated C-reactive protein (7.5 mg/dL); elevated Westergren sedimentation rate (>140 mm/h); negative HIV I & II; negative QuantiFERON-TB Gold; non-reactive treponemal and hepatitis C antibody. She presented with acute renal failure (Creatinine 2.3 mg/dL: her baseline is 1.73 mg/dL), BUN 28.2 mg/dL. Gram stain revealed many polymorphonuclear leukocytes and few Gram-positive bacilli. Bedside tissue debridement was performed without findings of an associated joint effusion. Routine tissue bacterial cultures demonstrating an unidentifiable, slow-growing, aerobic Gram-positive bacilli. A Peripherally Inserted Central Catheter (PICC) line was placed, and she was discharged home targeting a four week therapeutic course of empiric intravenous vancomycin. Unfortunately, local peri-patellar swelling persisted, prompting a repeat outpatient clinic arthrocentesis. Routine bacterial cultures, again, revealed the slow growing, aerobic Gram-positive bacilli. The repeated joint and tissue recovery of an unidentifiable, slow growing, aerobic Gram-positive bacilli, raised the possibility of an atypical microbial pathogen. A therapeutic decision was made to electively perform intraoperative debridement of the joint and bursa, and possible explantation of the arthroplasty hardware, and to include repeat cultures to rule out typical and/or atypical microbial infection, including AFB and fungi. Successful resection of the knee arthroplasty was completed, with the insertion of antimicrobial impregnated (vancomycin) cement. She was discharged home on oral levofloxacin and intravenous ampicillin-sulbactam for a planned six weeks antimicrobial course awaiting final culture results. Multiple cultures of the operative specimen were sent to specialty lab for Acid-Fast bacterial smear and culture, and ultimately Mycobacterium smegmatis group was identified from several tissue cultures sent. The specific species within the group was not identified. Antimicrobial susceptibility is listed in Table 1. Antimicrobials were adjusted to include oral doxycycline and levofloxacin targeting a 6-12 months course of preoperative antimicrobial therapy (Two step arthroplasty revision). Patient completed a 10 months antimicrobial course, noting that antimicrobial therapy was complicated by a transient doxycycline photosensitivity reaction. Several weeks' preoperative, repeat joint fluid analysis was negative for microbial growth, including AFB. A successful revision knee arthroplasty was completed; and operative cultures and joint fluid analysis, remained negative for ongoing infection. She was maintained on the same antimicrobial combination of oral doxycycline and levofloxacin for 30 days post-operative. Patient tolerated the therapy well; with a 10-month post-operative follow-up, there has been no infection relapse.

arthroplasty, atypical, infection, mycobacterium, prosthetic, smegmatis

PMC9124486_01

Female

A 68-year-old female patient with lumbosacral pain caused by a fall was admitted to a local 3rd tier hospital without fever, fatigue, and sweating. Blood tests showed that white blood cell (WBC) count was 7.42x109/L and neutrophils accounted for 64.3%, erythrocyte sedimentation rate (ESR) was 10mm/hr, and C-reactive protein (CRP) was 3mg/L. X-ray showed a wedge-shaped change of the L4 vertebra (Figure 1A and B). Magnetic resonance imaging (MRI) demonstrated hypointense signal of L4 vertebra with a clear horizontal fracture line on T1-weighted imaging (T1WI), mixed intensity signal of L4 vertebra on T2-weighted imaging (T2WI), hyperintense signal, and a clear horizontal fracture line of L4 vertebra on Fat-suppressed T2-weighted images (FS-T2WI), quasi-circular areas of high-intensity signal around L5 was due to MRI artifact (Figure 1C-E). Diagnosis of fresh OVCF of L4 was explicitly based on trauma history and assistant examinations. The patient received vertebroplasty immediately due to unbearable pain. Her lumbosacral pain was relieved, and the spinal X-ray showed bone cement of L4 vertebra was uniformly dispersed when discharged from hospital three days following operation (Figure 2A and B). While there was recurrent pain in the lumbosacral region with intermittent fever and fatigue two weeks after the procedure, her core temperature was up to 37.9 C. This patient's symptoms were progressively aggravated with radiation pain of both lower extremities, especially in the left lower extremity, during 4-month anti-inflammatory and analgesic treatment. Thus, she came to the orthopedic department of our hospital. Medical history showed the patient ate mutton while traveling in the epidemic area one week before vertebroplasty. Due to severe low back pain, she was unable to stand. Percussion pain of the lower lumbar and paraspinal regions was obvious, radiating to both lower limbs. There was hyperesthesia on the posterolateral thigh and anterior medial leg of the lower extremities, with the left side being more affected than the right. Motion in the lumbar region was constrained both actively and passively. Muscle strength of bilateral quadriceps femoris and extensor pollicis longus was grade 4. The femoral nerve stretch test, straight leg raise test, and Braggard's test were all positive on both sides. Thus, we suspect there was a great possibility of spinal infection, and further blood tests showed WBC 3.80x109/L with neutrophils accounting for 85.51%, ESR 32mm/hr, CRP 25.8mg/L, negative T-SPOT. TB assay (T-SPOT) and positive serum agglutination test (SAT) at a titer of 1:800. An X-ray, computerized tomography (CT) scan, and MRI of the spine were performed to determine the spinal segment affected. X-ray showed narrow intervertebral disc spaces at L3/4 and L4/5, and the osteophyte at the vertebra edge of L3-L5 proliferated obviously (Figure 2C and D). CT scan showed multiple destructive changes at L4 and L5 vertebra with paravertebral and intraspinal abscess formation around L4 vertebra (Figure 3A-D). MRI revealed hypointense signal of L3-L5 vertebra on T1WI of which T2WI demonstrated mixed intensity signal and FS-T2WI showed hyperintense signal (Figure 3E-H) consistent with infectious spondylitis with intraspinal abscess. During hospitalization, antibiotics were administered, including rifampicin (0.6g po qd), doxycycline (0.1g po bid), and cefotaxime-sulbactam (2.25g ivgtt q8h). When empiric antibiotics were ineffective for two weeks, posterior focus debridement with decompression, fusion and internal fixation was performed, and large amounts of intraspinal and paraspinal purulent fluid were apparent during the procedure (Figure 4A), of which real-time polymerase chain reaction (Real-time PCR) test revealed Brucella melitensis (B. melitensis). The postoperative pathological results of the intervertebral disc of L3/4 and L4/5 (Figure 4B) demonstrated that organisms consistent with Brucella were present by Giemsa staining and Mycobacterium tuberculosis was not present by negative acid-fast staining (Figure 5A and B). After being discharged from the hospital ten days following the surgery, this patient experienced significant pain relief in the lumbosacral region and low extremities. The femoral nerve stretch test, straight leg raise test, and Braggard's test on both sides all turned negative. The patient experienced a significant decline in infection indexes. X-ray showed postoperative changes of instrumentation placement (Figure 2E and F). Anti-brucellar medications were adjusted to rifampicin (0.6g po qd) and doxycycline (0.1g po bid) after discharge; the entire course of antibiotics treatment was half a year. Her discomforts wholly disappeared, and muscle strength of lower extremities was grade 5 at the last follow-up twelve months after discharge. The infection indexes all turned normal, and the titer of SAT dropped to 1:100. X-ray showed no abnormal changes in spinal instrumentation placement (Figure 2G and H); CT scan and MRI also demonstrated no abnormity (Figure 6A-H).

brucella, complication, spondylitis, vertebroplasty

PMC4863085_04

Female

A 26-year-old female student presented with 5-month history of upper back pain and 4-day weakness in the arms and legs with numbness from the chest down. Neurologically she had decreased sensation below T7, grade 4/5 power in the upper limbs, 3/5 power in the lower limbs with brisk reflexes, and increased tone and clonus. Weight loss in the past few months was noted, but there was no fever or productive cough. She was not immunised for tuberculosis and did not have family history positive for tuberculosis. MRI showed a paraspinal abscess from C7-T1, with collapse of the vertebral body and cervical cord compression. A mini transsternal approach, anterior C7-T1 vertebrectomy with decompression of the ventral sac, was performed. Reconstruction was achieved with a mesh, iliac bone graft, and an anterior plate. A week later patient received a C5-T4 posterior fixation for stability, which allowed early mobilisation of the patient. At 1-year follow-up her Frankel grade improved to grade E.

PMC5458690_01

Male

Informed consent was obtained from the patient for the use of all images and publication of this report before the beginning of this project. A 20-year-old basketball player presented with a 2-year duration of the left groin pain after a basketball-related injury. The pain was aggravated by athletic activity and prolonged sitting. Physical examination of the left hip showed pain with hip external rotation at 40 and internal rotation at 10 . Radiographs showed a lateral center-edge angle of 36 and an alpha angle of 83 on the anterior-posterior (AP) and 72 on the frog view (Fig. 1 and 2). Due to continued disability and failure of conservative management, the patient underwent hip arthroscopy. Intraoperative findings included chondral detachment at the chondrolabral junction in zone 3 and an adjacent partial labral tear. These were treated with chondroplasty, microfracture, acetabular osteoplasty and labral repair followed by osteoplasty of the femoral head-neck junction. No HO prophylaxis was given. Follow-up radiographs at 3 months after the left hip arthroscopy showed Grade 3 HO on the left side (Fig. 3 and 4). On the 2nd post-operative visit (following 6 weeks of non-weight bearing rehabilitation) the patient complained of contralateral (right-sided) hip pain. At 6 months, the patient returned his regular basketball activity with no left hip pain. Left hip external rotation and internal rotation improved to 60 and 30 respectively. However, in the right hip, the patient had a positive impingement test with pain on flexion, adduction, and internal rotation and flexion, abduction, and external rotation. AP radiographs showed a lateral center-edge angle of 30 and an alpha angle of 84 in the right hip. Due to continued symptoms on the right side 1 year after the left hip arthroscopy and failure to respond to conservative management the patient underwent right hip arthroscopy. Acetabular osteoplasty and labral repair were followed by osteoplasty of the femoral head-neck junction. Subsequently, HO prophylaxis was initiated with NSAID treatment (Etodolac) 600 mg/day for 14 days. Follow-up radiographs at 3 months after the right hip arthroscopy showed no HO (Grade 0) (Figure 5). Before the right hip arthroscopy, the patient presented with a modified Harris Hip Score (mHHS) of 95.7, furthermore, he presented with an SF-12 score of 52 Physical Component Score (PCS) and 39 Mental Component Score (MCS). He described his "General Activity Level" to be 90% of normal. An 18-month postoperatively, the patient reported an mHHS of 100. His SF-12 scores improved to 56 (PCS) and 57 (MCS). His "General Activity Level" was increased to 100% postoperatively and he returned to play basketball professionally.

case report, heterotopic ossification, hip arthroscopy

PMC3469196_01

Male

An intact male, 8 years-old Labrador (Canis lupus familiaris) was referred to the Pathology Department of Firat University for postmortem examination from a farm in Bingol Province where in the eastern Turkey. The dog born in coastal region of Bursa Province, western Turkey and one year ago transferred to the Bingol. According to personal information, the animal had been inappetant, coughing, with acute severe respiratory distress and hematuria. The dog died suddenly and was submitted for necropsy. Systemic necropsy was performed and all tissues were examined grossly and major organs including heart, lungs, liver, spleen, kidneys, brain, eyes and testis were fixed in 10% neutral formalin, embedded in paraffin, sectioned at 5 microm thickness and stained with hematoxylin and eosin and examined with a light microscope. For each organ, 10 microm-thick sections from paraffin-embedded tissues were cut and placed in 1.5 ml eppendorf tubes. To avoid cross-contamination of samples, the microtome blade was cleaned with xylene between each block. Sections were deparaffinized with 1 ml xylene for 10 min at 37 C. Subsequently, samples were centrifuged at 4000 rpm for 5 min and the supernatant was removed. This procedure was repeated once. After deparaffinization, rehydration in 100%, 90%, 80% and 70% ethanol followed. Thereafter 70% ethanol was removed and tissue lysis solution was added (Fermentas DNA Purification Kit). For DNA extraction, we chose a commercially available DNA extraction kit based on a simple salting out procedure. We used the manufacturers' protocol for paraffin-embedded tissues with a modification of the proteinase K step, namely, an overnight digestion and addition of 25 microl aliquots of proteinase K (20 mg/ml). The incubation was performed with constant agitation at 56 C. After extraction, the DNA pellet was air-dried and resuspended in 50 microl sterile distilled water and stored -20 C. DNA was also extracted from the adult worm as mentioned above for use as a positive control. The PCR was performed using two sets of primers. Initially, we used one primer pair: 5'-CATCAGGTGATGATGTGATGAT-3' (forward) and 5'-TTGATTGGATTTTAACG TATCATTT-3' (reverse), which have been described by Mar et al., for the amplification of a 302 bp ITS-2 gene segment. A second set of primers was used: 5'-AGTGTAGAGGGTCAGCCTGAGTTA-3' (forward) and 5'-ACAGGCACTGACAATA CCAAT-3' (reverse), identical to those described in a previous study for the amplification of a 203 bp cytochrome oxidase subunit 1 (CO1) gene fragment of D. immitis. Positive control DNA was used for each PCR and distilled water was used as a negative control. The amplified products were separated by gel electrophoresis in 2.5% agarose gel with a Tris-boric acid-EDTA (TBE, pH 8.3) buffer at 90 V for 30 min. Following electrophoresis, the amplified products were visualized with ethidium bromide staining for 30 min at room temperature. Subsequently, 203 bp bands were cut from the gel and amplified DNA fragments were purified by QIAquick Gel Extraction Kit (Qiagen, USA). The CO1 sequences were automatically obtained using a 377 ABI PRISM system (Applied Biosystems). Nucleotide sequence analysis was undertaken by BLAST algorithms and databases from the National Center for Biotechnology (http://www.ncbi.nlm.nih.gov).

dirofilaria immitis, dog, histopathology, pcr, paraffin

PMC3420650_01

Male

A 13-year-old boy presented to Department of Orthopedics with pain and swelling in the right ankle. Swelling had appeared about 1 year back and was gradually increasing in size. Examination revealed bony thickening over the lateral malleolus. Ankle and subtalar joints had full range of mobility. Parameters of complete blood count were within normal range. ESR was 68 mm at 1st hour. Plain radiography revealed a submetaphyseal lytic lesion in the distal tibia with a sclerotic margin around it (Figure 1). With these findings, a diagnosis of Brodie's abscess was made. Curettage was done under spinal anesthesia through the anterior approach. Curetted material was sent for histopathological and microbiological assessment. On gross examination, specimen consisted of multiple, soft, gray brown to gray white tissue bits, with largest measuring 0.5 x 0.5 x 0.3 cm. Histopathology showed small irregular necrotic bony fragments and degenerated cartilage, surrounded by mixed inflammatory cell infiltration consisting of plenty of foamy histiocytes along with lymphocytes and plasma cells (Figure 2). Few neutrophils and occasional histiocytic giant cells were also seen. Fibrosis was present. All these features were consistent with xanthogranulomatous osteomyelitis. From the tissue sent for culture, staphylococcus aureus was isolated. PCR study for Mycobacterium tuberculosis was negative. Patient recovered completely after the surgery.

PMC7142386_01

Female

A 40-year-old female patient presented to our service with a 5-day history of progressive right-sided low back pain, which radiated over the right buttock into the anterior thigh in an L4 distribution. The pain was nonpositional and exacerbated by coughing. She also complained of new bifrontal headaches, difficulty in concentrating, stool retention, and difficulty in passing urine. Two weeks previously, she had commenced an immunisation against adult tick-borne encephalitis (TBE) by self-injecting a vaccine (Encepur ) into the ipsilateral quadriceps muscle. Her medical history was otherwise unremarkable. Symptoms of a viral infection such as fever, rash, and oral or genital lesions were not present, and recent exposure to tics was denied. The patient was afebrile, her blood pressure was 170/110, and her heart rate was 92. The alignment of the spinal column was normal. On the right leg, there was a positive straight-leg raising test, weakness of knee extension, and a diminished patellar reflex. There was also slight hypaesthesia over the knee and the anterior aspect of the thigh. The Babinski sign was negative, and there was no evidence of meningism such as photophobia, neck-stiffness, or a positive Brudzinski sign. The ESR was 7 mm/hr, her CRP was 8.9 mg/L, and the blood differential was normal. The remaining blood chemistry was negative, including tests for paraproteins, ANA, and HIV. Abdominal ultrasound excluded urine retention and other intraabdominal pathology. On contrast-enhanced MRI, there was no compression of the spinal roots or the cauda equina and no involvement of the cranial meninges. The patient refused a lumbar puncture. We diagnosed a sensorimotor radiculitis of the fourth lumbar root secondary to TBE vaccination. A 5-day course of prednisolone (1 mg/kg) did not influence symptoms and was thus discontinued. Three months later, the patient still required analgesics (NSAIDS, tramadol, and pregabalin) and had developed a pronounced weakness and atrophy of the quadriceps muscle and a foot drop of the affected leg. The motor and sensory function had started to return to normal at 6 months, and by 12 months, the deficit had vanished. In contrast to this, the headaches and difficulties to concentrate persisted at the one-year mark.

PMC9897006_01

Male

The patient was a 62-year-old African American male, with a past medical history of HIV, latent TB, chronic kidney disease stage 3a, essential hypertension, hyperlipidemia, and type 2 diabetes mellitus, who was brought to the emergency department by ambulance with complaints of a one-day history of chest pain, body aches, and shortness of breath. His symptoms worsened with a cough and had no apparent alleviating factors. On arrival, his vital signs showed a temperature of 101.1 F and a heart rate of 129 beats per minute. His blood pressure was 132/65 mmHg, and his respiratory rate was 19, with an oxygen saturation of 95% on room air. He did not show any signs of acute distress on physical examination. A cardiac examination demonstrated tachycardia. He had been on elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya) for HIV. He had not been aware of his CD4 count before arrival. He had no previous reported history of opportunistic infection. He conveyed that he had completed treatment for his latent TB in the distant past. On arrival, EKG showed ST elevation in multiple leads (Figure 1), but his troponin was within normal limits. Other initial parameters were as follows - WBC: 7.4 x 109/L, hemoglobin: 11.0 g/dL, platelet count: 266 103/microl, erythrocyte sedimentation rate (ESR): 70 mm/hr, C-reactive protein (CRP): 9 mg/dL, and lactic acid: 0.70 mmol/L. As for imaging studies, cardiomegaly was present on his chest X-ray (Figure 2), and an echocardiogram showed a moderate to large pericardial effusion. A previous echocardiogram about 18 months ago had been within the normal range. The patient was hemodynamically stable with no signs of cardiac tamponade, but a pericardiocentesis was deemed necessary due to the volume of fluid observed on the echocardiogram. Approximately 700 mL of serosanguinous fluid was extracted through a subxiphoid pericardiocentesis the next day after his presentation. The pericardial fluid analysis was indefinite, showing only blood and proteinaceous debris and rare, intact, and benign-appearing mesothelial cells. No atypical cytologic features were seen. The acid-fast smear for Mycobacterium was negative. Further serum testing showed that his antinuclear antibody was in the normal range and his CD4 count was 265 cells/mm3. A Karius test was performed and revealed the presence of Epstein-Barr virus (EBV). However, an antibody panel later demonstrated that this was not an acute EBV infection. The patient received empiric antibiotics and continued improving symptomatically, but the definitive cause of the effusion remained undetermined. Since this was a large effusion without a sign of tamponade, it was likely a subacute or chronic effusion with acute viral or idiopathic pericarditis. Medication-induced pericardial effusion has been described, specifically with isoniazid. Our patient reported undergoing treatment for latent TB in the remote past, and hence this was an unlikely cause.

antiretroviral therapy, hiv, pericardial effusion, tuberculosis, viral pericarditis

PMC9744753_01

Male

A 75-year-old male patient (Han Chinese ethnicity) had headache and clusters of millet-sized blisters without fusion on the right side of the head and neck on February 24, 2022. The blisters were tight and shiny with surrounding redness, and the blister fluid was clear. The initial diagnosis was herpes zoster, and the patient was treated with 10 mg/kg of acyclovir every 12 h. On March 7, 2022, the patient's headache and herpes blisters were improved, so he stopped taking medicine. On March 12, 2022, the patient started to have left-sided headache, followed by herpes on the left side of the head and neck. He was diagnosed with recurrence of herpes zoster and was re-treated with acyclovir (10 mg/kg every 12 h). On March 16, 2022, the patient had hoarse voice and choking cough while keeping clear consciousness and movable limbs. He went to the Fifth People's Hospital of Jinan where he underwent clinical examinations on March 17, 2022. The CT scan of the lungs revealed pneumonia, and magnetic resonance brain imaging and CT imaging of the abdomen and pelvis did not demonstrate any significant abnormalities. An extensive biochemical assay revealed normal electrolytes, renal, thyroid, and parathyroid function, and negative serology for HIV, hepatitis B, and syphilis. The neurological examination showed the patient had clear consciousness and mental competence despite having decreased memory and impaired calculation, orientation, and judgment abilities. The patient could not speak clearly and fluently and had a choked cough when drinking water. Spasms were present with several minutes of paroxysmal painful muscle stiffness in the right upper limb, and the paroxysmal painful spasms were easily triggered by light touches and startling. The rest of the neurological examination was normal. On March 19, 2022, the spasms frequently developed as a cluster accompanied by paroxysmal sympathetic hyperactivity (PSH), which was characterized by sinus tachycardia (110-160 beats/min), elevated systolic blood pressure (180-227 mmHg), tachypnea (30-50 breaths/min), and hypoxemia. An emergent electrocardiogram revealed that the patient had paroxysmal supraventricular tachycardia. The symptoms lasted for 3 min and were self-relieved. On March 21, 2022, the patient began with spasms of the right upper limb, followed by spasms involving all four limbs with loss of consciousness. Two minutes later, these symptoms were self-relieved. Due to his critical condition, the patient was transferred to the intensive care unit on the same day. His blood test results were unremarkable except for elevated serum levels of leukocytes (16.99 x 109/L) and neutrophils (14.91 x 109/L). A chest CT scan revealed manifestation of inflammation in both lungs, which was more aggravated than before. A lumbar puncture showed 22*106 leukocytes/L (95% monocytes), and the rest of the biochemistry parameters were normal. At this point, the patient was diagnosed with central nervous system infection with high probabilities of varicella-zoster virus encephalitis, and the antibiotics treatment was switched to ceftriaxone sodium (2 g every 12 h) plus acyclovir (10 mg/kg every 12 h). Sedative and analgesic drugs as well as phenobarbital sodium were also given to control spasms. Recurrent spasms caused prolonged apnea, ultimately leading to a need for mechanical ventilatory support. The patient's condition did not improve with these treatments, so he was transferred to the intensive care unit of the First Affiliated Hospital of Shandong First Medical University on March 29, 2022. The patient had coronary atherosclerotic heart disease in the past, could tolerate general physical activities, and had been diagnosed with hypertension for 3 months. The admission examination revealed that the patient had low and coarse breath sounds with scattered moist rales in the lower part of both the lungs. The patient was kept under sedation and mechanical ventilatory support. Laboratory examinations (performed on 29 March 2022) showed a leukocyte count of 11.48 x 109/L, a neutrophil count of 9.96 x 109/L, and a myoglobin count of 355.2 ng/mL. The rest of the biochemistry parameters were normal. The cerebrospinal fluid (CSF) opening pressure was 17 cmH2O, with 9 x 106/L leukocytes/L and 43.4 mg IgG protein/L; normal protein and glucose levels; negative oligoclonal bands; and negative microscopy and culture for tuberculosis, fungi, and virology. Cardiac ultrasound and ultrasound of deep and superficial veins of bilateral lower extremities did not show any significant abnormalities. At that time, the patient was diagnosed with intracranial infection, so acyclovir (10 mg/kg every 8 h) was used. The sputum sucked from the patient was thick and purulent yellow, and the fungal 1-3-beta-D-glucan quantitative test result of the sputum was 683.3 pg/mL. Therefore, the patient was suspected to have fungal infection; thus, voriconazole was given for antifungal treatment. Midazolam, remifentanil, phenobarbital sodium, and sodium valproate were added to further control the spasms. Despite an increased dosage of drugs, the spasms gradually worsened with increased frequency and could be triggered by phlegm suction, turning over, and backslap. Spasms began in the right upper limb, followed by muscle spasms in the left upper limbs, lower limbs, shoulders, neck, and back, which triggered a generalized tonic-clonic seizure (Supplementary Video 1). The electroencephalogram (EEG) showed slow waves (4-7 Hz) interspersed with low amplitude of brain electrical activity. Spike waves occurred in the sphenoid bone (Figure 1). Blood and cerebrospinal fluid tissue-based assay (TBA) screening showed weakly positive antibodies against cell membranes in the brainstem (Figure 2). No significant abnormalities were found in paraneoplastic antibodies (Hu, Yo, Ri, CV2, PNMA2, amphiphysin, recoverin, SOX1, titin, Zic4, GAD65, and Tr), and demyelinating antibodies (AQP4, MOG, MAP, and GFAP). Serum and cerebrospinal fluid cell-based assay (CBA) screening for autoimmune encephalitis antibodies showed that IgG antibodies against glycine receptor (GlyR) was positive at 1:100 in both serum and cerebrospinal fluid (Figure 3), while the remaining proteins or receptor antibodies (NMDAR, LGI1, CASPR2, GABABR, AMPAR1, AMPAR2, IgLON5, DPPX, GAD65, and mGluR5, D2R) were all negative. Putting the patient's clinical symptoms and auxiliary test results together (Figure 4), a diagnosis of anti-GlyR antibody-positive PERM induced by varicella-zoster virus was made. The patient was then given 0.4 g/kg/d immunoglobulin treatment for 5 days. Considering fungal infection, he was also temporarily treated with methylprednisolone (120 mg/d). After the 5-day treatment, the spasms were significantly less frequent than before. However, the patient's family insisted on automatic discharge despite continuous persuasion from the medical staff and actively helping in raising funds for the hospitalization on April 8, 2022. The patient then passed away on April 13, 2022.

glycine receptor, herpes zoster, paroxysmal sympathetic hyperactivity, progressive encephalomyelitis with rigidity and myoclonus, varicella-zoster virus

PMC3343675_01

Female

A rare case of tubercular endometritis occurred in a 55-year-old Para 7, postmenopausal woman, who presented herself for cervical smear at the Medical Women's Centre in Enugu, the capital of Enugu State of Nigeria. The senior author (WO) observed at microscopy the diagnostic Langhans giant cells. This was the only case encountered among 3,267 smears examined between 1993 and 2010. Subsequently, laboratory tests were carried out. The Mantoux test was positive at 14 mm. The ESR measured 52 mm in the first hour. The Total White Count was 7,200/mm3. The differential count showed Neutrophils 51%, Lymphocytes 35%, Eosinophils 13%, and Monocytes 1%. Treatment for tuberculosis was instituted and the follow up has been successful. Pattern of abnormal Pap smears in developing countries is of epidemiological interest. In a Saudi Arabian series, there was no mention of tuberculosis. In an Italian study, tubercular endometritis was recorded as a rarity which was detected with fluid hysteroscopy. A Chinese study indicated that this disease may cause uterine adhesions, amenorrhea, and subsequently infertility. A previous report on the easterly Igbos or Ibos, one of the largest ethnic groups in Nigeria, led to the following conclusion: "Igbo women conceive and give birth before the onset of genital tuberculous lesions that lead to primary infertility." The parity of 5 in the instant case is in keeping with this conclusion. Agreeably, as a study centered in the Nigerian middle belt stated, "Endometrial TB is not a frequent cause of infertility in our set-up."

nigeria, pap smear, tuberculosis, endometrium, health education

PMC4735480_01

Male

In July 2013 a 53-year-old white homeless man with a history of alcoholism was admitted to the hospital with long-standing cough, fever and fatigue. Physical examination revealed malnutrition with severe weight loss, dyspnea and decreased lung sounds primarily in the upper lobes. Chest radiograph and computed tomographic imaging (Fig. 1) revealed bilateral upper lobe infiltrates with cavitation. Haematological analysis revealed a hemoglobin level of 9.8 g/dL and a leukocyte count of 6.9 x 109/L. HIV serology was negative. With a presumptive diagnosis of tuberculosis, two serial sputum samples and a bronchoalveolar lavage sample were sent to the national tuberculosis reference laboratory. All direct smears (stained with Auramine O and Ziehl-Neelsen) were positive for acid-fast bacilli. Antituberculosis treatment was started, with isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) provided according to the guidelines of the National Program of Tuberculosis of Uruguay. The bronchoalveolar lavage sample was decontaminated with the N-acetyl-l-cysteine-sodium hydroxide (NALC-NaOH) method and inoculated into mycobacterium growth indicator tubes (MGIT; BD Biosciences, Sparks, MD, USA) automated liquid culture system. After 26 days of incubation, the MGIT culture flagged positive; Ziehl-Neelsen stain of liquid culture was positive for acid-fast bacilli, and immunochromatographic test for the identification of Mycobacterium tuberculosis complex (TBC ID; Becton Dickinson, Franklin Lakes, NJ, USA) was negative. Cells were pelleted and DNA extracted. The GenoType Mycobacterium CM (common mycobacteria) and AS (additional species) assays (Hain Lifesciences, Nehren, Germany) for identification of nontuberculous mycobacteria were performed. The results were positive for M. heckeshornense. Subcultures on Ogawa medium, as well as the solid cultures from the two sputum samples, yielded small, hemispheric, smooth and yellow-pigmented colonies after 4 weeks of incubation. Phenotypic characterization was performed for all isolates (Table 1), and DNA was submitted to the Institut Pasteur at Montevideo for sequencing studies. To identify the isolates to the species level, the complete 16S rDNA gene and a fragment of hsp65 and rpoB genes were sequenced (GenBank accession numbers KP636957, KP636958 and KP636959, respectively). The DNA sequences obtained were compared with the GenBank/European Molecular Biology Laboratory sequence database. Gene sequencing unambiguously confirmed the identification of M. heckeshornense (100% similarity with M. heckeshornense type strain sequences for all targets). With these clinical, radiologic and microbiologic findings, the patient met the American Thoracic Society/Infectious Diseases Society of America diagnostic criteria of nontuberculous mycobacterial lung disease. Treatment was thus changed to isoniazid, rifampicin, ethambutol, levofloxacin and clarithromycin, all provided daily. Ethambutol had to be stopped owing to ocular toxicity. The patient improved clinically, and a regression of the lesions was observed radiologically. After 12 months of treatment with the macrolide-containing regimen, the patient had converted to negative cultures, and treatment was stopped. After 12 months of follow-up, his disease is clinically and radiologically stable and culture negative. M. heckeshornense was first reported in 2000 as a pathogenic, slowly growing scotochromogenic mycobacterium, phylogenetically related to Mycobacterium xenopi, that caused a bilateral cavitary lung disease in an immunocompetent patient. Since then, a limited number of cases were reported in humans, some of them involving severe pulmonary infections often identified as M. xenopi and also involving extrapulmonary infections. Furthermore, it was isolated from animal sources such as porcine lymph nodes and from a domestic cat with a severe generalized infection. This could indicate that this species is widely distributed in the environment. The new commercially available molecular biology methods can fast and precisely identify most common Mycobacterium species. In our case, we identified correctly M. heckeshornense using the Genotype CM/AS HAIN tests in 2 days. The patient was treated with standard therapy (HRZE) for 2 months, until the diagnosis of M. heckeshornense was confirmed. In the absence of guidelines for the treatment of M. heckeshornense disease, the patient was treated with isoniazid, rifampicin, ethambutol, levofloxacin and clarithromycin. This led to prolonged culture conversion and no relapse 12 months after treatment cessation. In some patients, resolution was reached with surgical procedures. In our case, the extent of the pulmonary lesions and the general condition of the patient prevented this approach. Although M. heckeshornense is genetically related to M. xenopi, its pathogenicity is noticeably higher. Cases have been reported in Asia, Europe and recently in Canada, showing that M. heckeshornense is an opportunistic pathogen present worldwide. This is the first case reported in Uruguay and the Latin America and Caribbean regions. A possible explanation of this fact is that in many countries of this region, tuberculosis disease is confirmed only by microscopy; culture and identification, particularly molecular identification, are not routinely done. In summary, we describe a case of fibrocavitary M. heckeshornense pulmonary disease, the first of its kind described in the Latin America and Caribbean region. A treatment regimen of isoniazid, rifampicin, clarithromycin and levofloxacin led to symptomatic improvement. M. heckeshornense is a serious nontuberculous mycobacterial pathogen with a worldwide spread.

epidemiology, mycobacterium heckeshornense, infection, mycobacterium, pulmonary

PMC5094598_01

Female

A 66-year-old lady presented with three-week history of night sweats, low-grade pyrexia and weight loss. She also had progressive dyspnoea on exertion over 3-4 weeks and non-productive cough that failed to respond to a seven-day course of oral amoxicillin. Her medical history included well controlled asthma, migraine, hypothyroidism and a tonsillectomy as child, with no hospitalisations. She is a non-smoker with minimal alcohol consumption, and no recent travel abroad. On examination she had a low grade pyrexia (37.9 C). Respiratory examination revealed respiratory rate of 24 breaths/min; oxygen saturations were 97% on air. There were minimal coarse crackles in the right lung base and subclavian lymphadenopathy. Cardiovascular, abdominal and neurological examinations were unremarkable. Rectal examination showed no evidence of melena. Full blood count revealed normocytic anaemia with a haemoglobin of 70 g/L (baseline haemoglobin 136 g/L), white cell count of 17.3 x 109/L (Neutrophil counts 14.7 x 109/L) and mildly raised C-reactive protein (74 mg/L). Platelet counts was also elevated (667 x 109/L). Erythrocyte sedimentation rate (ESR) was markedly elevated at 114 mm/hr. Her bilirubin was also slightly raised (29 mumol/L) with a low albumin (28 g/L), liver and renal function tests were otherwise unremarkable. A chest radiograph showed bilateral small pleural effusion. In light of the persistent cough, night sweats, weight loss and significantly raised ESR > 100mm/hr, initial differential diagnosis included infective (e.g. tuberculosis), inflammatory (e.g. polymyalgia rheumatica, rheumatoid arthritis) and malignant (e.g. lymphoma, multiple myeloma) aetiology. CT scan showed extensive mediastinal lymphadenopathy, with the largest lymph node seen in the paratracheal region measuring 22 mm and additionally in the subclavian, pretracheal and paratracheal distribution (Fig. 1). No pulmonary masses were found. Broncho-alveolar lavage showed no acid-fast bacilli on smear, and no growth after 6 weeks of culture. No malignant cells were detected on cytology. Myeloma screen was negative with normal serum immunoglobulins and absence of Bence Jones protein in urinalysis. Serum calcium was also within normal range (2.13 mmol/L). A haemolysis screen revealed raised lactate dehydrogenase (643 IU/L) and reticulocytes (9%, absolute count 292 x 109/L). Iron, folate and Vitamin B12 level and thyroid function test were all within normal range. Direct antiglobulin test (DAT) was positive for complement C3d, and negative for IgG, consistent with cold agglutinin haemolysis. Blood film confirmed multiple cold agglutinins, large platelets and target cells. Serology showed positive IgM for Mycoplasma pneumonia, and there was >4 fold increase in IgG between the initial sample and convalescent sample. The patient was initially treated with intravenous (IV) fluids and empirical broad-spectrum IV pipercillin-tazobactam as well as oral clarithromycin for the atypical presentation. Given her symptomatic anaemia, two units of warm packed red cells was transfused. Her observations post-transfusion remained stable, apyrexial with no further significant haemolysis, and she was discharged with oral clarithromycin. The patient was followed up in respiratory clinic one month following hospitalisation, and found to have a normal clinical examination. Interval CT scan showed improving but persistent lymphadenopathy (Fig. 1). Endobronchial ultrasound (EBUS) was therefore performed for mediastinal lymph node biopsy, which showed fragments of blood clots with lymphocytes/anthracotic lymphoid tissue. No malignant cells were seen. The patient remained symptom-free in two month follow up.

cold agglutinin, haemolysis, lymphadenopathy, mycoplasma

PMC10417011_01

Female

An 8-year-old patient presented to the Emergency Department of the Children's Clinical University Hospital (CCUH) in the late evening in August 2021, complaining of an acute febrile illness for 3 weeks with an intermittent febrile body temperature above 38 C, accompanied by submandibular oedema, abdominal pain, loose stools, joint pain, and pain and tightness in her chest. The general practitioner had previously diagnosed an Epstein-Barr virus infection clinically, but the EBV IgM was negative, while the EBV IgG was positive. The patient was treated with amoxicillin/clavulanate for a week and has since then developed persistent diarrhoea. The patient had a diagnosis of bronchial asthma for 1 year with a need for the intermittent use of inhalation with salbutamol and fluticasone propionate due to a dry cough, but with no severe asthmatic episodes. On admission, her body temperature was 37.7 C, tachycardia 165 beats/minute, normal arterial pressure 110/50 mmHg, no cardiac murmurs or pulmonary rales audible, a respiratory rate 40 times per minute, SpO2 96%, no hepatomegaly and negative meningeal symptoms. The patient's blood tests showed HES, fulfilling the criteria: severe leucocytosis WBC 102.34 x103 uL, eosinophilia 24.9%, absolute eosinophilia 25.53x103/uL, thrombocytopenia 72x103/ uL, erythrocytes 4.32x106/ microL, CRP 87 mg/L, LDH 994 U/L, ferritin 1306 ng/mL, total IgE > 2000 U/mL, EGA 48 mm/h, pANCA and cANCA negative, ANA positive 1:1280, EBV IgM positive, troponin I 1880.4 pg/ml (acute myocardial involvement/myocarditis suspected) and ProBNP 6786 pg/ml. While at the emergency department, the child complained about generalized pain in her body and was not able to move her right hand or her right leg. The computed tomography (CT) of the head without contrast showed no signs of haemorrhages but thickened mucous membranes in all paranasal sinuses. Magnetic resonance imaging (MRI) of the head was performed and revealed: acute cerebral infarcts of various sizes, localized in the cerebellum, in all lobes of the large hemispheres in the anterior, posterior, and inferior border basins. The finding might be consistent with hypereosinophilia syndrome. To exclude the diseases of the hematopoietic system, blood tests for flow cytometry and cytogenetics of peripheral blood were sent to the laboratory at Vilnius Hospital and excluded the myeloproliferative process. No significant findings related to HES were found by flow cytometry in the peripheral blood and bone marrow. No signs of clonality in TCRB, TCRG or TCRD genes were detected. In the bone marrow biopsy, hypercellularity was found with a predominance of eosinophils, but no atypical eosinophils, platelets or increased blast count were found, corresponding to secondary HES. Serology of the blood was performed to exclude parasitic diseases (toxoplasma, toxocara, taenia solium, trichinella or echinococcus), and cryptococcus antigens in the blood were excluded. Other probable causes such as tuberculosis, entero and coxacki, and HIV viruses were excluded. The patient had positive Toxocara canis IgA and a subsequent positive Western blot test. She, therefore, also received treatment with albendazole to treat the possible cause of hypereosinophilic syndrome. Echocardiography showed a normal cardiac anatomy with slightly decreased functioning of the right ventricle (TAPSE 14 mm), hypertrophy of the right ventricle (RV) (RV free wall 11 mm), normal functioning of the left ventricle, but mild hypertrophy of the ventricular septum. Her cardiac MRI was consistent with a presentation of acute myocarditis: late gadolinium enhancement, subendocardially diffuse in the right ventricle, and also in the inferior and lateral wall of the left ventricle, ejection fraction (EF) of the left ventricle of 41%, hypokinesia in the apex and posterior wall of the left ventricle, hypertrophy of the free wall of the right ventricle and severe hypertrophy of the apex of the right ventricle, diffuse oedema of the right ventricle and local oedema in the anterior and posterior walls of the left ventricle. A thoracic CT showed right-sided pleural effusion up to 1.5 cm, small infiltrates in the right lower lobe segments S8 and S9. No evident hyperplasia of the intrathoracic lymph nodes. Abdominal ultrasound and ophthalmological examinations were without pathology. The patient's treatment was discussed in a multidisciplinary consilium together with paediatric haematologists, paediatric rheumatologists, pneumonologists, cardiologists, neurologists, and immunologists. The diagnosis was hypereosinophilic syndrome with ischemic stroke and suspected eosinophilic myocarditis (the myocardial biopsy was not taken because of possible complications), but EGPA was considered as a possible differential diagnosis, as was the possibility of development of a myeloproliferative disorder. Based on the "Guidelines for the Investigation and Treatment of Eosinophilia": the patient received methylprednisolone bolus intravenously followed by oral methylprednisolone 40 mg (14 days), then 36 mg (7 days) and 32 mg (7 days), with slow weaning then according to the scheme. Long term treatment with Medrol (slowly weaning during the next 3 months as suggested by the rheumatologist) led to the development of exogenous Cushing's syndrome (initially the patient's weight was 49 kg (+2.42z, BMI 25.4 kg/m2, but her weight increased afterwards to 74 kg (+3.24z, BMI 33.3 kg/m2). With this acute episode, the patient was treated in the CCUH for 41 days. She received a low molecular weight heparin (enoxaparin) therapeutic dose for 7 days, then a prophylactic dose which was changed to oral rivaroxaban for 6 months. Due to initial persistent tachycardia, myocardial hypertrophy, and inflammation, she received carvedilol 3.125 mg twice a day in the long term. The patient underwent rehabilitation and the paresis of the right leg already disappeared during the hospital stay, and after discharge, her right hand function improved fully within the next 3 months (the patient regained her right handwriting skills). The patient's progress was followed up by a cardiologist, haematologist, pneumonologist and neurologist. In the echocardiography, hypertrophy of the right ventricle had decreased. Two months after her discharge from the hospital, her blood count showed eosinophilia 0% and absolute numbers of eosinophilia 0x103/uL. The follow-up MRI of the heart performed on February 2022, 6 months after the first MRI, showed significant improvement in both ventricular functions, with left and right ventricular volumes within normal limits and without enlargement. Myocardial hypertrophy was still visualized in the right ventricle and was more pronounced in the distal segment of the apical region, where the residual abnormal myocardial gadolinium enhancement with a subendocardial oedema had markedly decreased but was still persistent. The myocardial morphological lesion had markedly regressed. At the end of May 2022, the patient developed an oedema of the right upper eye lid. Tobradex (eye drops containing tobramycin and dexamethasone) were prescribed, but the oedema spread over the right side of the face and especially the right orbita during the next five days. The patient was hospitalized at the CCUH. Blood analyses showed eosinophilia 16.7%, leukocytes 10.74 x 103, erythrocytes 5x106 micro/L, thrombocytes 460 x 103 micro/L and CRP 1.61 mg/L. The ophthalmologist noted that the right eye was sensitive to the left and left downward view, and that there was restriction of movement to the upward view, but the left eye was mobile to a lesser extent. The left eye had a full range of movement. A conclusion of right sided pre-septal and post-septal cellulitis was made. The otolaryngologist detected that the mucous membrane was pink and slightly oedematous. To clarify the inpatient diagnosis, the patient underwent a biopsy of the inflammatory foci: in the ethmoid tissue there was constant lymphohistiocytic and eosinophilic inflammation with 30-50% eosinophilic ipsilateral infiltrate cells; granulomatous and chronic perivascular inflammation with eosinophils was found in the striated muscle tissue, which might be consistent with EGPA. Based on scientific articles, the early use of steroids (this patient received Medrol therapy) for a brief period could help to shorten hospitalization and prevent the progress of the inflammation. As the patient had Cushing's syndrome, and according to the bone marrow and blood tests, the consensus was to continue treatment with prednisolone (Medrol) orally 60 mg/day and, in parallel, to initiate pathogenetic therapy with anti-Il-5 antibody mepolizumab subcutaneously due to the relapsing course of the disease, long-lasting corticosteroid side effects and the suitability of the drug for idiopathic HES, L-HES phenotype and HES-eosinophilic granulomatosis with polyangiitis overlap.

churg–strauss syndrome, eosinophilic myocarditis, orbital involvement, paediatric hypereosinophilic syndrome, stroke

PMC8076683_01

Female

During the 2016 ZIKV outbreak in Merida, Mexico, a 27-year-old woman in the third trimester of pregnancy was referred to medical geneticist because multiple malformations detected in the fetus. Informed consent was obtained for sampling, clinical evaluations, and for the publication report. Exploring the medical records, she reported unquantified fever, preauricular nodes, pruritus and rash in the shoulder girdle and thorax in the first trimester when the pregnancy was unnoticed. No serological tests were performed for ZIKV at that time. Ultrasound was performed at 16.4 weeks of gestation with report of fetal growth within normal ranges; but at 23 weeks of gestation, the fetal hands were not identified. At 27.4 weeks of gestation, fetus was reported with microcephaly (DBP 58 mm); nuchal thickening, ventriculomegaly, hemisphere hypoplasia and cerebellar vermis were detected in the brain, and micrognathia, right radial aplasia, and arthrogryposis were also reported at that time. A stillbirth with generalized subcutaneous edema was obtained via cesarean section at 35 weeks of gestation. At physical exploration showed craniofacial disproportion, microcephaly, irregular anterior and lower posterior hairline. Posterior sloping of the forehead and hypertelorism were observed. The nasal bridge, the nostrils and the filtrum were normal. Retrognathia and normal oral cavity were found. The ears were cupped with low implantation and thickened helix. The shoulders were short, with internal rotation and presented limitation to abduction. The left upper limb presented an extended elbow with limitation to the reduction, pronation arm, flexed wrist, non-reducible hand with cyanotic coloration. The upper right limb was conformed only to the proximal third of the arm. At this level, soft tissue defect was found with the presence of an irregular cutaneous line, exposure of subcutaneous tissue and the humeral condyle, no tissue bleeding was detected (Figure 1). The lower extremities presented limitation to hip abduction, knee extension and flexion of both feet. The genitalia anatomy showed 1 cm penis and a complete rough scrotum without testes inside. On the skull x-ray, everted sutures and partial collapse of the cranial bones with a hypoplastic occipital was observed. The radiograph of the upper extremities shows a right humerus shorter than the left, with preserved of the distal region of the humerus (Figure 2). Computational axial tomography reported subcortical calcifications, lissencephaly, ventriculomegaly, and generalized cortical degeneration. The karyotype was normal, 46, XY. The serological test for toxoplasma, rubella, cytomegalovirus and herpes virus were negative in the mother and the patient. The RT-PCR for ZIKV/Dengue/Chikungunya in the patient's cerebrospinal fluid detected the presence of Zika viral RNA. Autopsy was not authorized.

zika virus, arthrogryposis, birth defects, congenital infection, disruption, microcephaly, sequence

PMC6718363_01

Male

A 70-year-old man was admitted to internal medicine department with complaints of heartburn and intolerable chest pain with irradiation to the left arm and shoulder, neck and back. Pain had appeared a day before during domestic physical activity. Based on positive troponine blood test, electrocardiography (ECG), echocardiography and standard clinical diagnostic measures the patient was diagnosed with: Coronary artery disease, non-ST segment elevation myocardial infarction of front-side and apex; Killip class II; heart failure class IV (NYHA classification); Grace scale 174 scores. The patient underwent primary coronarography, balloon angioplasty and left circumflex artery stenting. The time between admission and primary percutaneous coronary intervention (PCI) was 70 min. The patient tolerated the intervention well and was transferred from the IC unit to the internal medicine department ward on the second day after the PCI. On the 3rd day after breakfast the patient complained of severe diffuse abdominal pain and diarrhea. Clinical examination showed abdominal distention, active peristalsis and no signs of peritoneal irritation. Antispasmodic and nonsteroidal anti-inflammatory drugs did not cease the pain. Blood tests revealed leukocytosis of 21.2 x 10*12/L, alanine transaminase 49 IU/L, aspartate transaminase 89 IU/L, alkaline phosphatase 207 IU/L, D-dimer level of 500 ng/ml (laboratory test dynamics see Table 1). Abdominal ultrasound showed intense flatulence, no intraabdominal free fluid and no other pathology. Duplex scan was impossible due to poor visualization with bowel gas. In a view of this sudden diffuse continuous abdominal pain with no findings on clinical examination, patient's anamnesis data (age, myocardial infarction followed by vascular manipulation, hypertension, dyslipidemia) AMI was suspected. Then computed tomography with intravenous contrast was performed (Fig. 1). It revealed CT-signs of generalized abdominal aorta atherosclerosis and circular thrombus with 30 mm length in superior mesenteric artery right below its takeoff from the aorta. Small intestine was dilatated with horizontal liquid levels. The decision to perform superior mesenteric angiography with aspiration thrombectomy, percutaneous transluminal angioplasty and stenting was made. The time between abdominal pain onset and endovascular intervention was 8 h. Under local anesthesia with 0.5% lidocaine solution (5 ml), JR-4 6 F guide catheter (Vista Bright Tip, Cordis) was installed to the SMA through right femoral approach. The angiogram was performed showing proximal SMA occlusion in 35 mm from its arising (Fig. 2 (2.1)). 10,000 IU of heparin were administered intra-arterial. The guidewire (Hi-Torque Whisper ES, Abbott) was inserted through the occlusion into the distal segment of SMA (Fig. 2 (2.2)). Thrombus was aspired with extraction catheter (QuickCat, Spectranetics), and blood clots were removed (Fig. 3). During a control angiography, SMA was permeable; there was a stenosis and dissection of the artery in the proximal third. The coronary stent with a drug coating (3.5 x 23 mm, Abbott Xience) was positioned and expanded under the pressure of 14 atm to the dissection zone of the proximal part of the SMA. The control angiography showed a satisfactory result; residual stenosis and vessel dissection were not detected (Fig. 2 (2.3), (2.4)). The guidewire and catheter were removed; introducer was left until hemostasis was normalized. In total 200 ml of Ultravist contrast were introduced. Then the patient was transferred to ICU. The next day (4th in-hospital day) abdominal pain still persisted. Clinical examination showed abdominal distention, no peristalsis, no signs of peritoneal irritation. A diagnostic laparoscopy to exclude possible progression of bowel ischemia and recurrent thrombosis, and also in order differentiate with other possible reasons of abdominal pain, was performed. The operation revealed the dilated small bowel, but there seemed to be no necrotic bowel macroscopically. To confirm adequate bowel perfusion and viability a 0.25 mg of ICG was injected. We observed the bowel using the OPAL1 System (Karl Storz) (Fig. 4). The entire intestine wall showed satisfactory fluorescence emission, indicating no ischemia and necrotic changes. No other pathological changes in the abdominal cavity were detected. The patient tolerated the surgery well and was transferred to the intensive care unit where, together with cardiologists, we carried out infusion, cardioprotective, detoxification and antibiotic therapy. On the day 6 after SMA stenting (9th in-hospital day), the patient was prescribed enteral nutrition. On the 15th day the patient was discharged in a good state of health with medical recommendations. We had a confirmation that he was alive at 4 months after the operative treatment of AMI.

acute mesenteric ischemia, case report, endovascular intervention, indocyanine green imaging

PMC4077035_01

Female

A 59-year-old Chinese woman was admitted to the hospital with the chief complaint of a progressively enlarging mass in the left thoracic wall over the past seven months. At the initial examination, the tumor slightly protruded from the chest wall with the 2 cm in diameter, and gradually grew over in the past several months. In one month ago, she underwent a percutaneous transthoracic needle biopsy of the mass in another hospital. Following the puncture, the tumor promptly increased significantly in size, impacting blood flow to the left arm. On this admission, we conducted a physical examination and palpated the soft painless left lateral chest wall large mass with the 9 cm in diameter. She denied smoking history and had no family history of lung cancer. A review of her systems was noncontributory. The results of a peripheral blood count, baseline serum chemistry screening, and urinalysis were normal on admission, as were tumor biomarker tests and a purified protein derivative test for tuberculosis. Enhanced chest computed tomography (CT) with three-dimensional reconstruction of the ribs showed an enormous soft tissue mass in the left chest wall (Figure 1), which extended into the left lung and mediastinum, exerted pressure on the heart, skewing it to the right, and had eroded the middle portion of the fifth rib. The density of the tissue mass was uneven and a necrotic area was visible. The maximum cross-sectional diameter of the tumor mass was 13.3 x 15.7 cm2. Moreover, an ECT bone scan also demonstrated the destruction of the middle of the fifth rib. In additional, a CT scan of her abdomen and magnetic resonance imaging of her brain were all normal. Her bronchial tree also appeared normal on bronchoscopic examination, with no indication of malignancy in the biopsy and washings procured. After anesthesia and a double-lumen intubation had been established, a left posterolateral incision was performed. The chest wall tumor invaded the left upper pulmonary lobe as well as the fourth, fifth, and sixth ribs. The tumor had eroded the middle portion of the fifth rib; the heart was impacted by the tumor and mediastinal pleural adhesions were present. We freed-up the outer margin of the tumor and excised the fourth, fifth, and sixth ribs. Intercostal tissue was included with a margin over 5 cm. We extracted the tumor and the invaded left upper lobe of lung to remove the pressure on the heart. We then performed the left upper pulmonary lobectomy. Finally, we joined four 10 x 10 cm2 polyester surgical patches (knitted type) into one 20 x 20 cm2 patch and this patch was sutured to the chest wall defect for chest wall reconstruction. The neoplasm, which was removed by surgical resection, weighed 2.080 kg and was 20 cm x 18 cm x 9 cm in size, as shown in Figure 2A. There were multiple nodules on its surface and a cross section of the tumor was honeycombed in appearance. The pathology report described a giant cell malignant fibrous histiocytoma cell tumor (Figure 2B), with the immunohistochemistry of CD68 (+), Vimentin (+), SMA, CK and S-100 (-) (Figure 2C), invading the left upper lung lobe and the middle of the fourth, fifth, sixth ribs, with no metastases to the mediastinal lymph nodes. Her postoperative course was uneventful. She was discharged 12 days after surgery and showed no signs of local recurrence or distal disease at an 8-month follow-up visit (Figure 3).

PMC9720252_01

Female

A 43-year-old woman with a history of acute myeloid leukemia was admitted to our hospital in July 12, 2020 for repeated fever during the previous 2 months, and a persistent fever for the previous 4 days. Two months previously, she presented with a fever, cough, and expectoration. At that time she was diagnosed with "invasive pulmonary fungal disease" and was given oral voriconazole and biapenem as empirical therapy. Her condition improved gradually after this treatment. Four days prior to the current admission, she was admitted because of a relapse of fever, with a body temperature of 38.6 C. A physical examination showed that her underarm temperature was 38.6 C, pulse was 108 beats/min, breathing was 25 breaths/min, and blood pressure was 109/67 mmHg. There was dullness on lung percussion and strong vocal fremitus with fine crackles in the left lung. Laboratory investigations showed a white blood cell count of 3.61x109 per L (normal: 3.5-9.5), red blood cell count of 3.22x1012 per L (normal: 3.8-5.1), hemoglobin concentration of 112g/L(normal: 110-150 g/l), platelet count of 268x109 per L (normal: 125-350), and absolute neutrophil count of 2.02x109 per L (norma: 1.8-6.3). In addition, the 1,3-beta-D-glucan level was normal, and an aspergillus antigen test for serum galactomannan was negative. The liver function, renal function, and electrolyte levels were all normal. There were negative results for antinuclear antibody (ANA), extractable nuclear antigen (ENA), antineutrophil cytoplasmic antibodies (ANCA), TB spot test and TB blood culture. Computed tomography (CT) on July 14, 2020 indicated consolidation in the left lower lung ( Figure 1 ). Therefore, we made a preliminary diagnosis of CAP with acute myeloid leukemia. As the empirical anti-infective therapy, we administered biapenem (0.3 g, Q6H), but her condition did not improve. On day 3 after admission, the urinary antigen tests for Streptococcus pneumonia and anti-Legionella antibodies were negative. To identify the etiology, we collected BALF and tested it with mNGS using the MiSeq platform (Illumina). The results indicated 46 sequence readings of Legionella pneumophila ( Table 1 ) with a coverage of 0.07% ( Table 2 ). Sequencing of 16s rRNA sequencing using Nanopore GridION also detected the 17 L.pneumophila sequences in the same DNA sample. Combined with her medical history, clinical symptoms, physical signs, results from auxiliary examinations, and mNGS, we diagnosed the patient with Legionella pneumonia and adjusted the treatment plan to intravenous moxifloxacin and azithromycin. After 14 days of treatment in the hospital, the patient's fever had resolved, and she was discharged, and prescribed antimicrobial agents as sequential oral therapy. A CT follow-up after one month (August 16, 2020) indicated the pulmonary lesions in the left lower lung were significantly absorbed ( Figure 2 ). Records of her white blood cell count, C-reactive protein, body temperature, and other results indicated gradual improvements during her hospital stay ( Figure 3 ).

legionella pneumonia, case, literature review, metagenomic next-generation sequencing, pathogen diagnosis

PMC7175989_01

Male

A 74-year-old male was admitted to the Intensive Care Unit of our hospital with respiratory failure and was diagnosed with SARS. He was 9.5 years post orthotopic liver transplant for alcoholic cirrhosis. His current immunosuppression was cyclosporin 100 mg twice daily and prednisone 5 mg/day. His other medication included insulin and trimethoprim/sulfamethoxazole prophylaxis. The patient visited Hospital A for an outpatient podiatry appointment 5 days prior to the onset of his illness. He spent most of the day in the hospital but no specific exposure to an ill person was recounted. Hospital A was subsequently quarantined by the Public Health authority due to an unrecognized exposure and outbreak of SARS in this facility. Numerous people, of whom the majority were health care workers, developed SARS at this facility. Approximately 5 days after his outpatient appointment at Hospital A, the patient developed high fever, chills, nonproductive cough, and myalgias. He subsequently developed progressive shortness of breath and, after visiting his family physician, presented again to the Hospital A emergency. Due to impending respiratory failure, he was immediately transferred to the intensive care unit of another facility (Hospital B). In Hospital B, he required mechanical ventilation and was commenced on Ceftriaxone and levofloxacin for community-acquired pneumonia. Full isolation precautions were not used at this time as SARS was not suspected. Within 24 h, since he was a transplant patient, he was transferred to our facility's intensive care unit for ongoing care. On arrival at our hospital, the patient was placed in negative-pressure isolation with full precautions due to the suspicion of SARS. On admission, he was febrile (38.8 C) and hypotensive, requiring inotropic therapy for blood pressure support. His initial laboratory investigations were as follows: hemoglobin was 87 g/L; total white blood cell count was 2.0 bil/L with a lymphocyte count of 0.2 bil/L; platelets were 74 bil/L. His AST was slightly elevated at 51 U/L but ALT and bilirubin were normal. His arterial blood gas on 100% FiO2 was pH 7.45, PO2 57 mmHg, PCO2 34 mmHg. Chest radiograph demonstrated bilateral airspace and interstitial disease, more prominent on the right side ( Figure 1). Investigations including a broncho-alveolar lavage (BAL) were performed and he was treated with ceftriaxone and azithromycin. In addition, he received ribavirin 2 g intravenously loading and 1 g every 6 h intravenously for presumptive SARS. His cyclosporin was discontinued. The hospital course was complicated by progressive hypoxemia, and multisystem organ failure. Death occurred on day 18 of his illness. A BAL at the time of admission was negative for routine bacterial, fungal and mycobacterial stains and culture. Direct fluorescent antibody stains of BAL fluid were negative for influenza, parainfluenza, respiratory syncytial virus and adenovirus. Culture was negative for routine respiratory viruses, cytomegalovirus, and Legionella. Special stains for Legionella and Pneumocystis were negative, as were PCR for Mycoplasma and Chlamydia. CMV antigenemia, and urine Legionella antigen were negative. A coronavirus-specific RT-PCR was performed on BAL fluid and was positive. We obtained an amplicon of the expected size of 216 bp, which was sequenced. The sequence was identical to that found in another patient with SARS reported previously. The sequence internal to the primers was 100% homologous to the expected segment of the pol 1b coding region of the SARS coronavirus complete sequence from a Canadian isolate (BCCA Genome Science Center, British Columbia; GenBank accession number AY274119). We also performed RT-PCR for coronaviruses on plasma samples and peripheral blood mononuclear cells purified by buffy coat obtained on the first and fifth day of hospitalization, but coronavirus was not detected in these samples. The patient had not been in isolation until reaching our facility. During the course of his illness, several persons were exposed. These included his wife and two children, family physician (FP), FP's office staff and several other patients in the waiting room. At Hospital A, due to a large outbreak, it was not possible to determine those exposed as a direct result of this patient as several other SARS exposures had occurred at the same time. However, hundreds of individuals from this hospital were placed in isolation. The patient had two visitors during his emergency visit at Hospital A. Exposure also occurred in 11 individuals involved in transfer of the patient to hospital B and 68 staff at Hospital B, primarily those involved in the patient's ICU care. Subsequent illness compatible with suspect or probable SARS occurred in 10 persons: the patient's wife, family physician, two visitors at Hospital A, and six staff at Hospital B, resulting in one death due to SARS. This is likely an underestimate as we were unable to determine how many at Hospital A were exposed specifically due to this patient. Due to this outbreak of SARS in the greater Toronto area, all transplant programs in the city were temporarily closed. Prior to re-starting the transplant program, concern arose about unrecognized SARS in potential cadaveric organ donors, with the largely unknown potential for spread to multiple recipients. A donor may be at risk of incubating SARS or have active SARS due to exposure in a health care facility or specific epidemiological exposure within the community. Therefore, a donor SARS screening tool was developed and is shown in Figure 2. The screening tool is based on information regarding potential hospital exposure, clinical symptoms, and contact history. In section A, the category of the donor institution is listed. Hospital categorization is based on Canada's Ministry of Health guidelines and ranges from category 0 (no SARS cases in institution) to category 3 (SARS exposure and further spread from the exposed person to others) (Figure 2). This information is readily available from the infection control practitioner at a given institution. Section B is based on determining if any clinical or radiological evidence of SARS is present. Section C evaluates contact exposure to either someone with SARS (suspected or probable) or due to travel to areas with high risk of SARS exposure based on current governmental travel advisories (available at www.cdc.gov in the United States). With the above information, donors can be classified into high risk, intermediate (or indeterminate) risk, or low risk, based on categories shown at the bottom of Figure 2. Since implementation of the screening tool, our practice has been to accept low-risk donors and intermediate-risk donors, and generally exclude high-risk donors. This is done in discussion with the transplant team and the recipient. The screening tool can be modified for living related donors by labeling section A as category 0 if the donor has not visited any hospital within the previous 10 days. We have also implemented a modified version of this screening tool for potential recipients, to ensure that a patient incubating SARS is not inadvertently transplanted.

PMC8299116_01

Male

A 33-year-old man presented repeat seizures and progressive headache for six months. A complete blood count (CBC) showed: hemoglobin 123g/L, white blood cell count 7.73 x 109/L, and percentage of eosinophil 0.009. Liver function showed: alanine transaminase (ALT) 92.8 U/L, aspartate aminotransferase (AST) 44.9U/L, alkaline phosphatase (ALP) 135.1U/L, gamma-glutamyl transferase (gamma-GT) 313.4 U/L, total bilirubin (TBil) 22.7 mmol/L, direct bilirubin (DBil) 19.4 mmol/L. Head MRI (Figure 1) showed multiple masses with edema. Lung and abdominal CT (Figure 2) presented with several lesions in bilateral lungs, liver and right adrenal gland. Bacterial, tuberculosis and fungal infection were excluded by CSF examination. Serological evaluation of multiple parasite antigen by ELISA were applied. Cysticercosis Immunoglobulin G (IgG) and liver hydatid IgG antibody were both positive. Repeated target biopsy on the masses in the lung and liver showed fibrous connective tissue without positive findings. In addition, we performed positron emission tomography with fluorodeoxyglucose integrated with CT (18F-FDG PET/CT) that showed uptake in all masses with a maximum standardized uptake value of 7.2. Accordingly, it was still hard to draw a definitive pathogenic diagnosis. Therefore, the next-generation sequencing of CSF was performed. The CSF was collected according to standard procedures, and DNA was extracted directly from the sample with TIANamp Micro DNA Kit. The extracted DNA was sonicated to a size of 200-300 bp (Bioruptor Pico protocols). The DNA libraries were constructed and sequencing using the BGISEQ-100 platform. After removing human sequences, the remaining sequencing data were aligned to the microbial databases and detected 161 nucleic acid sequences of E. multilocularis (Table 1, E. multilocularis sequences which detected were provided as Supplementary Material). On this basis, the patient was diagnosed as having AE. Consequently, the patient was recommended a 1-year albendazole therapy. During 1 year of follow-up, symptoms and neurological signs were not aggravated, with decreased seizure frequency. Follow-up CT after 1 year of albendazole treatment revealed slightly decreased multiple lesions and partly relieved surrounding edema in brain. The lesion in the liver (red arrow) was evidently diminished and calcification was slightly increased. The thickened right adrenal gland (yellow arrow) has obviously decreased in size (Figure 3).

echinococcus multilocularis, adrenal gland, alveolar echinococcosis, diagnose, next-generation sequencing

Lung and abdominal CT images of the patient. Multiple Lesions were found in bilateral lung.

PMC8299116_01

Male

A 33-year-old man presented repeat seizures and progressive headache for six months. A complete blood count (CBC) showed: hemoglobin 123g/L, white blood cell count 7.73 x 109/L, and percentage of eosinophil 0.009. Liver function showed: alanine transaminase (ALT) 92.8 U/L, aspartate aminotransferase (AST) 44.9U/L, alkaline phosphatase (ALP) 135.1U/L, gamma-glutamyl transferase (gamma-GT) 313.4 U/L, total bilirubin (TBil) 22.7 mmol/L, direct bilirubin (DBil) 19.4 mmol/L. Head MRI (Figure 1) showed multiple masses with edema. Lung and abdominal CT (Figure 2) presented with several lesions in bilateral lungs, liver and right adrenal gland. Bacterial, tuberculosis and fungal infection were excluded by CSF examination. Serological evaluation of multiple parasite antigen by ELISA were applied. Cysticercosis Immunoglobulin G (IgG) and liver hydatid IgG antibody were both positive. Repeated target biopsy on the masses in the lung and liver showed fibrous connective tissue without positive findings. In addition, we performed positron emission tomography with fluorodeoxyglucose integrated with CT (18F-FDG PET/CT) that showed uptake in all masses with a maximum standardized uptake value of 7.2. Accordingly, it was still hard to draw a definitive pathogenic diagnosis. Therefore, the next-generation sequencing of CSF was performed. The CSF was collected according to standard procedures, and DNA was extracted directly from the sample with TIANamp Micro DNA Kit. The extracted DNA was sonicated to a size of 200-300 bp (Bioruptor Pico protocols). The DNA libraries were constructed and sequencing using the BGISEQ-100 platform. After removing human sequences, the remaining sequencing data were aligned to the microbial databases and detected 161 nucleic acid sequences of E. multilocularis (Table 1, E. multilocularis sequences which detected were provided as Supplementary Material). On this basis, the patient was diagnosed as having AE. Consequently, the patient was recommended a 1-year albendazole therapy. During 1 year of follow-up, symptoms and neurological signs were not aggravated, with decreased seizure frequency. Follow-up CT after 1 year of albendazole treatment revealed slightly decreased multiple lesions and partly relieved surrounding edema in brain. The lesion in the liver (red arrow) was evidently diminished and calcification was slightly increased. The thickened right adrenal gland (yellow arrow) has obviously decreased in size (Figure 3).

echinococcus multilocularis, adrenal gland, alveolar echinococcosis, diagnose, next-generation sequencing

Lung and abdominal CT images of the patient. Multiple Lesions were found in bilateral lung.

PMC8299116_01

Male

A 33-year-old man presented repeat seizures and progressive headache for six months. A complete blood count (CBC) showed: hemoglobin 123g/L, white blood cell count 7.73 x 109/L, and percentage of eosinophil 0.009. Liver function showed: alanine transaminase (ALT) 92.8 U/L, aspartate aminotransferase (AST) 44.9U/L, alkaline phosphatase (ALP) 135.1U/L, gamma-glutamyl transferase (gamma-GT) 313.4 U/L, total bilirubin (TBil) 22.7 mmol/L, direct bilirubin (DBil) 19.4 mmol/L. Head MRI (Figure 1) showed multiple masses with edema. Lung and abdominal CT (Figure 2) presented with several lesions in bilateral lungs, liver and right adrenal gland. Bacterial, tuberculosis and fungal infection were excluded by CSF examination. Serological evaluation of multiple parasite antigen by ELISA were applied. Cysticercosis Immunoglobulin G (IgG) and liver hydatid IgG antibody were both positive. Repeated target biopsy on the masses in the lung and liver showed fibrous connective tissue without positive findings. In addition, we performed positron emission tomography with fluorodeoxyglucose integrated with CT (18F-FDG PET/CT) that showed uptake in all masses with a maximum standardized uptake value of 7.2. Accordingly, it was still hard to draw a definitive pathogenic diagnosis. Therefore, the next-generation sequencing of CSF was performed. The CSF was collected according to standard procedures, and DNA was extracted directly from the sample with TIANamp Micro DNA Kit. The extracted DNA was sonicated to a size of 200-300 bp (Bioruptor Pico protocols). The DNA libraries were constructed and sequencing using the BGISEQ-100 platform. After removing human sequences, the remaining sequencing data were aligned to the microbial databases and detected 161 nucleic acid sequences of E. multilocularis (Table 1, E. multilocularis sequences which detected were provided as Supplementary Material). On this basis, the patient was diagnosed as having AE. Consequently, the patient was recommended a 1-year albendazole therapy. During 1 year of follow-up, symptoms and neurological signs were not aggravated, with decreased seizure frequency. Follow-up CT after 1 year of albendazole treatment revealed slightly decreased multiple lesions and partly relieved surrounding edema in brain. The lesion in the liver (red arrow) was evidently diminished and calcification was slightly increased. The thickened right adrenal gland (yellow arrow) has obviously decreased in size (Figure 3).

echinococcus multilocularis, adrenal gland, alveolar echinococcosis, diagnose, next-generation sequencing

Lung and abdominal CT images of the patient. and the liver.

PMC8299116_01

Male

A 33-year-old man presented repeat seizures and progressive headache for six months. A complete blood count (CBC) showed: hemoglobin 123g/L, white blood cell count 7.73 x 109/L, and percentage of eosinophil 0.009. Liver function showed: alanine transaminase (ALT) 92.8 U/L, aspartate aminotransferase (AST) 44.9U/L, alkaline phosphatase (ALP) 135.1U/L, gamma-glutamyl transferase (gamma-GT) 313.4 U/L, total bilirubin (TBil) 22.7 mmol/L, direct bilirubin (DBil) 19.4 mmol/L. Head MRI (Figure 1) showed multiple masses with edema. Lung and abdominal CT (Figure 2) presented with several lesions in bilateral lungs, liver and right adrenal gland. Bacterial, tuberculosis and fungal infection were excluded by CSF examination. Serological evaluation of multiple parasite antigen by ELISA were applied. Cysticercosis Immunoglobulin G (IgG) and liver hydatid IgG antibody were both positive. Repeated target biopsy on the masses in the lung and liver showed fibrous connective tissue without positive findings. In addition, we performed positron emission tomography with fluorodeoxyglucose integrated with CT (18F-FDG PET/CT) that showed uptake in all masses with a maximum standardized uptake value of 7.2. Accordingly, it was still hard to draw a definitive pathogenic diagnosis. Therefore, the next-generation sequencing of CSF was performed. The CSF was collected according to standard procedures, and DNA was extracted directly from the sample with TIANamp Micro DNA Kit. The extracted DNA was sonicated to a size of 200-300 bp (Bioruptor Pico protocols). The DNA libraries were constructed and sequencing using the BGISEQ-100 platform. After removing human sequences, the remaining sequencing data were aligned to the microbial databases and detected 161 nucleic acid sequences of E. multilocularis (Table 1, E. multilocularis sequences which detected were provided as Supplementary Material). On this basis, the patient was diagnosed as having AE. Consequently, the patient was recommended a 1-year albendazole therapy. During 1 year of follow-up, symptoms and neurological signs were not aggravated, with decreased seizure frequency. Follow-up CT after 1 year of albendazole treatment revealed slightly decreased multiple lesions and partly relieved surrounding edema in brain. The lesion in the liver (red arrow) was evidently diminished and calcification was slightly increased. The thickened right adrenal gland (yellow arrow) has obviously decreased in size (Figure 3).

echinococcus multilocularis, adrenal gland, alveolar echinococcosis, diagnose, next-generation sequencing

Lung and abdominal CT images of the patient. The right adrenal gland (yellow arrow) was obviously thickened (D).

PMC8072118_01

Female

A 63-year-old female patient was presented to hospital, in March 2019, with repeated dizziness and visual impairment. A computerized tomography/magnetic resonance imaging (CT/MRI) revealed a mass lesion in the left occipital lobe. In addition to the brain mass, positron emission tomography (PET)-CT also indicated a hyper-metabolic mass in the left thyroid as well as some opaque mottled shadows and pulmonary nodules in the lung ( Figure 1 ). Further ultrasound revealed multiple thyroid nodules, the largest calcified one located in the left thyroid and measuring 41*30*44 mm. The patient was subjected to brain tumor resection. IHC studies of the resected brain tumor positively identified cytokeratin 7 (CK7), napsin A and TTF-1, but TG was negative ( Figures 2A-C ; Details on IHC methods were showed in Supplementary Data ). Fine-needle aspiration (FNA) of the thyroid lesion identified clusters of undifferentiated tumor cells. Based on these results, the pathologist hypothesized that the lesions in brain and thyroid had migrated from undifferentiated lung adenocarcinoma. However, the NGS results from FSZ-Thyroid NGS Panel V1 (Genetronhealth) revealed TERT promoter mutation, RET fusion and TP53 mutation in the brain lesion ( Table 1 and Supplementary Figure 1 ). The details of NGS were shown in the Supplementary Data . These mutations combo are indicative of undifferential thyroid cancer, and rarely occur in lung cancers. Since the patient did not consent to further surgery, we did not obtain any operation samples on the thyroid or lung for further analysis. In addition, we positively detected PAX8 through IHC ( Figure 2D ). This factor is negative in lung adenocarcinoma, but always positive in thyroid cancer. Based on these results (positive PAX8, negative TG, cytopathology of thyroid FNA and the special genomic features), we concluded that the patient had undifferential thyroid cancer, with lung and brain metastasis. Due to the patient with brain metastasis and without BRAF mutations, RET-targeted BLU-667 clinical trial and BRAF inhibitor were not suitable for this patient. Therefore, indication therapy or off-label treatment were needed for this patient. After comprehensive consideration, we administered anlotinib, a novel multi-kinase inhibitor that has also been found to block RET. One month after treatment, the pulmonary nodules were found to be controlled, thyroid tumor drastically reduced and tracheal compression relieved ( Figure 3 ). Unfortunately, the patient stopped anlotinib treatment, after three months, owing to financial constraints. Only two weeks after discontinuation of anlotinib, the patient went back to the hospital exhibiting breathlessness and cough. A CT scan revealed a large mass outbreak in her lungs, and she eventually died of respiratory failure.

ret fusion, tert promoter mutation, anlotinib, next-generation sequencing, tumor origin, undifferential thyroid cancer

PMC7548324_01

Female

Systemic involvement was reported in 28/35 cases (80.0%). Patients with an abnormal chest study (fibrosis, granuloma, calcifications and other findings) but no mention of confirmed pulmonary disease by the original authors were not considered to have lung disease. Also, we considered miliary tuberculosis only when the authors used the term "miliary". Cases with central nervous system (CNS), abdominal, peritoneal, adrenal and pericardial involvement were reported separately. Confirmed pulmonary tuberculosis occurred in 15/35 (42.8%) of cases, miliary tuberculosis in 7/35 cases (20.0%), CNS involvement in 2/35 cases (5.7%) and abdominal and peritoneal involvement in 2/35 cases (5.7%). There was 1 case of TB adrenalitis and 1 case of TB pericarditis. All patients were started on antituberculous treatment (ATT). Treatment regimens were variable and medications included rifampin, isoniazid, pyrazinamide and ethambutol, among others. Case-by-case description of the ATT is available in Table 3. Death was reported in one case. This particular case was reported by Ni et al in 1982. The patient was a 30-year-old female with remote pulmonary tuberculosis who was diagnosed with syphilitic uveitis on presentation. The eye was enucleated and pathology revealed Langerhans giant cells (LGCs) which can be found in both TB and syphilis. The TB etiology was therefore not recognized and the patient died 6 months after presentation from generalized tuberculosis. In the remaining cases, patients were either referred to as alive or no mention of death was made by authors.

endophthalmitis, panophthalmitis, panuveitis, systematic review, tuberculosis

PMC7548324_02

Male

TB endophthalmitis was diagnosed in 18/44 (40.9%) of cases and TB panophthalmitis was seen in 25/44 (56.8%) of cases. One case reported the final diagnosis as "ocular tuberculosis". Ocular outcomes were generally poor with 36/43 cases (83.7%) requiring enucleation, evisceration or exenteration. Pre-phthisis or phthisis bulbi was reported in 3 cases (7.0%), final visual acuity 20/200 and worse was seen in 3 cases (7.0%) and a single case reported visual acuity better than 20/200 (2.3%). Only two authors reported a favorable visual outcome. In the case reported by Hase et al, visual acuity improved from light perception at presentation to 20/200 at 13 months' follow-up. The patient was treated with prompt PPV soon after presentation and was started on corticosteroids and ATT before culture results, based on the miliary lung disease discovered on CT scan. In the report by Yaghoubi et al, a 45-year-old man with concomitant TB pericarditis underwent a prompt tap-and-inject of vancomycin and amikacin. Oral corticosteroids were started early given the concomitant cardiac disease. Quadruple ATT could not be maintained for the total duration of treatment but isoniazid and ethambutol were given for 18 months. The visual acuity improvement from 20/630 to 20/32 was maintained for up to 3 years. Table 8 summarizes the best reported method of diagnosis and microbiologic findings. A TB etiology was confirmed on histopathologic specimen (HPS) after removal of the eye in 32/44 cases (72.7%). The earliest source of TB confirmation came from the vitreous (PPV or tap) in 6/44 cases (13.6%) and via an AC tap in 3/44 cases (6.8%). The studies reported a variety of microbiologic studies including microscopy to look for acid-fast bacilli (AFB) and LGCs. Mycobacterial cultures, PCR and genomic deletion analysis were also used. Microscopy revealed AFB in 33/43 cases (76.7%) and LGCs only in 7/43 cases (16.3%). Mycobacterial cultures from vitreous, anterior chamber or HPS were reported in 18/43 cases (41.9%) and were positive in 14/18 cases (77.8%). PCR was reported in 12/43 cases (27.9%) and was positive in all cases. Detailed case-by-case descriptions are available in Table 3. The most specific reported microbiologic finding was M. tuberculosis in 19/44 cases (43.2%), AFB in 17/44 cases (38.6%), LGCs in 6/44 cases (13.6%) and M. bovis in 1/44 case (2.3%). One case from 2006 reported "TB etiology" as their final microbiologic finding.

endophthalmitis, panophthalmitis, panuveitis, systematic review, tuberculosis

PMC10094453_01

Female

A 31-year-old woman felt epigastric discomfort without any obvious cause, along with glutted, nausea and vomit on December 28, 2018. She went to hospital two days later and treated with acid-inhibitory drug. However, there was no improvement with the patient. She underwent a gastroscopy showing chronic gastritis on January 4, 2019 and taken omeprazole and domperidone. There was also no remission. On January 7, 2019, she felt tolerable abdominal pain without any treatment. Then she felt abdominal pain intensified along with anus stopping exhaust and defecate on the next day. The patient went to the emergency room and taken a series of examinations. Blood routine examination showed leukocyte 7.4*10^9/L, neutrophil 80%, hemoglobin 94g/L. Routine urine test showed urine protein (++), ketone body (+), and occult blood (-). Other examinations such as blood electrolytes, abdominal elevation film, and color Doppler ultrasound of liver, bile, pancreas, spleen, and urinary system were normal. The patient felt better after treated by analgesia. The next day, severe abdominal pain attacked the patient again. On examination, the urine pregnancy experiment was negative and the abdominal computerized tomography (CT) scan was also normal. The abdomen was soft, and there was tenderness in hypogastrium without rebound pain and muscle tension. She was treated by enema and anti-infection with no anesis. A repeat blood routine examination showed leukocyte 9.9*10^9/L, neutrophil 84.2%, hemoglobin 102g/L. Liver function showed abnormal liver function (alanine transaminase [ALT] 401U/L, aspartate transaminase [AST] 77 U/L, total bilirubin [TB] 30.8umol/L, direct bilirubin [DB] 2.6 umol/L, indirect bilirubin [IB] 28.2 umol/L, glutamyl transpeptidase [GGT] 138 U/L). Routine urine test and gynecological sonography provided no positive result. As the patient's symptoms could not be improved and cause was unclear, she presented to the emergency department at our hospital on January 11, 2019. When in our hospital, her abdominal pain was worse with anus stopping exhaust defecate. On examination, the vital signs were normal. The blood routine examination showed leukocyte 14.8*10^9/L, neutrophil 88.1%, hemoglobin 100g/L. The abdominal CT scan revealed intestinal obstruction and small amount of pelvic effusion (Figure 1A-C). The electrocardiography was sinus rhythm. A diagnosis of acute intestinal obstruction was made, and she was dealt with ambrosia, anti-inflammation, acid-inhibitory, spasmolysis, and analgesia. That evening, the abdominal pain was recurrent and markedly increased, and the peregoric, such as dezocine or tramadol hydrochloride could remit briefly. Later, imageological examination of superior mesenteric blood vessels reconstruction was made, which showed no abnormal change in the blood vessels. The emergency department also could not get a definitive diagnosis, and the patient was transferred to colorectal surgery. On examination, the temperature was 37.2 C, the blood pressure was 131/83mmHg, the pulse was 71/min, and breathe was 20/min. There was pressing pain in the hypogastrium and the bowel sound was weak; the remainder of the examination was normal. The primary diagnosis was intestinal obstruction and the patient was treated with fast, anti-infection, acid-inhibitory, inhibition of enzyme, spasmolysis, and nutrition support. Magnesium sulfate and racolamine hydrochloride could relieve the abdominal pain, while the dezocine could not. On January 13, 2019, A repeat blood routine examination showed leukocyte 12.1*109/L, neutrophil 83.9%, hemoglobin 94g/L. Liver function showed abnormal liver function (ALT 181.2 U/L, AST 32 U/L, TB 23.3umol/L, DB 9.6 umol/L, GGT 138 U/L). The infectious disease indicators were all normal. Repeated severe abdominal pain attacked the patient today and magnesium sulfate helped her momentarily. The patient defecated today. Then she was treated with enema and taken for an electronic colonoscopy with nothing unusual. Up to now, the course of the disease continued for 16 days without a definite diagnosis. The common causes of acute abdominal diseases, such as gastrointestinal perforation, acute cholecystitis, acute pancreatitis, gynecological disease, and urologic diseases were all excluded. A series of test results mentioned above showed anemia and abnormal liver function. So we should consider the rare cause of abdominal pains, such as Porphyria, abdominal epilepsy, herpes zoster, heavy metal poisoning, and so on. We have made the physical examination carefully and found no herpes, so the herpes zoster was excluded. The electroencephalogram was normal and the abdominal epilepsy was not considered. Then, we took the patient's urine and place it in the sun for an hour without color change. So the Porphyria was also excluded. Blood levels of heavy metals were detected and the lead was 463.17 microg/L, which was very high (normal value was less than 100 microg/L). Therefore, the diagnosis of lead poisoning was made. The patient was treated with intravenous drip of calcium sodium edentate. The frequency of abdominal pain decreased gradually. She felt pain once a day on January 15 and 16. Later, she felt comfortable and resumed eating. Test results indicated an improvement in liver function. A week later, the blood level of lead dropped to 443.79 microg/L. According to the treatment guidelines, she should continue to receive intravenous drip of calcium sodium edentate. In addition, we have also paid attention to the source of lead poisoning. Combing the common causes of lead poisoning and living habit of the patient, we focused on a set of cosmetics without trademark (Figure 1D). She have used the cosmetics for more than half a year and got a very good whitening effect. We test the lead content of this cosmetic and found that the lead concentration was 65.3mg/kg, which was higher than the national safety standard significantly. Therefore, we thought this set of cosmetics was the cause of lead poisoning. She stopped using this set of cosmetics immediately.

abdominal pain, acute abdomen, calcium sodium edentate, lead poisoning

PMC8130703_01

Male

A 41-year-old male from Bangladesh presented to our hospital with complaints of dry cough, intermittent episodes of fever for the past 2 months, and weight loss of 17 kg over the previous 2 months. He was diabetic and had been on oral hypoglycemic agents and insulin for the past 1 year. He had no significant travel history to endemic regions. On presentation to our hospital, he was febrile with stable vitals. On examination, he was found to have swelling around the right knee joint which was warm to touch and with restricted movements (120 ). Laboratory test results showed an elevated serum C-reactive protein level of 165 mg/dl, elevated erythrocyte sedimentation rate of 93 mm/h, and normal white blood cell count. The differential diagnoses considered were tuberculosis, infective endocarditis, and malignancy. Two-dimensional echo was normal with no evidence of any valvular vegetations. Chest X-ray showed patchy inhomogeneous opacities in both lower zones and trace left pleural effusion. He was put on empirical antibiotics, but continued having fever with increase in swelling of joints. CT chest was acquired, which revealed multiple patchy alveolar opacities in the bilateral upper and right middle lobes with adjacent ground glassing, mild bilateral pleural effusion, and few reactive mediastinal lymph nodes. Ultrasound of the knee showed effusion and the fluid was aspirated. Blood and joint aspiration fluid were sent for microbiological cultures both of which grew B. pseudomallei. Since the organism was known for its multifocal involvement, an F-18 FDG PET/CT was planned. F-18 FDG PET/CT [Figure 1] revealed mildly FDG-avid fibrocavitatory changes in the apical segment of the right upper lobe (maximum standardized uptake value [SUVmax] 2.5) [Figure 2], non-FDG-avid nodules in the left lung, hypermetabolic subcarinal and left hilar lymph nodes [Figure 3], hypermetabolic hypodense lesion in segment VIII of the liver (size 1.0 cm x 1.2 cm SUVmax 2.6), hypermetabolic collection in the pericecal region (size 1.2 cm x 2.7 cm SUVmax 4.0) [Figure 4], effusion with FDG uptake in the right knee joint (SUVmax 4.7), and focal hypermetabolism noted in the left proximal tibia (SUVmax 3.4) [Figure 5]. He was started on ceftazidime 50 mg/kg Q6H for 3 weeks and levofloxacin 750 mg and cotrimoxazole 960 mg planned for 3 months. On follow-up after 1 month, his symptoms had come down, he was afebrile, and he had gained weight.

burkholderia pseudomallei, f-18 fludeoxyglucose positron emission tomography/computed tomography, fever of unknown origin, melioidosis, septic arthritis

PMC2821394_01

Male

A 49-year-old Caucasian man developed a cough in early 2004. A chest X-ray revealed bilateral hilar lymphadenopathy, confirmed by thoracic computed tomography (CT) scan. He had no other symptoms. A diagnosis of sarcoidosis was considered, but his symptoms were thought insufficient to warrant treatment. In July 2004, he developed numbness and pain behind the right knee which gradually spread to the lower back, right buttock and posterior thigh. Upon examination he had reduced sensation over the lateral border of the right foot, an absent right ankle tendon reflex and a positive Lasegue's sign at 70 . He also had a dusky discolouration of the skin of the right foot. He was admitted to our hospital in September 2004 because of progressive worsening of the symptoms. Lumbrosacral spinal magnetic resonance imaging (MRI) showed an increased heterogeneous signal within the S1 nerve root and of the nerve root ganglion on T2 images, thought to be due to oedema, with right piriformis wasting. His cerebrospinal fluid (CSF) contained no white cells, 0.52 g/l protein and 0.36 g/l glucose. Nerve conduction studies and an electromyogram (EMG) revealed abnormalities in the S1 segment, consistent with an S1 radiculopathy. Serum angiotensin converting enzyme (sACE) was persistently normal but an isotope-labelled gallium scan showed increased bilateral lung hilar and lachrymal gland uptake. He developed skin nodules on his right thigh which, when biopsied, were confirmed as erythema nodosum. The diagnosis of sarcoidosis was considered overwhelmingly likely, and in the absence of compression, the involvement of the S1 root was thought most likely due to neurosarcoidosis. He started treatment with prednisone 30 mg/day but his pain persisted; intravenous steroids and then local steroid nerve root injection was tried with temporary benefit. In April 2005, he started methotrexate (up to 12.5 mg per week) because of persistent pain and the need to lower his steroid dose because of his elevated glucose levels. In November 2005, he developed left peri-orbital and hemicranial headache, followed by diplopia on left gaze. He was found to have a partial left sixth nerve palsy and was re-admitted. MRI showed thickening and gadolinium enhancement in the left cavernous sinus with no parenchymal change. Repeat gallium scanning showed normal lung hilar and lachrymal gland uptake. Serum rheumatoid factor, plasma viscosity, C-reactive protein, urea and electrolytes, liver function, clotting, auto-immune profile, protein electrophoresis, acetylcholine receptor antibodies, anti-neuronal antibodies, anti-thyroid antibodies, creatine kinase and ACE were all normal. He was treated with a three-day course of intravenous methylprednisone and experienced significant improvement. The following month, he developed headache and further diplopia and he was found to have a painful pupil-sparing left third nerve palsy. His CSF was again entirely normal, including negative oligoclonal band assay. Brain and orbit MRI scanning were normal. EMG and nerve conduction studies suggested improvement of S1 radiculopathy. He also complained of left facial pain with tearing of the left eye. There was a patchy decrease in sensation on the left side of the face and scalp. Corneal reflex was diminished. Blink reflex and facial nerve conduction studies showed an afferent defect on the left suggesting a left trigeminal ophthalmic division neuropathy. His prednisone was increased to 60 mg/day, and cyclophosphamide was started instead of methotrexate. However, after reducing his steroids to 40 mg/day, severe facial pain recurred. In March 2006, he developed numbness and tingling on the left side of his face, and was found to have a left maxillary ophthalmic division Vth neuropathy. A month later he developed a lower motor neuron left seventh nerve palsy and numbness in the right shoulder and in the left thorax. His CSF was again normal and/or negative including cytological study, acid-fast bacilli staining, and fungal and Mycobacterium tuberculosis cultures and sACE was also still normal. His blood count showed mild lymphopenia and macrocytosis. Lactate dehydrogenase was normal. Borrelia, syphilis, cytomegalovirus, HIV and human T-lymphotropic virus Type 1 serology were negative. An ophthalmological examination was normal with no signs of granulomata. At this stage, new neurological symptoms developed while the patient was on treatment with steroids and cyclophosphamide. Because no diagnosis emerged other than sarcoidosis, alternative immunosuppressive therapy was administered. Intravenous immunoglobulins, however, had no impact. Infliximab was added in June 2006. Despite this, the patient's right shoulder became weak, his headache persisted and he also developed unsteadiness of gait and significant weight loss. He now had bilateral seventh nerve palsies with weakness of the left palate, right serratus anterior, right triceps, left triceps and left finger abductors. All the upper limb deep tendon jerks were absent. A left vocal cord palsy was noted. EMG and nerve conduction studies showed abnormalities compatible with a pre-ganglionic lesion at C5 and C6 level (right), but no generalised neuropathy. Repeat brain MRI scanning showed enhancement of the fifth, sixth, seventh and eighth cranial nerves (Figure 1). Spine MRI scanning was normal. MRI scanning of the upper brachial plexus was normal. A CT scan of the pelvis and abdomen were normal. A whole body fluorodeoxyglucose-positron emission tomography (FDG-PET) scan was normal. Urine thallium screening and lead level were negative. Upper gastrointestinal endoscopy was normal. The patient then developed three subcutaneous nodules, one in the left outer inferior breast quadrant, without lymphadenopathy. Biopsy of the nodules showed lymphomatous change, and the final diagnosis was diffuse large B-cell lymphoma involving cranial and peripheral nerves (neurolymphomatosis). Bone marrow was normal. He was transferred to the Oncology department and treated with chemotherapy including methotrexate. After chemotherapy he received total body irradiation and a bone marrow stem cell transplant. There was no significant improvement in his neurological condition.