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On topical application of fluorides and its inhibiting effect on caries. The observations of interest made in this investigation may be summarized as follows: 1. Conventional fluoride application by mouthrinsing with neutral NaF solution (0.025% daily for three weeks or three months; or 0.05% solution daily; or 0.2% solution weekly for three weeks) is found to result in only moderate and insignificant uptake of F in facial enamel surfaces. The gain is in the order of a hundred ppm within 10 to 15 microns' depth (as determined by an acid etching technique) and a few hundred ppm at 0.02 to 0.05 microns (according to pilot ion probe analysis). 2. Painting, at one week's interval for three weeks with 2% NaF (pH=5) solution and application of an APF-gel (Flura-Kerr 1.23% F) results in the significant uptake of a few hundred ppm F within the first 10 microns of the enamel. Painting with 2% NaF (pH=7), with 8% SnF2, or with 5% Na2PO3F solutions does not yield a significant gain in F in the first 10 microns of the facial enamel, as determined by the etching technique under similar conditions. 3. A varnish (Duraphat) containing 5% NaF (applied three times at weekly intervals) is found to deposit considerable amounts of fluorine in outer facial enamel. Within the first 10 microns gains of more than 1000 ppm F are detected by the etching technique. Uptakes of the order about 500 ppm F are seen even at depths beyond 10 microns; penetration of F is detected down to about 100 microns' depth. Ion probe experiments show a F gain of more than 2000 ppm at a depth of about 0.3 microns. 4. In teeth extracted one day after a single application of NaF varnish, the retained fluorine is higher than in teeth retained in oral environment for one or five weeks after application. This suggests that loss of F occurs particularly during the first days after treatment. 5. The varnish, when applied every six months in permanent dentition of 15 year old children, is cariostatic on all tooth surfaces. 6. The secondary ion microanalyzer ("ion probe") is a useful instrument for the study of fluorine concentrations in dental hard tissue, and provides a special approach to the outermost regions of enamel. 7. The ion probe renders quantitative F determinations in dental hard tissue; a calibration method is available when the positive secondary ion ratios CaF+/Ca+ or F+/Ca++ are recorded versus Ca++/Ca+.

Influence of Concussion Education Exposure on Concussion-Related Educational Targets and Self-Reported Concussion Disclosure among First-Year Service Academy Cadets. Concussion disclosure is often essential for military personnel to receive appropriate care following concussive injury. Concussion-related education and training may play a role in improving disclosure and recognition among peers, allowing for more timely concussion identification and treatment. The objectives of this study were to: (1) describe concussion education exposure among first-year service academy cadets and (2) examine the association between exposure to concussion education sources (multiple vs. only one) and concussion-related knowledge, attitudes, perceived social norms, intention to disclose symptoms, and disclosure behaviors. First-year service academy cadets completed a cross-sectional survey to assess perceptions of concussion disclosure during preseason concussion baseline testing sessions. Associations between key cadet characteristics and exposure to multiple concussion education sources were examined using odds ratios and 95% confidence intervals. Linear regression was used to model the continuous measures of concussion-related knowledge, attitudes, and perceived social norms. Log-binomial regression was used to model the categorical outcomes of high perceived control over concussion disclosure (higher vs. lower), intention to disclose (higher vs. lower), and disclosure of all possible concussive events at the time of injury (yes vs. no). The primary predictor for all models was exposure to multiple sources of concussion education (video, coach, medical professional, or other) vs. exposure to only one educational source. All models were adjusted for gender, high school contact sport participation, and previous concussion history. Of the 972 first-year cadets (85% response; age = 18.4 ± 0.9 years; 21.7% female, 29.0% NCAA student-athlete), 695 (71.5%) reported receiving some type of previous concussion education and 229 (23.6%) reported a previous concussion history (206/229 reported the actual number they experienced). Of those reporting previous concussion-related education (n = 695), 542 (78.0%) watched a video, 514 (74.0%) talked with a coach about concussion, 433 (62.3%) talked with a medical professional, and 61 (8.8%) reported other sources of education ranging from anatomy teachers to brochures. Overall, 527 (75.8%) reported receiving more than one source of concussion education. Having played a contact sport in high school and having a history of concussion were associated with having multiple concussion education exposures. Being female was associated with lower odds of multiple exposures. Exposure to multiple sources of concussion education was not associated with knowledge, attitudes, perceived norms, or higher intention to disclose concussion symptoms. However, among those with a concussion history, exposure to multiple sources of concussion education was associated with a nearly 40% higher prevalence of disclosing all concussions at the time of injury compared to only one source of educational exposure (67.1% vs. 48.3%; prevalence ratio = 1.4; 95% confidence interval: 0.9, 2.1). Thus, although multiple sources of education may not influence intermediate variables of knowledge, attitudes, perceived norms and intentions, exposure to multiple sources of concussion education may influence actual decision-making around concussion disclosure among first-year service academy cadets. These data suggest disparities in concussion education exposure that can be addressed in first-year cadets. Additionally, findings support the importance and use of multiple sources of concussion education in improving cadet's concussion-related decision-making.

Exploring substrate binding and discrimination in fructose1, 6-bisphosphate and tagatose 1,6-bisphosphate aldolases. Fructose 1,6-bisphosphate aldolase catalyses the reversible condensation of glycerone-P and glyceraldehyde 3-phosphate into fructose 1,6-bisphosphate. A recent structure of the Escherichia coli Class II fructose 1,6-bisphosphate aldolase [Hall, D.R., Leonard, G.A., Reed, C.D., Watt, C.I., Berry, A. & Hunter, W.N. (1999) J. Mol. Biol. 287, 383-394] in the presence of the transition state analogue phosphoglycolohydroxamate delineated the roles of individual amino acids in binding glycerone-P and in the initial proton abstraction steps of the mechanism. The X-ray structure has now been used, together with sequence alignments, site-directed mutagenesis and steady-state enzyme kinetics to extend these studies to map important residues in the binding of glyceraldehyde 3-phosphate. From these studies three residues (Asn35, Ser61 and Lys325) have been identified as important in catalysis. We show that mutation of Ser61 to alanine increases the Km value for fructose 1, 6-bisphosphate 16-fold and product inhibition studies indicate that this effect is manifested most strongly in the glyceraldehyde 3-phosphate binding pocket of the active site, demonstrating that Ser61 is involved in binding glyceraldehyde 3-phosphate. In contrast a S61T mutant had no effect on catalysis emphasizing the importance of an hydroxyl group for this role. Mutation of Asn35 (N35A) resulted in an enzyme with only 1.5% of the activity of the wild-type enzyme and different partial reactions indicate that this residue effects the binding of both triose substrates. Finally, mutation of Lys325 has a greater effect on catalysis than on binding, however, given the magnitude of the effects it is likely that it plays an indirect role in maintaining other critical residues in a catalytically competent conformation. Interestingly, despite its proximity to the active site and high sequence conservation, replacement of a fourth residue, Gln59 (Q59A) had no significant effect on the function of the enzyme. In a separate study to characterize the molecular basis of aldolase specificity, the agaY-encoded tagatose 1,6-bisphosphate aldolase of E. coli was cloned, expressed and kinetically characterized. Our studies showed that the two aldolases are highly discriminating between the diastereoisomers fructose bisphosphate and tagatose bisphosphate, each enzyme preferring its cognate substrate by a factor of 300-1500-fold. This produces an overall discrimination factor of almost 5 x 105 between the two enzymes. Using the X-ray structure of the fructose 1,6-bisphosphate aldolase and multiple sequence alignments, several residues were identified, which are highly conserved and are in the vicinity of the active site. These residues might potentially be important in substrate recognition. As a consequence, nine mutations were made in attempts to switch the specificity of the fructose 1,6-bisphosphate aldolase to that of the tagatose 1,6-bisphosphate aldolase and the effect on substrate discrimination was evaluated. Surprisingly, despite making multiple changes in the active site, many of which abolished fructose 1, 6-bisphosphate aldolase activity, no switch in specificity was observed. This highlights the complexity of enzyme catalysis in this family of enzymes, and points to the need for further structural studies before we fully understand the subtleties of the shaping of the active site for complementarity to the cognate substrate.

A Cross-sectional Study to Determine Whether Adjustment to an Ostomy Can Predict Health-related and/or Overall Quality of Life. Ostomy-specific adjustment may or may not predict health-related quality of life (HRQoL) and/or overall quality of life (QoL). A cross-sectional study was conducted among patients recruited from the customer registers of 8 surgical suppliers and pharmacies across Norway between November 2010 and March 2011 to determine which of the 34 items of the Ostomy Adjustment Scale (OAS) are the strongest predictors for HRQoL and overall QoL and to determine the HRQoL and overall QoL of individuals with an ostomy compared to a control group representing the general population. Persons who were >18 years old; had a permanent colostomy, ileostomy, or urostomy for >3 months; and could read and write Norwegian were invited to participate. The participants received information about the study in a letter from the researcher and returned their demographic information (addressing gender, age, marital status, education, diagnosis, time since surgery, and ostomy type) and study questionnaires using prepaid envelopes. The 158 participants (mean age 64 years [range 29-91], 89 [56%] men and 69 [44%] women) completed and returned by mail a sociodemographic questionnaire, the 34-item OAS (questions scored on a scale of 1 to 6, totally disagree to totally agree, score range 34 to 204), the Short Form-36 (SF-36, including 2 main components [physical and mental issues] divided into 8 subscales, scored from 0 to 100), and the 16-item Quality of Life Scale (QOLS) instrument (each response scored 1 to 7, from very dissatisfied to very satisfied; total score ranging from 16 to 112). Statistical analysis, including ordinary least square regression analyses, assessed whether the OAS independently predicted the sum scores of the SF-36 (physical component summary [PCS] and mental component summary [MCS]) and the QOLS score after adjusting for age, gender, marital status, education, diagnosis, time since surgery, and ostomy type. The OAS significantly predicted the SF-36 (PCS and MCS) and QOLS scores (P <0.001). Five (5) OAS items ("living a fulfilling life," "being free to travel where I want despite my ostomy," "realizing that this ostomy will be there forever," "worries about being left alone," and "embarrassing accidents in sexual activities") strongly predicted the composite score of the SF-36 (PCS and MCS) and QOLS measurements. The SF-36 scores in physical role functioning, general health, vitality, and MCS were lower in ostomy patients than controls (P < 0.05), whereas no difference was found for QOLS. Overall, ostomy-specific adjustment may be an important predictor of HRQoL and overall QoL, with the OAS factors described above having greater influence. More research such as prospective cohort studies are needed regarding patient adjustment to an ostomy.

An evaluation of an acuity system as it applies to a cardiac catheterization laboratory. Patient care using patient volume rather than acuity has been a long-standing problem in a cardiac catheterization laboratory in a central New Jersey Medical Center. The current pattern of staffing results in some of the nursing staff becoming unproductive from a patient care perspective. This recently has become a concern of the Vice President of Nursing who has the unpopular task of consolidating nursing positions. There is a very effective acuity measurement system, the Medicus Acuity System, in place for the various inpatient areas. This system also exists in the Emergency Department and is called EMERGE. The system collects and objectively weighs information regarding severity of patient needs or acuity. These data are collected daily and provide unit managers with information regarding hours of direct nursing care on their particular units. The information over time shows trends in direct care hours and allows these managers to target the average patient population. The system gives insight into units that require more and less nursing hours by hour of the day, day of the week, and month of the year. This makes overall housewide use of nursing personnel more patient-care appropriate and more financially sound, for example, in the summer months when acuity is shown to be higher. In today's managed care environment this author believes the practice of staffing units based on bed occupancy is now regarded as antiquated, inefficient, and impractical. This study investigated a modified version of the EMERGE tool and its ability to capture patient acuity as it relates to staffing in the cardiovascular laboratory (CVL). During the 5 days of data collection, 87 patients were cared for in the CVL. The modified EMERGE cards were completed on 54 of the 87 patients that week. This represented 62% of that total patient population. Each day data for 60% or more of the patients were entered into the study. The interrater reliability of the data collected was better than 98% each day with overall accuracy being 99.5%. This interrater reliability was based on the findings by the expert panel, who compared two or three (approximately 10%) of the actual nurses' notes to the matching EMERGE cards each day. More than 80% of the 54 patients were classified as Type 3, well above the Type 1 standard patient acuity category for the EMERGE system. Telemetry units with a majority of EMERGE Type 3 patients would require between 50 to 100 minutes of care per visit and would have a significant nursing workload. These units are where the CVL draws most of their patient population. In summary, this study reflects a growing trend in healthcare that requires justification of staffing through the productivity of workers. Acuity tools provide tangible and objective data about daily workload and productivity by measuring patient's needs. As managed care forces hospitals to cutt staff, acuity tools will become more important for evaluating productivity and retaining staff, especially nurses.

Cardiovascular consequences of early-onset growth hormone excess. Acromegaly has relevant effects on the cardiovascular system, but few data deal with the early effects of GH and IGF-I excess. To study the early stage of acromegalic cardiomyopathy and give indirect evidence of the mechanisms underlying GH and IGF-I action on the human heart, 25 patients with uncomplicated acromegaly [15 young subjects with short-term (< or =5 yr) disease and 10 with long-term (>5 yr) disease] and 25 sex- and age-matched controls were studied. Cardiovascular risk parameters were studied by standard methods; cardiac morphology by M-mode and Doppler echocardiography, cardiac function at rest and at peak exercise by equilibrium radionuclide angiography, and vascular disease at common carotid arteries by Doppler ultrasonography. In the patient group these measurements were repeated after 6 months of treatment with octreotide-LAR (20-40 mg, im, every 28 d). Glucose, glycosylated hemoglobin, insulin, low density lipoprotein cholesterol, triglycerides, and fibrinogen levels were higher, and high density lipoprotein cholesterol levels were lower in acromegalic patients than in controls. Resting blood pressure was similar in patients and controls, whereas heart rate at rest and systolic blood pressure at peak exercise were higher in the patients. The left ventricular mass index was higher in acromegalic patients than in controls (123.3 +/- 8.9 vs. 81.5 +/- 4.3 g/m(2); P < 0.001); seven patients had left ventricular hypertrophy. Diastolic function was similar in the two groups. The ejection fraction at rest, but not at peak exercise, was significantly increased in the patients compared with controls. As a consequence the exercise-induced changes in the ejection fraction were lower in patients than controls (8.7 +/- 1.1% vs. 21.9 +/- 3.5%; P < 0.001). At common carotid ultrasonography, young patients with acromegaly had increased diastolic peak velocity and increased intima media thickness, even if neither patient nor controls had atherosclerotic plaques. Six months after OCT-LAR treatment, GH and IGF-I levels remarkably decreased in all patients; 8 (53.3%) achieved disease control. Insulin, total cholesterol, and fibrinogen levels reduced, whereas high density lipoprotein cholesterol levels increased. Both at rest and at peak exercise, heart rate significantly decreased, whereas systolic and diastolic blood pressures did not change. The left ventricular mass index was significantly reduced, but it was still higher than the control value (101.6 +/- 3.5 g/m(2); P < 0.01). The left ventricular ejection fraction at rest was significantly reduced, but its response at peak exercise was increased (16.3 +/- 2.4%), becoming similar to the control value. At common carotids, the intima media thickness of right and left arteries was significantly reduced as was the diastolic peak velocity without any change in systolic peak velocity. Short-term GH excess, despite causing enhanced cardiac performance at rest, reduces cardiac performance on effort and impairs vascular morphology. These deleterious effects of early-onset acromegaly are ameliorated by suppressing GH/IGF-I levels for 6 months.

Novel 1:1 labeling and purification process for C-terminal thioester and single cysteine recombinant proteins using generic peptidic toolbox reagents. We developed a versatile set of chemical labeling reagents which allow dye ligation to the C-terminus of a protein or a single internal cysteine and target purification in a simple two-step process. This simple process results in a fully 1:1 labeled conjugate suitable for all quantitative fluorescence spectroscopy and imaging experiments. We refer to a "generic labeling toolbox" because of the flexibility to choose one of many available dyes, spacers of different lengths and compositions which increase the target solubility, a variety of affinity purification tags, and different cleavage chemistries to release the 1:1 labeled proteins. Studying protein function in vitro or in the context of live cells and organisms is of vital importance in biological research. Although label free detection technologies gain increasing interest in molecular recognition science, fluorescence spectroscopy is still the most often used detection technique for assays and screens both in academic as well as in industrial groups. For generations, fluorescence spectroscopists have labeled their proteins of interest with small fluorescent dyes by random chemical linking on the proteins' exposed lysines and cysteines. Chemical reactions with a certain excess of activated esters or maleimides of longer wavelength dyes hardly ever result in quantitative labeling of the target protein. Most of the time, more than one exposed amino acid side chain reacts. This results in a mixture of dye-protein complexes of different labeling stoichiometries and labeling sites. Only mass spectrometry allows resolving the precise chemical composition of the conjugates. In "classical" ensemble averaging fluorescent experiments, these labeled proteins are still useful, and quantification of, e.g., ligand binding experiments, is achieved via knowledge of the overall protein concentration and a fluorescent signal change which is proportional to the amount of complex formed. With the development of fluorescence fluctuation analysis techniques working at single molecule resolution, like fluorescence correlation spectroscopy (FCS), fluorescence cross correlation spectroscopy (FCCS), fluorescence intensity diffusion analysis (FIDA), etc., it became important to work with homogeneously labeled target proteins. Each molecule participating in a binding equilibrium should be detectable when it freely fluctuates through the confocal focus of a microscope. The measured photon burst for each transition contains information about the size and the stoichiometry of a protein complex. Therefore, it is important to work with reagents that contain an exact number of tracers per protein at identical positions. The ideal fluorescent tracer-protein complex stoichiometry is 1:1. While genetic tags such as fluorescent proteins (FPs) are widely used to detect proteins, FPs have several limitations compared to chemical tags. For example, FPs cannot easily compete with organic dyes in the flexibility of modification and spectral range; moreover, FPs have disadvantages in brightness and photostability and are therefore not ideal for most biochemical single molecule studies. We present the synthesis of a series of exemplaric toolbox reagents and labeling results on three target proteins which were needed for high throughput screening experiments using fluorescence fluctuation analysis at single molecule resolution. On one target, Hu-antigen R (HuR), we demonstrated the activity of the 1:1 labeled protein in ribonucleic acid (RNA) binding, and the ease of resolving the stoichiometry of an RNA-HuR complex using the same dye on protein and RNA by Fluorescence Intensity Multiple Distribution Analysis (FIMDA) detection.

[Urinary incontinence in degenerative spinal disease]. The aim of the study was to evaluate the presence of urinary incontinence in patients with chronic degenerative spinal disease and to identify factors affecting the occurrence and changes in urinary incontinence after surgery. The group evaluated comprised 214 patients undergoing surgery for degenerative spinal disease at our department between January 1 and December 31, 2008. The patients were categorised according to the type of their degenerative disease (cervical disc herniation, lumbar disc herniation, spinal stenosis, spinal instability or olisthesis) and the spine level involved (cervical or lumbar spine). The symptoms of urinary incontinence included leakage of urine and non-obstructive chronic urinary retention developing in association with the manifestation of vertebrogenic disorder. Patients with diseases known to increase the risk of incontinence were not included in the study. Based on a retrospective analysis of the patients' clinical notes, the occurrence of urinary incontinence in each type of degenerative spinal disease was assessed. The effect of gender, age, body mass index (BMI), neurological status and spinal disease type on the development of incontinence was statistically evaluated. The efficacy of surgical treatment was assessed on the basis of the patients' subjective complaints at the first follow-up one month after surgery. The data were evaluated by the statistical programme InSTAT (analysis of variance ANOVA, t-test). All tests were two-sided; a 0.05 level of statistical significance was used. Of the 214 patients with degenerative spinal disease, 27 (12.6%) had urinary incontinence. A higher risk of developing incontinence was found in women (p = 0.008) and in patients with radicular weakness (p = 0.023). The patients with urinary incontinence had their BMI significantly lower than patients without this disorder (p = 0.019). Age had no effect. The differences in the occurrence of urinary incontinence amongst the different types of degenerative disease were regarded as approaching statistical significance (p = 0.09). The surgical treatment resulted in incontinence control in 15 (55.5 %) affected patients. A comparison of the factors leading to the development of urinary incontinence in degenerative spinal disease and those associated with the development of incontinence in the general population suggests that the aetiology in each case is different. The relationship between low back pain and urinary incontinence remains unknown. Degenerative spinal disease can result in acute or chronic urinary incontinence. Factors associated with its development include gender, BMI, radicular weakness and the type of degenerative disease. Surgical treatment improved or eliminated the symptoms of urinary incontinence in more than half of the patients affected.

Characteristics of ossification of the spinal ligament; incidence of ossification of the ligamentum flavum in patients with cervical ossification of the posterior longitudinal ligament - Analysis of the whole spine using multidetector CT. Ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) are characterized by replacement of ligamentous tissue by ectopic new bone formation. Although the background of both diseases might be similar, there are some differences between two diseases. Some patients have both OPLL and OLF. However, the incidence of both OPLL and OLF is still unclear and the precise lesions have not been investigated, yet. This study was conducted to evaluate OLF of the whole spine in patients with cervical OPLL and to analyze the relationship of the ossified lesions between OLF and OPLL. One hundred seventy eight patients who were diagnosed as cervical OPLL by plain radiographs were included. CT images of the whole spine were taken. Ossified lesions were checked at each level of vertebral body and intervertebral disc. The ossification index of OPLL (OPLL OS index) was determined by the sum of the levels of vertebral bodies and intervertebral discs where OPLL existed. The same index was applied for detecting the level of OLF (OLF OS index). Age, gender and OPLL characteristics were compared between the OLF(+) group, OLF was seen at any levels of the spinal canal, and the OLF(-) group, OLF was not seen. The most frequent level of OPLL was at C5 vertebral level and OLF was predominant at upper and lower thoracic levels. Seventeen patients (9.6%) had OPLL and OLF at the same spinal level. The averaged OPLL OS index of the total spine in these patients was 8.7 ± 6.1, ranged from 1 to 36. The averaged OLF OS index of the total spine was 3.1 ± 2.2 (ranged from 1 to 13) in the patients who had OLF at any levels of the whole spine. One hundred fifteen patients (64.6%) with cervical OPLL had OLF at any levels of the whole spine. No relationship was found between the OPLL OS index and the OLF OS index. There was no significant difference among the data between the OLF(+) group and the OLF(-) group. This study demonstrated 64.6% of the patients with cervical OPLL had OLF, mainly in the thoracic spine. However, there was no relationship regarding the severity of the ossified lesions between OPLL and OLF. CT analysis of the whole spine should be carried out for the early detection of OPLL and OLF in patients with cervical OPLL.

[Diagnosis and treatment of BCR/ABL-negative myeloproliferative diseases--principles and rationale of CZEMP recommendations]. In 2009, the recommendations of the Czech Collaborative Group for Ph- Myeloproliferative Diseases (CZEMP) for diagnosis and treatment of BCR/ABL-negative myeloproliferative diseases (MPD), i.e., essential thrombocythemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF) were updated and extended. The present article gives the rationale of the recommendations in full detail. The CZEMP diagnostic criteria for ET and PMF are based on histopathological (HP) findings, which must unconditionally be in line with the given clinical and laboratory characteristics of ET or of a certain stage of PMF, respectively. The platelet count is not decisive for diagnosis. In cases lacking an adequately taken and read HP finding, the Polycythemia Vera Study Group (PVSG) criteria are recommended. The diagnosis of typical PV is based on demonstration of the V617F mutation of the JAK2 gene along with a significant increase of red cell parameters. If these are close to borderline, the demonstration of increased total red cell mass (RCM) is required. In atypical cases lacking polyglobulia or elevated RCM, the HP picture of PV (in accordance with WHO description) plus JAK2 V617F mutation is satisfactory for diagnosis, or, in cases lacking JAK2 V617F mutation, the HP picture of PV along with polyglobulia (or increased RCM) is sufficient. The treatment principles of ET and other MPDs with thrombocythemia (MPD-T; i.e., the early stages of PMF and PV) are identical. The patients are stratified by their thrombotic risk (preceding thrombosis, another thrombophilic state, jAK2 mutation), presence of disease symptoms (mainly microcirculatory), platelet count and age. Only patients up to 65 years lacking the above mentioned risks with a platelet count < 1000 x 10(9)/l are considered as low-risk and do not demand cytoreducing therapy. The others are high-risk ones and have an indication for thromboreduction. In patients older than 65 years, the potentially leukemogenic drug hydroxyurea (HU) may be used. In the younger ones, the choice is between anagrelide (ANG) or interferon-alpha (IFN). In high-risk patients, the treatment goal is to maintain platelet counts below 400, and in low-risk ones, below 600 x 10(9)/l. In PV, polycythemia itself is another thrombotic risk factor. The condition is treated by bloodletting or erythrocytaphereses. If hematocrit levels < or =45 are not achieved, cytoreductive therapy using HU in patients over 65 years, or IFN in younger individuals is required. All patients with thrombocythemia in PV are high-risk and have an indication for cytoreduction. Acetylsalicylic acid is given to all patients with MPD-T with platelets < 1000 x 10(9)/l (at higher counts, hemorrhage is imminent), and to all individuals with PV, unless contraindication is present. In case of platelet count normalization, it may be withdrawn in cases of low-risk ET or PMF, not in JAK2+ PV. The treatment of advanced stages of PMF is symptomatic, with substitution of blood derivatives being the basis. The only curative treatment is allogeneic stem cell transplantation, which should not be indicated too early seeing to its risks, but also not too late--we must not allow transition into acute leukemia, which is heralded by blasts in the blood picture. The indication is the presence of any of the following criteria: values of hemoglobin < 10 g/dl, WBC < 4 x 10(9)/l and platelets < 100 x 10(9)/l, any percentage of blasts or > or = 10% immature granulocytes in the differential picture, >1 erythroblast per 100 cells--all at repeated examinations within at least a 2-month interval, and in addition, rapid progression of hepato-/splenomegaly, presence of general symptoms of the disease, portal hypertension and extensive swellings.

Diagnostic performance of 18F-FET PET in newly diagnosed cerebral lesions suggestive of glioma. The aim of this study was to assess the clinical value of O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) PET in the initial diagnosis of cerebral lesions suggestive of glioma. In a retrospective study, we analyzed the clinical, radiologic, and neuropathologic data of 174 patients (77 women and 97 men; mean age, 45 ± 15 y) who had been referred for neurosurgical assessment of unclear brain lesions and had undergone (18)F-FET PET. Initial histology (n = 168, confirmed after surgery or biopsy) and the clinical course and follow-up MR imaging in 2 patients revealed 66 high-grade gliomas (HGG), 77 low-grade gliomas (LGG), 2 lymphomas, and 25 nonneoplastic lesions (NNL). In a further 4 patients, initial histology was unspecific, but during the course of the disease all patients developed an HGG. The diagnostic value of maximum and mean tumor-to-brain ratios (TBR(max/)TBR(mean)) of (18)F-FET uptake was assessed using receiver-operating-characteristic (ROC) curve analyses to differentiate between neoplastic lesions and NNL, between HGG and LGG, and between high-grade tumor (HGG or lymphoma) and LGG or NNL. Neoplastic lesions showed significantly higher (18)F-FET uptake than NNL (TBR(max), 3.0 ± 1.3 vs. 1.8 ± 0.5; P < 0.001). ROC analysis yielded an optimal cutoff of 2.5 for TBR(max) to differentiate between neoplastic lesions and NNLs (sensitivity, 57%; specificity, 92%; accuracy, 62%; area under the curve [AUC], 0.76; 95% confidence interval [CI], 0.68-0.84). The positive predictive value (PPV) was 98%, and the negative predictive value (NPV) was 27%. ROC analysis for differentiation between HGG and LGG (TBR(max), 3.6 ± 1.4 vs. 2.4 ± 1.0; P < 0.001) yielded an optimal cutoff of 2.5 for TBR(max) (sensitivity, 80%; specificity, 65%; accuracy, 72%; AUC, 0.77; PPV, 66%; NPV, 79%; 95% CI, 0.68-0.84). Best differentiation between high-grade tumors (HGG or lymphoma) and both NNL and LGG was achieved with a TBR(max) cutoff of 2.5 (sensitivity, 79%; specificity, 72%; accuracy, 75%; AUC, 0.79; PPV, 65%; NPV, 84%; 95% CI, 0.71-0.86). The results for TBR(mean) were similar with a cutoff of 1.9. (18)F-FET uptake ratios provide valuable additional information for the differentiation of cerebral lesions and the grading of gliomas. TBR(max) of (18)F-FET uptake beyond the threshold of 2.5 has a high PPV for detection of a neoplastic lesion and supports the necessity of an invasive procedure, for example, biopsy or surgical resection. Low (18)F-FET uptake (TBR(max) < 2.5) excludes a high-grade tumor with high probability.

Prevalence, pathophysiology, and clinical significance of post-heart transplant atrial fibrillation and atrial flutter. Atrial rhythm disturbances, in particular atrial fibrillation (AF) and flutter (AFL), are common in the denervated transplanted heart. However, there is a relative paucity of data in the prevalence, mechanism of arrhythmia, and long-term significance. (1) Determine the prevalence of AF and AFL in heart transplant patients, (2) define the echo/Doppler features associated with arrhythmia, and (3) evaluate the impact of arrhythmia on long-term survival. All patients who received an orthotopic heart transplant at the Mayo Clinic, Rochester, Minnesota, between 1988 and 2000 were included. Analysis of serial electrocardiograms and Holter monitor records provided evidence of AF or AFL development. Variables including general patient demographics, histology-proven rejection numbers and grades, results of serial coronary angiography, endomyocardial biopsy specimens, and echocardiographic studies performed at 6 weeks and 3 years after transplant were obtained to determine variables predictive of arrhythmia development. There were 167 heart transplant recipients, of which 16 (9.5%) developed AF and another 25 (15.0%) developed AFL over 6.5 +/- 3.4 years. Patients who developed AF or AFL had lower left ventricular (LV) ejection fractions (56.6% +/- 1.6% vs 62.5% +/- 1.5%, p < 0.05), higher LV end-systolic dimensions (LVESD) (33.6 +/- 1.12 mm vs 29.7 +/- 0.97 mm, p < 0.01), higher right atrial volume indexes (43.2 +/- 12.3 ml vs 35 +/- 5.3 ml, p < 0.03), lower mitral deceleration time (145 +/- 8 msec vs 160 +/- 12 msec, p < 0.05), and lower late mitral annulus tissue a' velocities (0.06 +/- 0.005 cm/sec vs 0.08 +/- 0.01 cm/sec, p < 0.02) compared with an age- and gender-matched Sinus Rhythm Group. Grade 3 rejection was a time-dependent covariate predictor of AFL risk (hazard ratio [HR], 2.95; 95% confidence interval [CI], 1.3-6.6, p < 0.008) but not AF (HR, 2.264; 95% CI, 0.72-7.1; p = 0.10). Thirty-nine of 167 patients died: 13 in the arrhythmia group and 26 in the normal sinus rhythm group. Development of atrial dysrhythmia adversely affected the outcome in the first 5 years (p < 0.001) compared with normal sinus rhythm. Predictors of long-term mortality included AF/AFL (HR, 2.88; 95% CI, 1.38-5.96; p < 0.004), age at transplant (HR, 1.04; 95% CI, 1.00-1.07, p < 0.03), coronary artery disease (HR, 2.655; 95% CI, 1.25-5.64; p = 0.01), pre-transplant cardiac amyloidosis (HR, 5.02; 95% CI 2.37-10.62; p < 0.001), right atrial volume index (HR, 1.03; 95% CI, 1.00-10.7; p = 0.03), mitral deceleration time <160 msec (p < 0.01), and LVESD >30 mm (p < 0.04). Development of AF/AFL post-heart transplantation is not uncommon and is associated with decreased long-term survival. Cumulative effects of repeated moderate-to-severe (grade 3 or more) rejections that result in increased cardiac fibrosis are associated with the development of AFL, but not AF. Similarly advanced restrictive diastolic dysfunction caused by fibrosis from repeated moderate-to-severe (grade 3 or more) rejections was predominant in the patients with arrhythmia and was a marker of poor long-term outcome.

On problems of calculating energy expenditure and substrate utilization from respiratory exchange data. Indirect calorimetry based on respiratory exchange measurement has been successfully used from the beginning of the century to obtain an estimate of heat production (energy expenditure) in human subjects and animals. The errors inherent to this classical technique can stem from various sources: 1) model of calculation and assumptions, 2) calorimetric factors used, 3) technical factors and 4) human factors. The physiological and biochemical factors influencing the interpretation of calorimetric data include a change in the size of the bicarbonate and urea pools and the accumulation or loss (via breath, urine or sweat) of intermediary metabolites (gluconeogenesis, ketogenesis). More recently, respiratory gas exchange data have been used to estimate substrate utilization rates in various physiological and metabolic situations (fasting, post-prandial state, etc.). It should be recalled that indirect calorimetry provides an index of overall substrate disappearance rates. This is incorrectly assumed to be equivalent to substrate "oxidation" rates. Unfortunately, there is no adequate golden standard to validate whole body substrate "oxidation" rates, and this contrasts to the "validation" of heat production by indirect calorimetry, through use of direct calorimetry under strict thermal equilibrium conditions. Tracer techniques using stable (or radioactive) isotopes, represent an independent way of assessing substrate utilization rates. When carbohydrate metabolism is measured with both techniques, indirect calorimetry generally provides consistent glucose "oxidation" rates as compared to isotopic tracers, but only when certain metabolic processes (such as gluconeogenesis and lipogenesis) are minimal or / and when the respiratory quotients are not at the extreme of the physiological range. However, it is believed that the tracer techniques underestimate true glucose "oxidation" rates due to the failure to account for glycogenolysis in the tissue storing glucose, since this escapes the systemic circulation. A major advantage of isotopic techniques is that they are able to estimate (given certain assumptions) various metabolic processes (such as gluconeogenesis) in a noninvasive way. Furthermore when, in addition to the 3 macronutrients, a fourth substrate is administered (such as ethanol), isotopic quantification of substrate "oxidation" allows one to eliminate the inherent assumptions made by indirect calorimetry. In conclusion, isotopic tracers techniques and indirect calorimetry should be considered as complementary techniques, in particular since the tracer techniques require the measurement of carbon dioxide production obtained by indirect calorimetry. However, it should be kept in mind that the assessment of substrate oxidation by indirect calorimetry may involve large errors in particular over a short period of time. By indirect calorimetry, energy expenditure (heat production) is calculated with substantially less error than substrate oxidation rates.

Chromosome mapping in barley by means of telotrisomic analysis. A total of 37 genetic markers located in chromosomes 2, 3, 4 and 5 were associated with specific arms by means of telotrisomic analysis in five telotrisomics (Triplo 2 L, 2 S, 3 S, 4 S, 5 L) of barley (Hordeum vulgare L.). The genes v, gp (= gp 2), li, gs 5, tr and msg2 showed a trisomic ratio with Triplo 2 L indicating that these genes were on the long arm of chromosome 2. A disomic ratio was obtained for genes wst 4, gs 5, and v with Triplo 2 S, confirming that these genes were on the long arm of chromosome 2(2 L). A disomic ratio was observed for genes e, f(= lg), sk, and gs6 with Triplo 2 L. Two genes, f(= lg) and gs6 showed a trisomic ratio with Triplo 2S. These results indicated that genes e, f(= lg), sk, and gs 6 are on the short arm of chromosome 2 (2S). Since only one telocentric chromosome was available for chromosome 3, 4 and 5, most of the well-mapped marker genes were tested with those telocentric chromosomes. The genes cu 2, uz, wst, als, gs 2, zb,f2, and cer-zn (348) showed trisomic ratio with the telocentric for chromosome 3. These genes were located on the short arm of chromosome 3 (Robertson 1971). This indicated that the telocentric chromosome is for the short arm of chromosome 3(3 S). A disomic ratio was obtained for genes yst, x c, al, yst2, a n, ari-a (6) and x s, indicating that these genes are on the long arm of chromosome 3. Two genes, f9 and K, showed trisomic ratio with the telocentric chromosome for 4, while genes gl(= gl2), br2, yh, lg 3, lg 4 and lk 5 showed disomic ratios. This indicated that the telocentric chromosome is for the short arm of chromosome 4. Two genes, fs 2 and g, were studied with Triplo 5 L. Both showed trisomic ratio, indicating that fs 2 and g are located on Triplo 5 L. The centromere position (C) on chromosome 2, 3 and 4 was thus located as (the left side of C is the short arm and the right is the long arm): chromosome 2: f - sk - gs6 - e - C - gs5 - msg2 - wst4 - v - gp - li - tr; chromosome 3: f2 - cer-zn (348) - uz - gs2 - als - cu2 - wst - zb - C - yst - x c - al - yst2 - a n - ari-a (6) - x s; chromosome 4: f9 - K - C - lg4 - lg (3) - gl2 - br2 - lk5 - yh. The centromere position on chromosome 5 was not precisely located.

Dry fractionation creates fractions of wheat distillers dried grains and solubles with highly digestible nutrient content for grower pigs. Nutrient digestibility in distillers dried grains with solubles (DDGS) is limited by constraints such as particle size and fiber. Wheat DDGS contains more fiber than corn DDGS that may reduce its nutritional value in swine feeds. Dry fractionation may create DDGS fractions with low and high fiber content; therefore, wheat DDGS was processed sequentially using a vibratory sifter and gravity table. Sufficient material was obtained from 3 wheat DDGS fractions that differed in particle size from fine to coarse (Fraction A [FA], Fraction C [FC], and Fraction D [FD]). Five cornstarch-based diets were mixed that contained either 40% wheat DDGS, 30% FA, 30% FC plus 10% soybean meal (SBM), 30% FD plus 15% SBM, or 35% SBM. A sixth, N-free diet served to subtract basal endogenous AA losses and as control for energy digestibility calculations. Six ileal-cannulated barrows (29 kg BW) were fed 6 diets at 2.8 times maintenance for DE in six 9-d periods as a 6 × 6 Latin square. Feces and ileal digesta were collected sequentially for 2 d each. Wheat DDGS FA, FC, and FD were 258, 530, and 723 μm in mean particle size and contained 44.8, 39.3, and 33.8% CP and 29.1, 35.1, and 37.5% in NDF, respectively. The apparent total tract digestibility (ATTD) of GE was greater (P < 0.05) for SBM than wheat DDGS, was greater (P < 0.05) for FA than wheat DDGS, and did not differ between FC, FD, and wheat DDGS. The standardized ileal digestibility (SID) did not differ between SBM and wheat DDGS (P > 0.05) for most AA. The SID of Arg, Lys, Trp, and available Lys was greater (P < 0.05) for FD than wheat DDGS but was similar for FA, FC, and wheat DDGS and was greater (P < 0.05) for FD than SBM. The DE and NE value was greater (P < 0.05) for SBM, FA, and FC than wheat DDGS and did not differ between FD and wheat DDGS. The SID content of indispensable AA and available Lys was greater (P < 0.05) for SBM than wheat DDGS. The SID content of Ile, Leu, Met, Phe, and Val was greater (P < 0.05) for FA than wheat DDGS but did not differ for indispensable AA between FC and wheat DDGS. The SID content of His, Ile, Leu, Met, and Phe was lower (P < 0.05) for FD than wheat DDGS. In conclusion, dry fractionation creates DDGS fractions with a differing chemical composition. Fine particle fractions contain less fiber and more CP than coarse particle fractions, but their AA digestibility was lower, likely due to most of the solubles being fine particles that are more susceptible to AA damage than protein entrapped in particles of larger size.

Orthopaedic issues in the musculoskeletal care of adults with cerebral palsy. Orthopaedic care of adults with cerebral palsy (CP) has not been well documented in orthopaedic literature. This paper focuses on some of the common problems which present themselves when adults with CP seek orthopaedic intervention. In particular, we review the most common orthopaedic issues which present to the Penn Neuro-Orthopaedics Program. A formal review of consecutive surgeries performed by the senior author on adults with CP was previously conducted. This paper focuses on the health delivery care for the adult with orthopaedic problems related to cerebral palsy. Ninety-two percent of these patients required lower extremity surgery. Forty percent had procedures performed on the upper extremities. The majority of problems seen in the Penn Neuro-Orthopaedics Program are associated with the residuals of childhood issues, particularly deformities associated with contractures. Patients are also referred for treatment of acquired musculoskeletal problems such as degenerative arthritis of the hip or knee. A combination of problems contribute most frequently to foot deformities and pain with weight-bearing, shoewear or both, most often due to equinovarus. The surgical correction of this is most often facilitated through a split anterior tibial tendon transfer. Posterior tibial transfers are rarely indicated. Residual equinus deformities contribute to a pes planus deformity. The split anterior tibial tendon transfer is usually combined with gastrocnemius-soleus recession and plantar release. Transfer of the flexor digitorum longus to the os calcis is done to augment the plantar flexor power. Rigid pes planus deformity is treated with a triple arthrodesis. Resolution of deformity allows for a good base for standing, improved ability to tolerate shoewear, and/or braces. Other recurrent or unresolved issues involve hip and knee contractures. Issues of lever arm dysfunction create problems with mechanical inefficiency. Upper extremity intervention is principally to correct contractures. Internal rotation and adductor tightness at the shoulder makes for difficult underarm hygiene and predispose a patient to a spiral fracture of the humerus. A tight flexor, pronation pattern is frequently noted through the elbow and forearm with further flexion contractures through the wrist and fingers. Lengthenings are more frequently performed than tendon transfers in the upper extremity. Arthrodesis of the wrist or on rare occasions of the metacarpal-phalangeal joints supplement the lengthenings when needed. The Penn Neuro-Orthopaedics Program has successfully treated adults with both residual and acquired musculoskeletal deformities. These deformities become more critical when combined with degenerative changes, a relative increase in body mass, fatigue, and weakness associated with the aging process.

MXene as a Charge Storage Host. The development of efficient electrochemical energy storage (EES) devices is an important sustainability issue to realize green electrical grids. Charge storage mechanisms in present EES devices, such as ion (de)intercalation in lithium-ion batteries and electric double layer formation in capacitors, provide insufficient efficiency and performance for grid use. Intercalation pseudocapacitance (or redox capacitance) has emerged as an alternative chemistry for advanced EES devices. Intercalation pseudocapacitance occurs through bulk redox reactions with ultrafast ion diffusion. In particular, the metal carbide/nitride nanosheets termed MXene discovered in 2011 are a promising class of intercalation pseudocapacitor electrode materials because of their compositional versatility for materials exploration (e.g., Ti2CT x, Ti3C2T x, V2CT x, and Nb2CT x, where T is a surface termination group such as F, Cl, O, or OH), high electrical conductivity for high current charge, and a layered structure of stacked nanosheets for ultrafast ion intercalation. Various MXene electrodes have been reported to exhibit complementary battery performance, such as large specific capacity at high charge/discharge rates. However, general design strategies of MXenes for EES applications have not been established because of the limited understanding of the electrochemical mechanisms of MXenes. This Account describes current knowledge of the fundamental electrochemical properties of MXenes and attempts to clarify where intercalation capacitance ends and intercalation pseudocapacitance begins. MXene electrodes in aqueous electrolytes exhibit intercalation of hydrated cations. The hydrated cations form an electric double layer in the interlayer space to give a conventional capacitance within the narrow potential window of aqueous electrolytes. When nonaqueous electrolytes are used, although solvated cations are intercalated into the interlayer space during the initial stage of charging, the confined solvation shell should gradually collapse because of the large inner potential difference in the interlayer space. Upon further charging, desolvated ions solely intercalate, and the atomic orbitals of the desolvated cations overlap with the orbitals of MXene to form a donor band. The formation of the donor band induces the reduction of MXene, giving rise to an intercalation pseudocapacitance through charge transfer from the ions to MXene sheets. Differences in the electrochemical reaction mechanisms lead to variation of the electrochemical responses of MXenes (e.g., cyclic voltammetry curves, specific capacitance), highlighting the importance of establishing a comprehensive grasp of the electrochemical reactions of MXenes at an atomic level. Because of their better charge storage kinetics compared with those of typical materials used in present EES devices, aqueous/nonaqueous asymmetric capacitors using titanium carbide MXene electrodes are capable of efficient operation at high charge/discharge rates. Therefore, the further development of novel MXene electrodes for advanced EES applications is warranted.

[The development of modern osteosynthesis]. Within the last 30 years, rigid fixation has revolutionized a wide range of treatment procedures in cranio-maxillofacial surgery. Rigid fixation allows for a three-dimensional reconstruction of the facial skeleton. In fracture treatment and following osteotomies in orthognathic surgery, any postoperative maxillo-mandibular fixation by dental arch bars can be avoided. Rigid plate and screw fixation began in 1886 when the Hamburg surgeon Carl Hansmann presented his experiences with the plate and screw system, which he had developed. Besides fractures of the extremities, Hansmann also reported about two cases of mandible fractures he had treated. Thus, Hansmann is the first representative of rigid plate fixation in maxillofacial surgery. Because of the high rate of complications, plate and screw osteosynthesis was not generally accepted for a long time. This changed when the Belgian surgeon Robert Danis in 1949 introduced the principle of axial compression of the fracture ends. His idea of axial compression was picked up by the ASIF Swiss research group and was further developed for clinical application in trauma surgery of the long bones in the early 1960s. Because of anatomical reasons, appliances used by the ASIF in the surgery of extremities could not be used in maxillofacial surgery. Therefore, in 1968, Luhr developed an automatic compression plate, which in a simple way realized the principle of axial compression. With this compression screw plate, Luhr performed, in 1967, the first compression plating in the maxillo-facial area in the world. Numerous publications by other authors about similar procedures followed. Different treatment principles using monocortical mini plates without axial compression for treatment of mandibular fractures and later also for fractures of the midface were introduced, namely, by Michelet and also by Champy. Based on the experiences of fracture treatment by plate and screw fixation, various systems for mandibular reconstruction following tumor resection or defect fractures were developed. With these reconstruction plates, a rigid alloplastic bridging of defects could be performed as well as rigid fixation of bone grafts using axial compression. The main advantage of these procedures was the avoidance of any postoperative MMF. Rigid fixation has also revolutionized orthognathic surgery. The avoidance of any MMF following osteotomies of the facial skeleton was the main advantage. The introduction of implant materials, which are highly resistant to corrosion (vitallium, titanium), and the development of plating systems of adequate dimensions for use within different areas of the complex facial skeleton has led to a high degree of perfection of rigid fixation in cranio-maxillofacial surgery.

The properties of free polymer surfaces and their influence on the glass transition temperature of thin polystyrene films. We present a detailed study of free polymer surfaces and their effects on the measured glass transition temperature (T(g)) of thin polystyrene (PS) films. Direct measurements of the near-surface properties of PS films are made by monitoring the embedding of 10 and 20 nm diameter gold spheres into the surface of spin-cast PS films. At a temperature T = 378 K( > T(g)), the embedding of the spheres is driven by geometrical considerations arising from the wetting of the gold spheres by the PS. At temperatures below T(g) (363 K < T < 370 K), both sets of spheres embed 3-4 nm into the PS films and stop. These studies suggest that a liquid-like surface layer exists in glassy PS films and also provide an estimate for the lower bound of the thickness of this layer of 3-4 nm. This qualitative idea is supported by a series of calculations based upon a previously developed theoretical model for the indentation of nanoscale spheres into linear viscoelastic materials. Comparing data with simulations shows that this surface layer has properties similar to those of a bulk sample of PS having a temperature of 374 K. Ellipsometric measurements of the T(g) are also performed on thin spin-cast PS films with thicknesses in the range 8 nm < h < 290 nm. Measurements are performed on thin PS films that have been capped by thermally evaporating 5 nm thick metal (Au and Al) capping layers on top of the polymer. The measured T(g) values (as well as polymer metal interface structure) in such samples depend on the metal used as the capping layer, and cast doubt on the general validity of using evaporative deposition to cover the free surface. We also prepared films that were capped by a new non-evaporative procedure. These films were shown to have a T(g) that is the same as that of bulk PS (370+/-1 K) for all film thicknesses measured (> 7 nm). The subsequent removal of the metal layer from these films was shown to restore a thickness-dependent T(g) in these samples that was essentially the same as that observed for uncapped PS films. An estimate of the thickness of the liquid-like surface layer was also extracted from the ellipsometry measurements and was found to be 5+/-1 nm. The combined ellipsometry and embedding studies provide strong evidence for the existence of a liquid-like surface layer in thin glassy PS films. They show that the presence of the free surface is an important parameter in determining the existence of T(g) reductions in thin PS films.

Current Legal Situation for Patients with Paraphilic disorders and Implications of the ICD-11 for Paraphilic Disorders for Germany. Recently the guidelines for the diagnosis of paraphilic disorders in the International Classification of Diseases and Related Health Problems, Eleventh Revision (ICD-11), have been published. This article analyzes legal, regulatory, and policy issues relevant to the potential effects of the changes for the classification of paraphilic disorders in the ICD-11 in Germany. A forensic and a legal expert in Germany worked with other international experts to conduct this evaluation using an assessment guide provided by the World Health Organization. Possible effects of the changes for the classification of paraphilic disorders in the ICD-11 on forensic practice, health systems, adjudication of individuals who have committed a sexual offense, and the provision of treatment in Germany. Results highlight the special situation of medical confidentiality in the German health system that facilitates the establishment of preventive networks for the treatment of pedophilic patients. The ICD-11 guidelines will help to clarify the boundary between pedophilic disorder and crimes of child sexual abuse. These will also establish a boundary with other paraphilic diagnostic concepts. We describe the central construct of criminal responsibility in the German legal system in relation to paraphilic disorders, the prominent role of expert witnesses, and the differences in the conceptualization of medical confidentiality within the health care system and within the legal system. The ICD-11 proposals for paraphilic disorders provide a clearer differentiation, as compared with ICD-10, between variants of normal sexual behavior and sexual behavior that involves a non-consenting person or entity. Particular patterns of sexual preference that are not of relevance to public health, the health care system, or the legal system, such as masochism and fetishism, will no longer be named psychiatric entities and will, therefore, be regarded as private behaviors and destigmatized. The assessment shows the specific legal situation in Germany for the treatment of paraphilic patients in a sexual medicine, psychiatric, and legal discourse. However, it was done only by a small number of experts. A conclusion of the analysis was that the more specific and narrower definitions in the ICD-11 diagnostic guidelines, compared with those in ICD-10, particularly for pedophilic disorder and coercive sexual sadism disorder, will result in a reduction in false-positive diagnoses. It is unlikely that significant unintended and negative consequences will occur as a result of implementing the ICD-11 guidelines for paraphilic disorders. Briken P, Boetticher A, Krueger RB, et al. Current Legal Situation for Patients with Paraphilic disorders and Implications of the ICD-11 for Paraphilic Disorders for Germany. J Sex Med 2019;16:1615-1622.

Cold transduction in rat trigeminal ganglia neurons in vitro. Three sub-populations of sensory neurons may be distinguished based on responses to a decrease in temperature: one has a relatively low threshold for activation (cool fibers), a second has a high threshold for activation (cold nociceptors), and the third is unresponsive to a decrease in temperature. Results from several recent studies suggest that the ability to detect a decrease in temperature reflects an intrinsic property(ies) of sensory neurons and therefore may be characterized via the study of the sensory neuron cell body in vitro. However, while three unique ionic mechanisms of cold transduction have recently been identified (i.e. activation of the transient receptor potential channel M8 [TRPM8] or an epithelial Na(+) channel [ENaC] or inhibition of two pore K(+) channel [TREK-1]), the possibility that these "mechanisms" may be differentially distributed among sensory neurons in a manner consistent with predictions based on in vivo observations has not been investigated. To investigate this possibility, we have characterized the influence of cooling on isolated trigeminal ganglion (TG) neurons from adult rats in vitro with Ca(2+) microfluorimetry in combination with a series of pharmacological interventions. We report that neurons responded to a decrease in temperature from approximately 34 degrees C to approximately 12 degrees C in one of two ways: 1) with a low threshold (30.1+/-0.6 degrees C) for activation demonstrating an increase in fluorescence with a minimal decrease in bath temperature (12.3%); 2) with a high threshold for activation (21.5+/-0.6 degrees C), demonstrating an increase in fluorescence only after a substantial decrease in bath temperature (13.3%); 74.4% did not respond to a decrease in temperature with an increase [Ca(2+)](i). These responses also were distinguishable on the basis of their rate of activation and degree of desensitization in response to prolonged application of a cold stimulus: low threshold responses were associated with a rapid (tau=12.0+/-5.7 s) increase in [Ca(2+)](i) and a time constant of desensitization of 85.8+/-20.7 s while high threshold responses were associated with a slow (tau=38.1+/-8.2 s) increase in [Ca(2+)](i) and demonstrated little desensitization over 4 min of stimulation. We refer to low threshold and high threshold cold responsive TG neurons as LT(cool) and HT(cool) neurons, respectively. LT(cool) and HT(cool) neurons were distributed among two distinct subpopulations of TG neurons distinguishable on the basis of cell body size and isolectin B4 staining. Both ENaC and TRPM8 appear to contribute to cold transduction, but neither is sufficient to account for all aspects of cold transduction in either population of TG neurons. Furthermore, inhibition of Ba(2+) and/or Gd(3+) sensitive two-pore K(+) channels (i.e. TREK-1 and TRAAK) was insufficient to account for cold transduction in HT(cool) or LT(cool) neurons. Our results suggest that cold transduction in sensory neurons is a complex process involving the activation and inhibition of several different ion channels. In addition, there appear to be both similarities and differences between mechanisms underlying cold transduction in LT(cool) and HT(cool) neurons. Identification of specific mechanisms underlying cold transduction in LT(cool) and HT(cool) neurons may enable the development of novel therapeutic interventions for the treatment of pathological conditions such as cold allodynia.

Effect of knee and hip position on hip extension range of motion in individuals with and without low back pain. A 2-group, nonrandomized, mixed design with 1 between-subjects factor (group) and 2 within-subjects factors (knee and hip position). To determine the amount of passive hip extension during changes in the knee angle in the sagittal plane, and the hip angle in the frontal plane in back-healthy (BH) subjects and subjects with low back pain (LBP). Information regarding the specific contributions of hip flexor muscles to limitations in hip extension range of motion (ROM) is necessary for the prescription of appropriate treatment. Thirty-five BH subjects (24 women and 11 men, mean age = 31.37 +/- 11.36) and 10 subjects with LBP (6 women and 4 men, mean age = 33.70 +/- 9.31) participated in the study. The passive length of the one- and two-joint hip flexor muscles was tested in 4 different conditions in which the positions of the knee and the hip were varied. The knee was positioned passively in full extension or 80 degrees of flexion while the hip was positioned passively in zero abduction or full abduction. Subjects with LBP displayed less passive hip extension than BH subjects (LBP, -5.61 degrees +/- 4.30; BH, -2.57 degrees +/- 4.18). Both groups had less hip extension when the knee was in flexion of 80 degrees than when the knee was fully extended (flexed, -5.51 +/- 4.50; extended, -0.98 degrees +/- 4.65), and when the hip was in zero hip abduction than when the hip was fully abducted (zero, -7.55 degrees +/- 5.03; full, 1.06 degrees +/- 4.31). The contribution of the different hip flexors to a hip extension limitation differed between BH and subjects with LBP. BH subjects demonstrated an effect of knee angle on hip extension when the hip was in zero abduction (flexed, -11.43 degrees +/- 5.81; extended, -2.49 degrees +/- 5.39), but not when the hip was in full abduction (flexed, 1.74 degrees +/- 3.91; extended, 1.89 degrees +/- 3.94). Subjects with LBP demonstrated an effect of knee angle on hip extension when the hip was in zero abduction (flexed, -12.60 degrees +/- 4.91; extended, -6.65 degrees +/- 5.03) and when the hip was in full abduction (flexed, -3.10 degrees +/- 5.53; extended, -0.10 degrees +/- 5.18). The results of this study provide evidence that changing the knee joint angle in the sagittal plane and the hip joint angle in the frontal plane, during the hip flexor length test, can affect the amount of passive hip extension ROM. The contribution of specific hip flexor muscles to a hip extension limitation may differ depending on the individual's movement dysfunction. Modifying the hip flexor length test, as described, should provide information about the specific muscles contributing to a hip joint extension limitation.

Colchicine poisoning: the dark side of an ancient drug. Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome. We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010. The search strategy included "colchicine" and "poisoning" or "overdose" or "toxicity" or "intoxication." Colchicine is readily absorbed after oral administration, but undergoes extensive first-pass metabolism. It is widely distributed and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. THERAPEUTIC AND TOXIC DOSES: The usual adult oral doses for FMF is 1.2-2.4 mg/day; in acute gout 1.2 mg/day and for gout prophylaxis 0.5-0.6 mg/day three to four times a week. High fatality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7-26 mg. CYP 3A4 and P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ketoconazole, ciclosporin, and natural grapefruit juice can increase colchicine concentrations. Co-administration with statins may increase the risk of myopathy. Colchicine's toxicity is an extension of its mechanism of action - binding to tubulin and disrupting the microtubular network. As a result, affected cells experience impaired protein assembly, decreased endocytosis and exocytosis, altered cell morphology, decreased cellular motility, arrest of mitosis, and interrupted cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure. REPRODUCTIVE TOXICOLOGY AND LACTATION: Colchicine was not shown to adversely affect reproductive potential in males or females. It crosses the placenta but there is no evidence of fetal toxicity. Colchicine is excreted into breast milk and considered compatible with lactation. Colchicine poisoning presents in three sequential and usually overlapping phases: 1) 10-24 h after ingestion - gastrointestinal phase mimicking gastroenteritis may be absent after intravenous administration; 2) 24 h to 7 days after ingestion - multi-organ dysfunction. Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion, and is generally a complete recovery barring complications of the acute illness. History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants suggest the diagnosis. Colchicine poisoning should be suspected in patients with access to the drug and the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia). Timely gastrointestinal decontamination should be considered with activated charcoal, and very large, recent (<60 min) ingestions may warrant gastric lavage. Supportive treatments including administration of granulocyte colony-stimulating factor are the mainstay of treatment. Although a specific experimental treatment (Fab fragment antibodies) for colchicine poisoning has been used, it is not commercially available. Although colchicine poisoning is relatively uncommon, it is imperative to recognize its features as it is associated with a high mortality rate when missed.

Glucose and alanine metabolism during bacterial infections in rats and rhesus monkeys. To investigate the effects of bacterial infection on glucose and alanine metabolism, a variety of studies were carried out in rat and monkey models. These included glucose turnover by a pulse-dose technique in infected rats; alanine and glucose production and utilization in control and septic monkeys; in vivo measurement of gluconeogenesis in rats, with and without an alanine load; the in vitro rate of glucose formation from various substrates by isolated liver perfusion and hepatic cells; and in vivo rates of oxidation of glucose labeled with 14C at the 1 or 6 carbon position. In rats, glucose turnover was markedly accelerated 24 hr after inoculation of either 10(4) or 10(7) Streptococcus pneumoniae. Glucose utilization and production were also accelerated during illness and early recovery from a pneumococcal infection in monkeys. The rates of gluconeogenesis as measured by either a pulse technique in rats or continuous infusion of labeled alanine in monkey were significantly elevated during pneumococcal septicemia. During the agonal stages (10(7) of the pneumococcal infection in rat, an alanine load resulted in a decreased rate of labeled glucose production and an increase in plasma glucose when compared to values of fasted control rats. However, early illness caused similar or increased rates of glucose production from alanine in vivo. Similar reduced rates of glucose formation were observed when the isolated livers or hepatocytes from rats during the agonal stages of infection were perfused with excess quantities of gluconeogenic substrates. Thus, in the rat, gluconeogenic capacity (ability to form glucose from excess substrates) appears to decrease only during the agonal stages of pneumococcal infection. During acute pneumococcal sepsis in the rhesus monkey, alanine production and utilization were significantly elevated and it was estimated that over 90% of the newly produced alanine was utilized for glucose synthesis. When arterial--venous differences were measured across the hindquarters, significantly more alanine was released, presumably from skeletal muscle of the septic monkey, compared to the recovery period or in the control groups. Thus, the increase in glucose synthesis in both rat and monkey appears to be correlated with substrate availability and kinetic rate, rather than gluconeogenic capacity of the liver. The major increase in glucose utilization during both S. pneumoniae and Francisella tularensis live vaccine strain (LVS) infections in rat was a progressive elevation in the rate of oxidation via the pentose phosphate shunt in the rat. Further, the rate of oxidation appeared to be correlated with the magnitude of the bacteremia, which is an indication of the severity of the infection...

First Report of Alternaria alternata Causing Black Leaf Spot of Rubber Tree in China. We first reported Alternaria heveae (E.G. Simmons ) to be the pathogen that caused black leaf spot of rubber tree (Hevea brasiliensis Muell. Arg) in Heikou county in July 2014 (1). Black leaf spots that resembled the symptoms caused by A. heveae were observed on the leaves of rubber trees of the whole propagule collection nursery in Jingping County (22°68' N and 103°05' E) of Yunnan Province. Black foliar spots (0.1 to 2 mm in diameter) surrounded by a yellow halo with lesions slightly sunken on the leaf surface were observed. To confirm whether the disease was caused by the same pathogen, 5-mm2 sections were removed from the leading edge of the lesion and were surface-sterilized in 75% ethanol, air-dried, plated on potato carrot agar (PCA), and incubated at 28°C in the dark. Colonies of the fungus on PCA had round margins and little aerial mycelia with gray-black coloration after 6 days of growth on PCA (2). Medium brown conidia were found to be in short chains of two to eight spores, ovoid, obclavate, and obpyriform, with or without a short conical or cylindrical-shaped apical beak. Conidia ranged from 22.5 to 67.5 μm long (mean 39.9 μm) × 10 to 15 μm wide (mean 12.5 μm; 100 colodia were measured), with three to six transverse septa and zero to three longitudinal or oblique septa. Morphological characteristics matched the descriptions of A. alternata [(Fries) Keissler] (4).The ITS1-5.8S-ITS2 region of one single-spore isolate, Ah02JP1, was amplified with primers ITS1 and ITS4. The PCR product was sequenced directly and deposited in GenBank (Accession No. KM111289). A BLAST search of the GenBank database revealed 100% similarity with A. alternata isolates KJ829535.1, KJ677246.1, and KF813070.1. Therefore, the pathogen was identified as A. alternata on the basis of its morphological characteristics and ITS sequence. Pathogenicity of a representative isolate, Ah02JP1 was confirmed using a field rubber tree inoculation method. Three rubber plants (the clone of rubber tree Yunyan77-4) were grown to the copper-colored leaf stage. Leaves were spray-inoculated (104 conidia per milliliter spore suspension) until drops were equally distributed using a manual pressure sprayer. Three rubber plants sprayed with sterile distilled water were used as controls. After inoculation, the plants were covered with plastic bags to maintain high relative humidity. The plastic bags were removed 2 days post-inoculation (dpi), and the plants were monitored daily for symptom development. Five days post-inoculation, spots similar to the original ones seen on the field trees developed on all inoculated leaves, while control leaves remained symptomless. A. alternata was re-isolated from spray-inoculated leaves, confirming Koch's postulates. A. alternata has been reported as the causal agent of leaf blight of rubber tree in India, which initially appeared as minute spots on leaves and enlarged with the growth of the leaves (3). However, in the present study, the symptoms (black leaf spots) remained small over time after inoculation. To our knowledge, this is the first report of A. alternata on rubber tree in China. Correct identification of pathogens is essential for disease management strategies. This report will establish a foundation for the further study of Alternaria alternata to address the disease effectively. References: (1) Z. Y. Cai et al. Plant Dis. 98:1011, 2014. (2) E. Mirkova. J. Phytopathol. 151:323, 2003. (3) C. B. Roy et al. J. Plantation Crops 34:499, 2006. (4) T. Y. Zhang. Page 32 in: Flora Fungorum Sinicorum, Vol. 16: Alternaria. Science Press, Beijing, 2003.

Where next with preoperative radiation therapy for rectal cancer? The basic question for radiation oncologists is what we hope to achieve from treatments that are adjuvant to surgery: better local (pelvic) control and, hopefully, because of that, fewer metastases. Chemotherapy could add to the local effect of irradiation and may also decrease distant metastases directly. Selection criteria for individual treatment could enhance the therapeutic index. Total mesorectal excision reduces the incidence of local recurrence, but preoperative (chemo) radiation is still indicated for more advanced tumors (T3-T4) and for lymph node involvement. Pelvic recurrences arise from tumor clonogens residual beyond the surgical margins. Thus, the practice of shrinking fields to boost the dose to the primary tumor makes no sense, except for tumors that invade residual structures, such as the sacrum. Subclinical disease beyond the future surgical margins grows more quickly than the primary tumor, and hence treatment should be as intense as tolerable. A short treatment course (e.g. 5 x 5 Gy) is desirable, but this regimen, which is currently the gold standard, should be compared (as in the recently closed randomized Polish trial) with higher-dose, longer-duration chemoradiotherapy regimens. The recently closed EORTC trial 22921 examines the benefit of pre- and postoperative chemotherapy combined with a long schedule of radiation. Likewise, continuous infusion of a cycle-active agent rather than bolus administration is a logical addition to radiation therapy in the treatment of fast-growing subclinical tumor extensions. The reduction in distant metastasis rates attributable to adjuvant chemotherapy varies greatly among reports. If the reduction is of the order of 10-25%, the efficacy of chemotherapy equates to as little as about 5 to 12.5 Gy and not more than 20 Gy of total body irradiation. Early excision after preoperative irradiation would be desirable if the primary tumor were still disseminating viable metastatic clonogens. Most tumors do not metastasize until they contain enough viable clonogens to render them clinically detectable. A dose of 10 Gy in 2 Gy fractions reduces at least 30-fold the absolute number of viable clonogens in the primary tumor, to levels that do not yield metastases from the untreated tumor. After a dose of 44-50 Gy in 2 Gy fractions, there is little chance that the surviving tumor clonogens could regrow to a metastasis-yielding volume in any reasonable radiation-surgery interval. Thus there is no tumor-related necessity for early postradiation surgery. The importance of the interval between radiation and surgery is currently being addressed in a Swedish randomized trial. Tumor volume should be included in the staging system. There are many tumor- and host-related characteristics that can be used to fingerprint the tumor to help select appropriate individual treatment.

Modulation of pituitary somatostatin receptor subtype (sst1-5) messenger ribonucleic acid levels by changes in the growth hormone axis. The role of individual components of the hypothalamic-pituitary-GH axis in the modulation of pituitary somatostatin (SRIF) receptor subtype (sst1-5) synthesis was assessed using multiplex RT-PCR to measure receptor messenger RNA (mRNA) levels in normal rats and spontaneous dwarf rats (SDRs). In SDRs, a strain with no immunodetectable GH, pituitary sst1 and sst2 mRNA levels were elevated, sst5 mRNA levels were reduced, and sst3 and sst4 mRNA levels did not significantly differ from those in normal controls. Treatment of SDRs with GH (72 h), but not insulin-like growth factor I, significantly decreased sst2 mRNA levels and increased sst4 and sst5 mRNA levels above vehicle-treated control levels. To test whether more rapid changes in circulating GH levels could alter SRIF receptor subtype expression, normal rats were infused (iv) with GH-releasing hormone (GHRH) for 4 h in the presence or absence of SRIF antiserum. GHRH infusion increased pituitary sst1 and sst2 and decreased sst5, but had no effect on sst3 and sst4 mRNA levels. Immunoneutralization of SRIF, which produced a rise in circulating GH levels, did not alter basal or GHRH-mediated SRIF receptor subtype expression. These observations indicate that acute suppression of SRIF tone does not regulate pituitary SRIF receptor subtype mRNA levels in vivo. The possibility that elevated circulating GH concentrations induced by GHRH infusion were responsible for the observed changes in SRIF receptor subtype mRNA levels was examined by infusing SDRs with GHRH for 4 h. GHRH did not increase sst1 mRNA levels in SDRs above their already elevated value. However, GHRH infusion produced an increase in sst2 and a decrease in sst5 mRNA levels similar to those observed in normal rats, indicating that the acute effects of GHRH on SRIF receptor subtype expression are independent of circulating GH levels. Primary rat pituitary cell cultures were incubated with GHRH (10 nM) or forskolin (10 microM) for 4 h to determine whether GHRH could directly mediate SRIF receptor subtype mRNA. GHRH treatment increased sst1 and sst2 mRNA levels and decreased sst5 mRNA levels, but had no effect on sst3 and sst4, similar to the results in vivo. The effect of forskolin mimicked that of GHRH on sst1, sst2, and sst5 mRNA, suggesting that GHRH acts through cAMP to directly mediate gene transcription or mRNA stability of these SRIF receptor subtypes. In addition, forskolin reduced sst3 and sst4 expression. These results strongly suggest that rat pituitary sst1, sst2, and sst5 mRNA levels are regulated both in vivo and in vitro by GHRH. The stimulatory action of GHRH on sst1 and sst2 and the inhibitory action on sst5 indicate that these receptor subtypes have independent and unique roles in the modulation of pituitary GH release.

Effects of dehydroepiandrosterone therapy on pubic hair growth and psychological well-being in adolescent girls and young women with central adrenal insufficiency: a double-blind, randomized, placebo-controlled phase III trial. The efficacy of oral dehydroepiandrosterone (DHEA) in the treatment of atrichia pubis and psychological distress in young females with central adrenal insufficiency is unknown. Our study aimed to evaluate this therapy. A total of 23 young females (mean age 18 yr, range 13-25) was enrolled in a double-blind randomized placebo-controlled trial. Inclusion criteria were ACTH deficiency plus two or more additional pituitary deficiencies, serum DHEA less than 400 ng/ml, and pubertal stage more than B2. Exclusion criteria were cerebral radiation with more than 30 Gy, tumor remission less than 1 yr, amaurosis, hypothalamic obesity, psychiatric disorders, and unstable hormone medication. Patients were randomized to placebo (n = 12) or 25 mg HPLC-purified DHEA/d (n = 11) orally for 12 months after stratification into a nontumor (n = 7) and a tumor group (n = 16). Clinical scoring of pubic hair stage was performed at 0, 6, and 12 months (primary endpoint), and psychometrical evaluation (Symptom Check-List-90-R and the Centre for Epidemiological Studies-Depression Scale) at 0 and 12 months (secondary endpoint). Androgen levels and safety parameters were measured at 0, 6, and 12 months; 24-h androgen urinary excretion rates were calculated at 0 and 12 months. In the placebo group, four patients dropped out because of recurrence of craniopharyngioma, manifestation of type 1 diabetes, and change of residence (n = 2); in the DHEA group, one patient dropped out because of recurrent anxiety attacks. DHEA substitution resulted in normalization of DHEA sulfate and androstanediol glucuronide morning serum levels 2 h after drug intake (P < 0.006), and of its 24 h urinary metabolite levels (P < 0.0001), placebo had no effect. Morning serum levels of androstenedione increased in the DHEA group (P < 0.02) but did not normalize. The DHEA group exhibited significant progress in pubic hair growth from Tanner stage I-III to II-V (mean: +1.5 stages), whereas the placebo group did not (relative risk 0.138; 95% confidence interval 0.021-0.914; P = 0.0046). Importantly, eight of the 10 Symptom Check-List-90-R scores, including those for depression, anxiety, and interpersonal sensitivity, and the global severity index improved in the DHEA group in comparison to the placebo group (P < 0.048). DHEA was well tolerated. In adolescent girls with central adrenal insufficiency, daily replacement with 25 mg DHEA orally is beneficial: atrichia pubis vanishes, and psychological well-being improves significantly.

[A historical review and some comments on the nuclear transplantation in fish]. In this review article, a brief history and main results of the studies on the nuclear transplantation (cloning) in fish was introduced. Late Professor T. C. Tung (TONG Di-Zhou), a noted Chinese Experimental Embryologist and his research group at the Institute of Zoology, the Chinese Academy of Sciences (CAS) in Beijing, China initiated and established successful technology of nuclear transplantation in fish in 1963. During the past 36 years, most of the studies on fish cloning were performed mainly by Chinese groups except only one article was published by authors in former USSR (Gasaryan et al. 1979), and the other one was published by Japanese authors in Japan (Niwa et al. 1999). The primary goals of the studies of Tung's group were: (1) to study the inter-relationship between the nucleus and the cytoplasm in terms of the controlling effects determined by nucleus or cytoplasm or both during the ontogenesis, cell differentiation and phenotypic expression in a developing animal; and (2) to produce fish clones of commercial importance for agricultural purposes. The most successful results that have been obtained by Tung's group in collaboration with the investigators at various fisheries institutions in China were the production of nucleocytoplasmic adult hybrid fish between different varieties, species, genera and subfamilies that produced viable offspring. Furthermore, these nucleocytoplasmic fish hybrid revealed that while most phenotypic characteristics are controlled by the nucleus, a few are controlled by the cytoplasm or by both. In addition, the resulting nucleocytoplasmic fish hybrids also showed some better characteristics of economic importance such as faster growth rate, increasing of protein content and reducing of fat content in muscle, etc. So far, no such kinds of evidences are available either in amphibian or in mammals. Another most important result obtained by other Chinese groups showed that the uncultured or cultured adult somatic cell in fish which can support the nuclear transplanted eggs developing into adults. They were: (1) a 17 month old gold-fish obtained by transplanting an adult erythrocytes into an enucleated egg (WU et al. 1982); (2) a subcultured kidney cell nucleus of Crucian carp (Carassius auratus) can support the transplanted enucleated egg of same species developing into a three years old adult with female sexual characteristics (CHEN et al. 1986) and (3) a cultured liver cell nucleus from grass carp (Ctenopharyngoden idellus) can support a nuclear transplanted unfertilized egg of the same species developing into an adult fish at least of one year old when that paper was published. Some discussions and comments for evaluating the results obtained from previous studies and suggestions for further investigations in this research field are also provided. More detailed information could be found in the book--"Cloning in Fish-nucleocytoplasmic Hybrids" which was written by Shaoyi Yan in English and published by International Union of Biological Sciences and Educational and Cultural Press Ltd. Hong Kong in 1998.

Structure of Dicopper Complexes of N,N,N',N'-Tetrakis[(2-benzimidazolyl)methyl]-2-hydroxy-1,3-diaminopropane with Coordinated Thiocyanate Counterions. The structures of five dicopper complexes of binucleating ligand HL-H (N,N,N',N'-tetrakis[(2-benzimidazolyl)methyl]-2-hydroxy-1,3-diaminopropane) with thiocyanate and some other counterions were investigated by the X-ray diffraction method. In Cu(2)(HL-H)(NCS)(2)Cl(2).6H(2)O.CH(3)OH, 1 (a = 12.524(5) Å, b = 14.429(4) Å, c = 16.343(3) Å, alpha = 109.01(2) degrees, beta = 92.62(2) degrees, gamma = 115.27(3) degrees, Z = 2, triclinic, P&onemacr;), one chloride is not coordinated. Distorted square pyramidal (SP) geometry is found for both CuN(3)ClN and CuN(3)ON coordination sites in which the N(3) tripodal coordination sites come from the two symmetric halves of HL-H and the other nitrogen atoms come from thiocyanate ions. In Cu(2)(HL-H)(NCS)(2)(ClO(4))(2).6H(2)O.2EtOH, 2 (a = 10.955(2) Å, b = 15.366(5) Å, c = 18.465(9) Å, alpha = 65.57(4) degrees, beta = 89.73(3) degrees, gamma = 79.81(2) degrees, Z = 2, triclinic, P&onemacr;), the coordination environments for the two copper ions are both CuN(3)ON. However, their geometries are different: one is distorted SP and the other is distorted trigonal bipyramid (TBP). In Cu(2)(HL-H)(NCS)(2)(ClO(4))(2)Cl.H(3)O.3.5H(2)O, 3 (a = 11.986(6) Å, b = 12.778(5) Å, c = 17.81(1) Å, alpha = 82.41(4) degrees, beta = 75.44(5) degrees, gamma = 78.46(4) degrees, Z = 2, triclinic, P&onemacr;), the chloride ion does not coordinate to copper ion, but it is hydrogen bonded to the hydroxy hydrogen. The coordination environments for the two copper ions are both CuN(3)ON with distorted SP geometries. In Cu(2)(HL-H)(NCS)Cl(3).6H(2)O, 4 (a = 12.026(5) Å, b = 14.369(6) Å, c = 16.430(6) Å, alpha = 111.64(3) degrees, beta = 90.51(4) degrees, gamma = 113.90(3) degrees, Z = 2, triclinic, P&onemacr;), one chloride does not coordinate. The coordination environments for the two copper ions are CuN(3)ON in severely distorted TBP geometry and CuN(3)Cl(2) in SP geometry. In Cu(2)(HL-H)(NCS)(3)OH.2H(2)O.3CH(3)OH.Et(2)O, 5 (a = 18.322(5) Å, b = 15.543(6) Å, c = 19.428(7) Å, beta = 102.78(3) degrees, Z = 4, monoclinic, P2(1)/c), the hydroxide ion does not coordinate. The coordination environments for the two copper ions are CuN(3)N(2) with a geometry inbetween SP and TBP but slightly closer to SP and CuN(3)ON in distorted SP geometry. The distances between the copper ions are in the range 4.45-7.99 Å, indicating negligible interaction between the copper ions. The hydroxy groups of HL-H in 1-5all coordinate to copper ions either in a terminal mode (in complexes 1, 4, and 5, denoted as OHR(t)) or in a bridging mode (in complexes 2 and 3, denoted as OHR(b)). These hydroxy groups do not lose their protons in all cases. All thiocyanate anions coordinate to copper ions through nitrogen atoms. All copper ions in 1-5 are pentacoordinated. The fact that the CuN(3) geometries of the tripodal coordination sites in HL-H do not allow the formation of a square planar complex, may be the driving force for the formation of pentacoordinated complexes. From the structurally known dicopper complexes of the HL-H type ligands, the relative coordinating abilities of ligands to CuN(3) are OHR(t) > NCS(-) > Cl(-)(t) > OHR(b) approximately Cl(-)(b), where the letters b and t in parentheses denote bridging and terminal coordination modes respectively.

EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer.[Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-2216.] We report here an update to these guidelines, including literature published through to November 2005. The results of this updated systematic literature review have enabled us to refine our guidelines based on the full body of data currently available. Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, and in patients undergoing cancer surgery. The addition of further Level I studies confirms our recommendation that in cancer patients receiving chemotherapy and/or radiotherapy, treatment with erythropoietic proteins should be initiated at a Hb level of 9-11 g/dL based on anaemia-related symptoms rather than a fixed Hb concentration. Early intervention with erythropoietic proteins may be considered in asymptomatic anaemic patients with Hb levels 11.9 g/dL provided that individual factors like intensity and expected duration of chemotherapy are considered. Patients whose Hb level is below 9 g/dL should primarily be evaluated for need of transfusions potentially followed by the application of erythropoietic proteins. We do not recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients undergoing chemotherapy or radiotherapy who have normal Hb levels at the start of treatment, as the literature has not shown a benefit with this approach. The addition of further supporting studies confirms our recommendation that the target Hb concentration following treatment with erythropoietic proteins should be 12-13 g/dL. Once this level is achieved, maintenance doses should be titrated individually. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia, with studies supporting the use of epoetin alfa and epoetin beta weekly and darbepoetin alfa given every week or every 3 weeks. We do not recommend the use of higher than standard initial doses of erythropoietic proteins with the aim of producing higher haematological responses, due to the limited body of evidence available. There is Level I evidence that, within reasonable limits of body weight, fixed doses of erythropoietic proteins can be used to treat patients with chemotherapy-induced anaemia. This analysis confirms that there are no baseline predictive factors of response to erythropoietic proteins that can be routinely used in clinical practice if functional iron deficiency or vitamin deficiency is ruled out; a low serum erythropoietin (EPO) level (only in haematological malignancies) appears to be the only predictive factor to be verified in Level I studies. Further studies are needed to investigate the value of hepcidin, c-reactive protein, and other measures as predictive factors. In these updated guidelines, we explored a new question of whether oral or intravenous iron supplementation increases the response rate to erythropoietic proteins. We found no evidence of increased response with the addition of oral iron supplementation, but there is Level II evidence of improved response to erythropoietic proteins with the addition of intravenous iron. However, the doses and schedules for intravenous iron supplementation are not yet well defined, and further studies in this area are warranted. The two major goals of erythropoietic protein therapy are prevention or elimination of transfusions and improvement of QoL. The total body of evidence shows that red blood cell (RBC) transfusion requirements are reduced following treatment with erythropoietic proteins. This analysis also confirms that QoL is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease following erythropoietic protein therapy, with more robust evidence now available that QoL was improved in studies investigating early intervention in cases of chemotherapy- or radiotherapy-induced anaemia. There is only indirect evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase. None of the studies addressed the question in a prospective, randomised fashion, and so the Taskforce does not recommend dose escalation as a general approach in all patients who are not responding. There is still insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. Our analysis of survival endpoints in studies involving patients receiving radio(chemo)therapy found that most studies were inconclusive, with no clear link between the use of erythropoietic proteins and survival. Likewise, we found no clear link between erythropoietic therapy and other endpoints such as local tumour control, time to progression, and progression-free survival. There is no evidence that pure red cell aplasia occurs in cancer patients following treatment with erythropoietic proteins, and the fear of this condition developing should not lead to erythropoietic proteins being withheld in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Additional trials are warranted, especially to define the optimal doses and schedules of intravenous iron supplementation during erythropoietic therapy. While our review did not address cost benefit evaluations in detail, the consensus is that studies taking into account all real determinants of cost and benefit need to be performed prospectively.

Drug resistance of Mycobacterium tuberculosis isolated from patients at a medical center in Taiwan. The advent of bactericidal drugs has had a major impact on the treatment of pulmonary tuberculosis. However, the main reasons for continuing tuberculosis prevalence are the resistance of mycobacteria and patients' lack of endurance to undergo the long-term therapy. In Taiwan, the prevalence of tuberculosis among the population of over 20-year olds has fallen from about 5.15% in 1957, to 0.88% in 1982, but then increased to 1.29% in 1987. Although it continued decreasing to 0.65% in 1994, tuberculosis remains a potential public health problem. To determine the temporal status of drug resistance pattern among the Mycobacterium tuberculosis (M. tuberculosis) isolated at Veterans General Hospital (VGH)-Taipei, analysis was undertaken of the drug susceptibility data reported by the central Mycobacterial Laboratory, using conventional indirect methods, between 1990 to 1992. The susceptibility pattern of 651 M. tuberculosis isolates obtained from patients admitted to VGH-Taipei during 1990 to 1992 were analyzed; 504/651 (77.4%) were sensitive to all drugs tested. Among veterans, 23.7% (95/401) had organisms resistant to one or more antituberculosis medications: 11.5% (46/401) to a single drug; 6.2% (25/401) to two drugs; 3.2% (13/401) to three drugs, and 2.7% (11/401) to four drugs. The overall resistance rates in isolates from 250 non-veterans (142 males and 108 females) were 22.5% (32/142) in male patients and 18.5% (20/108) in female patients. Among the 142 male patients, 6.3% were resistant to a single drug; 3.5% to two; 7.7% to three and 4.9% to four drugs. Among 108 female patients, 8.3% to a single drug; 1.9% to two drugs; 2.8% to three drugs, and 5.6% to four drugs. The proportion of drug-resistance was higher in the isolates from patients with a history of previous therapy (p < 0.05). Overall, of the 401 veterans with positive cultures, 4.0% had isolates resistant to only isoniazid (INH), 14.7% had isolates resistant to at least INH, and 7.5% had isolates resistant to both INH and rifampin (RIF). Of the 142 non-veteran males, 1.4% had isolates resistant to only INH, 16.9% had isolates resistant to at least INH, and 10.6% had isolates resistant to both INH and RIF. Of the 108 non-veteran females, 3.7% had isolates resistant to only INH, 12.0% had isolates resistant to at least INH, and 8.3% had isolates resistant to both INH and RIF. Among the 401 veterans, all the drug resistant isolates were found in patients older than 45 years, and of these, 66.3% (63/95) were over 65 years, whereas age was not a significant factor for predicting resistance rates among the non-veteran patients. There has been a marked increase in drug-resistant tuberculosis in old aged veterans. In contrast, age was not found to be a significant factor to predict resistance rates among the non-veterans. Previously treated patients are at increased risk for drug resistance. In view of these data, it is important to identify drug susceptibility patterns accurately from all tubercle bacilli isolated from patients as this has implications for control programs as well as for patient therapy. Surveillance of drug resistance is again being considered for patients admitted to this hospital, and all physicians are urged to remain alert to drug-resistance rates and patterns in the areas where they practice.

Second-generation dual-energy computed tomography of the abdomen: radiation dose comparison with 64- and 128-row single-energy acquisition. This study was designed to compare the radiation dose in abdominal dual-energy (DE) and single-energy (SE) acquisitions obtained in clinical practice with a second-generation DE computed tomography (DECT) and to analyze the dose variation in comparison with an SE acquisition performed with a 64-row SECT (SECT). A total of 130 patients divided into 2 groups underwent precontrast and portal abdominal 128-row CT examination. In group A, DE portal acquisition was performed using a detector configuration of 2 × 40 × 0.6 mm, tube A at 80 kVp and a reference value of 559 mAs, tube B at 140 kVp and a reference value of 216 mAs, pitch 0.6, and online dose modulation; group B underwent SE portal acquisition using a detector configuration of 64 × 0.6 mm, 120 kVp and a reference value of 180 mAs, pitch 0.75, and online dose modulation. Group C consisted of 32 subjects from group A previously studied with 64-row SECT using the following parameters: detector configuration 64 × 0.6 mm, 120 kVp and a reference value of 180 mAs, pitch 0.75, and online dose modulation. In each group, the portal phase dose-length product and radiation dose (mSv) were calculated and normalized for a typical abdominal acquisition of 40 cm. After normalization to standard 40-cm acquisition, a dose-length product of 599.0 ± 133.5 mGy · cm (range, 367.5 ± 1231.2 mGy · cm) in group A, 525.9 ± 139.2 mGy · cm (range, 215.7-882.8 mGy · cm) in group B, and 515.9 ± 111.3 mGy · cm (range, 305.5-687.2 mGy · cm) in group C was calculated for portal phase acquisition.A significant radiation dose increase (P < 0.05) was observed in group A (10.2 ± 2.3 mSv) compared with group B (8.9 ± 2.4) and group C (8.8 ± 1.9 mSv). No significant difference (P > 0.05) was reported between SE 64- and 128-row acquisitions. A significant positive correlation between radiation dose and body mass index was observed in each group (group A, r = 0.59, P < 0.0001; group B, r = 0.35, P < 0.0001; group C, r = 0.20, P = 0.0098). In clinical practice, abdominal DECT acquisition shows a significant but minimal radiation dose increase, on the order of 1 mSv, compared with 64- and 128-row SE acquisition. The slightly increased radiation dose can be justified if the additional information obtained using a spectral imaging approach directly impacts on patient management or reduce the overall radiation dose with the generation of virtual unenhanced images, which can replace the precontrast acquisition.

Alterations in growth hormone secretion and clearance in peripubertal boys with chronic renal failure and after renal transplantation. Cooperative Study Group of Pubertal development in Chronic Renal Failure. To elucidate the endocrine mechanisms underlying the pubertal growth failure observed in patients with chronic renal failure (CRF), we used deconvolution analysis to estimate the rates of GH secretion and elimination in nighttime plasma GH profiles of peripubertal boys with CRF and after renal transplantation (Tx). Forty-three boys with advanced CRF (conservative treatment with glomerular filtration rate < 25 mL/min.1.73 m2 or dialysis; CT/D group), 38 boys after Tx, and 40 healthy control boys were studied. The estimated plasma GH half-life (mean +/- SEM) was significantly higher (P < 0.05) in CRF (25 +/- 1.8 min) than in Tx patients (21 +/- 1.6 min) and controls (20 +/- 0.5 min). In the pre- and early pubertal CT/D boys, the calculated GH secretion rate was low normal or reduced when expressed in absolute numbers or normalized per unit distribution volume or body surface. In late puberty, whereas body surface-corrected GH secretion was double the prepubertal value in normal boys (389 +/- 56 vs. 868 +/- 113 micrograms/m2.11 h; P < 0.01), it did not differ significantly from the prepubertal rate in CT/D boys (281 +/- 59 vs. 389 +/- 56 micrograms/m2.11 h). GH hyposecretion resulted from a decrease in the mass of GH released within each burst, whereas burst frequency was unchanged. In the Tx group, GH secretion rates were significantly reduced in the prepubertal (221 +/- 39 micrograms/m2.11 h; P < 0.05) and late pubertal period (266 +/- 64 micrograms/m2.11 h; P < 0.01). The mass of hormone secreted per burst was significantly reduced at each pubertal stage, whereas GH secretory burst frequency tended to be increased (significant in prepubertal group, P < 0.05). The GH secretion rate was positively correlated with plasma testosterone levels (r = 0.58; P < 0.0001) in controls, but not in CT/D or Tx patients. GH secretion rates were lower than expected at each level of plasma testosterone in both patient groups except CT/D boys with plasma testosterone below 0.9 nmol/L. In the Tx group, GH secretion rate was positively correlated with relative height (r = 0.31; P < 0.05). The dosage of corticosteroids administered for immunosuppression was negatively correlated with GH burst mass (r = -0.42; P < 0.01) and GH secretion rate (r = -0.29; P = 0.08) and positively correlated with GH burst frequency (r = 0.49; P < 0.01). We conclude that in peripubertal boys with CRF, a state of GH hyposecretion is associated with an increase in the apparent plasma half-life of GH.(ABSTRACT TRUNCATED AT 400 WORDS)

High school allied health students and their exposure to the profession of EMS. Ensuring a stable Emergency Medical Services (EMS) workforce is a growing concern, and effective recruiting strategies are needed to expose young adults to the EMS profession. The objective of this study was to assess the exposure of high school allied health students to EMS as a career option, as well as measure their attitudes and beliefs about the EMS profession. Hypothesis Few high school allied health students are exposed to EMS educational and career opportunities. A convenience sample of allied health students in a rural high school system was surveyed about exposure to EMS, career intentions, factors impacting career decisions, and attitudes and beliefs about EMS. Descriptive statistics were calculated, and intention to pursue an EMS career was modeled using logistic regression. Of 171 students enrolled in allied health courses across six high schools, 135 (78.9%) agreed to participate; 85.2% were female. Almost all (92.6%) respondents intended to pursue a health career, but only 43.0% reported that their allied health course exposed them to EMS as a profession. Few participants (37.7%) were knowledgeable about EMS associate degree or baccalaureate degree (27.4%) programs. Only 20.7% of the respondents intended to pursue EMS as a career, although 46.0% wanted to learn more about the profession. Most (68.2%) students expressed interest in an emergency medical technician (EMT) course if one were offered, and 80.0% were interested in a ride-along program. Independent predictors of pursuing an EMS career included exposure to EMS outside of high school (OR = 7.4, 95% CI = 1.7-30.4); media influence on career choice (OR = 9.6, 95% CI = 1.8-50.1); and the belief that EMS was mentally challenging (OR = 15.9, 95% CI = 1.1-216.6). Negative predictors included the beliefs that an EMS career was stimulating (OR = 0.05, 95% CI = 0.00-0.53) and physically challenging (OR = 0.06, 95% CI = 0.00-0.63); as well as prior exposure to an EMS job advertisement (OR = 0.14, 0.03-0.53). Overall, there was a lack of exposure to career and educational options in EMS among allied health students in the school system studied, and few students intended to pursue an EMS career after graduation. However, the majority of students indicated they would like to learn more about EMS, and would enroll in an EMT course and ride-along program if available. These findings suggest that, with exposure to the profession, more allied health students could choose EMS as a career.

Use of test-day records beyond three hundred five days for estimation of three hundred five-day breeding values for production traits and somatic cell score of Canadian Holsteins. The Canadian Test-Day Model includes test-day (TD) records from 5 to 305 d in milk (DIM). Because 60% of Canadian Holstein cows have at least one lactation longer than 305 d, a significant number of TD records beyond 305 DIM could be included in the genetic evaluation. The aim of this study was to investigate whether TD records beyond 305 DIM could be useful for estimation of 305-d estimated breeding value (EBV) for milk, fat, and protein yields and somatic cell score. Data were 48,638,184 TD milk, fat, and protein yields and somatic cell scores from the first 3 lactations of 2,826,456 Canadian Holstein cows. All production traits were preadjusted for the effect of pregnancy. Subsets of data were created for variance-component estimation by random sampling of 50 herds. Variance components were estimated using Gibbs sampling. Full data sets were used for estimation of breeding values. Three multiple-trait, multiple-lactation random regression models with TD records up to 305 DIM (M305), 335 DIM (M335), and 365 DIM (M365) were fitted. Two additional models (M305a and M305b) used TD records up to 305 DIM and variance components previously estimated by M335 and M365, respectively. The effects common to all models were fixed effects of herd x test-date and DIM class, fixed regression on DIM nested within region x age x season class, and random regressions for additive genetic and permanent environmental effects. Legendre polynomials of order 6 and 4 were fitted for fixed and random regressions, respectively. Rapid increase of additive genetic and permanent environmental variances at extremes of lactations was observed with all 3 models. The increase of additive genetic and permanent environmental variances was at earlier DIM with M305, resulting in greater variances at 305 DIM with M305 than with M335 and M365. Model M305 had the best ability to predict TD yields from 5 through 305 DIM and less error of prediction of 305-d EBV than M335 and M365. Model M335 had smaller change of 305-d EBV of bulls over the period of 7 yr than did M305 and M365. Model M305a had the least error of prediction and change of 305-d EBV from all models. Therefore, the use of TD records of Holstein cows from 5 through 305 DIM and variance components estimated using records up to 335 DIM is recommended for the Canadian Test-Day Model.

Potential sensitivity of pork production situations aiming at high-quality products to the use of entire male pigs as an alternative to surgical castrates. The perspective of a possible ban on surgical castration of male pigs in the EU is a real challenge for pork production systems aiming at (very) high-quality products. Information was collected from a total of 272 situations in 16 European countries, including 170 situations related to EU protected designations (Database of Origin & Registration (DOOR) database) and 102 other situations related to high-quality products or differentiated production systems, in order to evaluate their potential sensitivity to the use of entire male pigs along four dimensions: BT_Inc, likelihood of increased levels of boar taint compounds compared with conventional production of entire males; BT_Per, extent to which (some of) the associated pork product(s) are susceptible to perception of boar taint by consumers; FatQQ, likelihood that the quality of (some of) the related products is decreased due to the lower fat quantity and quality in entire males; Manag, increased likelihood of animal management and welfare problems compared with conventional production of entire males. Situations corresponding to EU protected designations (DOOR situations) were on average more sensitive to entire male production but 11% of the non-DOOR situations were highly potentially sensitive, whereas one-third of the DOOR situations had low potential sensitivity. In total, 37% of the situations where castration is not formally specified as mandatory exhibited high potential sensitivity to entire male production. Three main patterns of situations were identified via ascending hierarchical clustering. A first pattern including 31% of the DOOR situations and 74% of the other ones, had potentially no increased risk compared with conventional production of entire males. A second pattern including 28% of the DOOR situations and 16% of the other ones had a high, moderate and low potential sensitivity for FatQQ, BT_Inc and Manag, respectively. The third pattern including 41% of the DOOR situations and 11% of the other situations had high potential sensitivity for BT_Inc and FatQQ, associated with moderate to high sensitivity for Manag. The approach used to evaluate the sensitivity to entire male pig production from the limited information collected for this study has many limitations. More precise approaches using more specific information are needed to evaluate the actual sensitivity of individual situations to the use of entire male pigs. Still, the present study provides a first global insight on the capacity of European production systems aiming at high-quality products to use entire male pigs as an alternative to surgical castration.

Modulation of the adhesion of hemopoietic progenitor cells to the RGD site of fibronectin by interleukin 3. The integrins are a class of adhesion molecules which have been implicated in the homing of hemopoietic stem cells and in their restriction within the bone marrow. Integrins function as mediators of cell-extracellular matrix (ECM) interactions amd also of cell-cell interactions. They are unique membrane receptors which are capable of activation, change in affinity, and change in expression. Because of their broad potential for modulation we examined the effect of a cytokine growth factor which is present constitutively in the marrow, interleukin 3 (IL3), on integrin-mediated adherence of hemopoietic progenitor cells to the matrix component fibronectin (FN). The multipotential murine cell line B6Sut and the committed granulocyte progenitor cell line FDCP-1 were used. Both of these cell lines have been shown to bind to FN-coated dishes and to dishes coated with the 120 kDa and 40 kDa chymotryptic fragments of FN. It was found that after a brief withdrawal of IL3 the cells lost 80% adherence to the 120 kDa FN fragment containing the RGD cell binding site. This loss of binding was not related to a loss of viability, appeared unrelated to the growth/survival activity of IL3, and was quickly reversible by readdition of the growth factor. Adhesion of these cells to the RGD site was likely mediated by alpha 5 beta 1 integrin which was identified in the cell membrane of both cell lines, but present in low copy number in B6Sut cells. Two antibodies against the external and internal domains of alpha 5 and one antibody against beta 1 were used to study expression of the integrin. By flow cytometry the expression of alpha 5 was found to decrease in both cell lines by 4 h in the absence of IL3. The relative mean fluorescence intensity for B6Sut cells decreased from 1.0 (control cells always in the presence of IL3) to 0.6 over 4 h, and for FDCP-1 cells the decrement was from 1.0 to 0.8. The loss of RGD-mediated adhesion in the absence of IL3 appeared to proceed through this decrement in expression of the integrin; a loss of affinity of the receptor for its substrate was not detected. The general modulation of integrin activity by growth factors is of great interest because of its potential negative impact on the endothelium in cytokine-treated patients, and also because of its potential positive impact on engraftment during clinical bone marrow transplantation.

Comparative proteomics of mitosis and meiosis in Saccharomyces cerevisiae. Precise and timely segregation of genetic material and conservation of ploidy are the two foremost requirements for survival of a eukaryotic organism. Two highly regulated cell division processes, namely mitosis and meiosis are central to achieve this objective. The modes of chromosome segregation are distinct in these two processes that generate progeny cells of equal ploidy and half the ploidy in mitosis and meiosis, respectively. Additionally, the nutritional requirement and intracellular processing of biological cue also differ in these two processes. From this, it can be envisaged that proteome of mitotic and meiotic cells will differ significantly. Therefore, identification of proteins that differ in their level of expression between mitosis and meiosis would further reveal the mechanistic detail of these processes. In the present study, we have investigated the protein expression profile of mitosis and meiosis by comparing proteome of budding yeast cultures arrested at mitotic metaphase and metaphase-I of meiosis using proteomic approach. Approximately 1000 and 2000 protein spots were visualized on 2-DE and 2D-DIGE gels respectively, out of which 14 protein spots were significant in 2-DE and 22 in 2D-DIGE (p<0.05). All the significant spots were reproducible in all biological replicates and followed the same trend. Identification of the proteins from these spots revealed that nine proteins were common in both 2-DE and 2D-DIGE. These proteins are found to be involved in various cellular processes and pathways such as cytoskeleton function and cytokinesis, carbon, nitrogen, lipid metabolism, general translation and protein folding. Among these, our further study with the cytoskeletal proteins reveals that, compared to mitosis, an up-regulation of actin cytoskeleton and its negative regulator occurs in meiosis. Mitosis and meiosis are two different types of cell division cycles with entirely different outcomes with definite biological implication for almost all eukaryotic species. In this work, we investigated, for the first time, the differential proteomic profile of Saccharomyces cerevisiae culture arrested at mitotic metaphase (M) and metaphase-I (MI) of meiosis using 2-DE and 2D-DIGE. Our findings of up-regulation of actin and its negative regulator cofilin during meiosis suggest that the rate of actin cytoskeleton turnover is more in meiosis and actin cytoskeleton may play more crucial role during meiosis compared to mitosis. Present study also suggests that actin cytoskeleton and its regulators accumulated during meiosis by forming stable protein structure even though the corresponding mRNAs are degraded as cells enter into meiosis. This is in accordance with recent studies in higher eukaryotes where actin cytoskeleton is found to play vital role during meiotic chromosome segregation. Information generated by this study is significant to reveal that even though a cell that, unlike mitosis, is metabolically inactive with no isotropic bulging of membranes as buds (in meiosis) can require more actin cytoskeleton presumably to support nuclear movements.

[Pediatric patient in adult age. Long-terms results of esophageal replacement]. Esophagocoloplasty is one of the most used procedures for esophageal replacement in children. Considering high life expectancy in these patients, long-term results must be considered when evaluating this technique. The aim of our study is to evaluate quality of life of adult patients who underwent surgery at pediatric age. We report a retrospective study of 99 patients who underwent esophageal replacement in our institution between 1966 and 2006. Eight of them have died and 63 out of the remaining 91 are over 18 years now and represent our study serie. Long-term results and actual situation of those patients, considering psychological, physic and social aspects, were evaluated through clinical review and telephonic interview. Karnofsky index was applied to mesure functional ability from 0-100% (bad, medium, good-excellent) according to the answers the patients gave to our questions. We also recorded their health personal experience and subjective evaluation of their quality of life. Sixty-three patients were reviewed (43 males and 20 females) with a mean age of 4.3 +/- 3.4 D.S. Mean follow-up time was 29.6 +/-7.7 years. Indications for esophageal replacement were as follows: caustication (n = 32), type III esophageal atresia (n = 15), type I AE (n = 13) and others (n = 3). In 48 patients the graft was placed in retroestenal position and in 15 cases retromediastic location was used. Postoperative period was uneventful in 44% of the patients, being the most frequent early complications in the remaining, cervical leakage and stenosis. Long-term, 56,8% did not have any sequelae, 28.5% required further surgery and the remaining 43.13% presented the following complications: symptomatic graft reflux (22), scoliosis and thoracic asymmetry (12), colonic redundancy or cervical diverticulum (7), food impaction (6) and failure to thrive (5). Only one 38 year old patient does not have intestinal tract continuity nowadays. Thirty-one patients have a Karnofsky index > or = 80-100%, being considered healthy and able to have a normal activity. Eighteen patients are included between 40-80%, being the most frequent limitation the need of medication to avoid reflux, backache and occasional episodes of food impact. Only 2 patients have Karnofsky index inferior to 40%. None of them are under 20%. Esophagocoloplasty allows restoration of intestinal tract continuity in almost all cases and the mortality of this procedure has decreased over time. Even though some risks are still remarkable, it offers long-term good results with little repercussion on functional ability in adult age. Most of the patients consider themselves healthy and enjoy an acceptable quality of life.

Assessing mercury exposure and effects to American dippers in headwater streams near mining sites. To evaluate mercury (Hg) exposure and possible adverse effects of Hg on American dipper (Cinclus mexicanus) reproduction, we collected eggs and nestling feathers and the larval/nymph form of three Orders of aquatic macroinvertebrates (Ephemeroptera, Plecoptera and Trichoptera = EPT) important in their diet from three major headwater tributaries of the upper Willamette River, Oregon in 2002. The Coast Fork Willamette River is contaminated with Hg due to historical cinnabar (HgS) mining at the Black Butte Mine; the Row River is affected by past gold-mining operations located within the Bohemia Mining District, where Hg was used in the amalgamation process to recover gold; and the Middle Fork Willamette River is the reference area with no known mining. Methyl mercury (MeHg) concentrations (geometric mean) in composite EPT larvae (111.9 ng/g dry weight [dw] or 19.8 ng/g wet weight [ww]), dipper eggs (38.5 ng/g ww) and nestling feathers (1158 ng/g ww) collected from the Coast Fork Willamette were significantly higher than MeHg concentrations in EPT and dipper samples from other streams. Total mercury (THg) concentrations in surface sediments along the same Hg-impacted streams were investigated by others in 1999 (Row River tributaries) and 2002 (Coast Fork). The reported sediment THg concentrations paralleled our biological findings. Dipper breeding territories at higher elevations had fewer second clutches; however, dipper reproductive success along all streams (including the lower elevation and most Hg-contaminated Coast Fork), was judged excellent compared to other studies reviewed. Furthermore, MeHg concentrations in EPT samples from this study were well below dietary concentrations in other aquatic bird species, such as loons and ducks, reported to cause Hg-related reproductive problems. Our data suggest that either dipper feathers or EPT composites used to project MeHg concentrations in dipper feathers (with biomagnification factor of 10-20x) may be used, but with caution, to screen headwater streams for potential Hg-related effects on dippers. When actual feather concentrations or projected feather concentrations are equal to or lower than concentrations reported for the Coast Fork, dippers are expected to reproduce well (assuming adequate prey and suitable nest sites). When Hg concentrations are substantially higher, more detailed investigations may be required. Birds feeding almost exclusively on fish (e.g., osprey [Pandion haliaetus]) and usually found further downstream from the headwaters would not be adequately represented by dippers given the higher MeHg concentrations in fish resulting from biomagnification, compared to lower trophic level invertebrates.

Does avoidance of cardiopulmonary bypass decrease the incidence of stroke in diabetics undergoing coronary surgery? The adverse effects of diabetes mellitus on the coronary circulation and the higher incidence of cardiovascular events in diabetic patients are well documented [Johnson 1982]. Improvements in myocardial protection, revascularization techniques, and anesthetic management have had favorable impacts on coronary artery bypass grafting (CABG) outcome in diabetic patients. Despite that, diabetic patients are significantly more likely to have a prior history of myocardial infarction, congestive heart failure, peripheral vascular disease, and hypertension, as well as having a significantly greater baseline serum creatinine. The aim of our study was to record, compare, and analyze the stroke rate among patients with a history of preoperative diabetes undergoing "off-pump" CABG (OPCAB) with conventional cardiopulmonary bypass (CPB) CABG to determine whether the stroke rate in this higher risk population could be decreased by off-pump techniques. The records of 1,227 patients with a pre-operative history of diabetes undergoing conventional CABG (973 patients, 79.3%) using cardiopulmonary bypass and off-pump CABG 254 (20.7%) were analyzed from 1995 through 1999. There were no differences in age, sex, or elective/urgent status of patients. Preoperative risk factors (gender distribution, carotid disease, ejection fraction, CHF, hypertension, previous MI) were identical in both groups. The goal of the operations were complete revascularization, which was achieved via median sternotomy in both groups. Our reported series reveals a stroke rate of 3.6% in the CPB group and 1.2% in the off-pump group. This evidence alone was not statistically significant, but two other high-risk criteria for stroke, re-do CABG and calcified aortas, revealed that the off-pump series had a higher percentage of each (26.4% redos in off-pump vs. 8.7% CPB redos, p < 0.005; 7.1% calcified aorta cases in the off-pump group vs. 2.9% in the CPB group, p < 0.004). The threefold reduction in stroke may be clinically significant in light of the higher-risk profile of the off-pump group. The limitations of this study are that it was retrospective, there were a small number of events, and different surgeons were involved in the two different approaches to these patients. Improvements in myocardial protection, revascularization techniques, and anesthetic management have made significant, favorable impacts on CABG outcome in diabetic patients. New diagnostic and therapeutic strategies must be developed to lessen the medical and economic implications of stroke. A larger series or a more effective way of analyzing preoperative risk may well have shown a statistically significant difference in the stroke incidence given the differences in preoperative risk factors/stroke predictors. Until such advances occur, a threefold reduction of stroke incidence using OPCAB certainly makes this technique a favorable one for high-risk diabetics requiring coronary revascularization.

Perinatal outcomes of women undergoing cesarean delivery after prior myomectomy. The American College of Obstetricians and Gynecologists recommends that women who have had a prior myomectomy that entered the endometrial cavity undergo cesarean delivery in order to avoid the possible complication of uterine rupture. Women with prior myomectomies may also have intraabdominal adhesions, complicating future surgery and if myomas remain after myomectomy, they may have more bleeding complications during their subsequent pregnancies. The purpose of this study was to evaluate maternal and neonatal outcomes after prior myomectomy in women undergoing planned cesarean delivery. We conducted a retrospective cohort study using the Maternal Fetal Medicine Units Cesarean Registry database comparing women undergoing a cesarean delivery with a history of prior myomectomy to women undergoing a cesarean delivery without a history of a prior myomectomy. Inclusion criteria were singleton gestations at term undergoing planned cesarean delivery. Exclusion criteria were stillbirth, cesarean delivery indication for nonreassuring fetal heart rate, macrosomia, abruption, previa or women undergoing planned trial of labor after cesarean. Primary outcome was incidence of blood transfusion. Maternal and neonatal outcomes were compared secondarily. Logistic regression was used to adjust for confounders. The entire study population included 73,257 deliveries; 34,002 women met inclusion criteria, of which 367 had a prior myomectomy and 33,635 were controls. The demographics, which varied by maternal age, race and number of prior cesareans were adjusted for when calculating maternal outcomes. The rate of intraoperative transfusion in the prior myomectomy group was 1.4% (5/367) compared to 0.4% (131/33,635) in the control group (aOR 2.8; 95% CI 1.15-6.79). The prior myomectomy group had a higher incidence of postpartum transfusion rate (2.5%, 9/367) compared to the control group (1.2%, 416/33,635) (aOR 2.03; 1.06-3.92), uterotonic usage (5.4%, 20/367) compared to the control group (3.5%, 1165/33,635; aOR 1.57; 95% CI 1.01-2.45), bowel injury (0.5%, 2/367) compared to the control group (0.0%, 14/33,635; aOR 8.13; 95% CI 2.05-32.28) and cesarean hysterectomy (1.4%, 5/367) compared to the control group (77/33,635; aOR 3.43; 95% CI 1.32-8.91). Neonatal outcomes were not different between groups. Prior myomectomy in women with term, singleton gestations undergoing planned cesarean delivery was associated with an 180% increased risk of intraoperative transfusion compared to the control group. We also found that women in the myomectomy group are 57% more likely to use uterotonics, 713% more likely to experience a bowel injury, 243% more likely to undergo a cesarean hysterectomy, and 227% more likely to need a classical uterine incision during delivery. Neonatal morbidity was not statistically different between the groups.

Investigation of training and support needs in rural and remote disability and mainstream service providers: implications for an online training model. Objectives It is known that there are difficulties in recruiting and retaining practitioners in rural and remote communities and that access to support and professional development can be key in breaking this cycle. Technology provides a possible solution not only for increasing access to these opportunities, but also in building community capacity to support children with autism. The aim of the present study was to investigate the current learning and support needs within rural and remote professionals prior to setting up a model of support. Methods An online survey was used to gather information from service providers in rural and remote communities on their demographics, current skills and confidence in working with clients on the autism spectrum, current supervision and professional development, identified learning and support needs, and the availability and uptake of technology for accessing professional development. Results Respondents reported below average levels of perceived confidence and skills when working with children with autism, most notably children with challenging behaviour. Half the respondents do not currently attend supervision sessions, with only 15% receiving regular supervision (fortnightly or more often), and 66% of respondents had travelled more than 3h to access professional development workshops. The majority of participants had access to technology and over half had already used this for online training. Conclusion Overall, service providers in rural and remote areas are generally not currently meeting their needs in terms of frequency of supervision and professional development. The present needs analysis identifies key areas for learning, the ideal frequency of support and the acceptability of using technology to deliver this support. This information will guide future researchers in the development of an evidence-based model that will be accessible and meaningful to its participants. What is known about the topic? It is known that there are difficulties in recruiting and retaining practitioners in rural and remote communities and that access to support and professional development can be key in breaking this cycle, which may be triggered by geographical isolation. Technology-delivered intervention and support, also known as eHealth or Telehealth, has been used successfully in the disability sector for medical rehabilitation, direct intervention, employment support and support groups, but there is little evidence as to how technology is received by and implemented with disability and mainstream service providers supporting children with autism living in remote regions. What does this paper add? This paper provides an insight into the current skills and confidence of a broad range of service providers, including educators, allied health therapists and therapy and community support workers, in working with children with autism. This paper also investigates the experience, feasibility and potential uptake of a technology-driven program of support and professional development in rural and remote Australia. Finally, this paper provides an insight into the desired frequency of training and support, as well as identified learning support needs. What are the implications for practitioners? These findings have and will continue to guide practitioners in the development of an evidence-based, technology-driven model of supporting rural and remote staff working with children with autism. Technology has the potential to provide practitioners in geographically isolated areas with access to more responsive, collaborative and individualised professional support and training. Such practice may improve the skills of practitioners and the level of support they can provide their clients with autism, with the added potential of increasing staff retention in rural and remote areas of Australia.

Investigation on the ability of an ultrasound bubble detector to deliver size measurements of gaseous bubbles in fluid lines by using a glass bead model. Detectors based on ultrasonic principles are today's state of the art devices to detect gaseous bubbles that may be present in extracorporeal circuits (ECC) for various reasons. Referring to theoretical considerations and other studies, it also seems possible to use this technology to measure the size of detected bubbles, thus offering the chance to evaluate their potential hazardous effect if introduced into a patient's circulation. Based on these considerations, a commercially available ultrasound bubble detector has been developed by Hatteland Instrumentering, Norway, to deliver bubble size measurements by means of supplementary software. This device consists of an ultrasound sensor that can be clamped onto the ECC tubing, and the necessary electronic equipment to amplify and rectify the received signals. It is supplemented by software that processes these signals and presents them as specific data. On the basis of our knowledge and experience with bubble detection by ultrasound technology, we believe it is particularly difficult to meet all the requirements for size measurements, especially if these are to be achieved by using a mathematical procedure rather than exact devices. Therefore, we tried to evaluate the quality of the offered bubble detector in measuring bubble sizes. After establishing a standardized test stand, including a roller pump and a temperature sensor, we performed several sets of experiments using the manufacturers software and a program specifically designed at our department for this purpose. The first set revealed that the manufacturer's recommended calibration material did not meet essential requirements as established by other authors. Having solved that problem, we could actually demonstrate that the ultrasonic field, as generated by the bubble detector, has been correctly calculated by the manufacturer. Simply, it is a field having the strongest reflecting region in the center, subsequently losing strength toward the ECC tubing's edge. The following set of experiments revealed that the supplementary software not only does not compensate for the ultrasonic field's inhomogeneity, but, furthermore, delivers results that are inappropriate to the applied calibration material. In the last set of experiments, we were able to demonstrate that the signals as recorded by the bubble detector heavily depend upon the circulating fluid's temperature, a fact that the manufacturer does not address. Therefore, it seems impossible to resolve all these sensor related problems by ever-increasing mathematical intervention. We believe it is more appropriate to develop a new kind of ultrasound device, free of these shortcomings. This seems to be particularly useful, because the problem of determining the size of gaseous bubbles in ECC is not yet solved.

First Report of Grapevine leaf roll-associated virus-2 and -3 in Ohio Vineyards. Grapevine leaf roll-associated viruses (GLRaVs) are a group of nine closely related viruses belonging to the Closteroviridae family that cause grapevine leaf roll disease in vineyards across the world (3). Within the continental United States, GLRaVs have been reported in the states of California, Michigan, Missouri, New York, Oregon, Washington, and Wisconsin, but not in Ohio (2,3). During 2012, grapevines with typical leaf roll symptoms were reported by owners of several Ohio vineyards. The symptoms included small, red leaves and downwardly rolled leaf margins, accompanied by tiny grape clusters with few fruits. A total of 20 symptomatic leaf samples were collected from two sites about 300 miles apart within Ohio, namely Valley Vineyards (cultivars Vidal Blanc and Fronterac) and South River Winery (cultivar Cabernet Franc). Total RNA was extracted from the samples using a previously reported procedure (1) and subjected to reverse transcription (RT)-PCR using specific primers for five known grapevine viruses including GLRaV-1 (1F: 5'-ACCTGGTTGAACGAGATCGCTT and 1R: 5'-GTAAACGGGTGTTCTTCAATTCTCT), GLRaV-2 [2F(FQ): 5'-GCTCCTAACGAGGGTATAGAAG and 2R(FQ): 5'-AGAGCGTACATACTCGCGAACAT], GLRaV-3 [3F(FQ): CAAGTGCTCTAGTTAAGGTCAG and 3R(FQ): 5'-CGGAACGTCGGTTCATTTAGA], Grapevine fan leaf virus (GFLVR1-F: 5'-TGAGATTAGTCATGGAGCAGCTT and GFLVR1-R: 5'-GGATAGACGTCTGGTTGATTTTG), and Tobacco ring spot virus (TRSVR1-1255F: 5'-GAGTGTTGTGCAATTATCT-GCATA and TRSVR1-1844R: 5'-CAAAGATGCCAAGAAAAGTTGCAAG). A 295-bp fragment of a grapevine actin cDNA (primers VvACT-F: 5'-ATCTCCATGTCAACCAAACTGAG and VvACT-R: 5'-GACAGAATGAGCAAGGAAATCAC) was used as a positive control for RT-PCR. The samples tested negative for GFLV, TRSV, or GLRaV-1 with our primer sets. However, four of the samples were positive for GLRaV-2, and 12 positive for GLRaV-3, as evidenced by the detection of PCR fragments of expected sizes (404 and 344 bp, respectively). All samples positive for GLRaV-2 were from a single field, whereas samples positive for GLRaV-3 were from both vineyards examined. The identities of GLRaV-2 and -3 were further confirmed by directly sequencing one GLRaV-2 and two GLRaV-3 (one from each location) PCR fragments from both ends. The 404 bp GLRaV-2-specific fragment shared 95 to 98% sequence identity with various GLRaV-2 isolates whose sequences were deposited at the GenBank. Similarly, the two 344-bp GLRaV-3 fragments share a 95 to 97% identity with known GLRaV-3 isolates. Notably, the sequences of the two GLRaV-3-specific fragments derived from two vineyards are not identical (97% identity), suggesting these two isolates might have different origins. As these viruses are known to be recalcitrant to mechanical transmission, we did not attempt to transmit these viruses to healthy plants. In summary, our results report for the first time the detection of GLRaV-2 and -3 in Ohio, suggesting that these two viruses are associated with the observed leaf roll symptoms, hence should be part of an effective management plan for grapevine viral diseases in the state. References: (1) C. Louime et al. Eur. J. Sci. Res. 22:232, 2008. (2) S. Lunden and W. Qiu. Plant Dis. 96:462, 2012. (3) A. M. Sharma et al. PLoS One 6:e26227, 2011.

Electron beam water calorimetry measurements to obtain beam quality conversion factors. To provide results of water calorimetry and ion chamber measurements in high-energy electron beams carried out at the National Research Council Canada (NRC). There are three main aspects to this work: (a) investigation of the behavior of ionization chambers in electron beams of different energies with focus on long-term stability, (b) water calorimetry measurements to determine absorbed dose to water in high-energy beams for direct calibration of ion chambers, and (c) using measurements of chamber response relative to reference ion chambers, determination of beam quality conversion factors, kQ , for several ion chamber types. Measurements are made in electron beams with energies between 8 MeV and 22 MeV from the NRC Elekta Precise clinical linear accelerator. Ion chamber measurements are made as a function of depth for cylindrical and plane-parallel ion chambers over a period of five years to investigate the stability of ion chamber response and for indirect calibration. Water calorimetry measurements are made in 18 MeV and 22 MeV beams. An insulated enclosure with fine temperature control is used to maintain a constant temperature (drifts less than 0.1 mK/min) of the calorimeter phantom at 4°C to minimize effects from convection. Two vessels of different designs are used with calibrated thermistor probes to measure radiation induced temperature rise. The vessels are filled with high-purity water and saturated with H2 or N2 gas to minimize the effect of radiochemical reactions on the measured temperature rise. A set of secondary standard ion chambers are calibrated directly against the calorimeter. Finally, several other ion chambers are calibrated in the NRC 60 Co reference field and then cross-calibrated against the secondary standard chambers in electron beams to realize kQ factors. The long-term stability of the cylindrical ion chambers in electron beams is better (always <0.15%) than plane-parallel chambers (0.2% to 0.4%). Calorimetry measurements made at 22 MeV with two different vessel geometries are consistent within 0.2% after correction for the vessel perturbation. Measurements of absorbed dose calibration coefficients for the same secondary standard chamber separated in time by 10 yr are within 0.2%. Drifts in linac output that would affect the transfer of the standard are mitigated to the 0.1% level by performing daily ion chamber normalization measurements. Calibration coefficients for secondary standard ion chambers can be achieved with uncertainties less than 0.4% (k = 1) in high-energy electron beams. The additional uncertainty in deriving calibration coefficients for well-behaved chambers indirectly against the secondary standard reference chambers is negligible. The kQ factors measured here differ by up to 1.3% compared to those in TG-51, an important change for reference dosimetry measurements. The measurements made here of kQ factors for eight plane-parallel and six cylindrical ion chambers will impact future updates of reference dosimetry protocols by providing some of the highest quality measurements of this crucial dosimetric parameter.

Effects of corn condensed distillers solubles supplementation on ruminal fermentation, digestion, and in situ disappearance in steers consuming low-quality hay. Two metabolism (4 x 4 Latin square design) experiments were conducted to evaluate the effects of corn condensed distillers solubles (CCDS) supplementation on intake, ruminal fermentation, site of digestion, and the in situ disappearance rate of forage in beef steers fed low-quality switchgrass hay (Panicum virgatum L.). Experimental periods for both trials consisted of a 9-d diet adaptation and 5 d of collection. In Exp. 1, 4 ruminally and duodenally cannulated steers (561 +/- 53 kg of initial BW) were fed low-quality switchgrass hay (5.1% CP, 40.3% ADF, 7.5% ash; DM basis) and supplemented with CCDS (15.4% CP, 4.2% fat; DM basis). Treatments included 1) no CCDS; 2) 5% CCDS; 3) 10% CCDS; and 4) 15% CCDS (DM basis), which was offered separately from the hay. In Exp. 2, 4 ruminally and duodenally cannulated steers (266.7 +/- 9.5 kg of initial BW) were assigned to treatments similar to Exp. 1, except forage (Panicum virgatum L.; 3.3% CP, 42.5% ADF, 5.9% ash; DM basis) and CCDS (21.6% CP, 17.4% fat; DM basis) were fed as a mixed ration, using a forage mixer to blend the CCDS with the hay. In Exp. 1, ruminal, postruminal, and total tract OM digestibilities were not affected (P = 0.21 to 0.59) by treatment. Crude protein intake and total tract CP digestibility increased linearly with increasing CCDS (P = 0.001 and 0.009, respectively). Microbial CP synthesis tended (P = 0.11) to increase linearly with increasing CCDS, whereas microbial efficiency was not different (P = 0.38). Supplementation of CCDS to low-quality hay-based diets tended to increase total DM and OM intakes (P = 0.11 and 0.13, respectively) without affecting hay DMI (P = 0.70). In Exp. 2, ruminal OM digestion increased linearly (P = 0.003) with increasing CCDS, whereas postruminal and total tract OM digestibilities were not affected (P > or = 0.37) by treatment. Crude protein intake, total tract CP digestibility, and microbial CP synthesis increased (P < or = 0.06) with increasing level of CCDS supplementation, whereas microbial efficiency did not change (P = 0.43). Ruminal digestion of ADF and NDF increased (P = 0.02 and 0.008, respectively) with CCDS supplementation. Based on this data, CCDS used in Exp. 2 was 86.7% rumen degradable protein. The results indicate that CCDS supplementation improves nutrient availability and use of low-quality forages.

[Reactive increase in blood pressure on immobilization, but not hypertension, prevents pressure ulcers]. Of 135 geriatric patients immobilized for at least 2 days, 37 (27.4%) had pressure ulcers (PU). Those without PU were the control comparison group. Gender, length of immobilization, number of blood pressure determinations and proportion with hypertension were similar in those with and without PU. Those with PU were slightly older than those in the comparison group: 75.5 +/- 8.8 and 74.7 +/- 9.6 years, respectively (p > 0.05). Of 66 patients with acute ischemic stroke, reactive increase of systolic or diastolic blood pressure to 140/90 mm Hg or above following immobilization, was seen in 60.6% and 22.7% of patients, respectively, and there were PU in 12.1%. Of 17 with recurrent ischemic stroke, corresponding figures were: 41.2%, 23.5% (p > 0.05), and 47.1% (p < 0.01). In 7 patients with previous ischemic stroke corresponding figures were: 14.3% and 0% (p < 0.01) and 100% (p < 0.001). In 36 operated for fracture of the femur, corresponding figures were: 50%, 11.1% (p > 0.05), and 27.8% (p > 0.05). For 9 patients with severe infections, sepsis or pneumonia, the corresponding figures were: 22.2% and 0.0% (p > 0.05), and 44.4% (p < 0.04). The proportion of patients with reactive increase in systolic blood pressure on immobilization was lower in the PU group than in the controls, 27% vs 59.2%, (p < 0.001). The corresponding figures for reactive increase in diastolic blood pressure were similar, 8.1% and 20.4%, respectively (p > 0.05). The mean systolic blood pressure on immobilization was higher in the control than in the PU group, 145.4 +/- 21.7 and 130.8 +/- 14.9 mm Hg, respectively (p < 0.001). The corresponding figures for the mean diastolic blood pressure were similar, 81.2 +/- 10.5 and 75.7 +/- 8.9 mm Hg, respectively (p < 0.01). An increase in systolic blood pressure on immobilization reduced the risk of developing PU (p < 0.05). There was no significant statistical relation between diagnosis of hypertension and proportion of patients with PU (p > 0.05). Of 67 patients with hypertension, in 23.9% and 74.6% of them there was no increase in systolic or diastolic blood pressure, respectively. Statistical difference between lack of diastolic or systolic response was very significant (p < 0.001). Reactive increase of blood pressure, but not hypertension, predicts reduced risk of PU on immobilization in the hospitalized elderly. Diminished reactive increase of blood pressure in response to stress of any kind may be a criterion of frailty and reduced physiological reserves. Efforts to reduce elevated blood pressure when a patient is immobilized appear irrational.

Single versus double-layer uterine closure at cesarean: impact on lower uterine segment thickness at next pregnancy. Uterine rupture is a potential life-threatening complication during a trial of labor after cesarean delivery. Single-layer closure of the uterus at cesarean delivery has been associated with an increased risk of uterine rupture compared with double-layer closure. Lower uterine segment thickness measurement by ultrasound has been used to evaluate the quality of the uterine scar after cesarean delivery and is associated with the risk of uterine rupture. To estimate the impact of previous uterine closure on lower uterine segment thickness. Women with a previous single low-transverse cesarean delivery were recruited at 34-38 weeks' gestation. Transabdominal and transvaginal ultrasound evaluation of the lower uterine segment thickness was performed by a sonographer blinded to clinical data. Previous operative reports were reviewed to obtain the type of previous uterine closure. Third-trimester lower uterine segment thickness at the next pregnancy was compared according to the number of layers sutured and according to the type of thread for uterine closure, using weighted mean differences and multivariate logistic regression analyses. Of 1613 women recruited, with operative reports available, 495 (31%) had a single-layer and 1118 (69%) had a double-layer closure. The mean third-trimester lower uterine segment thickness was 3.3 ± 1.3 mm and the proportion with lower uterine segment thickness <2.0 mm was 10.5%. Double-layer closure of the uterus was associated with a thicker lower uterine segment than single-layer closure (weighted mean difference: 0.11 mm; 95% confidence interval [CI], 0.02 to 0.21 mm). In multivariate logistic regression analyses, a double-layer closure also was associated with a reduced risk of lower uterine segment thickness <2.0 mm (odd ratio [OR], 0.68; 95% CI, 0.51 to 0.90). Compared with synthetic thread, the use of catgut for uterine closure had no significant impact on third-trimester lower uterine segment thickness (WMD: -0.10 mm; 95% CI, -0.22 to 0.02 mm) or on the risk of lower uterine segment thickness <2.0 mm (OR, 0.95; 95% CI, 0.67 to 1.33). Finally, double-layer closure was associated with a reduced risk of uterine scar defect (RR, 0.32; 95% CI, 0.17 to 0.61) at birth. Compared with single-layer closure, a double-layer closure of the uterus at previous cesarean delivery is associated with a thicker third-trimester lower uterine segment and a reduced risk of lower uterine segment thickness <2.0 mm in the next pregnancy. The type of thread for uterine closure has no significant impact on lower uterine segment thickness.

Evaluation of Adjusted and Unadjusted Indirect Comparison Methods in Benefit Assessment. A Simulation Study for Time-to-event Endpoints. With the Act on the Reform of the Market for Medicinal Products (AMNOG) in Germany, pharmaceutical manufacturers are obliged to submit a dossier demonstrating added benefit of a new drug compared to an appropriate comparator. Underlying evidence was planned for registration purposes and therefore often does not meet the appropriate comparator as defined by the Federal Joint Committee (G-BA). For this reason AMNOG allows indirect comparisons to assess the extent of added benefit. The aim of this study is to evaluate the characteristics and applicability of adjusted indirect comparison described by Bucher and Matching-Adjusted Indirect Comparison (MAIC) in various situations within the early benefit assessment according to §35a Social Code Book 5. In particular, we consider time-to-event endpoints. We conduct a simulation study where we consider three different scenarios: I) similar study populations, II) dissimilar study populations without interactions and III) dissimilar study populations with interactions between treatment effect and effect modifiers. We simulate data from a Cox model with Weibull distributed survival times. Desired are unbiased effect estimates. We compare the power and the proportion of type 1 errors of the methods. I) Bucher and MAIC perform equivalently well and yield unbiased effect estimates as well as proportions of type 1 errors below the significance level of 5 %. II) Both Bucher and MAIC yield unbiased effect estimates, but Bucher shows a higher power for detection of true added benefit than MAIC. III) Only MAIC, but not Bucher yields unbiased effect estimates. When using robust variance estimation MAIC yields a proportion of type 1 error close to 5 %. In general, power of all methods for indirect comparisons is low. An increasing loss of power for the indirect comparisons can be observed as the true treatment effects decrease. Due to the great loss of power and the potential bias for indirect comparisons, head-to-head trials using the appropriate comparator as defined by the Federal Joint Committee should be conducted whenever possible. However, indirect comparisons are needed if no such direct evidence is available. To conduct indirect comparisons in case of a present common comparator and similar study populations in the trials to be compared, both Bucher and MAIC can be recommended. In case of using adjusted effect measures (such as Hazard Ratio), the violation of the similarity assumption has no relevant effect on the Bucher approach as long as interactions between treatment effect and effect modifiers are absent. Therefore Bucher can still be considered appropriate in this specific situation. In the authors' opinion, MAIC can be considered as an option (at least as sensitivity analysis to Bucher) if such interactions are present or cannot be ruled out. Nevertheless, in practice MAIC is potentially biased and should always be considered with utmost care.

Vertebral compression fractures in patients under treatment with denosumab: a contraindication for percutaneous vertebroplasty? Denosumab (XGeva) is a receptor activator of nuclear factor-κB ligand (RANKL)-antibody that was approved by the Food and Drug Administration (FDA) in 2010 for the prevention of skeletal fractures in patients with bone metastases from solid tumors. Although there is a widespread use of such drug in patients under risk of pathological fractures, the compatibility of denosumab therapy with percutaneous vertebroplasty (an interventional procedure commonly used for pain control in such population) has not yet been established. To present the serial imaging findings and technical report of an attempted percutaneous vertebroplasty in a patient with refractory pain and a lytic pathological vertebral fracture related to small cell lung cancer spinal metastasis and who was actively under medical treatment with denosumab. Retrospective review and case report. The authors present the imaging findings and technical report of an attempted percutaneous vertebroplasty in the only patient found to be actively under treatment with denosumab after a retrospective review of the databank of patients with pathological fractures referred to the Department of Radiology of the Ohio State University for percutaneous vertebroplasty (a total sample of 20 patients) since the FDA approval of denosumab (November 2010) until June 2013 (a 30-month period). Although the computed tomography scan of the thoracic spine, performed 6 weeks after the initiation of the treatment with denosumab, presented a remarkable remodeling of the previously lytic vertebral lesion (which became markedly sclerotic in appearance), the clinical response in terms of pain improvement was not satisfactory. At the time of the percutaneous vertebroplasty (which was indicated for pain control), after advancing the 11-gauge needle through the pedicle with extreme difficulty, the needle repeatedly deviated laterally and, despite several attempts, it was not possible to penetrate the vertebral body and perform the cement injection. This is the first report of the technical peculiarities of percutaneous vertebroplasty in patients under medical treatment with denosumab. According to our experience, because of its RANKL-mediated effects on osteoclasts activity, denosumab has been shown to induce a fast and marked sclerotic response on vertebral bodies that may not be accompanied by a satisfactory improvement in pain control (especially in patients with mechanical type of pain) and which may actually prevent the successful performance of percutaneous vertebroplasty. Therefore, it is of paramount importance that future studies evaluating patients with vertebral fractures under treatment with denosumab include long-term pain outcome measures. Additionally, further investigation is warranted to determine the optimal order of treatment and the best timeframe for combining percutaneous vertebroplasty and denosumab therapy in patients presenting with acute vertebral compression fractures and refractory axial pain.

Characteristics of HIV-infected children seen in Western Kenya. To describe the characteristics and outcomes of children registered for care in a large HIV care programme in Western Kenya. A retrospective descriptive study. USAID-AMPATH HIV clinics in health centres; district and sub-district hospitals; Moi Teaching and Referral Hospital in Western Kenya. HIV-infected children below age of 15 years seen in a network of 18 clinics in Western Kenya. Paediatric HIV diagnosis and care including treatment and prevention of opportunistic infections and provision of combination antiretroviral therapy (CART). Diagnosis, clinical stage and immune status at enrollment and follow-up; hospitalisation and death. Descriptive statistical analyses and chi square tests were performed. Four thousand and seventeen HIV-infected children seen between June 2002 and April 2008. Median age at enrollment was four years (0-14.2 years), 51% girls, 25% paternal orphans, 10% total orphans and 13% maternal orphans. At enrollment, 25% had weight-for-Age Z scores (WAZ) > or = -1 and 21% had WAZ scores < or = 3. Orphaned children had worse WAZ scores (p=0.0001). Twenty five per cent of children were classified as WHO clinical stage 3 and 4, 56% were WHO clinical stages 1 and 2 with 19% missing clinical staging at enrollment. Cough (25%), gastroenteritis (21%), fever (15%), pneumonia (10%) were the commonest presenting features. Twenty six per cent had been diagnosed with tuberculosis and only 25% started on cotrimoxazole preventive therapy (CPT). Median CD4% at enrollment was 16% (0-64%); latest recorded values were 22% (0-64). Sixty four per cent were on cART (cART+), median age at start was 5.4 (014.4 years). The median initial CD4% among cART+ was 13 (0-62) compared to 24 (0-64) for those not on ART (cART-). Median CD4% for cART+ improved to 22% (0-59); whereas cART- was 23% (0-64) at last appointment. During the period of follow-up, one fifth (19%) of children on cART were lost to follow-up compared to slightly over one third (37%) for those not on cART. Thirty four percent were hospitalised; 41% diagnosed with pneumonia. Six per cent of 4017 were confirmed dead. HIV-infected children were enrolled in care early in childhood. Orphanhood was prevalent in these children as were gastroenteritis, fever, pneumonia and advanced immuno-suppression. Orphans were more likely to be severely malnourished. Only a quarter of children were put on cotrimoxazole preventive therapy. Children commenced on cART late but responded well to treatment. Loss to follow-up was less prevalent among those on cART.

Bone marrow stem cells and polymer hydrogels--two strategies for spinal cord injury repair. 1. Emerging clinical studies of treating brain and spinal cord injury (SCI) led us to examine the effect of autologous adult stem cell transplantation as well as the use of polymer scaffolds in spinal cord regeneration. We compared an intravenous injection of mesenchymal stem cells (MSCs) or the injection of a freshly prepared mononuclear fraction of bone marrow cells (BMCs) on the treatment of an acute or chronic balloon-induced spinal cord compression lesion in rats. Based on our experimental studies, autologous BMC implantation has been used in a Phase I/II clinical trial in patients (n=20) with a transversal spinal cord lesion. 2. MSCs were isolated from rat bone marrow by their adherence to plastic, labeled with iron-oxide nanoparticles and expanded in vitro. Macroporous hydrogels based on derivatives of 2-hydroxyethyl methacrylate (HEMA) or 2-hydroxypropyl methacrylamide (HPMA) were prepared, then modified by their copolymerization with a hydrolytically degradable crosslinker, N,O-dimethacryloylhydroxylamine, or by different surface electric charges. Hydrogels or hydrogels seeded with MSCs were implanted into rats with hemisected spinal cords. 3. Lesioned animals grafted with MSCs or BMCs had smaller lesions 35 days postgrafting and higher scores in BBB testing than did control animals and also showed a faster recovery of sensitivity in their hind limbs using the plantar test. The functional improvement was more pronounced in MSC-treated rats. In MR images, the lesion populated by grafted cells appeared as a dark hypointense area and was considerably smaller than in control animals. Morphometric measurements showed an increase in the volume of spared white matter in cell-treated animals. In the clinical trial, we compared intraarterial (via a. vertebralis, n=6) versus intravenous administration of BMCs (n=14) in a group of subacute (10-33 days post-SCI, n=8) and chronic patients (2-18 months, n=12). For patient follow-up we used MEP, SEP, MRI, and the ASIA score. Our clinical study revealed that the implantation of BMCs into patients is safe, as there were no complications following cell administration. Partial improvement in the ASIA score and partial recovery of MEP or SEP have been observed in all subacute patients who received cells via a. vertebralis (n=4) and in one out of four subacute patients who received cells intravenously. Improvement was also found in one chronic patient who received cells via a. vertebralis. A much larger population of patients is needed before any conclusions can be drawn. The implantation of hydrogels into hemisected rat spinal cords showed that cellular ingrowth was most pronounced in copolymers of HEMA with a positive surface electric charge. Although most of the cells had the morphological properties of connective tissue elements, we found NF-160-positive axons invading all the implanted hydrogels from both the proximal and distal stumps. The biodegradable hydrogels degraded from the border that was in direct contact with the spinal cord tissue. They were resorbed by macrophages and replaced by newly formed tissue containing connective tissue elements, blood vessels, GFAP-positive astrocytic processes, and NF-160-positive neurofilaments. Additionally, we implanted hydrogels seeded with nanoparticle-labeled MSCs into hemisected rat spinal cords. Hydrogels seeded with MSCs were visible on MR images as hypointense areas, and subsequent Prussian blue histological staining confirmed positively stained cells within the hydrogels. 4. We conclude that treatment with different bone marrow cell populations had a positive effect on behavioral outcome and histopathological assessment after SCI in rats; this positive effect was most pronounced following MSC treatment. Our clinical study suggests a possible positive effect in patients with SCI. Bridging the lesion cavity can be an approach for further improving regeneration. Our preclinical studies showed that macroporous polymer hydrogels based on derivatives of HEMA or HPMA are suitable materials for bridging cavities after SCI; their chemical and physical properties can be modified to a specific use, and 3D implants seeded with different cell types may facilitate the ingrowth of axons.

Association of CLOCK gene variants with semen quality in idiopathic infertile Han-Chinese males. Recent experimental animal studies suggested that the circadian locomotor output cycles kaput protein gene (CLOCK) may play an important role in male reproduction. So far, such data for humans are not available. This study used single-nucleotide polymorphisms (SNP) to examine the association between CLOCK and semen quality in a human population with idiopathic infertility. Three-variant genotyping of CLOCK and semen analysis were performed in 478 men with idiopathic infertility by SNP genotyping assays and computer-aided sperm analysis. Subjects carrying a C allele at rs3749474 (CC and TC) presented significantly lower semen volume (P=<0.001 and 0.001, respectively) compared with the TT genotype. Subjects carrying the rs3749474 CC genotype had significantly lower sperm number per ejaculate (P=0.026) and sperm motility (P=0.021) than TT genotype carriers. rs1801260 TC genotype carriers had significantly lower sperm motility compared with the TT genotype (P=0.028). For the rs3817444 genotypes, CA and AA genotype carriers presented significantly lower semen volume compared with the CC genotype (P=0.022 and 0.001, respectively). The findings suggest, as far as is known for the first time, an association between CLOCK genetic variants and altered semen quality in a human population with idiopathic infertility. The gene encoding the circadian locomotor output cycles kaput protein (CLOCK) functions as an important positive enhancer of the circadian system. The observations reported in recent experimental animal studies suggested that CLOCK may play an important role in male reproduction. So far, such data for humans are not available. In this study, single-nucleotide polymorphisms (SNP) were used to examine the association between CLOCK and semen quality in human population with idiopathic infertility. Three-variant genotyping of CLOCK and semen analysis were performed in 478 males with idiopathic infertility by SNP genotyping assays and computer-assisted semen analysis. The results showed that the subjects carrying a C allele at rs3749474 (CC and TC) presented significantly lower semen volume compared with the TT genotype. For subjects carrying the CC genotype, sperm number per ejaculate and sperm motility were significantly lower compared with TT genotype carriers. The rs1801260 TC genotype carriers also had significantly lower sperm motility compared with the TT genotype. For the rs3817444 genotypes, the CA and AA genotype carriers presented significantly lower semen volume compared with the CC genotype. The findings suggested, as far as is known for the first time, an association between CLOCK genetic variants and altered semen quality in a human population with idiopathic infertility.

[Has been changed numbers and characteristics of patients with major amputations indicated for the diabetic foot in our department during last decade?] One of the most serious complications of the diabetic foot (DF) is a major amputation, which is associated with poor patient prognosis. The occurrence of major amputations may be influenced by a variety of factors including deep infection caused by resistant pathogens.The aims of our study were to compare the incidence of major amputations in podiatric center, characteristics of amputated patients with the DF and other factors contributing to major amputations in last decade. We included into our study all patients hospitalized for the DF in our center whose underwent major amputations from 9/2004 to 9/2006 (group 1) and from 9/2013 to 9/2015 (group 2). Risk factors such as severity of DF ulcers based on Texas classification, duration of previous anti-biotic therapy, the presence and severity of peripheral arterial disease (PAD) according to Graziani classification, the number of revascularizations, renal failure/hemodialysis, osteomyelitis, infectious agents found before amputations and their resistance were compared between the study groups. During the 1st study period (9/2004-9/2006) 373 patients were hospitalized for the DF, of whom 3.2 % underwent major amputation (12/373 - group 1), during the 2nd study period (9/2013-9/2015) 376 patients, of whom 5.1 % absolved major amputation (19/376 - group 2). As the numbers of major amputations as their indications were similar in both study groups. The study groups did not differ significantly in the age, BMI, duration and type of diabetes, duration of DF and severity of DF ulcers, the presence of renal failure/hemodialysis, osteomyelitis and PAD. Group 2 had milder forms of PAD by Graziani classification (4.4 ±1.4 vs 5.7 ± 0.9; p = 0.012) and a higher number of revascularizations before major amputations (2.5 ± 1.5 vs 1 ± 1; p = 0.003) compared to the group 1. These patients were significantly longer treated by antibiotics (5.4 ± 2.4 vs 2.5 ± 2 months; p = 0.002) and underwent more resections and minor amputations (3.1 ± 2.1 vs 0.9 ± 0.5; p = 0.0004) before major amputations in contrast to the group 1. There was a trend to higher incidence of Gram-negatives (65.1 % vs 61.5 %; NS) with a predominance of Enterobacteriacae species (60.7 % vs 56 %; NS) and a trend to the increase of Pseudomonas (25 % vs 18.8 %; NS) and Enterococci sp. (46.7 % vs 20 %; NS) in the group 2 compared to the group 1. The incidences as of MRSA, multidrug resistant Pseudomonas sp. of other resistant microbes were similar in both study groups. The incidence of major amputations in patients hospitalized for the DF remains unchanged during the last decade. The therapy of factors leading to amputations has evidently intensified. This is in accordance with the latest international recommendations for the therapy of DF. In the future, it is appropriate to focus on the improvement of detection and treatment of infection and ischemia in such risk group of patients.Key words: diabetic foot - major amputation.

In vitro metabolism of 4-vinylcyclohexene in rat and mouse liver, lung, and ovary. 4-Vinylcyclohexene (4-VCH), the dimer of 1,3-butadiene, is an ovarian toxicant in mice due to the formation of a diepoxide metabolite, but the tissue-specific site of formation of the metabolites is unknown. Microsomal preparations from liver, lung, and ovaries obtained from female Crl:CD BR rats and female B6C3F1 mice were tested for their ability to metabolize the following reactions: 4-VCH to 4-VCH-1,2-epoxide and 4-VCH-7,8-epoxide; 4-VCH-1,2-epoxide to 4-VCH diepoxide and 4-VCH-1,2-diol; 4-VCH-7,8-epoxide to 4-VCH diepoxide and 4-VCH-7,8-diol; and hydrolysis of 4-VCH diepoxide. Microsomes were incubated with the test chemical and the reaction products were analyzed by gas chromatography. Rat liver and lung microsomes and mouse liver and lung microsomes metabolized 4-VCH to 4-VCH-1,2-epoxide at detectable rates. Mouse liver had a Vmax for the reaction that was 56-fold higher than that for rat liver (11.1 and 0.20 nmol/min/mg protein, respectively). The Vmax for mouse lung was 2-fold higher than that for rat lung. 4-VCH-1,2-epoxide formation was not detected in ovarian microsomes from rats or mice. Metabolism of 4-VCH to 4-VCH-7,8-epoxide was detected in microsomes from rat liver and mouse liver and lung, at rates very low compared to those for metabolism to the 1,2-epoxide. Rat and mouse liver had very similar K(m) and Vmax values for metabolism of 4-VCH-1,2-epoxide to 4-VCH diepoxide. The Vmax for rat liver was 3.69 and for mouse liver was 5.35 nmol/min/mg protein. Rat and mouse ovaries did not have detectable capacity to metabolize 4-VCH-1,2-epoxide to the diepoxide. Rat and mouse liver and lung have very similar K(m) and Vmax values for metabolism of 4-VCH-7,8-epoxide to the diepoxide, while ovaries did not have detectable rates for this reaction. Hydrolysis of 4-VCH-1,2-epoxide to 4-VCH-1,2-diol was at similar rates in rat and mouse liver microsomes. Hydrolysis of 4-VCH-7,8-epoxide to 4-VCH-7,8-diol was detected only in rat liver microsomes. Hydrolysis of 4-VCH diepoxide was detected in rat and mouse liver and lung, and in rat ovary microsomes. The Vmax for rat liver was 9-fold greater than that for mouse liver (5.51 and 0.63 nmol/min/mg protein, respectively), and lung and ovary tissues were not as active as rat liver. The balance of activation versus detoxication reactions in rats and mice suggests that the mouse may be more susceptible to 4-VCH toxicity because of generation of high levels of epoxide metabolites. In general, the mouse is more efficient at metabolism of 4-VCH to epoxides than is the rat. In contrast, the rat may be more efficient at hydrolysis of epoxides. Thus, the rat would tend to produce a lower concentration of epoxide metabolites than the mouse, at equal doses of 4-VCH.

A comparative study of calcipotriol and anthralin for chronic plaque psoriasis in a day care treatment center. Eighteen patients with symmetric plaque-type psoriasis were recruited for an open, controlled, bilateral half-body comparison study to evaluate the efficacy of calcipotriol/tar/UVB vs. anthralin/tar/UVB in a day care treatment setting. No patient had been on systemic antipsoriatic agents for at least 3 months prior to enrolment. One half-body was arbitrarily assigned to treatment with gradually increasing concentrations of anthralin as tolerated. The other half-body received calcipotriol ointment twice daily. Both sides received UVB and additional coal tar distillate in accordance with our standard day care regimen. Patients who were admitted to the day care program attended the clinic for UVB, anthralin, and calcipotriol on weekdays for two consecutive weeks. Anthralin was applied to psoriatic plaques on one side in the following fashion: anthralin 0.1% with salicylic acid 3% in zinc oxide paste on days 1 and 2; anthralin 0.2% with salicylic acid 3% in zinc oxide paste on days 3-5; anthralin 1% with salicylic acid 3% in hydrophilic petrolatum for 60 min on days 8-10 to thicker lesions; and anthralin 2% with salicylic acid 3% in hydrophilic petrolatum for 60 min on day 11 to thicker lesions. On the contralateral side, calcipotriol ointment 0.05 microgram/mL (Leo Pharmaceuticals, Ajax, Ontario) was applied to lesions twice daily. No anthralin or calcipotriol was applied on weekends. All patients applied coal tar oil 50% (Doak Oil Forte, Trans CanaDerm, St-Laurent, Québec, equivalent to 5% coal tar distillate) with salicylic acid 5% in hydrophilic petrolatum to their lesions at home in the evenings and on weekends. UVB (FSX72T12 lamps, National Biologic Corporation, Twinsburg, Ohio) was administered twice daily on weekdays in increasing doses as tolerated (to erythema) prior to the application of the topical medications. No trial medications were applied to the face, scalp, or genital regions. For clinical evaluation, the standard Psoriasis Activity and Severity Index (PASI) score was modified by splitting the score for area under 10%; the modified score (mPASI) for an area of coverage of 1%-4% was 0.5 and for an area of 5%-9% was 1. The head and neck area was excluded from the analysis since neither anthralin nor calcipotriol was used at these sites. Each half-body was considered to represent 100% in the area score determination. The maximum modified score for each side was 64.8 (vs. 72 in the standard PASI scoring system). Clinical evaluations were completed at days 0 (baseline), 3, 7, 10, and 42. The primary end-point was day 10. On day 10, patients were asked to compare the calcipotriol ointment to the anthralin on a five-point scale in terms of efficacy and irritancy and to state their future preferred treatment modality. Following discharge from day care, patients were continued on outpatient UVB and tar treatments three times weekly and asked to return for a repeat clinical assessment after 4 weeks (day 42). Blood samples taken prior to treatment and at day 10 were analyzed for serum calcium. Comparisons of treatment efficacy were based on changes in the mPASI scores from onset of treatment to day 10, as well as on the corresponding percentage changes. Analyses were carried out using the Wilcoxon test. Subjective patient comparisons of effectiveness and irritancy, as well as patient preference, were tested for equiprobability using the chi-square goodness-of-fit test with an examination of the adjusted residuals.

Supplemental algal meal alters the ruminal trans-18:1 fatty acid and conjugated linoleic acid composition in cattle. The effects of dietary algal supplementation, a source of docosahexaenoic acid, on the fatty acid profile of rumen lipids in cattle were evaluated, with special emphasis on CLA and trans fatty acids produced by rumen microbes. A diet based on corn silage was fed with supplements containing the following: 1) no algal meal and fed at 2.1 kg of DM/d (control), 2) algal meal and fed at 1.1 kg of DM/d (low algal meal), 3) algal meal and fed at 2.1 kg of DM/d (medium algal meal), and 4) algal meal and fed at 4.2 kg of DM/d (high algal meal). A modified lipid extraction procedure was developed to analyze the lipid changes in rumen fluid. The percentage of stearic acid (18:0) in rumen fluid was decreased by algal meal supplementation (P < 0.001) compared with control and was linearly dependent on the level of algal meal supplementation (P = 0.005). Total trans-18:1 in rumen fluid of cattle fed the control diet was 19% of total fatty acids. Addition of algal meal increased (P < 0.001) total trans-18:1 up to 43%, mostly due to 18:1 trans-10 that increased (P = 0.002) to 29.5% of total rumen fatty acids. This increase in 18:1 trans-10 seems to suggest a change in the rumen microbial population. Vaccenic acid (18:1 trans-11) increased quadratically (P = 0.005) with increasing level of algal meal supplementation in the diets. The total CLA content was low in the control (<0.9%) and increased with dietary algal meal addition, although not significantly; the greatest level was 1.5% with the medium algal meal diet. The increase of rumenic acid (cis-9, trans-11 CLA) was quadratic (P = 0.05) with algal meal supplementation, whereas trans-10, cis-12 CLA increased linearly with increased level of algal meal from 0.08 to 0.13% (P = 0.03). The ratio of trans-11 (cis-9, trans-11 CLA + 18:1 trans-11) to trans-10 (trans-10, cis-12 CLA + 18:1 trans-10) decreased from 2.45 to 0.77, 0.87, and 0.21 for the control, low algal meal, medium algal meal, and high algal meal diets, respectively. The content of docosahexaenoic acid in rumen fluid increased (P = 0.002) from 0.3 to 1.4% of total fatty acids with increasing level of algal meal supplementation in the diets. Our results suggest that algal meal inhibits the reduction of trans-18:1 to 18:0, giving rise to the high trans-18:1 content. In conclusion, algal meal could be used to increase the concentration in rumen contents of trans-18:1 isomers that serve as precursors for CLA biosynthesis in the tissues of ruminants.

Magnitude of change in fetal cerebroplacental ratio in third trimester and risk of adverse pregnancy outcome. To evaluate whether the magnitude of change in the cerebroplacental ratio (CPR) after 30 weeks' gestation is a better predictor of adverse pregnancy outcome compared with a single CPR measurement at 35-37 weeks. A secondary aim was to evaluate whether the utility of CPR at 35-37 weeks was enhanced after adjusting for change in gestational age. This was a retrospective cohort study of women who had at least two ultrasound scans between 30 and 37 weeks' gestation, with the final scan at 35-37 weeks. Exclusion criteria were major congenital abnormality, aneuploidy, multiple pregnancy and unknown middle cerebral artery pulsatility index or umbilical artery pulsatility index. A normal reference range for CPR was derived from a separate cohort of women with normal outcome and a Generalised Additive Model for Location, Scale and Shape was fitted to derive standardized centiles. These reference centiles were then used to calculate Z-scores for the study cohort. Logistic regression models and receiver-operating characteristics (ROC) curves were used to evaluate the predictive utility of CPR Z-score at last CPR measurement and the change in CPR on mode of delivery, neonatal outcome and composite neonatal outcome. The area under the ROC curve (AUC) for each model was compared before and after adjustment for parity, hypertension, diabetes, body mass index and smoking status. A total of 1860 women met the inclusion criteria. There was no association between the magnitude of change in CPR and composite adverse pregnancy outcome (P = 0.92). Of the outcomes that made up the composite, an increase in CPR Z-score over time was associated with a lower risk for emergency Cesarean delivery (P < 0.001) and emergency Cesarean delivery for non-reassuring fetal status (P = 0.02). It was also associated with a lower risk of birth weight < 10th centile (P = 0.01) and hypoglycemia (P = 0.001). There was no significant difference between the AUCs of last CPR Z-score and last CPR Z-score adjusted for the change in gestational age in predicting pregnancies at risk for adverse outcome. Our results suggest that both the individual CPR Z-score and the magnitude and direction of change in CPR Z-score can identify pregnancies at risk of various adverse perinatal outcomes. However, the CPR Z-score at 35-37 weeks' gestation appears to be a better predictor. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. The blockade of epidermal growth factor receptor (EGFR) function with monoclonal antibodies has major antiproliferative effects against human tumors in vivo. Similar antiproliferative effects against some of these same tumors have also been observed with specific inhibitors of the EGFR-associated tyrosine kinase. One such inhibitor, the p.o. active ZD1839 (Iressa), has pronounced antiproliferative activity against human tumor xenografts. We now show that coadministration of ZD1839, as with anti-EGFR, will enhance the efficacy of cytotoxic agents against human vulvar (A431), lung (A549 and SK-LC-16 NSCL and LX-1), and prostate (PC-3 and TSU-PR1) tumors. Oral ZD1839 (five times daily x 2) and cytotoxic agents (i.p. every 3-4 days x 4) were given for a period of 2 weeks to mice with well-established tumors. On this schedule, the maximum tolerated dose (150 mg/kg) of ZD1839 induced partial regression of A431, a tumor that expresses high levels of EGFR, 70-80% inhibition among tumors with low but highly variable levels of EGFR expression (A549, SKLC-16, TSU-PR1, and PC-3), and 50-55% inhibition against the LX-1 tumor, which expresses very low levels of EGFR. ZD1839 was very effective in potentiating most cytotoxic agents in combination treatment against all of these tumors, irrespective of EGFR status, but dose reduction of ZD1839 below its single-agent maximum tolerated dose was required for optimum tolerance. The pronounced growth inhibitory action of the platinums, cisplatin and carboplatinum, as single agents against A431 vulvar, A549 and LX-1 lung, and TSU-PR1 and PC-3 prostate tumors was increased several-fold when ZD1839 was added, with some regression of A431 and PC-3 tumors. Although the taxanes, paclitaxel or docetaxel, as single agents markedly inhibited the growth of A431, LX-1, SK-LC-16, TSU-PR1, and PC-3, when combined with ZD1839, partial or complete regression was usually seen. Against A549, the growth inhibition of doxorubicin was increased 10-fold (>99%) with ZD1839. The folate analogue, edatrexate, was highly growth inhibitory against A549, LX-1, and TSU-PR1, whereas edatrexate combined with ZD1839 resulted in partial or complete regression in these tumors. Against the A431 tumor, paclitaxel alone either was highly growth inhibitory or induced some regression, but when combined with ZD1839, pronounced regression was obtained. Combination with gemcitabine neither added nor detracted from baseline cytotoxic efficacy, whereas ZD1839 combined with vinorelbine was poorly tolerated. Overall, these results suggest that potentiation of cytotoxic treatment with ZD1839 does not require high levels of EGFR expression in the target tumors. They also suggest significant clinical benefit from ZD1839 in combination with a variety of widely used cytotoxic agents.

Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial. Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection are being explored with the goal of achieving a functional cure (sustained off-treatment response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics, safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV core protein. This phase 1, randomised, placebo-controlled study was done in two parts. In part 1, healthy adults without hepatitis B aged 18-65 years at one clinical research centre in New Zealand (eight participants per dose cohort) were randomly assigned (3:1) to receive single oral doses of ABI-H0731 (100, 300, 600, or 1000 mg) or matching placebo, or once-daily or twice-daily doses of ABI-H0731 800 mg or matching placebo for 7 days. In part 2, adults aged 18-65 years at clinical research centres in New Zealand, Australia, the UK, Hong Kong, Taiwan, and South Korea with chronic HBV (12 participants per dose cohort) were randomly assigned (5:1) to receive ABI-H0731 (100, 200, 300, or 400 mg) or matching placebo once daily for 28 days. In part 2, participants were required to have HBeAg-positive or HBeAg-negative chronic HBV infection, with serum HBV DNA concentrations of at least 2 × 104 IU/mL (HBeAg-positive) or 2 × 103 IU/mL (HBeAg-negative) and serum alanine aminotransferase concentrations less than seven times the upper limit of normal. Both parts used simple randomisation, with study participants, site personnel, and study monitors masked to treatment assignments. The primary study objective was dose-related safety and tolerability of ABI-H0731 in healthy volunteers and in participants with chronic HBV infection, assessed in all treated participants. Key secondary assessments included pharmacokinetic analyses and virological responses. This study is registered with ClinicalTrials.gov, identifier NCT02908191 and is completed. 48 [61%] of 79 healthy volunteers were enrolled in the single-ascending or multiple-ascending dose phase of part 1 between Nov 16, 2016, and Jan, 27, 2017. 38 [55%] of 69 HBV-infected participants were enrolled in part 2 between June 15, 2017, and March 15, 2018. All adverse events were non-specific and of mild or moderate intensity apart from a single HBV-infected participant given the 400 mg dose who developed a severe (grade 3) maculopapular rash and terminated treatment. Overall, the most frequent adverse events of any grade among the 74 participants who received ABI-H0731 were headache (11 [15%]), influenza-like illness (seven [9%]), and dizziness (six [8%]); the most frequent adverse events considered treatment-related were rash (four [5%]) and dizziness (three [4%]). In part 1, ABI-H0731 reached maximum plasma concentrations (Tmax) in 2·50-4·17 h; the mean plasma half-life (t1/2) was 23·5-28·4 h. In part 2, mean maximum HBV DNA declines from baseline were 1·7 log10 IU/mL in the 100 mg dose cohort, 2·1 log10 IU/mL in the 200 mg dose cohort, and 2·8 log10 IU/mL in the 300 mg dose cohort. Across dose cohorts, serum HBV RNA declines correlated with HBV DNA declines. No pattern of treatment-emergent adverse events was observed at ABI-H0731 doses up to 300 mg in individuals with chronic hepatitis B. ABI-H0731 was rapidly absorbed and exhibited a plasma half-life supportive of once-daily dosing. Dose-dependent decreases in serum HBV DNA and RNA concentrations are consistent with the proposed mechanism of action. Assembly Biosciences.

The value and limitations of L-arginine infusion on glomerular and tubular function in the ischemic/reperfused kidney. The nitric oxide precursor, L-arginine, has been shown to have a salutary effect on ischemia and reperfusion injury in skeletal muscle, skin, and intestines. Because L-arginine also increases renal blood flow, glomerular filtration, and urine flow in experimental animals with normal renal function, we postulated that L-arginine may also improve renal function after renal ischemic injury. Eighteen adult New Zealand white rabbits weighing 3 to 3.5 kg were subjected to bilateral normothermic renal ischemia by clamping both renal pedicles for 1 hour followed by 2 hours of reperfusion. The animals were randomized into three groups: group I (control, n = 6) received no additional treatment; group II (pretreatment, n = 6) received systemic intravenous L-arginine at 150 mg/kg over 20 minutes before induction of ischemia; group III (posttreatment, n = 6) received systemic intravenous L-arginine at 150 mg/kg over 20 minutes from the onset of reperfusion. Urine flow, creatinine clearance (CCR), fractional excretion of sodium (FENa), and renal failure index (RFI) were calculated before ischemia and 2 hours after reperfusion, by use of standard formulas. The changes of the various renal parameters were compared among the three groups. Bilateral normothermic renal ischemia for 1 hour produced a significant deterioration of glomerular filtration as evidenced by a CCR decrease from 11.1 +/- 1.8 to 2.49 +/- 0.9 ml/min (p < 0.01), FENa increase from 2.9% +/- 1.0% to 20.8% +/- 1.5% (p < 0.01) and RFI increase from 4.0 +/- 1.3 to 28.8 +/- 2.6 (p < 0.01). Pretreatment with L-arginine (group II) minimized the deleterious effects caused by ischemia on glomerular filtration (CCR of 2.49 +/- 0.9 ml/min in group I vs 4.95 +/- 2.5 ml/min in group II, p < 0.05) and tubular function (FENa of 20.8% +/- 1.5% in group I vs 13.0% +/- 5.6% in group II and RFI of 28.8 +/- 2.6 in group I vs 18.6 +/- 8.0 in group II, p < 0.05). Infusion of L-arginine at the onset of reperfusion (group III) produced a significant diuretic effect (urine flow from 32.6 +/- 13.4 ml/hr in group I to 63.3 +/- 18.8 ml/hr in group III, p < 0.05) and also minimized glomerular damage (CCR from 2.49 +/- 0.9 ml/min in group I to 4.80 +/- 1.2 ml/min in group III, p < 0.05); however, no beneficial effect was observed on tubular function. Induction of nitric oxide production by systemic L-arginine infusion can best preserve glomerular and tubular function in the ischemic/reperfused kidney when given before the ischemic insult.

[Analysis of microRNA expression profile in serum of patients with electrical burn or thermal burn]. Objective: To explore the differential expression of microRNAs in the serum among patients with electrical burn or thermal burn and healthy persons and to explore the significance. Methods: In this study we included three patients with electrical burn and three patients with thermal burn, conforming to the inclusion criteria and hospitalized in our burn ward from June to August 2015, and three healthy adult volunteers. Their serum samples were separated from whole blood and divided into electrical burn group, thermal burn group, and normal control group. Total RNA was extracted from their serum samples using Trizol method. The differentially expressed microRNAs (with differential ratio larger than or equal to 2.000, less than or equal to 0.500) among the three groups were screened by microRNA chip technique. Then cluster and Venn diagram analysis of the differentially expressed microRNAs were performed. Enrichment analysis of Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway was performed on the distinctly changed microRNAs (with differential ratio larger than or equal to 5.000, less than or equal to 0.500). Results: There were 220 differentially expressed microRNAs among serum of the three groups. MicroRNA expression profiles in serum of electrical burn and thermal burn groups were different from that in serum of normal control group. Compared with those in serum of normal control group, the expressions of 59 microRNAs changed more than 2.000 times in serum of electrical burn group, with 50 up-regulated microRNAs and 9 down-regulated microRNAs; the expressions of 40 microRNAs changed more than 2.000 times in serum of thermal burn group, with 21 up-regulated microRNAs and 19 down-regulated microRNAs. Compared with those in serum of thermal burn group, the expressions of 167 microRNAs changed more than 2.000 times in serum of electrical burn group. There were 17 exclusively expressed microRNAs in serum of thermal burn group and 26 exclusively expressed microRNAs in serum of electrical burn group, compared with those in serum of normal control group. Enrichment analysis of KEGG signaling pathway showed that compared with those in serum of normal control group, microRNAs which changed distinctly in serum of electrical burn group took part in the insulin secretion signaling pathway, arrhythmogenic right ventricular cardiomyopathy signaling pathway, hypertrophic cardiomyopathy signaling pathway, glutamatergic synapse signaling pathway, calcium signaling pathway, cyclic adenosine monophosphate signaling pathway, glycerophospholipid metabolism, pyrimidine metabolism, serotonergic synapse signaling pathway, etc, while microRNAs which changed distinctly in serum of thermal burn group took part in the tumor transcription misregulation signaling pathway, proteoglycans in tumor signaling pathway, microRNAs in tumor signaling pathway, long-term potentiation signaling pathway, citrate cycle signaling pathway, tumor necrosis factor signaling pathway, focal adhesion signaling pathway, endocytosis signaling pathway, insulin secretion signaling pathway, p53 signaling pathway, and estrogen signaling pathway, etc. Conclusions: MicroRNA expression profiles in serum of electrical and thermal burn are different from that in serum of healthy adult. The signaling pathways enriched with target genes which are regulated by the differentially expressed microRNAs are related to the pathological changes and clinical manifestations after electrical or thermal burn.

Intrinsic projections of the retrohippocampal region in the rat brain. I. The subicular complex. The intrahippocampal projections of the subicular complex were studied in the rat with the aid of the anterogradely transported lectin Phaseolus vulgaris leucoagglutinin (PHA-L). After iontophoretic injections of the lectin into the subiculum proper, presubiculum, or the parasubiculum, axons and terminal processes immunoreactive for PHA-L were traced to their respective terminal fields within the hippocampal region. After subicular injections PHA-L-stained axons could be followed both in a caudal and a rostral direction. The caudally directed fibers course around or within the angular bundle to enter layers VI and V of the medial entorhinal area (MEA). Many fibers penetrate through these layers to terminate in layer IV of the medial and the lateral entorhinal area, which contains a major terminal field of this projection. At more ventral levels, all layers of the entorhinal area are innervated by cells located in the subiculum. Other retrohippocampal projections of the subiculum proper include the deep and the outer two layers of the presubiculum and the medial sector of the parasubiculum, in addition to a massive projection which terminates in the retrosplenial cortex. The rostrally directed projections from the subiculum form a dense innervation of strata lacunosum, radiatum, oriens, and of individual pyramidal cells in the regio superior of the Ammon's horn. All these projections of the subiculum are exclusively ipsilateral. After injections of PHA-L into layers II and III of the presubiculum, both ipsi- and contralateral projections were traced to the outer three layers of the medial entorhinal area; the lateral entorhinal area apparently receives no innervation from the presubiculum. The innervation of layer III is very dense while in layer II and deep layer I, restricted zones of innervation are found. The fibers reach these layers via the deep layers of the MEA and through the molecular layer after first coursing around the parasubiculum. In addition, a minor projection from the presubiculum to the pyramidal cell layer of the subiculum and to the molecular layer of the hippocampal formation was found. PHA-L injections into the parasubiculum labeled fibers that form a dense innervation of layer II in the MEA and the medial part of the lateral EA, and of the most medial sector of layer III in the MEA. Layer I and the superficial part of layer II of the contralateral MEA also contain a dense terminal network after PHA-L injections into the parasubiculum.(ABSTRACT TRUNCATED AT 400 WORDS)

[Floral biology, reproductive system and reproductive success of Macroptilium fraternum (Fabaceae)]. Observations about the floral biology and the reproductive system of Macroptilium fraternum were made in two populations in Argentina, with different edaphic conditions, situated at the southern area of distribution of the species. The coexistence of two kind of flowers in the same plant was detected in both populations and in herbarium material from other localities: a) cleistogamous preanthesis flowers and b) pseudocleistogamous flowers. The cleistogamous preanthesis flowers possessed wings longer than 5 mm and were disposed in pubescent, erect, racemes exposed above the level of the foliage. The anthesis lasted approximately 5 hours on sunny days or 9 hours on rainy days, the right wing covered the left wing, the corolla acquired a bilabiate aspect, offering the left wing as landing platform; they produced a low quantity of nectar (0.18 +/- 0.13 microliter); they did not receive pollinator visits; approximately four hours after the beginning of the anthesis on sunny days the ovary started to grow; in the bud, the receptive stigma was covered with germinating pollen grains from the same floral unit. The pseudocleistogamous flowers possessed wings shorter than 5 mm that were disposed in brief, hirsute and prostrate racemes, non subterranean as in other Macroptilium species; the banner started to spread exposing partially the wings, the left wing limb surrounded the keel and never spread; the right wing started to spread and after 2 seconds refolded and began to wither, the ovary began to grow immediately; the flower did not offer a surface to allow visitors to settle; in the buds the stigma was receptive and found with pollen grains from the same floral unit emitting their tubes. The relative reproductive success was low (natural pollination = 8%; spontaneous self-pollination = 3%), probably due to the low pollen viability, the high percentage of seed abortion and the lack of pollinator's visits. The production of both flower types is not conditioned by edaphic factors, as they were found in plants belonging to different environments. Study of the progeny of both floral types in both populations has demonstrated that each one produces a similar amount of seeds contributing to the next generation with plants of similar characteristics (slow development, low resistance to infections and high mortality). The absence of pollinators in these flowers (in part because they preferred to visit flowers of other species with more reward and in part because of the fragmentation of the habitats), would be producing inbreeding depression in the studied populations; if the germplasm variability is not preserved, these populations situated at the Southern end of the distribution range of the species could become extinguished.

Brief periods of monocular deprivation in kittens: effects of delay prior to physiological study. 1. Brief periods of selective visual exposure in 4-wk postnatal kittens can cause pronounced alterations in striate cortex. The processes underlying these changes may be similar to those of other short-term neural events such as memory or learning, and attempts have been made to link these areas. In particular, it has been reported that the effects of selective visual exposures are consolidated if a delay is interposed between rearing and physiological study. 2. We have tested this notion directly. Normally reared kittens were monocularly occluded for 8 or 24 h on postnatal day 29. Half of the 8-h and of the 24-h groups were tested physiologically immediately following monocular exposure, while the other halves were recorded after an intervening session of 8 or 48 h, respectively, during which the kittens were kept in darkness. 3. Extracellular responses of cortical neurons were analyzed, and primary attention was paid to absolute and relative interocular response strengths of each cell. Ocular dominance distributions from all kittens were significantly abnormal, but invariably, effects were less extensive for those who had experienced a period of dark rearing prior to physiological study. 4. These results are clearly at odds with the idea that the effects of monocular deprivation were consolidated by allowing a period of delay between exposure and physiological recording. On the contrary, during the time the kittens spent in darkness, it appears that some functional recovery of binocular pathways occurred. 5. To explore the minimal period of monocular occlusion that could cause cortical disruption, we studied an additional group of normally reared kittens that were occluded for only 4 h on postnatal day 29. Effects for this group were small but ocular dominance patterns were significantly abnormal. 6. An alternative procedure was used for the delay period between 24-h monocular occlusion and physiological study. Prior to recording, these kittens spent 48 h in a normally illuminated colony. Ocular dominance histograms were normal, indicating that complete recovery had occurred from the initial monocular deprivation. 7. Histological reconstructions were made to estimate effects in different cortical laminae, but conclusions must be tentative because of small samples. In the group that had been monocularly occluded for 4 h and then recorded, inactivation of binocular pathways was most apparent in layers IV and V. This results suggest that the process deprivation disconnection during monocular deprivation occurs frist in these layers. Findings from the groups in which a delay was imposed between monocular exposure and recording indicate that functional binocular recovery occurs frist in layer IV and above and last in layer VI.

Plume persistence caused by back diffusion from thin clay layers in a sand aquifer following TCE source-zone hydraulic isolation. This paper concludes that back diffusion from one or a few thin clayey beds in a sand aquifer can cause contaminant persistence above MCLs in a sand aquifer long after the source zone initially causing the plume is isolated or removed. This conclusion is based on an intensive case study of a TCE contaminated site in Florida, with the processes evaluated using numerical modeling. At this site, the TCE DNAPL zone formed decades ago, and was hydraulically isolated by means of an innovative system performing groundwater extraction, treatment and re-injection. Treated water is re-injected in a row of injection wells situated a short distance downgradient of the extraction wells, creating a clean-water displacement front to efficiently flush the downgradient plume. This scheme avoids the creation of stagnation zones typical of most groundwater pump-and-treat systems, thereby minimizing the time for aquifer flushing and therefore downgradient cleanup. The system began operation in August 2002 and although the performance monitoring shows substantial declines in concentrations, detectable levels of TCE and degradation products persist downgradient of the re-injection wells, long after the TCE should have disappeared based on calculations assuming a nearly homogenous sand aquifer. Three hypotheses were assessed for this plume persistence: 1) incomplete source-zone capture, 2) DNAPL occurrence downgradient of the re-injection wells, and 3) back diffusion from one or more thin clay beds in the aquifer. After careful consideration, the first two hypotheses were eliminated, leaving back diffusion as the only plausible hypothesis, supported by detailed measurements of VOC concentrations within and near the clay beds and also by numerical model simulations that closely represent the field site hydrogeologic conditions. The model was also used to simulate a more generalized, hypothetical situation where more thin clayey beds occur in a sand aquifer with an underlying aquitard. While there is no doubt that DNAPL source mass reduction can eventually improve downgradient groundwater quality, the magnitude and time scale over which the improvement occurs is the major uncertainty given current characterization approaches. This study shows that even one thin clay bed, less than 0.2 m thick, can cause plume persistence due to back diffusion for several years or even decades after the flux from the source is completely isolated. Thin clay beds, which have a large storage capacity for dissolved and sorbed contaminant mass, are common in many types of sandy aquifers. However, without careful inspection of continuous cores and sampling, such thin clay beds, and their potential for causing long-term back-diffusion effects, can easily go unnoticed during site characterization.

Pharmacokinetics and Safety of Posaconazole Administered by Intravenous Solution and Oral Tablet in Healthy Chinese Subjects and Effect of Food on Tablet Bioavailability. New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole. The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug. Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0-∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0-∞ and Cmax of 2.06 (90% confidence interval 1.86-2.30) and 1.95 (90% confidence interval 1.65-2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae. Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries.

Interfraction and intrafraction performance of the Gamma Knife Extend system for patient positioning and immobilization. The Extend system for the Gamma Knife Perfexion makes possible multifractional Gamma Knife treatments. The Extend system consists of a vacuum-monitored immobilization frame and a positioning measurement system used to determine the location of the patient's head within the frame at the time of simulation imaging and before each treatment fraction. The measurement system consists of a repositioning check tool (RCT), which attaches to the Extend frame, and associated digital measuring gauges. The purpose of this study is to evaluate the performance of the Extend system for patient repositioning before each treatment session (fraction) and patient immobilization between (interfraction) and during (intrafraction) each session in the first 10 patients (36 fractional treatments) treated at the University of Virginia. The RCT was used to acquire a set of reference measurements for each patient position at the time of CT simulation. Repositioning measurements were acquired before each fraction, and the patient position was adjusted until the residual radial difference from the reference position measurements was less than 1 mm. After treatment, patient position measurements were acquired, and the difference between those measurements and the ones obtained for patient position before the fraction was calculated as a measure of immobilization capability. Analysis of patient setup and immobilization performance included calculation of the group mean, standard deviation (SD), and distribution of systematic (components affecting all fractions) and random (per fraction) uncertainty components. Across all patients and fractions, the mean radial setup difference from the reference measurements was 0.64 mm, with an SD of 0.24 mm. The distribution of systematic uncertainty (Σ) was 0.17 mm, and the distribution of random uncertainty (σ) was 0.16 mm. The root mean square (RMS) differences for each plate of the RCT were as follows: right = 0.35 mm; left = 0.41 mm; superior = 0.28 mm; and anterior = 0.20 mm. The mean intrafractional positional difference across all treatments was 0.47 mm, with an SD of 0.30 mm. The distribution of systematic uncertainty was 0.18 mm, and the distribution of random uncertainty was 0.22 mm. The RMS differences for each plate of the RCT were 0.24 mm for the right plate, 0.22 mm for the left plate, 0.24 mm for the superior plate, and 0.34 mm for the anterior plate. Data from 1 fraction were excluded from the analysis because the vacuum-monitoring interlock detected patient motion, which in turn required repositioning in the middle of the fraction. The Extend system can be used to reposition and immobilize patients in a radiosurgical setting. However, care should be taken to acquire measurements that can implicitly account for rotations of the patient's head. Further work is required to determine the sensitivity of the vacuum interlock to detect patient motion.

Changes in the molar relationship between the deciduous and permanent dentitions: a longitudinal study. The purpose of this study was to describe the changes in the molar relationship from the deciduous dentition to the permanent dentition in 121 subjects from the Iowa Longitudinal Growth Study. In addition, an attempt was made to determine the association between the various dentofacial variables and the changes in the molar relationship in 55 persons (33 male and 22 female subjects) with normal occlusion. All subjects were evaluated at three stages of dental development: stage I, completion of the deciduous dentition (means age = 4.94 years); stage II, when permanent first molars initially erupt into occlusion (means age = 6.91 years); and stage III, at the completion of eruption of the permanent dentition excluding third molars (means age = 13.01 years). The following sets of variables were evaluated: molar relationship, mesiodistal crown diameters of single and groups of deciduous and permanent teeth, dental arch widths, arch lengths, and various cephalometric dentofacial variables. Correlation coefficients and regression analyses were used to assess the relationships between these measurements and the changes in the molar relationship from the deciduous to the permanent dentition. The findings indicate that of the 242 sides evaluated in the deciduous dentition, 61.6% developed into a Class I molar relationship, 34.3% into Class II, and 4.1% into Class III. Those sides that started with a distal step in the deciduous dentition proceeded to develop into a Class II molar relationship in the permanent dentition. Of the sides with a flush terminal plane relationship in the deciduous dentition, 56% progressed to a Class I molar relationship and 44% to Class II in the permanent dentition. The presence of a mesial step in the deciduous dentition indicates a greater probability for a Class I molar relationship and a lesser probability for a Class II molar relationship. In the 55 subjects who achieved normal occlusion, the magnitude of change in the molar relationship was 1.91 mm in male subjects and 1.64 mm in female subjects. On the average, these cases had a mesial step in the deciduous dentition of 0.8 mm in male subjects and 1.0 mm in female subjects. There was a favorable difference between the maxillary and mandibular leeway spaces of 1.3 mm in male subjects and 1.1 mm in female subjects. There was also a favorable decrease in the Wits appraisal of 1.2 mm in male subjects and 0.6 mm in female subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Bladder and bowel continence in bilateral cerebral palsy: A population study. The attainment of continence is an important milestone in all children, including those with disability. To describe the age of bladder and bowel continence in children with bilateral cerebral palsy (BCP), and the association with intellectual impairment (II) and severity of motor disability. The parents of 346 children with BCP were interviewed as part of a population-based prospective study of the children at 3, 7, and 17 years of age. The age of bladder and bowel continence by day and night was ascertained and compared with controls from the Avon Longitudinal Study of Parents and Children (ALSPAC). The median age for daytime bladder and bowel continence in BCP children was 5.4 years compared with 2.4 years in the controls. At 13.8 years of age, 59.4% of BCP children and 99% of controls were continent by day. In BCP children, there was no difference between the attainment of daytime bladder and bowel control. Night-time bladder and bowel control was slower and less completely attained, with 50% of BCP children continent by the age of 11.8 years compared with 3 years in control children. At 13.8 years of age, 51.9% of BCP children compared with 99.4% of controls were continent for bowel and bladder at night. Gross Motor Functional Classification Score (GMFCS) and intellectual ability (IA) (II) were strongly associated with continence attainment (P < 0.0001), but gender was not. Delayed and less complete continence attainment was noted in other clinic series of children with cerebral palsy (including hemiplegics) and children with II. Severity of motor disability (GMFCS), and II impacted on other aspects of toilet training, such as: motivation, understanding, communication, and independence skills. The presence of neurogenic bladder and bowel dysfunction can occur in all levels of GMFCS. Thus, there are many reasons that can prevent continence attainment. Children with BCP achieved day and night-time bladder and bowel continence more slowly and less completely than controls, with 60.8% being continent by day and 54.6% by night at the age of 17 years. The majority of BCP children who were continent by day had achieved this by the age of 5.5 years (86%). At least 88% of BCP children with GMFCS I/II and normal, specific or mild learning impairment were continent for bladder and bowel by day and night. Expectations should be shared with parents, and failure to attain expected continence should be actively investigated.

A prospective feasibility and safety study of laparoscopy-assisted distal gastrectomy for clinical stage I gastric cancer initiated by surgeons with much experience of open gastrectomy and laparoscopic surgery. The aim of this prospective study was to evaluate the feasibility and safety of laparoscopy-assisted distal gastrectomy (LADG) initiated by surgeons with much experience of open gastrectomy and laparoscopic surgery. Three surgeons who each had experience with more than 300 cases of open gastrectomy, more than 100 cases of laparoscopic cholecystectomy, more than 5 cases of laparoscopic colectomy, and more than 5 cases of laparoscopic partial gastrectomy were nominated as LADG operators. All three operators received training for LADG with study materials including videotapes, a box simulator, and an animal laboratory, with lectures and assistance from LADG instructors who each had experience of more than 50 LADG operations. Then the nominated LADG operators performed LADG with the instructors, in which their skills were evaluated and certified. Thereafter, they performed LADG without assistance from the instructors. The target of this study was clinical stage I gastric cancer that was resectable by distal gastrectomy. D1 + alpha, D1 + beta, or D2 dissection was performed laparoscopically. Basically reconstruction was done extracorporeally with a Billroth-I gastroduodenostomy. An extramural review board checked the surgical quality of the operations performed by the three surgeons. The primary endpoint was morbidity and mortality. A total of 193 patients were enrolled in this study between August 2004 and July 2009. The median blood loss was 35 ml and the median operation time was 250 min. Conversion to open surgery was seen in 6 patients; 4 due to bleeding and 2 due to advanced disease. Overall morbidity was 1.6 %, including grade 2 anastomotic leakage in 0.5 % and grade 2 pancreatic fistula in 0.5 %. No mortality was observed. The number of cases required until the LADG operators acted as LADG surgeons without an instructor was 3 for each of the three surgeons. When comparing the data between that in the training period (n = 9) and the operators' data (n = 174), the median operation time was significantly longer in the training period (355 min) than in the latter period (247.5 min) (p = 0.015). Median blood loss was also greater in the training period (150 ml) than the latter period (32.5 ml), but the difference did not reach statistical significance (p = 0.084). During the training period, no patient developed any complications of ≥ grade 2. These results suggested that LADG could be initiated and performed feasibly and safely if surgeons with much experience of open gastrectomy and laparoscopic surgery received adequate training for LADG.

Quality of life in patients on chronic dialysis: self-assessment 3 months after the start of treatment. The Necosad Study Group. The aim of the present multicenter study was to assess quality of life of Dutch dialysis patients 3 months after the start of chronic dialysis treatment. The quality of life was compared with the quality of life of a general population sample, and the impact of demographic, clinical, renal function, and dialysis characteristics on patients' quality of life was studied. New end-stage renal disease (ESRD) patients who were started on chronic hemodialysis or peritoneal dialysis in 13 dialysis centers in The Netherlands were consecutively included. Patients' self-assessment of quality of life was measured by the SF-36, a 36-item Short Form Health Survey Questionnaire encompassing eight dimensions: physical functioning, social functioning, role-functioning physical, role-functioning emotional, mental health, vitality, bodily pain, and general health perceptions. One hundred twenty hemodialysis and 106 peritoneal dialysis patients completed the SF-36. Quality of life of hemodialysis and peritoneal dialysis patients was substantially impaired in comparison to the general population sample, particularly with respect to role-functioning physical and general health perceptions. Mean role-functioning physical and general health perceptions scores of the hemodialysis patients corresponded with the lowest scoring 8% and 12%, respectively, of the reference group. Mean role-functioning physical and general health perceptions scores of the peritoneal dialysis patients corresponded with the lowest scoring 10% and 12%, respectively, of the reference group. Hemodialysis patients showed lower levels of quality of life than peritoneal dialysis patients on physical functioning, role-functioning emotional, mental health, and pain. However, on the multivariate level, we could only demonstrate an impact of dialysis modality on mental health. A higher number of comorbid conditions, a lower hemoglobin level, and a lower residual renal function were independently related to poorer quality of life. The variability of the SF-36 scores explained by selected demographic, clinical, renal function, and dialysis characteristics was highest for physical functioning (29.7%). Explained variability of the other SF-36 dimensions ranged from 6.9% for general health perceptions to 15.4% for vitality. We conclude that quality of life of new ESRD patients is substantially impaired. Comorbid conditions, hemoglobin, and residual renal function could explain poor quality of life only to a limited extent. Further research exploring determinants and indices of quality of life in ESRD patients is warranted. From a clinical perspective, we may conclude that quality of life should be considered in the monitoring of dialysis patients.

The prediction of the dissolution rate constant by mixing rules: the study of acetaminophen batches. The purpose of this article is to promote two simple and scalable methods to accelerate the formulation development of formulated granules using acetaminophen as a model system. In method I, formulated granules made from the batch of small particle-sized acetaminophen (1) by ball milling the batch of large particle-sized acetaminophen (2), and the mixture of the two batches at equal weights (mix) gave the dissolution rate constants (k) of k(1) = 0.43 +/- 0.15 minutes(-1), k(2) = 0.18 +/- 0.01 minutes(-1), and k(mix) = 0.30 +/- 0.03 minutes(-1) for 75 wt percent formulation; k(1) = 0.75 +/- 0.01 minutes(-1), k(2) = 0.18 +/- 0.01 minutes(-1), and k(mix) = 0.34 +/- 0.03 minutes(-1) for 62 wt percent formulation; and k(1) = 0.28 +/- 0.01 minutes(-1), k(2) = 0.16 +/- 0.01 minutes(-1), and k(mix) = 0.22 +/- 0.02 minutes(-1) for 30 wt percent formulation. In method II, the mixture of the formulated granules produced by mixing the formulated granules from the two batches at equal weights gave dissolution rate constants of k(mix) = 0.30 +/- 0.03 minutes(-1), 0.30 +/- 0.02 minutes(-1), and 0.22 +/- 0.01 minutes(-1) for 75 wt percent, 62 wt percent, and 30 wt percent formulations, respectively. After fitting the three data points of k(1), k(2), and k(mix) to the 10 mixing rules in materials science--series mixing rule, Hashin and Shtrikman upper bound, logarithmic mixing, Looyenga mixing rule, effective media approximation (EMA), three-point lower bound, Torquato approximation, three-point upper bound, Maxwell mixing rule, and parallel mixing rule--we found that the selection of the best suited mixing rules based on k(1), k(2), and k(mix) was solely dependent on the formulations under a given operating condition and regardless of whether the system was a powder mixture or a granular mixture. The values of k(1), k(2), and k(mix) in both the 75 wt percent and 30 wt percent formulations were enveloped by the parallel mixing rule and Maxwell mixing rule, whereas the values of k(1), k(2), and k(mix) for the 62 wt percent formulation were encompassed by the logarithmic mixing rule, Hashin and Shtrikman upper bound, and the series mixing rule. Apparently, the best suited mixing rules could be used to predict the right proportions of either the powder mixture (Method I) or the granular mixture (Method II) for obtaining any other desired dissolution rate constant, k(mix), whose value fell in between the values of k(1) and k(2).

Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.

Prevalence of Lyme Disease Attributable to Military Service at the USMA, West Point NY: FY2016-2018. Lyme disease incidence rates have steadily increased since its official recognition in 1975. Since exposure to Lyme is associated with activities conducted in and around tick-habitats including tall grass, shrubs, deciduous forest, and leaf litter, it has been suggested that service members, who are thought to spend higher amounts of time in these habitats due to training requirements, may have higher risk for exposure. Specifically, this study looks at service member and family member exposure to Ixodes scapularis, the vector for Lyme in the Northeastern and Midwestern United States. While literature pertaining to occupational and military specific exposures to Lyme vectors have attempted to quantify the possible elevated risk of Lyme disease for service members, thus far, studies have not consistently confirmed that service members are at a greater risk than family members. This cross-sectional study looks at cases of Lyme disease at Keller Army Community Hospital (KACH) on the West Point Military Reservation in New York during Fiscal Year (FY) 2016 through FY2018. Lyme cases were pulled from Military Health System Mart using current ICD-10-CM codes for Lyme related conditions (A69.20 and A69.29). In total, 144 cases were considered for the analysis. Totaling all service members and family members enrolled at KACH over the three-year period account for 35,526 person-years. Period prevalence, attributable risk percentage, population attributable risk percentage, and corresponding 95% confidence intervals were calculated for service members and family member categories. This study was conducted on human subject research according to 32CFR219 and meets the requirements of exempt status under 32CFR219.101(b)(4) because it is a cross-sectional study on existing de-identified patient data. During FY2016-2018, service members accounted for 63 cases of Lyme totaling 21,595 person-years with a period prevalence of 292 cases per 100,000 (219.8, 363.7). Family members accounted for 81 cases with a total of 13,931 person-years with a period prevalence of 581 cases per 100,000 (455.2, 707.7). The percentage of attributable risk during the three-year period credited to military status is -99.30% (-145.69%, -52.91%). The population attributable risk percentage is -43.4%. While this study was unable to capture the military specific occupational exposure to I. scapularis, it does show a difference in period prevalence between service members and family members with the family members being at higher risk to contract Lyme instead of service members as is commonly suggested in the literature. Additional studies may be conducted to see if this holds true across service member Military Occupational Specialties as a proxy for occupational exposure. Similar studies should be conducted at military installations situated in Lyme endemic areas to determine if these results are comparable across the military or specific to West Point. Future research should attempt to identify all the service member protective factors against Lyme with attribution to permethrin-treated uniforms and other military interventions designed to defend soldiers against vector-borne diseases.

Trans sodium crocetinate with temozolomide and radiation therapy for glioblastoma multiforme. OBJECTIVE A new drug, trans sodium crocetinate (TSC), has been developed to enhance the delivery of oxygen to hypoxic tissues. Cancerous tumors, such as glioblastoma multiforme (GBM), are very hypoxic, and it has been suggested that radiation therapy (RT) is more beneficial if tumors are better oxygenated. A Phase I/II clinical trial was conducted to determine the effect of adding TSC to RT sessions. METHODS An open, single-arm clinical trial incorporating the standard of care (SOC) for GBM was conducted at 18 clinical sites. There were 6 weeks of RT consisting of 2 Gy/day for 5 days/week, beginning after an initial resection or stereotactic biopsy to confirm GBM. Temozolomide (TMZ), 75 mg/m2, was given before each RT session. The TSC, 0.25 mg/kg, was intravenously administered around 45 minutes before an RT session 3 days/week, usually on Monday, Wednesday, and Friday. A Phase I run-in period included 2 cohorts. The first cohort contained 3 patients who were given a half dose of the intravenous TSC (that is, 0.25 mg/kg, 3 times per week for only the first 3 weeks of RT). After a Safety Monitoring Committee (SMC) had verified that no dose-limiting toxicity (DLT) had occurred, a second cohort of 6 patients was given the same dosage of TSC but for the full 6 weeks of RT. After the SMC verified that no DLTs had occurred, Phase II began, with the administration of the full 18 doses of TSC. Fifty additional patients were enrolled during Phase II. Following the completion of RT, the patients rested for a month. After that, SOC TMZ chemotherapy (150-200 mg/m2) was administered for 5 days of the 1st week of 6 monthly cycles. No TSC was administered during this chemotherapy phase or later in the trial. Any other follow-up therapies were administered at the discretion of the individual investigators. RESULTS Kaplan-Meier analysis showed that 36% of the full-dose TSC patients were alive at 2 years, compared with historical survival values ranging from 27% to 30% for the SOC. Survival for the biopsy-only subset of patients was 40%, as compared with 42.9% for those patients having a complete resection before treatment. In addition, 2 of the 3 Phase I, Cohort 1 patients survived at 2 years. Contrast MRI data suggested that considerable pseudoprogression had occurred. Both Karnofsky Performance Status (KPS) scores and quality of life (QOL) questionnaires indicated that a good quality of life existed for most patients throughout the trial. No serious adverse events occurring in the trial were attributed to TSC. CONCLUSIONS This trial contained a single arm consisting of 59 patients. The results strongly suggested that adding TSC during RT is beneficial for the treatment of GBM. Trans sodium crocetinate offers a novel, easily implemented way to combat hypoxia in tumor tissue. Clinical trial registration no.: NCT01465347 ( clinicaltrials.gov ).

An in vivo mouse reporter gene (human secreted alkaline phosphatase) model to monitor ovarian tumor growth and response to therapeutics. Developing new anticancer therapeutic regimens requires the measurement of tumor cell growth in response to treatment. This is often accomplished by injecting immunocompromised mice with cells from cancer tissue or cell lines. After treating the animals, tumor weight or volume is measured. Such methods are complicated by inaccuracies in measuring tumor mass and often animals must be killed to measure tumor burden. An in vivo tumor model system is presented in which the tumor cell line was stably transfected with a constitutively expressed marker gene: secreted human placental alkaline phosphatase protein (SEAP). The SEAP gene codes for a heat-stable protein that is produced at levels proportional to the amount of tumor cells in the animal. The SEAP protein is detectable in small blood samples so that animals can be repeatedly sampled over the trial period to monitor the course of tumor progression. OCC1 ovarian carcinoma cells were stably transfected with pCMV-SEAP. The OCC1-SEAP cells were maintained in vitro to monitor the relationship between cell number and SEAP production. Experiments were performed in vivo to determine whether SEAP levels in blood corresponded to tumor burden. OCC1-SEAP cells were injected s.c. or intraperitoneally into nude mice and tumor volume was measured as well as plasma SEAP levels as the tumors developed. S.c. tumor volume correlated well with plasma SEAP levels ( R(2)=0.95). OCC1-SEAP cells were also injected intraperitoneally into nude mice and grown as abdominal tumors. After 3 weeks the animals were killed and the tumors were dissected and weighed. SEAP levels in plasma samples from the time of death correlated with intraperitoneal tumor weight ( R(2)=0.87). Experiments were performed to determine whether measuring SEAP levels could be used to monitor ovarian carcinoma cell response to platinum-containing chemotherapeutic drugs. OCC1-SEAP cells cultured in vitro were treated with the platinum-containing drug carboplatin. Carboplatin treatment decreased both cell proliferation and SEAP levels in culture medium. The constitutive rate of SEAP secretion per cell (nanograms SEAP per microgram DNA) was found not to be altered by carboplatin treatment. Therefore changes in SEAP level reflect changes in OCC1 tumor cell number, and not changes in regulation of SEAP secretion due to platinum containing chemotherapeutic drug treatment. OCC1 cells were injected intraperitoneally into nude mice and the mice were treated with the platinum-containing drugs cisplatin or carboplatin. Measurements of plasma SEAP over the treatment period showed OCC1-SEAP ovarian carcinoma growth to be inhibited by cisplatin and carboplatin treatment. The SEAP marker protein is constitutively expressed by tumor cells and blood levels are correlated with tumor cell number and burden. The results of these studies indicate that SEAP may be used as an in vivo reporter gene in a mouse model to monitor tumor growth and response to therapeutics. Future studies will utilize this model to investigate novel chemotherapeutic approaches to treating ovarian cancer.

The decompensated back. There is no single circumstance or combination of circumstances which precipitate all clinical instances of back discomfort. This simple statement should be so obvious that one must question the finality and accuracy of the diagnostic effort in those reports which relate to large series of patients treated by one method. There is no thought of impugning the basic honesty of the reporting physician in this statement, but rather of raising the fair question of whether the "slipped disc" (or whatever the etiological diagnosis) is all that happened to produce the symptoms, and whether its removal (or whatever) is all that occurred in accomplishing clinical cure improvement. If there is doubt that the answer to both questions is in the affirmative, then serious consideration must be given to those other factors, if the medical profession is ever to be a science instead of a trade. The back structures are different from comparable structures elsewhere in the body, principally in their neurological organization and controlmthere is the specific, discrete, segmental arrangement of both sensory and motor functions of muscular and nonmuscular structures via the posterior primary rami of the spinal nerves. Coupled with this is a different mechanism of segmental innervation of the vascular and nonmuscular structures which line the vertebral canal, via the sinu-vertebral nerves. Both are modulated by higher level influences. The sinu-vertebral nerves, through the sympathetic chain, may provide an additional avenue of response which may avoid or alter the influence of higher levels. The Melzack-Wall hypothesis would seem to provide an acceptable explanation for the need to modulate nociceptive afferent stimuli before they evoke pain perception and response. Since this modulation mechanism decompensates under numerous conditions, pain perception and responses do occur. Among those responses are the alterations in normal function of the low back structures, perhaps the disastrously effective one of which is decompensation of the muscular strength necessary to accomplish the demands of daily use. This problem is not so simply solved by a handout sheet of exercises. The primary consideration is to modify or relieve pain by a careful evaluation of its source and the employment in combination of those therapeutic efforts which a logical treatment plan indicates. If these be accomplished, the final and most important consideration, then, is the improvement of neuromuscular function to the level compatible with normal activities by a carefully guided activity program. There is no method for instant reversal of the status of the decompensated heart--nor the decompensated back.

A framework for human relevance analysis of information on carcinogenic modes of action. The human relevance framework (HRF) outlines a four-part process, beginning with data on the mode of action (MOA) in laboratory animals, for evaluating the human relevance of animal tumors. Drawing on U.S. EPA and IPCS proposals for animal MOA analysis, the HRF expands those analyses to include a systematic evaluation of comparability, or lack of comparability, between the postulated animal MOA and related information from human data sources. The HRF evolved through a series of case studies representing several different MOAs. HRF analyses produced divergent outcomes, some leading to complete risk assessment and others discontinuing the process, according to the data available from animal and human sources. Two case examples call for complete risk assessments. One is the default: When data are insufficient to confidently postulate a MOA for test animals, the animal tumor data are presumed to be relevant for risk assessment and a complete risk assessment is necessary. The other is the product of a data-based finding that the animal MOA is relevant to humans. For the specific MOA and endpoint combinations studied for this article, full risk assessments are necessary for potentially relevant MOAs involving cytotoxicity and cell proliferation in animals and humans (Case Study 6, chloroform) and formation of urinary-tract calculi (Case Study 7, melamine). In other circumstances, when data-based findings for the chemical and endpoint combination studied indicate that the tumor-related animal MOA is unlikely to have a human counterpart, there is little reason to continue the risk assessment for that combination. Similarly, when qualitative considerations identify MOAs specific to the test species or quantitative considerations indicate that the animal MOA is unlikely to occur in humans, such hazard findings are generally conclusive and further risk assessment is not necessary for the endpoint-MOA combination under study. Case examples include a tumor-related protein specific to test animals (Case Study 3, d-limonene), the tumor consequences of hormone suppression typical of laboratory animals but not humans (Case Study 4, atrazine), and chemical-related enhanced hormone clearance rates in animals relative to humans (Case Study 5, phenobarbital). The human relevance analysis is highly specific for the chemical-MOA-tissue-endpoint combination under analysis in any particular case: different tissues, different endpoints, or alternative MOAs for a given chemical may result in different human relevance findings. By providing a systematic approach to using MOA data, the HRF offers a new tool for the scientific community's overall effort to enhance the predictive power, reliability and transparency of cancer risk assessment.

Discharge education delivered to general surgical patients in their management of recovery post discharge: A systematic mixed studies review. Discharge education is essential for postoperative general surgery patients for their self-management of care at home post discharge. The first 30 days' post-surgery is pivotal to the post-operative recovery process as this is when most post-operative complications occur. Insufficient discharge education can compromise patients' recovery process causing postoperative complications and unplanned hospital readmissions. To identify the discharge education provided to general surgery patients. Systematic mixed studies review. Literature data sources were searched from December 2017 to January 2018 using the four databases: EBSCO CINAHL Plus, EBSCO MEDLINE, Ovid EMBASE and COCHRANE Library. Searches were supplemented with hand searching of reference lists. The relevance of the articles was reviewed using the inclusion and exclusion criteria; included data were extracted and presented in a summary table. Two reviewers appraised the methodological quality of the articles using the Mixed Methods Appraisal Tool. Discussions were held to examine emergent themes, quality scores of the studies, and agreement reached by consensus. Themes were derived through inductive analysis. A total of 468 records were screened for titles and abstracts and 7 studies met the inclusion criteria. There was a mix of qualitative and quantitative studies. The majority of the included sample were patients with one quantitative study including patients' family and nurses. Discharge education was delivered at various timing and at different doses during the surgical process. Education delivered was mostly standardised and some of the discharge interventions were tailored and included a checklist for stoma care and a discharge warning tool. Four themes were identified: quality of discharge education influences its uptake, health care professionals' perceptions of their role in the delivery of discharge education to patients, patients' preferences for education delivery and patients' participation in their self-care. The quality of discharge education has an influence on patient participation in their management of care post discharge. Assessing patients' preparedness for discharge is an essential component of discharge planning process. The presentation, timing and frequency of discharge education was important in the delivery of information. Tailored education reflecting the learning needs of patients using multiple media delivered in varying doses enhanced patients' overall knowledge for successful management of recovery post discharge. The scarcity of recent literature in discharge education indicates that the quantity of evidence regarding discharge education intervention in general surgery patients is low and further work in this area needs to be undertaken.

[Maternal-fetal mortality in advanced age]. In order to compare the maternal-fetal outcome in pregnant women of advanced age (bigger than 35 years old) with those smaller than 30 years. 268 pregnant women were studied that went for their control and attention of the childbirth, corresponding 134 patients of more than 35 years and 134 patients between 20-29 years (control group). Cases were excluded if presented confounding variables (smoking, obesity, multiparity and maternal illnesses associated to the pregnancy). Data of maternal-fetal morbimortality were written down both groups and they were analyzed by means of X2 test or Fisher exact test for assessing differences between the groups, P < 0.05 was considered statistically significant, with a power of 80%, with a delta of 12%. The only two variables that had statistical significant were the number of cesarean sections 66 (49.2%) in the group of older women against 43 (32%) in the control group (P < 0.01) and normal vaginal deliveries (45 cases in the study group and 80 cases in the control group (P < 0.001). The rest of the analyzed variables none had difference statistically significant between both groups and they are described next: Forceps delivery was documented in 6 patients of the older group and 4 of the control group; 7 abortions were observed in a group and 17 in the other group of patients; there were not maternal deaths in both groups. The premature rupture of membranes was presented in 22 cases of the study group and in 24 cases of the control group; 8 congenital anomalies were presented in women's of advanced age children and 2 in mother's of the group control children; admission to the unit of therapy intensive neonatal happened in 17 products of the study group and in 9 cases of the control group; there were 3 stillbirths in the women of advanced age and 1 stillbirth in the control group; 3 perinatal deaths were presented in the patients of advanced age and 2 cases in the control group, all these variables had a value of P greater than 0.05 (not significant). When controlling confounding variables that can influence in the increase of the maternal-fetal morbimortality, it was observed that the only two significant variables were smaller normal vaginal deliveries (P < 0.001) and higher number of cesarean sections (P < 0.01) in patients with advanced age, owing to most of them are subjected to cesarean section without evaluating the possibility to obtain the product by means of a childbirth, for what the indication of cesarean section should be revalued in advanced age multiparous pregnant and in case of not having factors of associated risk to attempt the birth for childbirth, reducing by this way the incidence of cesarean sections as well as the morbidity that this procedure may imply.

SIRT1 signalling protects mouse oocytes against oxidative stress and is deregulated during aging. Is SIRT1 involved in the oxidative stress (OS) response in mouse oocytes? SIRT1 plays a pivotal role in the adaptive response of mouse germinal vesicle (GV) oocytes to OS and promotes a signalling cascade leading to up-regulation of the MnSod gene. OS is known to continuously threaten acquisition and maintenance of oocyte developmental potential during in vivo processes and in vitro manipulations. Previous studies in somatic cells have provided strong evidence for the role of SIRT1 as a sensor of the cell redox state and a protector against OS and aging. GV oocytes obtained from young (4-8 weeks) and reproductively old (48-52 weeks) CD1 mice were blocked in the prophase stage by 0.5 µM cilostamide. Groups of 30 oocytes were exposed to 25 µM H2O2 and processed following different times for the analysis of intracellular localization of SIRT1 and FOXO3A, and evaluation of Sirt1, miRNA-132, FoxO3a and MnSod gene expression. Another set of oocytes was cultured in the presence or absence of the SIRT1-specific inhibitor Ex527, and exposed to H2O2 in order to assess the involvement of SIRT1 in the activation of a FoxO3a-MnSod axis and ROS detoxification. In the last part of this study, GV oocytes were maturated in vitro in the presence of different Ex527 concentrations (0, 2.5, 5, 10, 20 µM) and assessed for maturation rates following 16 h. Effects of Ex527 on spindle morphology and ROS levels were also evaluated. SIRT1 and FOXO3A intracellular distribution in response to OS was investigated by immunocytochemistry. Real-time RT-PCR was employed to analyse Sirt1, miR-132, FoxO3a and MnSod gene expression. Reactive oxygen species (ROS) production was evaluated by in vivo measurement of carboxy-H2DCF diacetate labelling. Spindle and chromosomal distribution in in vitro matured oocytes were analysed by immunocytochemistry and DNA fluorescent labelling, respectively. Specific changes in the intracellular localization of SIRT1 and up-regulation of Sirt1 gene were detected in mouse oocytes in response to OS. Moreover, increased intracellular ROS were observed when SIRT1 activity was inhibited by Ex527. In aged oocytes Sirt1 was expressed more than in young oocytes but SIRT1 protein was undetectable. Upon OS, significant changes in miR-132 micro-RNA, a validated Sirt1 modulator, were observed. A negative correlation between Sirt1 mRNA and miR-132 levels was observed when young oocytes exposed to OS were compared with young control oocytes, and when aged oocytes were compared with young control oocytes. FoxO3a and MnSod transcripts were increased upon OS with the same kinetics as Sirt1 transcripts, and up-regulation of MnSod gene was prevented by oocyte treatment with Ex527, indicating that SIRT1 acts upstream to the FoxO3a-MnSod axis. Finally, the results of the in vitro maturation assay suggested that SIRT1 might be involved in oocyte maturation by regulating the redox state and ensuring normal spindle assembly. The main limitation of this study was the absence of direct quantification of SIRT1 enzymatic activity due to the lack of an appropriately sensitive method. The present findings may provide a valuable background for studying the regulation of SIRT1 during oogenesis and its relevance as a sensor of oocyte redox state and energy status. The antioxidant response orchestrated by SIRT1 in oocytes seems to decrease with aging. This suggests that SIRT1 could be an excellent pharmacological target for improving oocyte quality and IVF outcome in aging or aging-like diseases. The work was supported by the Ministero dell'Università e della Ricerca Scientifica (MIUR) to C.T., F.A., C.D., A.M.D. The authors declare no conflict of interest.

Non-pharmacological interventions for preventing secondary vascular events after stroke or transient ischemic attack. Stroke is the second leading cause of death among adults worldwide. Individuals who have suffered a stroke are at high risk of having another stroke likely leading to greater disability and institutionalization. Non-pharmacological interventions may have a role to play in averting a second stroke. To determine the effectiveness of multi-modal programs of non-pharmacological interventions compared with usual care in preventing secondary vascular events and reducing vascular risk factors after stroke or transient ischemic attack (TIA). We searched the Cochrane Stroke Group Trials Register (September 2012); The Cochrane Library databases CENTRAL, CDSR, DARE, HTA and NHS EED (2012 Issue 2); MEDLINE (1950 to February 2012); EMBASE (1974 to February 2012); CINAHL (1982 to February 2012); SPORTDiscus (1800 to February 2012); PsycINFO (1887 to February 2012) and Web of Science (1900 to February 2012). We also searched PEDro, OT Seeker, OpenSIGLE, REHABDATA and Dissertation Abstracts (February 2012). In an effort to identify further published, unpublished and ongoing trials we searched trials registers, scanned reference lists, and contacted authors and researchers. We included randomized controlled trials evaluating the use of non-pharmacological interventions that included components traditionally used in cardiac rehabilitation (CR) programs in adults with stroke or TIA. Primary outcomes were a cluster of second stroke or myocardial infarction or vascular death. Secondary outcomes were (1) secondary vascular events: second stroke, myocardial infarction, and vascular death, as well as (2) vascular risk factors: blood pressure, body weight, lipid profile, insulin resistance and tobacco use. We also recorded adverse events such as exercise-related musculoskeletal injuries or cardiovascular events. Two review authors independently scanned titles and abstracts and independently screened full reports of studies that were potentially relevant. At each stage, we compared results. The two review authors resolved disagreements through discussion or by involving a third review author. We identified one study, involving 48 participants, of a 10-week CR program for patients post-stroke that met the inclusion criteria. The results of this completed pilot trial show that patients post-stroke had significantly greater improvement in cardiac risk score in the CR group (13.4 ± 10.1 to 12.4 ± 10.5, P value < 0.05) when compared with usual care (9.4 ± 6.7 to 15.0 ± 6.1, P value < 0.05). In addition, five trials, which are ongoing, will likely meet the inclusion criteria for this review once completed. There is limited applicable evidence. Therefore, no implications for practice can be drawn. Further research is required and several trials are underway, the findings of which are anticipated to contribute to the body of evidence.

A novel LC-MS/MS method for the quantitative measurement of the acetate content in pharmaceutical peptides. Most pharmaceutical peptides are supplied as acetate salts and the relative amount of acetate to peptide in the final product is one quality criterion required by regulatory agencies to approve the product for clinical use. The objective of the present study was to develop a validated LC-MS/MS method that allows the quantitative determination of the acetate content in pharmaceutical peptide preparations and simultaneous monitoring and collection of qualitative and quantitative information on the peptide during manufacture and in the final product. The method uses reversed phase C18-chromatography to elute the acetate ions under acidic conditions, pH 3, followed by post-column infusion of ammonium hydroxide 0.6M, methanolic solution (30:70) at a rate of 0.5mL/hr. The acetate ions were monitored in negative polarity mass spectrometry by pseudo multiple reaction monitoring (pseudo MRM) against 1, 2- 13C labelled acetate, the internal standard used in the method. The method was linear for acetate concentrations between 0.4 and 25μg/mL with a coefficient of determination (r2) equal to 0.9999. The minimum level of detection and minimum level of quantification were at 0.06μg/mL and 0.18μg/mL respectively. Accuracy of the method was judged by determining the acetate content in a commercial product of the peptide pharmaceutical tetracosactide (TCS) and parallel comparison to the amounts determined by a reversed phase HPLC method with detection at a wavelength of 210nm. The amounts determined by the two methods were in agreement with a RSD that was less than 2%. Additional confirmation of method accuracy was determined by spiking the pharmaceutical peptide with varying amounts of acetate. The recoveries ranged on average between 101 and 102% for the spiked amounts. Accuracy was also determined by calculating the percentage relative error of the predicted to actual acetate concentration in quality controls and was determined to be less than 5%. The LC-MS/MS method was precise with an intra- and inter-day RSD of less than 5%. The standard solutions were stable for at least one month when kept frozen at -80°C with no loss in response and an inter-day RSD of less than 5%. The method was applied to quantify the acetate content in the clinically available product of TCS and to simultaneously evaluate the average peptide molecular weight and detect known impurities by switching from negative polarity MRM analysis to positive polarity MS analysis following the elution of the acetate peak. The method reported herein should corroborate quantitative determinations of the acetate content in pharmaceuticals by the traditional compendial HPLC method.

Decreased insulin-mediated but not non-insulin-dependent glucose disposal rates in glucose intolerance and type II diabetes in African (Ghanaian) immigrants. The authors evaluated the significance of beta cell function, non-insulin-dependent glucose disposal (glucose effectiveness [Sg]), and insulin-dependent glucose disposal (insulin sensitivity) in African immigrants with varying degrees of glucose tolerance. Thirty-two African immigrants residing in Franklin County, Ohio, were studied. There were 16 subjects with normal glucose tolerance (NGT), 11 with intermediate glucose tolerance (IGT), and 5 with type II diabetes mellitus (DM). Insulin sensitivity index and Sg were measured by an insulin-modified, frequently sampled intravenous glucose tolerance test. The mean fasting and post-glucose serum glucose levels were lowest in the NGT, intermediate in the IGT group, and highest in the DM group. Mean serum insulin and c-peptide responses rose briskly by threefold to a peak in the NGT and the IGT groups. In the DM group, mean serum insulin and c-peptide responses were severely blunted to glucose stimulation. The sensitivity index was highest in the NGT (3.09 +/- 0.27), intermediate in the IGT (1.81 +/- 0.47), and lowest in the DM (0.48 +/- 0.28 x 10(-2).mins-1 (microU/ml)-1). The Sg was identical in the NGT (2.78 +/- 0.22) and IGT (2.78 +/- 0.27) groups but was slightly but not significantly lower in the DM (2.20 +/- 0.35 x 10(-2).mins-1). In addition, the glucose decay constant was not statistically different in the NGT (3.00 +/- 0.38) and IGT (2.25 +/- 0.19) group, but the mean values were significantly greater than in the patients with diabetes (0.78 +/- 0.15 percent/mins). The mean disposition index (sensitivity index X beta cell function as assessed by both insulin and c-peptide) was significantly greater in NGT than in the IGT (P<0.05) and in the diabetic group (P<0.001). In summary, the authors demonstrate that, in native African immigrants, type II diabetes is associated with significant reduction in beta cell function, insulin sensitivity, and glucose decay constant, but not in Sg. In patients with intermediate or impaired glucose tolerance, there is moderate insulin resistance and evidence of inadequate compensation by beta cell, but the Sg, the Sg at theoretical insulin concentration, and glucose decay constant remain normal. They conclude that, unlike other ethnic and racial groups, in glucose intolerant native African patients, alterations in Sg or non-insulin dependent glucose disposal (ie, tissue glucose sensitivity) do not appear to play a significant role in the impairment of glucose tolerance and type II diabetes in African immigrants.

[Technological and pharmacotherapeutic properties of selected drugs with modified release of diclofenac sodium]. Diclofenac and its sodium salt is one of the best-known and popular therapeutic agents from the group of NSAIDs used in medicine in many various pharmaceutical forms. Therapeutic products containing diclofenac sodium salt in doses of 100 mg and 75 mg with a qualitatively and quantitatively diversified share of excipients and a variable dosage form of the drug (solid capsules, tablets with modified release) were subjected to technological and pharmaceutical analysis. The effect of solid formulation components of polymer character making the core and the coating of the pharmaceutical form of therapeutic products on the disintegration time and pharmaceutical availability in pharmacopoeial receptor fluids was estimated. Market therapeutic products with diclofenac sodium in doses of 75 mg and 100 mg, technological analysis of the drug dosage form was conducted, disintegration time of solid oral dosage forms of the drug with diclofenac sodium salt was examined and research on pharmaceutical availability of diclofenac sodium salt from tested therapeutic products was conducted using the acid phase and the buffer phase according to the FP standards for delayed release enteral dosage forms. The experimental data was supplemented with the statistical analysis. There are three formulations in the form of solid capsules and one formulation in the form of a coated tablet. All therapeutic products bear features of a dosage form of modified release of diclofenac sodium salt, frequently of a delayed release formula in the duodenum or the small intestine with regard to the limitation of typical undesirable effects after taking NSAIDs. Considerable diversity between solid capsules and the tablet with modified release during disintegration or hydration and swelling has been observed. In the environment of a receptor fluid--purified water (pH = 7) the capsule Dicloberl retard disintegrates at the fastest rate in 5,49 minutes, and then in the order: DicloDuo 75 mg--8,13 minutes and Olfen 100 SR--11,27 minutes. The hydration degree of gelatin walls of capsules depends on the pH of the receptor fluid. The availability of diclofenac sodium salt in given receptor fluids confirms the fact of significant connection of clinical effectiveness of the tested pharmaceutical forms with the activity of hydrogen ions (pH) of the environment in which there are therapeutic products, and excipients used for making the pharmaceutical phase. Tested therapeutic products with diclofenac sodium salt are differentiated by the type of a dosage form. Dicloberl retard contains the minimally indispensable number of simple, commonly used excipients. The research on the disintegration time may only be related to the products Dicloberl retard, Olfen 100 SR and DicloDuo 75 mg treating it as the time of deformation and disintegration of a capsule. In all three types of receptor fluids, the capsule Dicloberl retard has the fastest disintegration rate. The "acid phase" demonstrated stability of the products with a slight dissolution of diclofenac sodium salt on the level 1,3-4,18% of the Q release coefficient. In the environment of artificial intestinal juice, Dicloberl retard is more effective releasing larger amounts of diclofenac sodium salt during 4 hours of exposition (differences from 10% to 14% of the Q release coefficient).

Longitudinal study on the health status of children in a rural Tanzanian community: parasitoses and nutrition following control measures against intestinal parasites. Three repeated cross-sectional surveys were undertaken among children (1 month to 15 years) of a rural community in southeastern Tanzania. The study was part of a longitudinal project on the interactions among nutrition, parasitic infections and immunity within a primary health care programme emphasizing village health workers. All children underwent interviews and parasitological, anthropometric, anamnestic and clinical examinations. Out of 550-590 children examined each year, a cohort of 170 children could be followed for three consecutive years. Malaria was holo- to hyperendemic in the community, P. falciparum accounting for greater than 90% of the infections. The parasite and spleen rates were 88% and 67%, respectively, and the average enlarged spleen index was 2.0 among children from 2-9 years in 1982. Transmission of malaria was high and stable as indicated by a parasite rate of 80% among infants between 1 month and 1 year during the whole period of study. G. lamblia, hookworm (N. americanus), Strongyloides spp. and Schistosoma haematobium were highly prevalent and annual incidence rates were high, while Entamoeba histolytica, Ascaris and Trichuris were of minor importance. Prevalence and incidence of parasitic infections did not differ by sex. Multiparasitism was very frequent and less than 11% of all children were parasite-free in each year. Not a single child remained parasite-free for three consecutive years. An anthropometric assessment showed a high degree of stunting (35-71%) and a substantial proportion of wasting (3-20%). The growth potential was normal in girls and boys during the whole period of study. There were indications that malaria was the main contributory factor to growth retardation among young children. Hookworm infection did not significantly affect the packed-cell volume of the children, probably owing to the low intensity of infection. Due to the multiparasitism and the lack of parasite-free individuals, single-parasite and single-nutrient effects were difficult to unravel. A latrine campaign followed by a single mass treatment against hookworm (single oral dose of albendazole, 400 mg) and/or G. lamblia (single oral dose of ornidazole, 40 mg/kg) only temporarily affected the prevalence and incidence of G. lamblia, and only resulted in a decrease in the intensity of hookworm infections up to six months after the interventions. As the effects of the latrine campaign and a single mass treatment on the parasite load were only transient, no sustained impact on nutritional variables was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Barrier-relevant crash modification factors and average costs of crashes on arterial roads in Indiana. The objective of this study was to develop crash modification factors (CMFs) and estimate the average crash costs applicable to a wide range of road-barrier scenarios that involved three types of road barriers (concrete barriers, W-beam guardrails, and high-tension cable barriers) to produce a suitable basis for comparing barrier-oriented design alternatives and road improvements. The intention was to perform the most comprehensive and in-depth analysis allowed by the cross-sectional method and the crash data available in Indiana. To accomplish this objective and to use the available data efficiently, the effects of barrier were estimated on the frequency of barrier-relevant (BR) crashes, the types of harmful events and their occurrence during a BR crash, and the severity of BR crash outcomes. The harmful events component added depth to the analysis by connecting the crash onset with its outcome. Further improvement of the analysis was accomplished by considering the crash outcome severity of all the individuals involved in a crash and not just drivers, utilizing hospital data, and pairing the observations with and without road barriers along same or similar road segments to better control the unobserved heterogeneity. This study confirmed that the total number of BR crashes tended to be higher where medians had installed barriers, mainly due to collisions with barriers and, in some cases, with other vehicles after redirecting vehicles back to traffic. These undesirable effects of barriers were surpassed by the positive results of reducing cross-median crashes, rollover events, and collisions with roadside hazards. The average cost of a crash (unit cost) was reduced by 50% with cable barriers installed in medians wider than 50ft. A similar effect was concluded for concrete barriers and guardrails installed in medians narrower than 50ft. The studied roadside guardrails also reduced the unit cost by 20%-30%. Median cable barriers were found to be the most effective among all the studied barriers due to the smaller increase in the crash frequency caused by these barriers and the less severe injury outcomes. More specifically, the occupants of vehicles colliding with near-side cable barriers tended to have less severe injuries than occupants of vehicles entering the median from median's farther side. The near-side cable barriers provided protection against rollover inside the median and against a potentially dangerous collision with or running over the median drain; therefore, the greatest safety benefit can be expected where cable barriers are installed at both edges of the median. The CMFs and unit crash costs for 48 road-barrier scenarios produced in this study are included in this paper.

Testing the relative influence of instrinsic and extrinsic variation in food availability on feral pig populations in Australia's rangelands. Instrinsic variation in the availability of food to animal populations reflects the influence of foraging by the animals themselves. Instrinsic variation in food availability provides a link between population density, subsequent food availability and variation in the rate of population increase (r), operating through density-dependent food shortage. In contrast, extrinsic variation in food availability is caused by environmental influences on food or animal abundance, which are independent of animal foraging. Extrinsic variation in food availability is random relative to that arising through intrinsic shortage. Intrinsic and extrinsic variation in food availability can influence animal populations simultaneously. Intrinsic variation will impart a tendency towards an equilibrium between animal and food abundance. which will be progressively obscured by density-independent variation as the influence of extrinsic factors increases. This study used a large-scale field experiment, in which the density of food-limited feral pig (Sus Scrofa L.) populations was manipulated on six sites, to assess the relative influence of intrinsic and extrinsic variation in food availability. The experiment evaluated the influence of pig population density on r and the abundance of food resources measured as pasture biomass. It was predicted that if intrinsic shortages dominated variation in food availability, pasture biomass and r would decline with increasing pig density. If extrinsic factors dominated variation in food availability, pig density would have no systematic effect on either pasture biomass or r. If intrinsic and extrinsic sources simultaneously affected variation in food availability, higher pig densities would have no systematic effect on r, but would reduce pasture biomass. The simultaneous model predicts reduced pasture biomass because, in the absence of compensatory changes in other sources of variation, the effects of intrinsic and extrinsic factors will be additive. To examine further the degree of interdependence in pig and pasture abundance, a series of stochastic models of the grazing system were estimate and the feedback loop comprising the functional and numerical responses of feral pigs to variation in pasture biomass was manipulated. In the large-scale experiment, neither pasture biomass nor r declined with increasing pig density, suggesting that food availability was dominated by extrinsic factors. However, limitations of the experiment meant that a minor decline in pasture biomass may have gone undetected. Comparison of simulation models, which included and omitted pasture offtake by pigs, indicated that because they were less efficient grazers and persisted at lower average densities relative to other large herbivores, pigs had little influence on variation in pasture biomass.

The impact of the physical and urban environment on mental well-being. To examine the strength of association between physical and social factors in the built environment and mental well-being, and to determine which factors are the most important. A postal survey based on a theoretical model of domains that might link the physical and urban environment with mental well-being was sent to 2696 adults aged 18 years or over, in four areas of Greenwich, London. Mental health was measured using the SF36 subscales for mental health (MH) and vitality (V). Additional household and area level data were appended for each respondent from a range of sources. 1012 questionnaires were returned (38% response rate). At the univariate level significant confounders that were associated with poorer mental well-being were being female, 85+ years, unemployed or retired, on housing benefit, council tenant, two or more children, and having requested re-housing Better mental well-being was associated with being aged 65 years to 84 years (better MH and V). Within domain analysis, adjusting for each of the confounding factors, resulted in the following factors being significantly associated with being in the lowest quartile for MH score: (i) control over the internal environment (damp), (ii) design and maintenance (not liking the look of the estate/road, (iii) noise (neighbour noise), (iv) density and escape (feeling over-crowded in the home, being dissatisfied with green spaces, dissatisfied with social and entertainment facilities) being dissatisfied with community facilities (such as libraries and community centres) was only significant for vitality, (v) fear of crime and harassment (feeling unsafe to go out in the day, feeling unsafe to go out at night, agreeing that needles and syringes left lying around are a problem) (vi) social participation (not enough events to get people together, not enough places to stop and chat). When these 12 factors were entered into a single model with the significant confounders five remained significantly associated with being in the lowest quartile for MH or V: neighbour noise MH OR 2.71 [95% CI 1.48, 4.98]; feeling over-crowded in the home MH OR 2.22 [1.42, 3.48]; being dissatisfied with access to green open spaces MH OR 1.69 [1.05, 2.74]; access to community facilities V OR 1.92, [1.24, 3.00]; feeling unsafe to go out in the day MH OR 1.64 [1.02, 2.64]; V OR 1.58 [1.00, 2.49]. This study confirms an association between the physical environment and mental well-being across a range of domains. The most important factors that operate independently are neighbour noise, sense of over-crowding in the home and escape facilities such as green spaces and community facilities, and fear of crime. This study highlights the need to intervene on both design and social features of residential areas to promote mental well-being.

Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis. Is there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment? In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose. In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists. Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping. In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-Müllerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95% CI, -0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = €275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were €35). The analysis based on AMH as a tool for dose individualization suggested comparable results. Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response. Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research. This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other autors have nothing to declare. Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.

Tyrosine kinase inhibitors. 6. Structure-activity relationships among N- and 3-substituted 2,2'-diselenobis(1H-indoles) for inhibition of protein tyrosine kinases and comparative in vitro and in vivo studies against selected sulfur congeners. A small series of 2,2'-diselenobis(1H-indoles) was synthesized as redox-modified congeners of our earlier reported 2,2'-dithiobis(1H-indole) series. Utilizing chemistry similar to that developed earlier for the disulfur series, compounds were made from 2-halogeno-3-indolecarboxylic acid precursors bearing various polar functionality at the C-3 position and small alkyl substituents at the N-1 position of the indole nucleus. Additional compounds were derived from (R)- or (S)-tryptophan via a novel application of diselenium dichloride as an electrophilic source of diselenium, and a much improved process to a 2,2'-dithiobis(1H-indole) congener was developed utilizing disulfur dichloride as a source of disulfur. Against isolated epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), and v-src tyrosine kinases, compounds in this series displayed broad inhibitory activity with IC50 = 0.9 to > 100 microM vs EGFr, 3.4 to > 50 microM vs PDGFr, and 0.4-6.7 microM vs v-src. In general, compounds derived from tryptophan displayed the greatest potency against EGFr and those from 2-halogeno-3-indolecarboxylic acids greater potency against PDGFr and v-src. Enzyme kinetics studies showed that both classes of compounds display primarily noncompetitive inhibition with respect to either ATP or peptide substrate. The sulfhydryl reducing agent dithiothreitol (DTT) caused a general decrease in inhibition of the EGFr and v-src tyrosine kinases by both the diselenium and disulfur series with the reversal of enzyme inhibition occurring less readily within the diselenium series. In whole cell studies, compounds of this class were growth inhibitory against Swiss 3T3 mouse fibroblasts with IC50 values from 0.5 to 19.5 microM, and the observed SAR was different from that of the 2,2'-dithiobis(1H-indoles). A comparative study in the same cell line on the effects of the 2,2'-diselenobis(1H-indole) derived from (R)-tryptophan vs its disulfur congener on growth factor mediated tyrosine phosphorylation showed that this compound significantly inhibited EGFr and PDGFr (in response to its ligand) autophosphorylation with complete suppression at 25 and 5 microM, respectively. Tyrosine phosphorylation of an 85 kDa protein typically phosphorylated in response to bFGF was also exquisitely sensitive to this compound, and it displayed inhibitory effects on DNA, RNA, and protein synthesis at submicromolar concentrations. The disulfur congener exhibited a qualitatively similar pattern; however, its potency was 10-fold less. This same diselenium/disulfur pair was evaluated in vivo against the B16 melanoma, colon carcinoma 26, and M5076 sarcoma murine tumors, and the A431 epidermoid, and C6 glioma human tumor xenografts. At maximum tolerated doses (1.8 and 5.0 mg/kg/injection, respectively), neither the diselenium nor disulfur congener was effective against the C6 glioma when administered intraperitoneally on a d1-9 schedule. Studies were also carried out against the A431 epidermoid xenograft to evaluate the same pair of compounds via continuous subcutaneous infusion from Alzet miniosmotic pumps. The maximum dose that could be administered daily was limited by compound solubility. Neither compound produced an antitumor effect in a 7-day continuous infusion study. In the 27-day study, the disulfur compound was inactive whereas the diselenium compound produced a 10.8-day growth delay without appreciable treatment related weight loss. The in vitro and in vivo findings offer a mechanistic rationale as to why the 2,2'-diselenobis(1H-indoles) are more potent inhibitors than their disulfur congeners.

A comparative research on obesity hypertension by the comparisons and associations between waist circumference, body mass index with systolic and diastolic blood pressure, and the clinical laboratory data between four special Chinese adult groups. The obesity-hypertension pathogenesis is complex. From the phenotype to molecular mechanism, there is a long way to clarify the mechanism. To explore the association between obesity and hypertension, we correlate the phenotypes such as the waist circumference (WC), body mass index (BMI), systolic blood pressure (SB), and diastolic blood pressure (DB) with the clinical laboratory data between four specific Chinese adult physical examination groups (newly diagnosed untreated just-obesity group, newly diagnosed untreated obesity-hypertension group, newly diagnosed untreated just-hypertension group, and normal healthy group), and the results may show something. To explore the mechanisms from obesity to hypertension by analyzing the correlations and differences between WC, BMI, SB, DB, and other clinical laboratory data indices in four specific Chinese adult physical examination groups. This cross-sectional study was conducted from September 2012 to July 2014, and 153 adult subjects, 34 women and 119 men, from 21 to 69 years, were taken from four characteristic Chinese adult physical examination groups (newly diagnosed untreated just-obesity group, newly diagnosed untreated obesity-hypertension group, newly diagnosed untreated just-hypertension group, and normal healthy group). The study was approved by the ethics committee of Hangzhou Center for Disease Control and Prevention. WC, BMI, SB, DB, and other clinical laboratory data were collected and analyzed by SPSS. Serum levels of albumin (ALB)，alanine aminotransferase (ALT), low density lipoprotein cholesterol (LDLC), triglyceride (TG), high density lipoprotein cholesterol (HDLC), alkaline phosphatase (ALP), uric acid (Ua), and TC/HDLC (odds ratio) were statistically significantly different between the four groups. WC statistically significantly positively correlated with BMI, ALT, Ua, and serum levels of glucose (GLU), and TC/HDLC, and negatively with ALB, HDLC, and serum levels of conjugated bilirubin (CB). BMI was statistically significantly positively related to ALT, Ua, LDLC, WC, and TC/HDLC, and negatively to ALB, HDLC, and CB. DB statistically significantly positively correlated with ALP, BMI, and WC. SB was statistically significantly positively related to LDLC, GLU, serum levels of fructosamine (FA), serum levels of the total protein (TC), BMI, and WC. The negative body effects of obesity are comprehensive. Obesity may lead to hypertension through multiple ways by different percents. GGT, serum levels of gamma glutamyltransferase; ALB, serum levels of albumin; ALT, serum levels of alanine aminotransferase; LDLC, serum levels of low density lipoprotein cholesterol; TG, serum levels of triglyceride; HDLC, serum levels of high density lipoprotein cholesterol; FA, serum levels of fructosamine; S.C.R, serum levels of creatinine; IB, serum levels of indirect bilirubin; ALP, serum levels of alkaline phosphatase; CB, serum levels of conjugated bilirubin; UREA, Urea; Ua, serum levels of uric acid; GLU, serum levels of glucose; TC, serum levels of the total cholesterol; TB, serum levels of the total bilirubin; TP, serum levels of the total protein; TC/HDLC, TC/HDLC ratio.

Retrolisthesis and lumbar disc herniation: a postoperative assessment of outcomes at 8-year follow-up. Lumbar disc herniation and retrolisthesis have been shown to be significant degenerative changes that can be associated with back pain. Current literature has shown evidence that retrolisthesis is associated with similar baseline function in patients with L5-S1 disc herniation, but worse postoperative outcomes 2 years after lumbar discectomy. However, literature comparing long-term postoperative outcomes at 8-year follow-up in patients with L5-S1 disc herniation with retrolisthesis is lacking. The purpose of the present study is to compare long-term postoperative outcomes at 8-year follow-up in patients with retrolisthesis and L5-S1 disc herniations to patients with L5-S1 disc herniations without retrolisthesis. Retrospective review of prospectively collected data from the Spine Patients Outcomes Research Trial (SPORT) database. Sixty-five patients who underwent lumbar discectomy for L5-S1 disc herniations with 8-year follow-up from the SPORT. Short Form (SF)-36 bodily pain scale, SF-36 physical function scale, Oswestry Disability Index, Sciatica Bothersomeness Index, and reoperation rate. Baseline surgical parameters, length of stay, complication rates, reoperation rates, and outcome measures were recorded in the SPORT database. Follow-up data were collected at 6 weeks, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, and 8 years. Retrolisthesis was defined as posterior subluxation ≥8%. Patients with and without retrolisthesis were compared using a mixed-effects model of longitudinal regression. Outcomes were calculated as time-weighted averages over 8 years. Reoperation rates were compared using the log-rank test based on time to first reoperation. One hundred-twenty five patients met inclusion criteria for the present study, including 29 patients with retrolisthesis (23.3%) and 96 patients who did not have retrolisthesis (76.7%). The greatest difference in clinical outcome measures was found at 2 years postoperatively. This was the only point at which both the Short Form-36 Bodily Pain scale (SF-36 BP) and PF showed significant differences between the retrolisthesis and nonretrolisthesis group. At 3 years, SF-36 BP was significantly lower in patients with retrolisthesis (39.9 vs. 52, p=.046). At 8-year follow-up, the presence of retrolisthesis in patients undergoing L5-S1 discectomy was not associated with worse outcome measure scores based on the area under the curve analysis for any metric investigated (SF-36 BP 41.4 vs. 47.1, p=.18; SF-36 Physical Function scale 38.9 vs. 45.4, p=.12; Oswestry Disability Index -39.4 vs. -34.8, p=.23; -11.6 vs. -10.4, p=.25) or a difference in reoperation rate (retrolisthesis group 10%, nonretrolisthesis group 17%, p=.41). While retrolisthesis can contribute to low back pain and dysfunction in patients undergoing lumbar discectomy for L5-S1 herniated nucleus pulposus in early follow-up, no significant difference was found in postoperative outcomes after 3 years. Additionally, retrolisthesis was not found to be associated with different reoperation rates at 8 years postoperatively.

[Mid-term results of shoulder arthroplasty for primary osteoarthritis]. Primary osteoarthritis of the glenohumeral joint is less common than that of the hip and knee, but it is not so rare. The use of prosthetic arthroplasty for the management of end-stage osteoarthritis remains the treatment of choice. We reviewed our experience of shoulder arthroplasties in 48 patients (51 shoulders) with 60 months average follow-up (24-124). Forty-eight patients (51 shoulders) underwent shoulder replacement for primary osteoarthritis. There were 15 men and 36 women. Average age was 65 years. A total shoulder arthroplasty was performed in 43, and a hemiarthroplasty in 8. A Neer II monobloc implant was used in 27, and a modular implant in 24. The humeral implant was cemented in all cases but 3. An all-polyethylene cemented glenoid implant was used in all total shoulder arthroplasties. A rotator cuff tear was found in 8 cases. According to Neer rating scale, an excellent result was found in 19 cases (37%), a satisfactory result in 27 (53%), and a non-satisfactory result in 5 (10%). According to Constant's criteriae, pain improved from 1.5 to 12 points, activity from 7 to 16.5 points, and mobility from 14 to 31 points. Active anterior elevation improved from 73 to 140 degrees, with a gain of 67 degrees; active external rotation improved from 9 to 40 degrees, with a gain of 31 degrees. Internal rotation improved also from the ability of the thumb to reach the sacrum to T12. The ponderated Constant score calculated for 22 patients was 91 p.cent. Radiographic analysis showed lucent lines around the humeral component in 10 cases (19%), and around the glenoid in 29 cases (67%). A complete lucent line not greater than 1mm size, was present in only 15 glenoid implants (35%). There was no case of component loosening in our series at the longest follow-up, as well as no revision procedure. Only the preoperative rotator cuff status influenced statistically the final result. Best results were obtained with total shoulder arthroplasties compared to hemiarthroplasty, and with modular implants compared to monobloc. Shoulder arthroplasty has become the standard for the treatment of primary osteoarthritis. Proximal humeral head prosthetic replacement can be a very successful procedure in patients with glenohumeral arthritis; however the degree and consistency of pain relief is not as great nor as predictable as in total shoulder arthroplasties. Also, clinical results seem to deteriorate with time. Revision rate is approximatively of 20%, usually for persistant pain. The clinical results of total shoulder arthroplasty continue to be excellent with longer follow-up period. The frequency of complications and the need for revision is low. However, when revision surgery is needed, the most common reason is for glenoid loosening. Good results can be expected especially in primary osteoarthritis with pain relief in almost all cases, good motion (three-fourths or four-fifths normal), improvement of functional activities, and patient satisfaction in at least 90% of the cases.

Oscillatory firing of single human sphincteric alpha 2 and alpha 3-motoneurons reflexly activated for the continence of urinary bladder and rectum. Restoration of bladder function in paraplegia. 1. By recording with 2 pairs of wire electrodes from human sacral nerve roots (S3-S5) rhythmic as well as occasional firing was observed in alpha 2 and alpha 3-motoneurons in response to physiologic stimulation of the urinary bladder and the anal canal. The rhythmic firing consisted of periodically occurring impulse trains, most likely produced by true spinal oscillators which drove the motoneurons. 2. Alpha 2-motoneurons, innervating fast fatigue-resistant muscle fibres, were observed to fire with impulse trains of about 2 to 4 action potentials (Ap's). These impulse trains occurred every 110 to 170 msec (5-9 Hz). Alpha 3-motoneurons, innervating slow fatigue-resistant muscle fibres, fired about every 1400 msec (approximately 0.7 Hz) with impulse trains of about 11 to 60 Ap's. Alpha 1-motoneurons, innervating fast fatigue muscle fibres, and gamma-motoneurons were not observed in the continuous oscillatory firing mode. 3. Sphincteric motoneurons were observed most likely in the oscillatory firing mode in response to the sustained stretch (reflex) of the external and sphincter or to retrograde filling of the bladder (urethro-sphincteric guarding reflex), in order to preserve continence. A urethral sphincteric alpha 2-motoneuron increased its mean activity from 0.5 to 18 Ap's/sec during retrograde filling by changing its firing pattern from the occasional spike mode via the transient oscillatory firing mode to the continuous oscillatory mode. Up to a filling of the bladder of 500 ml the mean activity of the stretch receptors, measuring probably mural tension, increased roughly proportionally and the sphincteric motoneuron increased its activity to about 1 Ap/sec in the occasional spike mode. Up to 600 ml, the motoneuron responded in the transient oscillatory mode with mean activities of up to 5 Ap's/sec. With higher bladder fillings, the flow receptors afferents fired additionally, probably according to pressure symptoms, and the motoneuron switched into the continuous oscillatory firing mode and increased its activity up to 18 Ap's/sec at 700 ml. When the bladder was about 800 ml full, the stretch afferent activity decreased, the flow receptor activity increased strongly and the alpha 2-motoneuron activity decreased; the overflow incontinence had probably started. Micturition was not observed, probably because of brain death. 4. It is suggested that one adequate stimulus for an alpha 2-motoneuron of the external anal sphincter to jump into the oscillatory firing mode, was the activity from secondary spindle afferent (SP2) fibres from external anal sphincter muscle spindles.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison between sheep and human cervical spines: an anatomic, radiographic, bone mineral density, and biomechanical study. The quantitative anatomic, radiographic, computerized tomographic, and biomechanical data of sheep and human cervical spines were evaluated. To compare the anatomic, radiographic, computerized tomographic, and biomechanical data of human and sheep cervical spines to determine whether the sheep spine is a suitable model for human spine research. Sheep spines have been used in several in vivo and in vitro experiments. Quantitative data of the normal sheep cervical spine are lacking, yet these data are crucial to discussion about the results of such animal studies. In this study, 20 fresh adult female Merino sheep cervical spines and 20 fresh human cadaver cervical spines were evaluated anatomically, radiographically, computerized tomographically, and biomechanically. Three linear and two angular parameters were evaluated on four digital radiographic views: anteroposterior, right lateral in neutral position, flexion, and extension. Quantitative computed tomography scans at the center of each vertebral body and 3 mm below both endplates were analyzed for bone mineral density measurements. Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending by a nondestructive stiffness method using a nonconstrained testing apparatus. Range of motion and stiffness of each motion segment were calculated. Additionally, 10 linear anatomic parameters of each vertebra were measured using a digital ruler. Anterior and mean disc space height in the sheep cervical spine increased constantly from C2-C3 to C6-C7, whereas middle disc space height decreased and posterior disc space height remained unchanged. Anterior and mean disc space height were significantly higher in sheep. In both sheep and human cervical spines, intervertebral angles were not significantly different. Standard deviations of bone mineral density in the human cervical spine were fourfold higher than in the sheep cervical spine, yet no significant differences were found in bone mineral density values between the two species. Range of motion differed significantly between the two species except in flexion-extension of C3-C4, C5-C6, axial rotation of C2-C3, and lateral bending of C2-C3, C3-C4, and C4-C5. Stiffness also was significantly different except in flexion-extension of C2-C3, C4-C5, C5-C6, and lateral bending of C2-C3, C3-C4, and C4-C5. Anatomic evaluation showed no difference in upper endplate parameters for C4 and C5. Although several differences were found between human and sheep cervical spines, the small intergroup standard deviations and the good comparability with the human spine encourage the use of the sheep cervical spine as a model for cervical spine research. On the basis of the quantitative data obtained in this study, the sheep motion segment C3-C4 seemed to be the most reliable model for the corresponding human motion segment.

Rehospitalization after kidney transplantation during the first year: length, causes and relationship with long-term patient and graft survival. There is a wide interest in epidemiologic studies assessing different causes of post-kidney transplantation rehospitalization. However, there is a paucity of knowledge on the long-term survival and graft function of rehospitalized kidney transplant recipients during the first year. Knowledge of posttransplant rehospitalization causes may help guide the preventive program at the first year. In our study, we assess causes for hospitalization and investigate the long-term patient and graft survival after non-fatal rehospitalization in kidney recipients during the first year. We retrospectively studied the medical histories of 419 kidney transplant recipients whose operations were performed between 1986 and 2009 at Charles Nicolle Hospital, in Tunis, Tunisia. Among these patients, a total of 296 posttransplant rehospitalizations of kidney transplant recipients during the first year occurring in 191 (45.5%) patients were assessed. Clinical characteristics of the patients, including gender, age, reason for kidney failure, weight, height, blood group, length of pretransplant dialysis, immunosuppressive regimen, postoperative complications, the length of hospital stay, transplantation-admission interval, causes of rehospitalizations, graft loss, and mortality rate were reviewed. For donors, these demographics included age, gender, blood group, type of donor (deceased or living), and relationship to the recipient. Because rehospitalizations are possible for more than one cause, the sum of frequencies of rehospitalization causes is more than 100%. There was 1 rehospitalization in 121 patients, 2 rehospitalizations in 47 patients, 3 rehospitalizations in 15 patients, 4 rehospitalizations in 5 patients, 5 rehospitalizations in 2 patients and 6 rehospitalizations in 1 patient. Rehospitalization was more frequent for diabetic patients without significant association. The causes of rehospitalization were infection in 221 cases (55.5%), renal dysfunction in 106 cases (26%), cardiovascular event in 10 cases (2.4%), and diabetic ketoacidosis in 11 cases (2.7%). The length of hospital stay was 22.5 ± 29.6 days, 20.15 ± 22.16 days, 25 ± 30 days and 23.4 ± 27.5 days, respectively, in the first, second, third, and fifth rehospitalizations. Median hospital stay for all rehospitalizations was between 14 and 16 days. The risk factors of rehospitalization were: use of mycophenolate mofetile (P = .0072), use of cyclosporine (P = .0073), and cytomegalovirus infection (P < .001). There was no significant correlation between rehospitalization and either lost of graft and death. During the first year after kidney transplantation, rehospitalization was especially required because of infections and renal dysfunction. The risk factors of rehospitalization were cadaveric graft, use of mycophenolate mofetil, use of cyclosporine, and cytomegalovirus infection. To prevent and minimize rehospitalizations during the first year, a specific preventive program based on infection prevention and graft function monitoring should be established.