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Combination of Thrombolysis and Statins in Acute Stroke Is Safe: Results of the STARS Randomized Trial (Stroke Treatment With Acute Reperfusion and Simvastatin).

The STARS trial (Stroke Treatment With Acute Reperfusion and Simvastatin) was conducted to demonstrate the efficacy and safety of simvastatin treatment in acute stroke. STARS07 was a multicentre, phase IV, prospective, randomized, double-blind, placebo-controlled trial. Patients with Acute ischemic stroke recruited within 12 hours from symptom onset were randomized to oral simvastatin 40 mg or placebo, once daily for 90 days. Primary outcome was proportion of independent patients (modified Rankin Scale score of ≤2) at 90 days. Safety end points were hemorrhagic transformation, hemorrhagic events, death, infections, and serious adverse events. From April 2009 to March 2014, 104 patients were included. Fifty-five patients received intravenous tissue-type plasminogen activator. No differences were found between treatment arms regarding the primary outcome (adjusted odds ratio, 0.99 [0.35-2.78]; P=0.98). Concerning safety, no significant differences were found in the rate of hemorrhagic transformation of any type, nor symptomatic hemorrhagic transformation. There were no differences in other predefined safety outcomes. In post hoc analyses, for patients receiving tissue-type plasminogen activator, a favorable effect for simvastatin treatment was noted with higher proportion of patients experiencing major neurological recovery (adjusted odds ratio, 4.14 [1.18-14.4]; P=0.02). Simvastatin plus tissue-type plasminogen activator combination seems safe in acute stroke, with low rates of bleeding complications. Because of the low recruitment, the STARS trial was underpowered to detect differences in simvastatin efficacy. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01073007.

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Comparison of CHOP with THP-COP for peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma: a retrospective analysis using data from the population-based Osaka Cancer Registry.

Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) are common subtypes of T-cell lymphoma. Although CHOP is a standard regimen for T-cell lymphoma, it has unsatisfactory outcomes. Pirarubicin is an anthracycline antibiotic with lower cardiotoxicity than doxorubicin. THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisone) is sometimes used for elderly patients with non-Hodgkin's lymphoma in Japan. We performed a retrospective analysis using data from the population-based Osaka Cancer Registry as well as administrative data from 2010 to 2015. Of 82 enrolled patients, 51 received CHOP and 31 received THP-COP. The median age was 65 years in the CHOP group and 75 years in the THP-COP group. The probability of 3-year overall survival (OS) was 49.0% in the CHOP group and 44.9% in the THP-COP group. In the propensity score-adjusted analysis, there was no significant difference between the THP-COP and CHOP groups in the OS of the total sample [hazard ratio (HR) 0.46, 95% CI 0.14-1.55, P = 0.2]. Although our study was limited by its retrospective nature, it showed that clinical outcomes with the THP-COP regimen were comparable to those with the CHOP regimen in PTCL-NOS and AITL. Our findings should be re-assessed in larger studies in the future.

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[Increased vagal activity after administration of the calcium antagonist diltiazem in patients with coronary heart disease].

The effects of the calcium channel blockers diltiazem on the parasympathetic nervous system were studied by using spectral analysis of heart rate variability, and were compared with the effects of the beta-receptor blocker metoprolol. The area under the curve of the high-frequency range (f = 0.18-0.35 Hz) during controlled respiratory rate (f = 0.25 Hz) was used as a quantitative index of parasympathetic activity. Twenty-four male patients with proven coronary artery disease and normal left ventricular function (LVEF > 60%) were studied 2 weeks after chronic treatment with diltiazem (3 x 60 mg daily) or metoprolol (3 x 50 mg daily) before and after administration of the drug. Twelve patients received diltiazem and 12 patients metoprolol. After administration of diltiazem the peripheral systolic blood pressure was reduced, but the parasympathetic activity was significantly higher than compared with the initial measurement. The same effect was seen for metoprolol, but a significant lower heart rate was present after administration. The relative area under the high-frequency range significantly increased at rest, by 110% after diltiazem and 70% after metoprolol. Diltiazem and metoprolol enhance the vagal influence at the heart, thereby leading to an enhancement of barosensitivity and of the respiratory sinus arrhythmia. This action may contribute to the beneficial effects of both drugs in patients with coronary artery disease.

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Inhaled Corticosteroids Use and Risk of Invasive Pneumococcal Disease in a Population-based Study.

<b>Rationale:</b> The use of inhaled corticosteroids (ICS) is associated with increased pneumonia risk, but the risk of invasive pneumococcal disease (IPD) associated with ICS is not characterized.<b>Objectives:</b> The aim was to test the hypothesis that the use of ICS increases the risk of IPD.<b>Methods:</b> Cases were persons 20-65 years of age included in a Swedish national registry of invasive infection caused by <i>Streptococcus pneumoniae</i> classified as any IPD as well as the subset of IPD with pneumonia. The case index date was the day the infection was diagnosed. Six control subjects for each case (matched for sex, age, and region) were selected from the Swedish National Population Registry and were assigned the index date of their corresponding case. Current and past users of ICS were defined by the last prescriptions dispensed within 60 or 61-365 days of the index date. Nonusers were defined as those with no dispensed prescription the last 365 days. Current users were characterized by use of fluticasone or budesonide. We used conditional logistic analysis, including matching and covariates, to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of IPD, IPD with pneumonia, and IPD without pneumonia associated with current or past use of ICS.<b>Results:</b> Current use of ICS increased the risk for IPD and IPD with pneumonia (OR, 1.71; 95% CI, 1.39-2.10 and OR, 1.94; 95% CI, 1.53-2.47, respectively), but there was no statistical association between current use of ICS and IPD without pneumonia (OR, 1.18; 95% CI 0.78-1.80). Past use of ICS increased the risk for IPD and IPD with pneumonia but not for IPD without pneumonia. Among current ICS users, the odds for IPD were similar for budesonide (OR, 1.34; 95% CI, 1.14-1.57) and fluticasone (OR, 1.41; 95% CI, 1.04-1.90). Among current ICS users, the odds for IPD with pneumonia were slightly higher but of similar magnitude for both budesonide and for fluticasone.<b>Conclusions:</b> ICS use is associated with an increased risk of IPD and IPD with pneumonia. The risk is driven by IPD with pneumonia. We found similar risks for budesonide and fluticasone.

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Suppressive therapy with levothyroxine for solitary thyroid nodules.

To evaluate the effect of treatment with TSH suppressive dose of levothyroxine in patients with benign thyroid nodules. Prospective randomized study. Group A (n = 20) patients received levothyroxine and group B (n = 20) patients did not. The dose of levothyroxine was adjusted to obtain an effective suppression of TSH. A clinical, analytical and morphological (with ultrasound) review was performed every 3 months. The mean +/- SD follow-up period was 10.6 +/- 2.2 months. Forty euthyroid women with solitary thyroid nodule on palpation, cold on scintigraphy and cytologically benign without contraindication participated. At entry: biochemical and hormonal parameters, thyroid scintigraphy and thyroid ultrasonography. Every 3 months additional determinations of thyroid hormones and TSH levels were carried out, if necessary, to verify effective TSH suppression. Every 6 months thyroid ultrasound imaging was performed. Patients were euthyroid at entry into the study. The mean dose of levothyroxine necessary to obtain TSH suppression was 2.82 +/- 0.6 micrograms/kg/day. No significant modification in the thyroid nodule diameter (mean +/- SD 2.6 +/- 1.2 vs 2.5 +/- 1.2 cm) or in the thyroid nodule volume (10.3 +/- 11.9 vs 10.1 +/- 12.2 ml) were observed in group A. In group B the results were similar (2.8 +/- 0.9 vs 2.7 +/- 1.8 cm and 9.2 +/- 6.4 vs 9.2 +/- 9.5 ml, respectively). No differences were found in either group in the number of nodules that reduced significantly their volume (four and three, respectively). The suppressive therapy with levothyroxine was not effective in reducing nodule sizes in patients with solitary benign thyroid nodules.

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Preliminary support for gender differences in response to fluoxetine for generalized anxiety disorder.

Women have a higher prevalence of generalized anxiety disorder (GAD) than do men, but few studies have assessed gender differences in response to pharmacotherapy. In this study we examined gender as a correlate of response to 6 weeks of open, prospective fluoxetine treatment in 23 men and 22 women with a primary diagnosis of GAD. There was no difference by gender in age or prevalence of mood and anxiety comorbidity; however, GAD onset occurred at a significantly younger age in women compared with men. Despite a lack of difference in baseline severity measures, women had a significantly poorer response to fluoxetine as measured by both the Hamilton Anxiety Rating Scale (HAM-A) and Clinician Global Impression-Severity Scale (CGI-S). In multivariate analyses, there was a significant interaction between age of onset and gender: men with younger age of onset and women with older age of onset exhibited poorer response on the HAM-A. These data, though limited in sample size and by the post hoc nature of our analyses, offer preliminary support that women with GAD, particularly those with a later age of onset, may have a poorer response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Larger placebo-controlled trials are needed to more definitively examine gender and treatment response in anxiety disorders.

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Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin.

In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4. To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate. Nine healthy male subjects were treated in a three-period randomised crossover study with: (A) bosentan 125 mg twice daily for 5.5 days; (B) simvastatin 40 mg once daily for 6 days; and (C) bosentan 125 mg twice daily and simvastatin 40 mg once daily for 5.5 and 6 days, respectively. Plasma concentration-time profiles of bosentan and its metabolites (treatments A and C) and simvastatin and beta-hydroxyacid simvastatin (treatments B and C) were determined on day 6. Steady-state conditions for bosentan and its metabolites were attained on day 4 of treatment. The pharmacokinetic parameters of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: areas under the plasma concentration-time curve over one administration interval of 12 hours (AUC(tau)) [geometric mean and 95% CI] were 4586 (3719-5656) and 4928 (3945-6156) micro g * h/L. In contrast, bosentan significantly reduced exposure to simvastatin and beta-hydroxyacid simvastatin by 34 and 46%, respectively. AUC(tau) values for simvastatin were 30.5 (23.1-40.2) and 20.0 (15.9-25.1) micro g * h/L and for beta-hydroxyacid simvastatin 43.0 (32.1-57.8) and 23.4 (16.7-32.6) micro g * h/L in treatments B and C, respectively. Concomitant treatment with bosentan reduces the exposure to simvastatin and beta-hydroxyacid simvastatin by approximately 40%, indicating that in vivo bosentan is also a mild inducer of CYP3A4.

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Comparison of haemodynamic responses to dobutamine and salbutamol in cardiogenic shock after acute myocardial infarction.

Nine patients with critically reduced cardiac output after acute myocardial infarction underwent a single cross-over comparison of dobutamine and salbutamol to compare the haemodynamic effects of these drugs, which have, respectively, predominantly beta 1-adrenergic and beta 2-adrenergic agonist activity. The responses were used to select the more appropriate treatment for individual patients. Only relatively small responses were obtained: those with poorest baseline measurements tended to show the least effect. When the results from the series were averaged, dobutamine (250-750 microgram/min) caused a small but progressive increase in cardiac index (1.8 to 2.2 1/min/m2) throughout the dose range. Systemic blood pressure was not increased, and calculated systemic vascular resistance fell from 25 to 19 units. Heart rate rose from 107 to 118 beats/min and stroke index from 17 to 19 ml/beat/m2. Pulmonary artery end-diastolic pressure fell from 18 to 15 mm Hg. Salbutamol (10-40 microgram/min) produced a similar progressive increase in cardiac index, from 1.6 to 2.21/min/m2. Systemic blood pressure was not altered, and systemic vascular resistance fell from 25 to 20 units. Heart rate rose from 105 to 119 beats/min and stroke index from 16 to 19 ml/beat/m2. Pulmonary artery end-diastolic pressure did not fall. Dobutamine and salbutamol have closely similar haemodynamic effects when used in cardiogenic shock after acute myocardial infarction. Both drugs increase cardiac index but heart rate also rises, and the increase in stroke index is relatively small. Mean arterial pressure is altered little by either agent, but dobutamine (in contrast with dopamine) tends to reduce pulmonary artery end-diastolic pressure, which may be beneficial.

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A double blind placebo controlled study to determine the effects of intermittent cyclical etidronate on bone mineral density in patients on long-term oral corticosteroid treatment.

A double blind, placebo controlled study was undertaken to determine the effects of 104 weeks of intermittent cyclical etidronate therapy on bone mineral density (BMD) in patients undergoing long-term oral corticosteroid therapy. Forty nine patients of mean age 59 years on long-term (> 6 months) corticosteroid treatment were randomised to receive either 400 mg/day etidronate or placebo for 14 days followed in both groups by calcium (equivalent to 97 mg elemental Ca/day) with vitamin D (400 IU) for 76 days. The cycle was repeated a total of eight times over a period of two years. Dual energy x ray absorptiometry (DEXA) measurements of the lumbar spine and hip BMD and biochemical bone marker analyses were performed at baseline and every six months. Twenty six patients (10 men) received cyclical etidronate and 23 (nine men) received placebo. The mean (SD) dose of corticosteroid (prednisone or equivalent) at baseline in the etidronate group was 8 (4) mg/day and in the placebo group was 7 (4) mg/day. Most of the patients (43%) suffered from asthma. Forty one patients completed the study (22 in the etidronate group and 19 in the placebo group). All had a low BMD at entry and with treatment a significant difference was observed between groups in the mean (SE) percentage change from baseline in lumbar spine BMD at week 104 of 4.5 (1.65)% (p = 0.007) with a 95% confidence interval (CI) of 1.12 to 7.87%. No clinically or statistically significant treatment differences were observed at the hip or with bone markers. The incidence of adverse events was similar in the two groups. The results show that intermittent cyclical etidronate therapy with calcium and vitamin D supplementation significantly increases lumbar spine BMD in patients with osteoporosis resulting from long-term treatment with corticosteroids.

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Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome.

Tuberculosis immune reconstitution inflammatory syndrome (IRIS) is a common cause of deterioration in human immunodeficiency virus (HIV)-infected patients receiving tuberculosis treatment after starting antiretroviral therapy (ART). Potentially life-threatening neurological involvement occurs frequently and has been suggested as a reason to defer ART. We conducted a prospective study of HIV-infected, ART-naive patients with tuberculous meningitis (TBM). At presentation, patients started tuberculosis treatment and prednisone; ART was initiated 2 weeks later. Clinical and laboratory findings were compared between patients who developed TBM-IRIS (TBM-IRIS patients) and those who did not (non-TBM-IRIS patients). A logistic regression model was developed to predict TBM-IRIS. Forty-seven percent (16/34) of TBM patients developed TBM-IRIS, which manifested with severe features of inflammation. At TBM diagnosis, TBM-IRIS patients had higher cerebrospinal fluid (CSF) neutrophil counts compared with non-TBM-IRIS patients (median, 50 vs 3 cells ×10(6)/L, P = .02). Mycobacterium tuberculosis was cultured from CSF of 15 TBM-IRIS patients (94%) compared with 6 non-TBM-IRIS patients (33%) at time of TBM diagnosis; relative risk of developing TBM-IRIS if CSF was Mycobacterium tuberculosis culture positive = 9.3 (95% confidence interval [CI], 1.4-62.2). The combination of high CSF tumor necrosis factor (TNF)-α and low interferon (IFN)-γ at TBM diagnosis predicted TBM-IRIS (area under the curve = 0.91 [95% CI, .53-.99]). TBM-IRIS is a frequent, severe complication of ART in HIV-associated TBM and is characterized by high CSF neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation. The combination of CSF IFN-γ and TNF-α concentrations may predict TBM-IRIS and thereby be a means to individualize patients to early or deferred ART.

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Plasma tryptophan and tyrosine ratios to competing amino acids in relation to antidepressant response to citalopram and maprotiline. A preliminary study.

Pretreatment plasma ratios of tryptophan (Trp) and tyrosine (Tyr) to other large neutral amino acids were determined in 27 depressed patients who completed a double-blind trial of citalopram, a selective serotonin uptake inhibitor, against maprotiline, a selective noradrenaline uptake inhibitor. The Trp ratio and the Tyr ratio were decreased in the total patient sample as compared with healthy controls. Plasma Tyr ratio was normal in the endogenous, but significantly decreased in the non-endogenous depressives. There was no significant relationship between the plasma Trp ratio and the probenecid-induced accumulation of 5-HIAA in the CSF, or between the plasma Tyr ratio and HVA level in CSF, whereas the CSF level of MHPG correlated significantly with the plasma Tyr ratio. There was a significantly positive correlation between the Trp ratio, the Tyr ratio, their sum and the final Hamilton depression score in 14 patients treated with citalopram; on the whole, this association was evident also in the endogenous and non-endogenous subgroups. In 13 patients on maprotiline there was a significantly positive correlation between the plasma Tyr ratio and the percent reduction of Hamilton depression score; this association was poor in the endogenous, whereas a trend towards a correlation remained in the non-endogenous subgroup. The results suggest that the plasma Trp and Tyr ratios may be determinants of clinical improvement in depressed patients to treatment with citalopram and maprotiline. However, further studies are needed on larger patient samples to allow a firm conclusion.

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Outcome of treatment of respiratory tract infections due to Streptococcus pneumoniae, including drug-resistant strains, with pharmacokinetically enhanced amoxycillin/clavulanate.

The efficacy of a new pharmacokinetically enhanced formulation of amoxycillin/clavulanate (AMX/CA) 2000/125 mg, twice daily, designed to provide adequate levels of amoxycillin over the 12-h dosing interval to eradicate penicillin-resistant Streptococcus pneumoniae (PRSP) with amoxycillin (+/-clavulanic acid) MICs of </=4 mg/l, was evaluated in patients with respiratory infections caused by S. pneumoniae, including PRSP (penicillin MICs 2-16 mg/l). Data from nine clinical studies were combined (total intent-to-treat N=5531). Six randomized, double-blind studies used levofloxacin 500 mg od in acute bacterial sinusitis (ABS), levofloxacin 500 mg od in acute exacerbations of chronic bronchitis (AECB), clarithromycin 500 mg bid in AECB, AMX/CA 875/125 mg bid and tid in community-acquired pneumonia (CAP) and AMX/CA 1000/125 mg tid in CAP as comparators. The three remaining studies (two in ABS and one in CAP) were non-comparative. In the AMX/CA 2000/125 mg bid-treated patients evaluable at follow-up (Day 14-39), outcome was successful in 60/64 (93.7%) patients with S. pneumoniae infections in the comparative studies and 348/363 (95.9%) in the non-comparative studies, including 95.6% of all patients and 95.2% of patients whose isolates had AMX/CA MICs of >/=4 mg/l. In the pooled comparator group, the success rate at follow-up was 86.5% (45/52). For PRSP (AMX/CA MICs of 0.5-8 mg/l), the overall success rate was 98.2% (55/56) at follow-up for AMX/CA 2000/125 mg and 50.0% (2/4) for comparators. AMX/CA 2000/125 mg shows efficacy comparable to that of the comparators evaluated against S. pneumoniae infections. Due to its favorable pharmacokinetic/pharmacodynamic profile and promising clinical success, the new AMX/CA 2000/125 mg formulation should be considered for the empirical treatment of respiratory tract infections in regions with a high prevalence of antimicrobial-resistant S. pneumoniae and in patients at high risk of antimicrobial-resistant S. pneumoniae infection as this formulation covers many PRSP that are non-susceptible to amoxycillin (+/-clavulanic acid) (MICs of >/=4 mg/l) as well as common beta-lactamase-producing respiratory pathogens.

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A prospective randomized trial of prednisone versus no prednisone maintenance therapy in cyclosporine-treated and azathioprine-treated renal transplant patients.

The purpose of this study was to evaluate early (6-12 days) prednisone withdrawal in cyclosporine- and azathioprine-treated renal transplant recipients. Patients, including 8 recipients of live-related donor kidneys and 59 recipients of cadaver donor kidneys, were prospectively randomized to receive maintenance prednisone (PRED) therapy or not (NOPRED) in addition to antilymphocyte globulin, cyclosporine, and azathioprine. Rejection episodes were initially treated with methylprednisolone pulses, and OKT3 monoclonal antibody was used to treat steroid resistant rejections that were verified by biopsy. NOPRED patients were declared protocol failures and returned to PRED therapy if they sustained 2 steroid-sensitive rejection episodes in the first 3 months or an OKT3-treated rejection at any time. Patient and graft survival for the LRD patients in both treatment categories were 100% at 12 months. Patient and graft survival for CAD recipients at one year was 94% and 83% (PRED) and 88% and 77% (NOPRED), respectively. Rejection episodes were more frequent (26 of 32 NOPRED patients vs. 19 of 35 PRED patients P = 0.02) and occurred earlier (4.5 weeks in NOPRED vs. 7.7 weeks in PRED patients) in patients not taking maintenance steroids. Rejection severity was also greater in the NOPRED group, as 15 OKT3-treated rejections occurred in that group whereas only 7 OKT3-treated rejections were observed in the PRED group (P = less than 0.01). The incidence of serious infection was similar in each group. Finally, protocol failure occurred in 40% of the LRD patients and 59% of the CAD patients. These data indicate that initiating maintenance therapy without PRED is safe but is attended by a greater risk of developing rejection. Because of this increased incidence and severity of early rejection episodes in NOPRED patients, we do not advise use of this immunosuppressive strategy in renal transplantation.

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Randomized, open label, multicenter trial of cefixime compared with amoxicillin for treatment of acute otitis media with effusion.

Cefixime, a new third generation cephalosporin antibiotic for oral use, was evaluated for safety and efficacy in the treatment of children with acute otitis media with effusion. Fifteen United States clinical investigators participated in the multicenter clinical trial. One hundred twenty children were randomly assigned to a 10-day course of either cefixime, 8 mg/kg, given daily (qd) (60 patients) or amoxicillin, 40 mg/kg/day, administered in three divided doses (60 patients). Tympanocentesis was performed on each patient before therapy was initiated. Pathogens were isolated from a middle ear aspirate in 88% of the cases. Of the specimens from which pathogens were cultured, 33% yielded Haemophilus sp., 41% Streptococcus pneumoniae and 6% Branhamella catarrhalis. Of the 120 patients, 64 (30 cefixime and 34 amoxicillin) were evaluable for assessment of efficacy. Favorable clinical responses (cure or improvement) were obtained in 93% of cefixime-treated patients and in 94% of amoxicillin-treated patients. Overall, bacteriologic eradication rates (as determined by clinical criteria) were 94 and 95%, respectively. Clinical failure or relapse was documented in 2 of 30 (7%) patients treated with cefixime and in 2 of 34 (6%) patients treated with amoxicillin. Gastrointestinal disturbance and rash were significantly more common in children treated with cefixime (22 and 15%, respectively) than in those taking amoxicillin (8 and 2%, respectively), but in only one case was it necessary to discontinue medication because of these adverse effects (rash). Results of this study demonstrate that cefixime given once daily is as safe and effective as amoxicillin in the treatment of acute otitis media with effusion in children and has the possible advantage of less frequent dosing.

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Effect of low doses of atorvastatin on adiponectin, glucose homeostasis, and clinical inflammatory markers in kidney transplant recipients.

Various studies describe the pleiotropic antiinflammatory and antioxidant effects of atorvastatin, in addition to its hypolipemic effects. It has been suggested that statins modify glucose homeostasis via their antiinflammatory effects. A further hypothesis suggests that the incidence of posttransplantation diabetes is lower in statin-treated patients. This study sought to ascertain whether atorvastatin modifies glucose homeostasis, adiponectin, and inflammatory markers in kidney transplant recipients. Sixty-eight kidney transplant recipients (41 men, 27 women; mean age, 53 +/- 12 years) with stable renal function and dyslipidemia were treated with atorvastatin (10 mg/d) for 12 weeks. Glucose, insulin, homeostasis model assessment (HOMA-IR) index, adiponectin, tumor necrosis factor (TNF)-alpha, and serum C-reactive protein (CRP) concentrations were determined at baseline and at 3 months. The lipid profile, renal function parameters (creatinine, creatinine clearance, and proteinuria), as well as GOT, GPT, and CK were determined at baseline and at 3 months. Treatment with atorvastatin achieved a statistically significant decrease in lipid profile. After 3 months of treatment, 74.6% of patients had total cholesterol and 78.7% low-density lipoprotein (LDL) cholesterol concentrations within reference range (<5.2 and 3.3 mmol/L, respectively). Furthermore, 47.5% of patients attained an LDL concentration <2.59 mmol/L. A greater reduction in total cholesterol (P = .05) and LDL cholesterol (P = .04) was achieved in patients with creatinine clearance <60 mL/min. Atorvastatin did not modify glucose homeostasis parameters, adiponectin, TNF-alpha, or CRP. At baseline and after 3 months of treatment, an inverse correlation was found between adiponectin and glucose, insulin, HOMA- IR index, and creatinine clearance, and a positive correlation was found between adiponectin and high-density lipoprotein (HDL) cholesterol. Atorvastatin at a dose of 10 mg/d in kidney transplant recipients does not modify glucose homeostasis or alter inflammatory markers, despite its hypolipemic effects. Its efficacy to reduce total cholesterol and LDL cholesterol was greater in patients with worse renal function.

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In-hospital management and outcome of patients on warfarin undergoing coronary stent implantation: results of the multicenter, prospective WARfarin and coronary STENTing (WAR-STENT) registry.

The in-hospital management of patients on warfarin undergoing coronary stent implantation (PCI-S) is variable, and the in-hospital outcome incompletely defined. To determine the adherence to the current recommendations, and the incidence of adverse events, we carried out the prospective, multicenter, observational WARfarin and coronary STENTing (WAR-STENT) registry (ClinicalTrials.gov identifier NCT00722319). All consecutive patients on warfarin undergoing PCI-S at 37 Italian centers were enrolled and followed for 12 months. Outcome measures were: major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, need for urgent revascularization, stroke, and venous thromboembolism, and major and minor bleeding. In this paper, we report the in-hospital findings. Out of the 411 patients enrolled, 92% were at non-low (ie, moderate or high) thromboembolic risk. The radial approach and bare-metal stents were used in 61% and 60% of cases, respectively. Drug-eluting stents were essentially reserved to patients with diabetes, which in turn, significantly predicted the implantation of drug-eluting stents (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.29-3.17; P=.002). The in-hospital MACE and major bleeding rates were 2.7% and 2.1%, respectively. At discharge, triple therapy (TT) of warfarin, aspirin, and clopidogrel was prescribed to 76% of patients. Prescription of TT was significantly more frequent in the non-low thromboembolic risk group. Non-low thromboembolic risk, in turn, was a significant predictor of TT prescription (OR, 11.2; 95% CI, 4.83-26.3; P<.0001). In conclusion, real-world warfarin patients undergoing PCI-S are largely managed according to the current recommendations. As a consequence, the risk of in-hospital MACE and major bleedings appears limited and acceptable.

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Duloxetine in military posttraumatic stress disorder.

The objective of this prospective study was to assess the efficacy and tolerability of duloxetine in the treatment of in military veterans with posttraumatic stress disorder (PTSD).Twenty subjects were enrolled in this 12-week, open-label trial. Diagnosis and symptom severity were assessed with the Clinician Administered PTSD Scale (CAPS). Depressive symptoms were assessed the Hamilton Depression Rating Scale. All subjects had a CAPS score of at least 60 at baseline. Subjects with lifetime history of psychotic disorders or bipolar illness were excluded. Fifteen participants completed 12 weeks of treatment, five dropped-out from the trial, 3 due to side effects. For patients who discontinued, missing values were estimated using "the last observation carried forward" method. Significant improvements were seen on: CAPS total and all subscales, depression and sleep measures. Most of the improvement was observed by week 2 of treatment. Nine participants (45%) were classified as responders, defined by 20% or greater improvement on CAPS total score. The mean daily dose of duloxetine was 81 mg. The most common side effects were constipation (20%) diarrhea (25%) and nausea (20%). Two subjects developed tachycardia, one withdrew from the trial due to this problem. Duloxetine had a fast onset of action and was effective in about half of the subjects, it was well tolerated in most subjects. These preliminary results in a difficult to treat population warrant the conduction of a double blind, placebo-controlled study of duloxetine in PTSD.

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Psychopharmacology of compulsive buying.

No standard treatment exists for the DSM-IV Impulse Control Disorders, Not Elsewhere Classified, including Compulsive Buying Disorder. This paper reviews the suggested pharmacotherapies for this disorder and their theoretical basis. McElroy et al. first reported benefit from antidepressant therapy in three cases of Compulsive Buying Disorder with comorbid depression and anxiety. In a retrospective chart review, McElroy's group reported on 20 patients that benefited from antidepressants, often in combination with mood stabilizers. Lejoyeux reported on two patients in whom treatment of a comorbid mood disorder led to remission of compulsive buying behavior. Black reported fluvoxamine to be effective in patients without comorbid major depression, suggesting that improvement was independent of the treatment of mood symptoms. Kim reported improvement with naltrexone, an opioid antagonist, in a case series. Two double-blind placebo-controlled trials found fluvoxamine no better than placebo; however, in both studies patients kept shopping logs, which may have confounded the results. An open-label trial of citalopram and a double-blind crossover trial which excluded shopping logs both reported positive results. Twelve-month follow-up data for the open-label group found that remission rates at quarterly time points were independent of continuing drug therapy. The data reviewed above suggest that pharmacologic interventions may be effective for compulsive buying disorder. Whether pharmacological treatment is superior to placebo and whether it is more, less or equally effective compared to psychotherapeutic interventions remains to be established.

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Cardiac injury in patients with COPD presenting with dyspnea: a pilot study.

The aim of this pilot study was to test the hypothesis that myocardial ischemia complicates the management of some patients with chest-pain-free chronic obstructive pulmonary disease (COPD) exacerbations. In this prospective, observational, cohort study, patients admitted to a 350-bed community teaching hospital, with dyspnea and a primary diagnosis of COPD exacerbation, were followed for enzymatic and electrocardiographic evidence of myocardial ischemia for the first 24 hours of hospital admission. A total of 114 patients were studied. Overall, four patients had definite myocardial infarctions, one had definite myocardial ischemia and 14 had possible myocardial ischemia. In multiple logistic regression models, age, number of coronary risk factors, and amount of administered albuterol were not associated with myocardial injury. While unrecognized myocardial injury is relatively rare in patients with an exacerbation of COPD, it occurs frequently enough to warrant some caution since beta-agonists are the mainstays of therapy.

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[Effect of CYP2C19 genetic polymorphism on treatment efficacy of Helicobacter pylori infection with rabeprazole-based triple therapy in Chinese].

To investigate the effect of different S-mephenytoin 4'-hydroxylase (CYP2C19) genotype on the eradication rate of Helicobacter pylori (Hp) by different rabeprazole-based triple therapy in Chinese. 128 subjects with Hp positive gastritis or peptic ulcers were randomly assigned to receive 10 mg rabeprazole twice daily with 1000 mg amoxicillin twice daily and 500 mg clarithromycin (RAC group) or 400 mg metronidazole (RAM group) twice daily for 1 week. The CYP2C19 genotype (homozygous extensive metabolizer, hom-Ems; heterozygous extensive metabolizer, het-Ems; or poor metabolizer, PMs) was determined by the polymerase chain reaction-restriction fragment length polymorphism method. More than 4 weeks after completion of treatment, Hp status was assessed by (13)C-urea breath test. The hom-Ems, het-Ems and PMs were 30.5%, 50.0% and 19.5% in 128 subjects, respectively. The eradication rates in the rabeprazole-amoxicillin-clarithromycin (RAC) for clarithromycin-sensitive strains and rabeprazole-amoxicillin-metronidazole (RAM) for metronidazole-sensitive strains groups were 98.1% and 91.3%, respectively, on a per protocol basis. It decreased significantly eradication rates of Hp because the prevalence of primary antimicrobial resistance was 66.8% for metronidazole. When the statistical significance of each parameter associated with treatment outcome was assessed with logistic regression analysis, CYP2C19 genetic polymorphism did not show significant effect on the efficacy of anti-Hp therapy with rabeprazole-based triple regimens. The efficacy of rabeprazole-based triple regimens is less affected by the CYP2C19 genotype, the RAC regimen can be considered in Chinese.

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Validation of the sleep impact scale in patients with major depressive disorder and insomnia.

Chronic insomnia and depression are often associated. Measuring the impact on quality of life associated with changes in sleep in co-treatment of insomnia and depression requires a valid and reliable patient reported outcome (PRO) instrument. This study aimed to assess the validity of the Sleep Impact Scale (SIS), a sleep-specific PRO instrument, in a population comorbid with Major Depressive Disorder (MDD) and insomnia to support its use in clinical or clinical trial applications. Data from 379 subjects enrolled in a 27 week US, multi-center, phase IV, randomized, double-blind, parallel group, placebo-controlled trial of zolpidem tartrate extended-release taken in combination with escitalopram vs. placebo combined with escitalopram were pooled across treatment groups. Results from multi-trait analyses, tests of internal consistency and test-retest reliability, concurrent validity, known-groups validity, responsiveness, and thresholds for minimal important difference (MID) were examined. Mean baseline scores on the SIS ranged from 22.85 (+/-13.41) on Satisfaction with Sleep to 43.49 (+/-21.12) on Mental Fatigue, reflecting impairments due to sleep problems. The SIS was found to be internally consistent (alpha > or = 0.70 for all domains) and have good construct validity. The item-domain correlations were > or = 0.52 with no instance of an item correlating more highly with a domain other than its own. There were some floor and no ceiling effects. The test-retest reliability of the SIS domains ranged between 0.68 and 0.83. Clinical validity assessed through known groups methods was supported. The SIS was responsive to changes on all domains. Preliminary estimates of minimum important difference (MID) were obtained to interpret changes in SIS domains. Limitations include the need for further qualitative research on content validity and the lack of a patient global assessment of change. This study yielded adequate evidence of the validity of the SIS for use in clinical trials and research on MDD patients with comorbid insomnia.

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Impact of metoprolol treatment on cardiac function and exercise tolerance in heart failure patients with neuropsychiatric disorders.

To investigate the impact of neuropsychiatric disorders on the effect of metoprolol on cardiac and motor function in chronic heart failure (CHF) patients. From February 2013 to April 2016, CHF patients with clinical mental disorders received metoprolol (23.75 or 47.5 mg, once daily, orally) at the Second Affiliated Hospital of Kunming Medical University. Mental status was confirmed by means of the Hospital Anxiety and Depression Scale (HADS) and the Copenhagen Burnout Inventory (CBI) scale. Cardiac function parameters such as systolic blood pressure (SBP), ejection fraction (EF) and cardiac index (CI) as well as motor function including the 6 meter walk test (6MWT) and the Veteran's Specific Activity Questionnaire (VSAQ) were assessed as primary outcomes of the study. A total of 154 patients (median age, 66.39 years; men, n = 101) were allocated into eight groups based on their mental status. There were no significant differences in heart rate (HR) or SBP control achieved by metoprolol in any groups compared with the control (patients with normal mental status). Furthermore, biphasic ejection fraction (EF) changes were observed in all the groups with a decrease in the first month and increase from the sixth month. However, this increase was significantly lower (p < .001) than the EF achieved with metoprolol treatment in the control group except for the anxiety group. A similar pattern was seen for CI, 6MWT and VSAQ changes in all the groups. Patients in the anxiety group responded similarly to the patients with normal mental status. Depressive and high burnout symptoms, but not anxiety, lower the improvement of cardiac and motor function by metoprolol treatment in CHF.

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Use of nicotine replacement therapy and stop-smoking medicines in a national sample of Aboriginal and Torres Strait Islander smokers and ex-smokers.

To examine the use of nicotine replacement therapy (NRT) and the stop-smoking medicines (SSMs) varenicline and bupropion in a national sample of Aboriginal and Torres Strait Islander smokers and recent ex-smokers. The Talking About The Smokes (TATS) project used a quota sampling design to recruit a nationally representative sample of 1721 smokers and ex-smokers who had quit ≤ 12 months before from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. Baseline surveys were conducted from April 2012 to October 2013. These were compared with 1017 daily smokers from the general Australian population surveyed by the International Tobacco Control Policy Evaluation Project (ITC Project) from July 2010 to May 2011. Past and intended use of NRT and SSMs, duration of use, and whether participants thought NRT and SSMs help smokers to quit. Compared with other daily Australian smokers, lower proportions of Aboriginal and Torres Strait Islander daily smokers had ever used any NRT or SSMs (TATS, 37% v ITC, 58.5%) or used them in the past year (TATS, 23% v ITC, 42.1%). Nicotine patches were most commonly used by Aboriginal and Torres Strait Islander smokers and recent ex-smokers (24%), followed by varenicline (11%) and nicotine gum (10%); most (74%) had got their last NRT at no cost. Among dependent Aboriginal and Torres Strait Islander daily smokers, those who were more socioeconomically advantaged were more likely than the disadvantaged to have used NRT or SSMs. Similar proportions of Aboriginal and Torres Strait Islander daily smokers and other Australian daily smokers said that NRT or SSMs help smokers to quit (TATS, 70% v ITC, 74.2%). Dependent Aboriginal and Torres Strait Islander smokers who had previously used NRT or SSMs were more likely to believe they help in quitting and to intend to use them in the future. Aboriginal and Torres Strait Islander daily smokers, particularly those who are most disadvantaged, are less likely to have used NRT or SSMs than other Australian daily smokers. Some of the barriers to use, including cost, are being overcome, but further improvements are possible.

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Metoprolol with and without chlorthalidone in hypertension.

After a control period on a placebo, 45 patients with mild to moderate hypertension were treated with metoprolol, 100 mg twice daily alone and in free combination with chlorthalidone 50 mg daily using a double-blind crossover technique. The beta-blocker alone induced a significant fall in blood pressure; the diastolic pressure was reduced to 100 mg Hg or less in 37 of the 45 patients and to 95 mm Hg or less in 19 patients. The addition of chlorthalidone enhanced the antihypertensive effect so that in 33 patients diastolic pressure fell to 95 mm Hg or less. The drugs were well tolerated even by a small number of patients with chronic bronchitis and diabetes mellitus. None of the patients developed cardiac failure. Adding a diuretic caused a small reduction in serum potassium concentrations, and the relevance of this observation is discussed.

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Pharmacometric analysis of the effect of furosemide on suramin pharmacokinetics.

To characterize the effects of furosemide on the pharmacokinetics of suramin, a renally eliminated investigational antineoplastic agent. Retrospective population pharmacokinetic analysis. Government biomedical research facility. Twenty-six men with hormone-refractory prostate cancer and one with adrenocortical carcinoma. Patients received suramin by continuous or intermittent infusion with and without concomitant furosemide. Optimum suramin regimens were achieved by adaptive feedback control, and pharmacokinetic data were collected both in the presence and absence of furosemide. Suramin concentrations were determined by high-performance liquid chromatography (coefficient of variation < 8%). Suramin concentrations were fit to a three-compartment linear model with six coefficients and two rate inputs, which allowed furosemide to affect suramin pharmacokinetics. Individual and population parameter estimates were determined using the iterative two-stage approach. Concomitant furosemide was associated with a median decrease in total body clearance of suramin by 36% (range 0-63%, p < 0.0001). No other parameter was significantly altered, and there was no trend for change in any pharmacokinetic value with time. Suramin plasma concentrations were simulated with and without prolonged furosemide therapy in 26 patients for 12 weeks. The average suramin concentration increased by greater than 33% in 12 patients; 2 patients had a greater than 67% increase in this extreme case model. Coadministration of furosemide with suramin can cause an increase in suramin concentrations; however, due to suramin's long half-life, its rate of accumulation is very slow. Nonetheless, in individuals receiving suramin by nonadaptive control, appropriate precautions should be taken when prolonged furosemide therapy is begun.

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Transplant immunosuppressive agents in non-transplant chronic autoimmune hepatitis: the Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus.

Conventional treatment of autoimmune hepatitis consists of either prednisone alone or in combination with azathioprine. Ten to 20% of patients do not respond to or are intolerant of this treatment. Novel drug treatments include immunosuppressive drugs such as tacrolimus (TAC), mycophenolate mofetil (MMF), methotrexate and cyclosporine. We describe a multi-centre Canadian experience with MMF and TAC. To study a multi-centre patient population who had failed conventional therapy and were treated with non-conventional medical therapy for autoimmune hepatitis and document response. Members of the Canadian Association for the Study of Liver (CASL) obtained MMF from Hoffmann-La Roche Ltd, as part of a compassionate release program, were contacted for standardized data on patients with AIH who received MMF or TAC. Response definitions based on aminotransferase changes were: Complete response (CR)-sustained normalization, partial response (PR)-improvement by greater than 50%, non-response (NR)-less than 50% improvement and relapse (RP)-initial CR or PR followed by an increase in aminotransferases. A total of 16 patients were identified: six in Ontario, one in Quebec, five in Alberta and four in British Columbia. Three were treated with TAC, eleven with MMF and two with combination MMF and TAC. CR was observed in 50%, PR in 12.5%, RP in 25% and NR occurred in 12.5%. The CR for MMF without TAC was approximately 64%. MMF is effective and well tolerated by patients with autoimmune hepatitis who do not respond to, or are intolerant of, conventional immunosuppressive agents.

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Delayed elimination of methotrexate associated with co-administration of proton pump inhibitors.

We conducted a retrospective non-interventional cohort study to analyze the impact of proton pump inhibitors co-administration on methotrexate elimination in cancer patients receiving treatment protocol with the antifolate at high dose (>1 g/m(2) intravenously). Between 2005 and 2008, 79 patients (mean age: 48.8 years; range: 16-76 years) were treated by high dose methotrexate for 197 cycles. Delayed methotrexate elimination (i.e., plasma concentration >15 μmol/l at 24 h, >1.5 μmol/l at 48 h and/or >0.15 μmol/l at 72 h) occurred in 16% (32/197) of the cycles. The co-prescription of a proton pump inhibitor (pantoprazole, lansoprazole, omeprazole, esomeprazole) was found in 53% (17/32) of the courses with delayed elimination and in 15% (24/165) of the cycles without delayed elimination. We identified co-administration of proton pump inhibitors as a major risk factor for delayed elimination (odds ratio 6.66, 95% confidence interval 3.13, 14.17). Proton pump inhibitors should not be administered during methotrexate treatment.

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Thyroid function and IVF outcome: when to investigate and when to intervene?

To summarize the evidence regarding the need to assess thyroid function in women undergoing ovarian stimulation as well as the need to intervene when thyroid function is suboptimal. There is now evidence that ovarian stimulation can influence thyroid function not only via hyperestrogenism but also directly, since thyroid-related receptors are present in human granulosa cells and in the endometrium. Prospective and retrospective observational studies, as well as a few clinical trials, have been conducted in an effort to clarify the association between ovarian stimulation and thyroid function with controversial results. The need of thyroid function screening with thyroid stimulating hormone (TSH) in infertile women attempting pregnancy is recognized by many international societies. Since TSH is a simple, cheap screening tool and levothyroxine (LT4) supplementation is an easy to apply, cheap and well tolerated intervention, universal thyroid screening in women undergoing IVF represents a reasonable policy. In case of subclinical hypothyroidism, when TSH exceeds the threshold of 4.0 or 4.5 μIU/ml before IVF, LT4 replacement should be administered, while the same intervention might also be justified for women with TSH concentration more than 2.5 μIU/ml before IVF.

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Evaluation of oral zinc sulfate effect on obsessive-compulsive disorder: a randomized placebo-controlled clinical trial.

Obsessive-compulsive disorder is a common neuropsychiatric condition. Although various pharmaceutical agents are available for the treatment of obsessive-compulsive disorder, psychiatrists often find that many patients cannot tolerate the side effects of these medications, the patients do not respond properly to the treatment, or the medications lose their effectiveness after a period of treatment. The augmentation with safe supplementation of medication, such as with trace elements, may be a solution to some of these problems. This study was a prospective, double-blinded, 8-wk trial. Twelve patients were given fluoxetine (20 mg/d) plus zinc (440 mg/d) and 11 patients were given fluoxetine plus placebo for 8 wk. Both groups showed a decrease in the mean Yale-Brown Obsessive-Compulsive Scale score. Based on t tests, in weeks 2 and 8, patients treated with fluoxetine plus zinc had significantly lower scores than those treated with fluoxetine plus placebo. The results show that zinc, as adjuvant agent for obsessive-compulsive disorder, produces improved outcomes.

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Clinical findings and prognosis of polyarteritis nodosa and Churg-Strauss angiitis: a study in 165 patients.

Factors influencing the prognosis were studied in 165 patients with polyarteritis nodosa (PAN) and Churg-Strauss angiitis. One hundred and forty-seven of the patients fulfilled histological and/or arteriographic diagnostic criteria, and in 18 patients the diagnosis was based on clinical criteria. The patients' mean age on diagnosis was 48.4 +/- 16.4 years. The main symptoms were fever (69%), weight loss (66%), arthritis (44%), mononeuritis multiplex (67%), cutaneous signs (46%), renal involvement (26%), gastrointestinal symptoms (31%), asthma (29%), hypertension (31%) and cardiac failure (18%). Ninety-two per cent of the patients survived for at least 1 year after diagnosis of the disease, 79% for 2 years, and 63% for 5 years. The immediate causes of death were gastrointestinal bleeding or peritonitis in 11 cases, pancreatitis in two, renal insufficiency in six, cardiac failure in five, infectious complications in four, stroke in three and other causes in 11. We studied the prognosis of necrotizing angiitis in relation to clinical symptoms and laboratory findings. The association of four conditions were associated with a poor prognosis: age over 50, gastrointestinal problems, cardiomyopathy and renal signs. The survival rates in patients with these conditions were: for gastrointestinal problems, 55% 5-year survival (versus 67%); and for age over 50, 68% 3-year survival (versus 78%; p less than 0.09). One hundred and fifty-nine patients were treated with steroids for at least 18 months. Forty-eight also received cytotoxic agents (27%) and 46 plasma exchange. Patients who were treated with plasma exchange and prednisone were randomly assigned to additional treatment with cyclophosphamide. Survival rates were comparable in both groups.

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Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease patients with and without the metabolic syndrome: subgroup analyses of the Scandinavian Simvastatin Survival Study (4S).

To assess the effect of simvastatin treatment on the risk of cardiovascular events in nondiabetic patients with coronary heart disease (CHD) with and without the metabolic syndrome, as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III). Subgroup analyses were performed on data from 3933 nondiabetic patients with clinically established CHD, serum total cholesterol level 5.5-8.0 mmol/l, and serum triglyceride level <or=2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S), a randomized, placebo-controlled trial. End points were total mortality, coronary mortality, major CHD event, myocardial revascularization, any CHD event, stroke, and any atherosclerotic event. Over the 5.4-year median follow-up period, simvastatin produced similar changes in serum lipid levels in 893 patients with the metabolic syndrome and in 3040 patients without the metabolic syndrome. The relative risks of main end points in simvastatin-treated patients compared with placebo-treated patients with the metabolic syndrome were as follows: total mortality 0.54 (95% CI 0.36-0.82), coronary mortality 0.39 (0.23-0.65), major CHD event 0.59 (0.45-0.77), and any atherosclerotic event 0.69 (0.56-0.84). The corresponding RRs in patients without the metabolic syndrome were 0.72 (0.56-0.91), 0.62 (0.45-0.84), 0.71 (0.61-0.82), and 0.76 (0.68-0.85). Nondiabetic CHD patients with or without the metabolic syndrome realize from simvastatin treatment a similar, substantial relative reduction in the risk of cardiovascular events. The absolute benefit may be greater in patients with the metabolic syndrome because they are at a higher absolute risk.

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A prospective randomized study of two alternating, non cross-resistant chemotherapies for advanced Hodgkin's disease.

Fifty-four newly diagnosed patients with advanced Hodgkin's disease were randomized between two alternating non cross-resistant chemotherapies: MOPP-ABVD (MOPP: Mustine, Vincristine, Procarbazine, Prednisone-ABVD: Adriamycin, Bleomycin, Vinblastine, Dacarbazine) and MOPP-ABVD-CEM (CEM: Carmustine, Etoposide, methyl-GAG). There were no significant differences between the two therapies as far as complete remission, survival, relapse free survival and toxicity were concerned. This study does not support the use of MOPP-ABVD-CEM for improving the long-term outcome of patients with advanced Hodgkin's disease.

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The analgesic effect of tramadol combined with butorphanol on uterine cramping pain after repeat caesarean section: a randomized, controlled, double-blind study.

This study aimed to explore the effect of patient-controlled intravenous analgesia (PCIA) using tramadol combined with butorphanol on uterine cramping pain in women undergoing repeat caesarean section. A total of 126 patients, who were scheduled to undergo repeat caesarean section under spinal anesthesia, were included. PCIA using tramadol combined with butorphanol or sufentanil was randomly performed for postoperative pain control. Postoperative uterine cramping pain and wound pain within 48 h after surgery were evaluated. Postoperative analgesic consumption, early activity time, and length of hospital stay were also recorded and analyzed. Uterine cramping pain intensity in women undergoing repeat caesarean section was significantly higher compared with their wound pain (P < 0.05). The mean visual analog scale (VAS) score for uterine cramping pain in the tramadol-butorphanol group was significantly lower than that in the sufentanil group at rest, and at 6 h and 12 h after surgery. VAS scores for uterine cramping pain during movement at 6 h, 12 h, and 24 h after surgery in the tramadol-butorphanol group were also significantly lower than that in sufentanil group (P < 0.05). There was no significant difference in VAS score for wound pain at the different time points between the tramadol-butorphanol and sufentanil groups (P > 0.05). Patient-controlled intravenous analgesia with tramadol accelerated early rehabilitation and decreased the length of hospital stay (P < 0.05). PCIA using tramadol combined with butorphanol provided a better analgesic effect and accelerated postoperative rehabilitation compared with sufentanil, and may be an optimal analgesic strategy for women undergoing repeat caesarean section. The trial was registered at Chinese Clinical Trial Registry ( www.chictr.org.cn ) with ID: ChiCTR-1800014986.

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Limited application of fluticasone propionate ointment, 0.005% in patients with psoriasis of the face and intertriginous areas.

Facial and intertriginous skin is more susceptible to corticosteroid-induced atrophy. Dosing regimens are needed for long-term management of corticosteroid-sensitive sites. The safety and efficacy of 0.005% fluticasone propionate ointment were assessed in the short-and long-term management of moderate to severe psoriasis of facial and intertriginous areas compared with nonfacial, nonintertriginous areas. Affected areas in 20 patients with psoriasis were treated twice daily for 2 weeks, then once daily for 2 consecutive days every week for 8 more weeks. More than 50% improvement occurred after 2 weeks (day 15) in 100% of facial and intertriginous lesions and was maintained during long-term therapy in more than 85% of facial and intertriginous lesions. More than 50% improvement for nonfacial, nonintertriginous areas reached only 80% by day 15. Recurrence rates for facial and intertriginous areas were lower than in the nonfacial, nonintertriginous areas. Skin atrophy and telangiectasia did not occur. Facial and intertriginous sites responded more quickly to topical fluticasone propionate ointment than nonfacial, nonintertriginous skin. Limited application of fluticasone propionate ointment over a period of 10 weeks is effective and delays lesion recurrence without causing skin atrophy in patients with moderate to severe psoriasis in areas at risk for corticosteroid application, such as facial and intertriginous areas.

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Proton pump inhibitors may enhance the risk of citalopram- and escitalopram-associated sudden cardiac death among patients receiving hemodialysis.

Polypharmacy is common in the hemodialysis population and increases the likelihood that patients will be exposed to clinically significant drug-drug interactions. Concurrent use of proton pump inhibitors (PPIs) with citalopram or escitalopram may potentiate the QT-prolonging effects of these selective serotonin reuptake inhibitors through pharmacodynamic and/or pharmacokinetic interactions. We conducted a retrospective cohort study using data from the U.S. Renal Data System (2007-2017) and a new-user design to examine the differential risk of sudden cardiac death (SCD) associated with citalopram/escitalopram initiation vs. sertraline initiation in the presence and absence of PPI use among adults receiving hemodialysis. We studied 72 559 patients:14 983 (21%) citalopram/escitalopram initiators using a PPI; 26 503 (36%) citalopram/escitalopram initiators not using a PPI;10 779 (15%) sertraline initiators using a PPI; and 20 294 (28%) sertraline initiators not using a PPI (referent). The outcome of interest was 1-year SCD. We used inverse probability of treatment weighted survival models to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with sertraline initiators not using a PPI, citalopram/escitalopram initiators using a PPI had the numerically highest risk of SCD (HR [95% CI] = 1.31 [1.11-1.54]), followed by citalopram/escitalopram initiators not using a PPI (HR [95% CI] = 1.22 [1.06-1.41]). Sertraline initiators using a PPI had a similar risk of SCD compared with those not using a PPI (HR [95% CI] = 1.03 [0.85-1.26]). Existing PPI use may elevate the risk of SCD associated with citalopram or escitalopram initiation among hemodialysis patients.

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[Effect of 12-week treatment with amlodipine on plasma renin activity and adrenal cortex function in patients with essential hypertension].

The present study aimed to assess the influence of 12-week treatment with Amlodipine (Am) on plasma renin activity (PRA), baseline and ACTH stimulated secretion of cortisol (C) and aldosterone (A). 21 patients with mild or moderately severe essential hypertension (EH) were examined. PRA was assessed under baseline and stimulatory conditions, C and A were estimated in blood samples withdrawn before (0') and 30, 60, 90, 120, 150, 180 minutes after i.v. administration of 0.25 mg of Synacthen. All parameters were performed twice: before and after 12-week treatment with 5-10 mg/d of Am. The control group (not treated with Am) consisted of 15 healthy volunteers. In EH patients PRA was significantly higher after 12 weeks of Am administration. Patients with EH before Am treatment showed a reduced response of C and A secretion to Synacthen as compared with controls, which became normalized after Am treatment. 1. Patients with EH are characterized by reduced response of C and A secretion to ACTH. 2. 12-week treatment with Am exerts a stimulatory effect on Synacthen induced C and A secretion and PRA in EH patients.

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Multimodal compared to pharmacologic treatments for chronic tension-type headache in adolescents.

Chronic tension-type headache (CTTH) in children and adolescents is a serious medical condition, with considerable morbidity and few effective, evidence-based treatments. We performed a chart review of 83 adolescents (age range = 13-18 years; 67 girls and 16 boys) diagnosed with CTTH. Two treatment protocols were compared: multimodal (osteopathic manipulative treatments, mindfulness, and qi gong) and pharmacologic (amitriptyline or gabapentin). Four outcomes (headache frequency, pain intensity, general health, and health interference) were assessed at three time points (baseline, 3 months, and 6 months). A fifth outcome, number of bilateral tender points, was recorded at baseline and 6 months. All five were evaluated statistically with a linear mixed model. Although both multimodal and pharmacologic treatments were effective for CTTH (time effects for all measures were significant at p < .001), results from each analysis favored multimodal treatment (the five group by time interaction effects were significant at or below the p < .001 level). Headache frequency in the pharmacologic group, for example, reduced from a monthly average (95% Confidence Interval shown in parentheses) of 23.9 (21.8, 26.0) to 16.4 (14.3, 18.6) and in the multimodal group from 22.3 (20.1, 24.5) to 4.9 (2.6, 7.2) (a substantial group difference). Pain intensity (worst in the last 24 hours, 0-10 scale) was reduced in the pharmacologic group from 6.2 (5.6, 6.9) to 3.4 (2.7, 4.1) and from 6.1 (5.4, 6.8) to 2.0 (1.2, 2.7) in the multimodal group (a less substantial difference). Across the other three assessments, group differences were larger for general health and number of tender points and less so for pain restriction. Multimodal treatment for adolescent CTTH appears to be effective. Randomized controlled trials are needed to confirm these promising results.

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Do gender and race impact the use of antithrombotic therapy in patients with stroke/TIA?

The authors examined the relationships between sex and race and antithrombotics prescribed at discharge in the Michigan Medicare population using retrospective medical record abstraction (n = 2,715) for the period January 1, 2001, to June 30, 2001. There were no differences in the use of antithrombotics at discharge by race or sex and no differences in the prescribing of aspirin, warfarin, aspirin/extended release dipyridamole, or clopidogrel by race or sex after adjustment for confounders.

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Associations between visit-to-visit variability in blood pressure measured in the office and antihypertensive drugs: the J-HOME-Morning study.

The factors associated with visit-to-visit variability in blood pressure (BP) measured in the office between the two visits were identified in 1379 treated hypertensive patients (mean age, 66.1 ± 11.0 y; women, 53.8%). Multivariate regression analysis showed that office BP and visit-to-visit heart rate variability were positively associated with visit-to-visit BP variability, whereas body mass index, duration of antihypertensive medication, and taking amlodipine were negatively associated with visit-to-visit BP variability. Further prospective studies are required to clarify the causal relationships between these factors and visit-to-visit BP variability among treated hypertensive patients.

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Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization. Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years. Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73-1.00; <i>P</i>=0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94; <i>P</i>=0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04; <i>P</i>=0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98; <i>P</i>=0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91; <i>P</i>=0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95; <i>P</i>=0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86; <i>P</i>=0.011) with ezetimibe added to simvastatin therapy. The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.

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Periodic fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in adults.

The new syndrome, known as PFAPA, of periodic fever characterized by abrupt onset of fever, malaise, aphthous stomatitis, tonsillitis, pharyngitis and cervical adenopathy has been described only in pediatric patients. It usually begins before the age of 5 years and in most cases resolves spontaneously before age 10. To describe a series of adults with PFAPA syndrome. This 6 year retrospective descriptive study includes all newly diagnosed incident adult cases aged 18 years and over referred to our center with symptomatology suggestive of PFAPA syndrome. Patients' medical records were reviewed for past history of the disease, demographic characteristics, symptoms and signs, course of the disease, laboratory findings, and outcome following corticosteroid therapy. The comparison group included our pediatric cohort children (N=320, age 0-18 years) followed for the last 14 years (1994-2008). Fifteen adult patients were diagnosed with PFAPA syndrome. Episodes of fever occurred at 4.6 +/- 1.3 week intervals, beginning at the age of 20.9 +/- 7.5. All patients had monthly attacks at the peak of the disease, with attacks recurring at 4-8 week intervals over the years. Between episodes the patients were apparently healthy, without any accompanying diseases. Attacks were aborted by a single 60 mg dose of oral prednisone in all patients. This study reports the presence of PFAPA syndrome in adult patients. Although the disease is rare, an increased awareness by both patients and family physicians of this clinical syndrome has resulted in more frequent diagnosis in adult patients.

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Tapering clonazepam in patients with panic disorder after at least 3 years of treatment.

High-potency benzodiazepines, such as clonazepam, are frequently used in the treatment of panic disorder (PD) because of their rapid onset of action and good tolerability. However, there is concern about their potential to cause withdrawal symptoms. We aimed to develop a protocol for safely tapering off clonazepam in patients with PD who had been receiving treatment for at least 3 years. A specific scale for judging withdrawal was also developed, the Composite Benzodiazepine Discontinuation Symptom Scale. We selected 73 patients with PD who had been asymptomatic for at least 1 year and who wished to discontinue the medication. The trial consisted of a 4-month period of tapering and an 8-month follow-up period. The dosage of clonazepam was decreased by 0.5 mg per 2-week period until 1 mg per day was reached, followed by a decrease of 0.25 mg per week. The mean dosage at the start of tapering was 2.7 +/- 1.2 mg/d. In total, 51 (68.9%) of the patients were free of the medication after the 4 months of tapering according to the protocol, and 19 (26.0%) of the patients needed another 3 months to be free of medication. Clonazepam discontinuation symptoms were mostly mild and included mainly: anxiety, shaking/trembling/tremor, nausea/vomiting, insomnia/nightmares, excessive sweating, tachycardia/palpitations, headache, weakness, and muscle aches. The improvement in PD and general well-being was maintained during both the taper and follow-up phases. Clonazepam can be successfully discontinued without any major withdrawal symptoms if the dose is reduced gradually. We recommend reducing the dosage of clonazepam after intermediate-term use by 0.25 mg/wk.

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Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [NCT02456974].).

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Comparative drug effects: the case of GERD therapies.

The results of clinical trials and approved Food and Drug Administration Drug Applications inform decision makers that a drug was effective in its labeled indications without causing unacceptable side effects. But purchasers for large medical organizations and members of health insurer or managed care organizations need relative effectiveness data to enable them to select the product from among the four, six, or ten competing alternative drug products available in that family. Retrospective studies are capable of providing this data after about a year of use by utilizing a database containing a large number of patients. An alternative means of determining this was explored using a new technique from a nationwide patient satisfaction study. Using GERD as an example, the authors were able to determine differences in patient satisfaction between proton pump inhibitors (PPIs), H(2) antagonists, and antacids, and even within the PPI category, down to individual products. The piloted method is rapid and inexpensive and can be an alternative for clinicians developing disease management protocols for specific conditions.

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Single-dose gabapentin pharmacokinetics and safety in healthy infants and children.

Gabapentin (Neurontin) is a gamma-aminobutyric acid analogue indicated in adults for adjunctive treatment of partial seizures with or without secondary generalization. Two studies were conducted to determine the single-dose pharmacokinetics of gabapentin in healthy subjects age 1 month to 12 years and to guide dose selection in safety and efficacy trials in pediatric patients. Forty-eight subjects were given single oral doses of gabapentin (10 mg/kg) while fasting. Enrollment was homogeneously distributed throughout the age range. Plasma samples were drawn predose and then serially for 24 hours postdose. Single doses of gabapentin were well tolerated by healthy pediatric subjects. Plots of pharmacokinetic parameters versus age suggested significant differences between younger (1 month to < 5 years) and older (> or =5 to 12 years) subjects. Mean area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was 25.6 microg x h/mL in younger subjects and 36.0 microg x h/mL in older subjects (p < 0.001). Corresponding mean peak plasma concentrations (Cmax) were 3.74 and 4.52 microg/ml (p < 0.05). Oral clearance (normalized for body weight) was 7.40 and 4.41 mL/min/kg in younger subjects and older subjects, respectively (p < 0.001). It was concluded that children between 1 month and < 5 years of age require approximately 30% higher daily doses of gabapentin than those > or =5 to 12 years of age.

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Pain levels and patient comfort after lower limb arthroplasty comparing i.v. patient-controlled analgesia, continuous peripheral nerve block and neuraxial analgesia: a retrospective cohort analysis of clinical routine data.

Insufficient pain control after lower limb arthroplasty results in delayed recovery and increased risk for pain chronicization. The ideal kind of analgesia is still discussed controversially. We conducted a retrospective analysis of single-center routine data from a German university hospital, including patients receiving either total hip (THA) or knee arthroplasty (TKA). All patients received general anesthesia. Patients undergoing THA received either continuous epidural ropivacaine infusion (0.133%, Epi) or patient-controlled analgesia (PCA) with the Wurzburg Pain Drip (tramadol, metamizole and droperidol, WPD) or with piritramide (Pir). After TKA, patients received either continuous femoral nerve block (ropivacaine 0.2%, PNB) or Pir. The analyzed cohort comprised 769 cases. Use of WPD after THA (n = 333) resulted in significantly reduced Numeric Rating Scale (NRS) values at rest, compared to Epi (n = 48) and Pir (n = 72) (.75 [IQR 1.14] vs. 1.17 [1.5], p = .02 vs. 1.47 [1.33], p < .0001) as well as maximum NRS scores (2.4 [1.7] vs. 3.29 [1.94], p < .001 vs. 3.32 [1.76], p < .0001). Positive feedback during follow-up visits was significantly increased in patients with a WPD PCA (p < .0001), while negative feedback (senso-motoric weakness/technical problems/nausea/dizziness/constipation) was particularly increased in Epi patients and lowest in those with WPD (p < .0001). After TKA, Pir (n = 131) resulted in significantly reduced NRS values at rest, compared to PNB (n = 185) (1.4 [1.4] vs. 1.6 [1.68], p = .02). Positive feedback was increased in patients with a Pir PCA in comparison with PNB (p = .04), while negative feedback was increased in PNB patients (p = .04). Overall, WPD presented with the lowest rate of any complications (8.7%), followed by Pir (20.2%), PNB (27.6%) and Epi (31.3%) (p < .001). In the assessed population, the use of a WPD PCA after THA offered better pain control and patient comfort in comparison with continuous epidural or piritramide-based analgesia. After TKA, the use of a Pir PCA provided superior analgesia and a lower complication rate compared to continuous PNB.

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Transition to Nonopioid Analgesia Does Not Impair Pain Control After Major Aesthetic Plastic Surgery.

Multimodal analgesic protocols are increasingly favored over traditional opioid regimens due to decreased adverse side effects and reduced opioid consumption. Concomitant use of selective cyclooxygenase (COX)-2 inhibitor celecoxib and anticonvulsant gabapentin have been proposed to adequately control acute postoperative pain. To determine efficacy of postoperative pain control using nonopioid pain regimen vs traditional opioids for all aesthetic plastic surgery procedures. A retrospective chart review was performed on 462 consecutive outpatient plastic surgery procedures by a single surgeon between November 2015 and July 2017. Procedures in the historical control group (n = 275) received traditional postoperative narcotic, hydrocodone-acetaminophen. Patients in the more recent nonopioid study group (n = 187) received a pre-, peri-, and postoperative regimen of celecoxib and gabapentin. Similar demographic characteristics between the control and study groups were observed: mean age, 39.7 vs 39.5 years; BMI, 24.6 vs 24.4 kg/m2; and ratio of female patients 92.7% vs 92.4%. A significant reduction in rescue analgesia (meperidine 44.6% vs 14.9%, P < 0.001) and antiemetic use (ondansetron 24.2% vs 16.3%, P < 0.05; promethazine 17.0% vs 4.7%, P < 0.001) in postanesthesia recovery unit (PACU) was noted in the nonopioid group compared to the control. The average stay in PACU also decreased in the study group (82 ± 39 min vs 70 ± 22 min, P < 0.001). Both groups reported low numbers of adverse events and need for additional pain prescriptions. These findings were reproducible in the breast subgroup. This nonopioid regimen is as effective as traditional opioid use for acute postoperative pain control and decreased recovery time for outpatient aesthetic plastic breast surgeries.

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Effect and tolerability of omeprazole in the treatment of duodenal ulcer disease.

In an open clinical trial, 16 hospital outpatients with endoscopically proven duodenal ulcer were given 30 mg omeprazole once daily for four weeks. After two weeks' treatment 14 of the 16 patients had healed and after four weeks all patients were healed. Reduction of pain was rapid and occurred during the first part of the trial. No serious adverse events or clinically significant deviations from normal laboratory values were reported. Serum gastrin levels significantly increased during treatment but returned to normal levels after the treatment was discontinued.

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High performance liquid chromatography - tandem mass spectrometric determination of cyclovirobuxine D in human plasma.

A sensitive, specific and rapid high performance liquid chromatography - tandem mass spectrometric (LC/MS/MS) method for the determination of cyclovirobuxine D in human plasma was developed and validated. The triple-quadrupole tandem mass spectrometric detector with an electrospray interface (ESI) was operated under the selected reaction monitoring (SRM) mode. After the addition of citalopram as an internal standard (IS), plasma samples were extracted with ethyl acetate. Chromatographic separation of the analytes was performed on a Kromasil CN column with a mobile phase of methanol/water (88/12, v/v) containing 0.4% formic acid. Linearity was established for the range of concentration 0.2-40ng/ml. Under optimized conditions, the mean recovery was 86.6%. The intra-day precision ranged from 4.56% to 7.81%, while the intra-day accuracy ranged from 2.75% to 11.0%. The inter-day precision was in the range 3.87-10.7%, and the inter-day accuracy was in the range -4.00% to 2.50%. The cyclovirobuxine D was stable in human plasma after three freeze-thaw cycles, under storage at room temperature for 12h, in a freezer at -20 degrees C for 15 days and during processing (in autosampler) at 10 degrees C for 24h. The validated method is suitable for quantitative determination of cyclovirobuxine D in human plasma in pharmacokinetics study and has been successfully applied to the analysis of clinical samples.

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Comparison of the effects of salmeterol and salbutamol on clinical activity and eosinophil cationic protein serum levels during the pollen season in atopic asthmatics.

In atopic asthma there is strong evidence of eosinophils playing an active role in pathogenesis. Some investigations demonstrated that eosinophil cationic protein (ECP) serum levels increased in atopic patients with asthma during pollen season. The aim of the study was to evaluate the effects of short-term (1 week) beta 2-agonist treatment on lung function and eosinophil activity in asthmatic patients. We used an open, randomized, cross-over design to compare the effects of salbutamol (200 micrograms q.i.d.) and salmeterol (50 micrograms b.i.d.) on peak expiratory flow rate (PEFR), blood eosinophil count and serum levels of ECP as a measure of eosinophil activity in 20 mild atopic asthmatics. Morning and evening PEFR values were both significantly higher during salmeterol treatment than during the salbutamol period. Conversely, both morning and evening daily asthma symptom scores were significantly lower during salmeterol treatment compared with those recorded during the salbutamol period. The mean basal eosinophil blood count on salmeterol treatment (601 +/- 189 mm3) was not higher than the mean count on salbutamol treatment (612 +/- 204 mm3). After both treatments the mean eosinophil blood counts were unchanged (619 +/- 189 mm3 and 576 +/- 212 mm3, respectively). No significant differences in blood eosinophil counts were observed between or within treatments at any time. No significant difference was observed in baseline mean ECP serum concentration (43.8 +/- 26.3 micrograms/L on salmeterol treatment and 41.7 +/- 29.8 micrograms/L on salbutamol treatment, respectively). After salmeterol treatment the mean ECP serum concentration had fallen significantly to 20.9 +/- 18.6 micrograms/L (P < 0.01), whereas after salbutamol treatment it was unchanged (42.0 +/- 25.1 micrograms/L). Salmeterol treatment produced a decrease in ECP serum levels without any changes in blood eosinophil count. This study demonstrates that salmeterol affords a significant improvement in asthma control during the pollen season, measured by both subjective and objective parameters, compared with salbutamol. This greater efficacy may be related to inhibition of eosinophil degranulation during the pollen season.

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Comparison of alternate day steroids and daily steroids in renal transplant recipients.

This retrospective study examined whether alternate day steroid therapy decreased the incidence or severity of side effects of prednisone without decreasing renal function. We conclude that alternate day steroid therapy is indicated in adult renal transplant recipients to treat steroid-induced diabetes, hypertension and minor prednisone side effects, but is not useful for obesity. Further, alternate day steroid therapy can be used safely without compromising renal function or graft survival.

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The use of gabapentin in chronic cluster headache patients refractory to first-line therapy.

Chronic cluster headache (CCH) is a rare but challenging condition. About 20% of CCH patients get refractory to treatment. Gabapentin has recently been reported to be efficacious in the treatment of CCH. To test the potential of gabapentin as second-line drug, we prospectively studied the efficacy of gabapentin as add-on drug in eight patients suffering from CCH refractory to first-line treatment. Six of eight CCH patients responded to treatment. After the end of the study phase, the patients' clinical course was further followed up until January 2006. The longest period of being continuously pain-free under gabapentin treatment was 18 months. In some individuals, increasing doses were needed with time. We conclude that gabapentin may be offered as treatment trial in patients refractory to first-line treatment. However, patients may fail to respond to treatment and drug tolerance may occur with time.

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Relationship between histological subtypes and clinical characteristics at presentation and outcome in biopsy-proven temporal arteritis. Identification of a relatively benign subgroup.

Temporal arteritis (TA) may offer major complications, whilst high dosage of prednisone may result in serious side effects. We tried to identify a subgroup of TA, which can be treated with a lower dosage of prednisone. Retrospectively, clinical and laboratory data were studied at presentation, as well as the outcome in 44 consecutive patients with biopsy-proven temporal arteritis. These data were related to three particular histological subgroups, (a) classical giant cell arteritis, (b) atypical arteritis, and (c) 'healed arteritis', defined according to Allsop and Gallagher (The American Journal of Surgical Pathology 5:317-332, 1981). At presentation in subgroup c, erythrocyte sedimentation rate was lower and the level of haemoglobin was higher than in the other two subgroups. During follow-up in the healed arteritis group, reactivation, recurrence, or early death were not observed, whilst prednisone dosage after 2 and 3 years was lower compared to subgroup b. Major complications (permanent blindness and cerebrovascular accident) were only observed in subgroups a and b. We believe that the healed arteritis subgroup represents a relatively benign subgroup with a mild clinical presentation and a good prognosis. Therefore, a much lower initial prednisone dosage (15 mg/day) is suggested for patients in subgroup c than in the other two subgroups (40-60 mg/day).

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Childhood suppurative otitis media in Abakaliki: isolated microbes and in vitro antibiotic sensitivity pattern.

Suppurative otitis media (SOM) is the most common pediatric problem seen by otolaryngologists in Nigeria. Devising simple and effective ways of treating pediatric patients with suppurating ears, especially in situations without a specialist care, will help prevent chronicity. Our experience with som at the ebonyi state university teaching hospital (ebsuth), abakaliki, is reviewed in this study. it may serve as a guide in patient care. Determine the bacteriology of SOM in children in Abakaliki and ascertain their sensitivity to common antibiotics. A 2-year retrospective analysis of ear swabs culture results and case files of children aged 0-18 years with SOM managed in EBSUTH. Sixty-five patients with discharging ears were reviewed. Of these, 73% were ≤ 5 years, of which 41.5% were infants. About 83% had unilateral ear discharge. Acute suppuration was seen in 67%. Overall swab yield was 87.7%; Pseudomonas was (57.4%), Klebsiella (16.4%), and Proteus species (11.5%). Ciprofloxacin showed 60% sensitivity, Gentamicin (58%), and Ceftazidime (35%). Amoxicillin/Clavulanic acid, ceftriaxone, and cefuroxime showed sensitivity of 4.3%-9.7%. Treatment protocols of SOM in children should emphasize the use of Ciprofloxacin or Gentamicin, especially in situations with limited access to laboratory services or specialist care.

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Variance comparison as a tool in clinical pharmacology: an example with two loop diuretics.

Comparison of variances can be usefUl in assessing the regularity of drug effects. In order to compare the variances of the saluretic effects of piretanide and frusemide, two loop diuretics with different bioavailabilities, a double-blind cross-over study was carried out in 34 normal volunteers. The diuretics were given in randomized order, with an interval of 7 days, in single equipotent doses (frusemide 6.25 mg and piretanide 1.0 mg chosen from previous results) adjusted by body weight. The dispersion of individual values (comparison of variances from paired measures) for Na+, Cl- and Ca++ excretion, urine osmolality and excretion of the drugs, was significantly smaller for piretanide than for frusemide. It is concluded that the saluretic effect of a single dose of piretanide varies less than that of an equipotent dose of frusemide. The methodology may be useful in trials of drugs for which regularity of effect is important.

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Helicobacter pylori: antibiotic resistance and eradication rates in Suffolk, UK, 1991-2001.

Helicobacter pylori infection causes a number of gastrointestinal diseases and its current treatment is based on multidrug regimes including acid suppression and antimicrobials. The success of these regimes is determined by a number of factors including antibiotic resistance, which varies widely but is an increasing problem. Local data are important in establishing the most cost-effective eradication regime. Data have been collected prospectively on antibiotic resistance at Ipswich Hospital (Suffolk, UK) in all consecutive isolates of H. pylori from 1991 to 2001. The success of regimes consisting of a proton pump inhibitor, amoxycillin and metronidazole (PPI/A/M) has also been evaluated in patients found positive on serological testing in primary care using urea breath testing. Overall, metronidazole resistance was found in 31.7 % of isolates and clarithromycin resistance in 5.3 %. A significant increase in metronidazole resistance from 29.1 to 37.0 % (P = 0.022) and a decrease in clarithromycin resistance from 10.3 to 3.8 % (P = 0.014) was seen over the study period. Metronidazole resistance was significantly more common in women (P < 0.001) and young patients (P < 0.001). Eradication with PPI/A/M was successful in 89.9 % of patients and did not change significantly over the study period. Eradication rates were lower in young patients (P < 0.001). Whilst metronidazole resistance is increasing in Suffolk, this does not seem to have a significant effect on eradication rates. Metronidazole-based regimes are still effective first-line treatments in most patients.

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Influence of technical factors and different immunosuppressive regimens on kidney graft survival. Retrospective analysis on 300 kidney transplants.

300 patients underwent kidney transplantation. Uretero-neocystostomy was performed by means of the Politano-Leadbetter technique in the first 185 patients and direct ureterovesical anastomosis in the other 115 patients. Immunosuppression included conventional therapy (steroids, antilymphocyte globulins, azathioprine) and the association cyclosporine A and steroids. Retrospective analysis on these 300 patients indicates that the improved 1 year graft survival rate (85% vs 64%) we observed in the latest years has depended to the same extent, on improved surgical technique and on advent of cyclosporine A in our therapeutic protocols. Cyclosporine A at low starting doses immediately adjusted on whole blood trough levels (200-400 ng/ml) proved to be superior to other therapeutic schedules reported in this study (1-year graft survival rate: 94% vs 84%-73%). Direct ureterovesical anastomosis was characterized by a net reduction of urologic complications (2.5% vs 9.7%).

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Noninvasive tracking of coronary atherosclerosis by electron beam computed tomography: rationale and design of the Felodipine Atherosclerosis Prevention Study (FAPS).

The Felodipine Atherosclerosis Prevention Study is designed to evaluate the efficacy of the calcium antagonist felodipine ER and combined felodipine/simvastatin therapy on retarding the progression of atherosclerosis, estimated by serial changes in coronary calcium evaluated by noninvasive electron beam computed tomography. Subjects include 180 men and women aged 40 to 69 and 50 to 69 years, respectively, with moderate type IIa dyslipidemia, with either cardiovascular disease or risk factors. All subjects receive simvastatin lipid-lowering therapy, and are randomized either to felodipine or placebo for a treatment period of 2 years. Monitoring of blood chemistry, measures of lipids and apolipoproteins, blood pressure, evaluation of symptoms, and interim clinical event monitoring are done at routine follow-up visits. Baseline and 2-year follow-up electron beam computed tomography, measuring changes in total calcium score, area, and mass, evaluate the effects of intervention on the progression of calcified atherosclerosis. The results from the Felodipine Atherosclerosis Prevention Study will provide valuable information about the effect of felodipine alone and in combination with simvastatin on progression of calcified atherosclerosis evaluated noninvasively.

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Histological Response to Fluticasone Propionate in Patients With Eosinophilic Esophagitis Is Associated With Improved Functional Esophageal Mucosal Integrity.

The esophageal mucosal integrity is impaired in patients with eosinophilic esophagitis (EoE). We aimed to evaluate the effect of fluticasone propionate on inflammation and functional and structural markers of esophageal mucosal barrier integrity in adult patients with EoE. In this prospective study, we included 15 EoE patients (median age (IQR), 43 (30-45) years). Patients underwent upper endoscopy before and after an 8-week course of swallowed fluticasone propionate 500 μg BID. Several parameters of esophageal mucosal barrier integrity were evaluated: esophageal electrical tissue impedance in vivo during endoscopy, transepithelial electrical resistance (TER) and transepithelial molecule flux in Ussing chambers using esophageal biopsy specimens, and intercellular spaces as a structural marker of permeability using electron microscopy. Esophageal eosinophils and mast cells were counted, and expression of inflammatory cytokines and barrier integrity proteins was investigated using qPCR. Esophageal symptoms and signs were also assessed. Peak eosinophil and mast cell counts decreased significantly after fluticasone propionate treatment. The esophageal mucosal integrity increased substantially during treatment, as shown by increased extracellular impedance and TER (both P<0.01) and decreased transepithelial molecule flux in Ussing chambers (P<0.05). Whereas expression of genes encoding for inflammatory cytokines (IL5, IL13, eotaxin-3, periostin, TSLP) decreased after treatment, expression of genes encoding for barrier integrity proteins (filaggrin and desmoglein-1) increased. Fluticasone propionate treatment decreases eosinophilic inflammation and improves the esophageal mucosal barrier integrity in adult EoE patients. Improvement of the mucosal barrier integrity correlates with normalization of expression of desmoglein-1 and filaggrin marker genes.

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Factors predictive of early death in patients receiving high-dose CHOP (ACVB regimen) for aggressive non-Hodgkin's lymphoma: a GELA study.

Death during the induction phase of chemotherapy remains a common event in patients with aggressive non-Hodgkin's lymphoma (NHL). In a series of patients with aggressive NHL homogeneously treated with intensive induction chemotherapy [ACVB (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) regimen], we determined the clinical and biological parameters that were predictive of early death. Early death was defined as death, for whatever reason, occurring within 100 d of randomization. Predictive factors were identified by logistic regression and an index predictive for individual risk of early death was designed. Among the 2210 patients treated with ACVB, there were 162 (7.3%) early deaths. There was no significant reduction in the rate of early death between 1987 and 1998. In a multivariate analysis, age > 60 years, Eastern Cooperative Oncology Group performance status > 1, serum lactate dehydrogenase > normal, serum albumin < 30 g/l, leucocyte counts > 10 x 10(9)/l and haemoglobin levels < 8.5 g/dl were found to be independent predictive factors for early death. An early death index was designed, enabling the evaluation of the individual risk of early death in young (range 2-31% risk of early death) and elderly patients (range 5-53%). Clinical and biological parameters available at diagnosis can help physicians identify patients with aggressive lymphoma at low or high risk of early death.

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Sertraline in pregnancy - Therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood.

This study is the first to measure and correlate sertraline concentrations in maternal blood, amniotic fluid and umbilical cord blood and account for distribution of the drug between these three compartments. Concentrations of sertraline were measured in six mother infant pairs at the time of delivery. Data are provided as median values, first and third quartiles as well as ranges. To account for the penetration ratio into amniotic fluid and cord blood, the concentration of sertraline in both environments was divided by the concentration in maternal serum. Daily doses were correlated with maternal serum- and umbilical cord blood-concentrations, and serum levels were correlated with levels in amniotic fluid. The median daily dose of sertraline was 75mg (Q1: 43.75mg, Q3: 100mg; range 25-100mg). Amniotic fluid concentrations of sertraline strongly correlated with the daily dose (r=0.833, p=0.039) while neither maternal serum concentrations nor cord blood concentrations correlated with the daily dose (p>0.05). The median penetration ratio for sertraline into amniotic fluid was 0.57 (Q1: 0.28, Q3: 0.75; range: 0.22-0.88). The median penetration ratio into the fetal circulation, calculated on the basis of umbilical cord blood-concentrations, was found to be 0.36 (Q1: 0.28, Q3: 0.49; range: 0.17-0.65). Sertraline concentrations in amniotic fluid gave evidence that maternally administered sertraline is constantly accessible to the fetus via amniotic fluid in a manner not previously appreciated. A relatively low penetration into fetal circulation may contribute to a sufficient safety profile of sertraline during pregnancy although in our study APGAR Scores were relatively low in three infants. Our data support the important role of therapeutic drug monitoring in maintaining the safety of pregnant women and exposed infants.

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An observational cohort study of Chlamydia trachomatis treatment in pregnancy.

Currently, azithromycin is not considered a first-line treatment for Chlamydia trachomatis in pregnant women. We evaluated the use, efficacy, and safety of azithromycin compared with erythromycin and amoxicillin in the treatment of genital chlamydial infection during pregnancy. This was a retrospective cohort study of pregnant women with genital chlamydial infection. Data on antibiotics prescribed, test-of-cure (TOC) results, and maternal and infant complications were collected from medical records. Of the 277 women in the study sample, 69% were initially prescribed azithromycin, 9% amoxicillin, and 19% erythromycin. Eight-one percent of subjects had a TOC 7 or more days after diagnosis and before delivery. Treatment efficacy, as defined by a negative TOC, was 97% (95% confidence interval [CI], 92.9-99.2) for azithromycin, 95% (95% CI, 76.2-99.9) for amoxicillin, and 64% (95% CI, 44.1-81.4) for erythromycin. The efficacy of azithromycin was significantly higher than erythromycin (P < 0.0001). There were no significant differences in efficacy by age, race/ethnicity, concurrent sexually transmitted disease diagnosis, partner treatment, or substance use. Furthermore, there was no difference in complications for women or infants exposed to azithromycin compared with those treated with other regimens. Clinical outcome data from this study population of women and infants support both efficacy and safety of azithromycin for treatment of C. trachomatis in pregnancy.

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The efficacy of omeprazole-based short-term triple therapy in Helicobacter pylori-positive older patients with dyspepsia.

To evaluate the efficacy of 1-week triple therapy with omeprazole, clarithromycin,and tinidazole (OCT) in Helicobacter pylori-positive older patients with dyspepsia. A prospective, nonrandomized therapeutic study. The primary care and referral center of a gastroenterological outpatient clinic at a central university hospital serving an urban population (>1 million) in Israel. The study group consisted of 134 patients (71 men, and 63 women) more than 60 years old who were referred for evaluation of symptoms of dyspepsia and were endoscopically diagnosed as H. pylori positive. The patients were divided into two groups: those who received their first course of anti-H. Pylori therapy during this study (Group 1) and those who had previously received standard metronidazole and bismuth combination therapies that failed to eradicate the H. pylori (Group 2). All the patients underwent upper gastrointestinal endoscopy, and H. pylori infection was confirmed by a rapid urease test (CUTest) and/or histological staining. Therapeutic efficacy was assessed by a 13C-urea breath test 4 weeks after completion of treatment. The mean age of the study population was 68.8 years (range 60-87). There were 112 patients in Group 1 and 22 patients in Group 2. Endoscopic findings were: gastritis (in 46), gastric ulcer (8), duodenal ulcer (52), and duodenitis (28). The H. pylori eradication rate was significantly higher in Group 1 patients (104/112, 92.9%) than in patients of Group 2 (15/22, 68.2%). There was no difference in the eradication rate in relation to gender, endoscopic diagnosis, more advanced age, place of birth, or smoking habits. The compliance in both groups was equally good, and no major side effects were recorded. A 1-week OCT triple therapy is well tolerated and effective as first line therapy for H. pylori among older people. It is less effective in patients previously treated.

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Obese but not normal-weight women with polycystic ovary syndrome are characterized by metabolic and microvascular insulin resistance.

Polycystic ovary syndrome (PCOS) and obesity are associated with diabetes and cardiovascular disease, but it is unclear to what extent PCOS contributes independently of obesity. The objective of the study was to investigate whether insulin sensitivity and insulin's effects on the microcirculation are impaired in normal-weight and obese women with PCOS. Thirty-five women with PCOS (19 normal weight and 16 obese) and 27 age- and body mass index-matched controls (14 normal weight and 13 obese) were included. Metabolic Insulin sensitivity (isoglycemic-hyperinsulinemic clamp) and microvascular insulin sensitivity [endothelium dependent (acetylcholine [ACh])] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation with laser Doppler flowmetry was assessed at baseline and during hyperinsulinemia. Metabolic insulin sensitivity (M/I value) and the area under the response curves to ACh and SNP curves were measured to assess microcirculatory function at baseline and during insulin infusion (microvascular insulin sensitivity). Obese women were more insulin resistant than normal-weight women (P < 0.001), and obese PCOS women were more resistant than obese controls (P = 0.02). In contrast, normal-weight women with PCOS had similar insulin sensitivity, compared with normal-weight women without PCOS. Baseline responses to ACh showed no difference in the four groups. ACh responses during insulin infusion were significantly greater in normal-weight PCOS and controls than in obese PCOS and controls. PCOS per se had no significant influence on ACh responses during insulin infusion. During hyperinsulinemia, SNP-dependent vasodilatation did not significantly increase, compared with baseline in the four groups. PCOS per se was not associated with impaired metabolic insulin sensitivity in normal-weight women but aggravates impairment of metabolic insulin sensitivity in obese women. In obese but not normal-weight women, microvascular and metabolic insulin sensitivity are decreased, independent of PCOS. Therefore, obese PCOS women in particular may be at increased risk of metabolic and cardiovascular diseases.

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Antibiotic prophylaxis in clean neurosurgery.

Two regimens of antibiotic prophylaxis are in use at our institution. These protocols consist in perioperative administration of a single dose of amoxicillin-clavulanic acid of 2.2 g at induction and 8 h later and irrigation of the surgical wound with rifamycin before closure. In cases of dirty surgery, placement of external shunts or foreign bodies, we administer vancomycin 1.5 g/die and ceftazidime 6 g/die for 72 h. A retrospective study of all the clean operations we performed in the last 2 years yielded a total of 793 consecutive procedures with three postoperative wound infections. These results are in agreement with the majority of series reported in literature, although different prophylactic protocols are applied and in some cases no prophylactic antibiotics are administered at all. The use of these agents in clean neurosurgery remains, as a matter of fact, controversial. In order to further investigate this issue we took three or more intraoperative samples for culture in 40 clean cases. Only in 2% of these samples were cultures positive. Although lacking statistical significance, these results are interesting indications of the appropriateness of antimicrobial prophylaxis in clean neurosurgery and invite further investigation in that direction.

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Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone.

Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536). The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II). Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors. The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.

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The effect of Olanzapine and Sertraline on personality disorder in patients with methadone maintenance therapy.

Various drugs have been suggested for treatment of Borderline Personality Disorder (BPD)-a disabling disease affecting two percent of the general population. If a drug could alleviate a wide range of symptoms, it would be more suitable. In these disorders drug addiction is very common. This fact makes the symptoms complicated and the treatment more difficult. This study is designed to evaluate the effect of Olanzapine and Sertraline in patients suffering from personality disorders who are on methadone maintenance therapy. This study is a clinical trial. 120 males and females were chosen for methadone maintenance therapy through interview by a psychiatrist based on DSM-IV-TR diagnostic criteria for BPD. Afterwards they were randomly divided into two groups. These groups separately received Olanzapine (5-10 mg daily) and Sertraline (50-100 mg daily) therapy. The SCL-90 questionnaire was filled by all participants before treatment and at the 4th, 8th and 12th weeks of treatment. According to this clinical trial, Olanzapine and Sertraline are effective in ameliorating symptoms of depression, anxiety and aggression, reducing sensitivity in interpersonal relationships and alleviating obsessive symptoms, pessimistic behaviors and somatization disorders in patients with personality disorders on methadone maintenance therapy. As result of this study it appears that Olanzapine and Sertraline are definitely effective in alleviating symptoms of patients with personality disorder, prescribing theses drugs are recommended for these patients.

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Long-term sertraline treatment of children and adolescents with obsessive-compulsive disorder.

To evaluate the safety and effectiveness of sertraline in the long-term treatment of pediatric obsessive-compulsive disorder (OCD). Children (6-12 years; n= 72) and adolescents (13-18 years; n = 65) with DSM-III-R-defined OCD who had completed a 12-week, double-blind, placebo-controlled sertraline study were given open-label sertraline 50 to 200 mg/day in this 52-week extension study. Concomitant psychotherapy was allowed during the extension study Outcome was evaluated by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), National Institute of Mental Health Global Obsessive-Compulsive Scale, and Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I) scores. Significant improvement (p < .0001) was demonstrated on all four outcome parameters on an intent-to-treat analysis for the overall study population (n = 132), as well as the child and the adolescent samples. At endpoint, 72% of children and 61% of adolescents met response criteria (>25% decrease in CY-BOCS and a CGI-I score of 1 or 2). Significant (p < .05) improvements were also demonstrated from the extension study baseline to endpoint on all outcome parameters in those patients who received sertraline during the 12-week, double-blind acute study. Long-term sertraline treatment was well tolerated, and there were no discontinuations due to changes in vital signs, laboratory values, or electrocardiograms. Sertraline (50-200 mg/day) was effective and generally well tolerated in the treatment of childhood and adolescent OCD for up to 52 weeks. Improvement was seen with continued treatment.

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Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study.

To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric acid (rosuvastatin/fenofibric acid) compared with simvastatin in patients with high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Combination therapy with a statin and a fibrate is one of the treatment options to manage multiple lipid abnormalities in patients with hypercholesterolemia and elevated TGs. In this randomized, double-blind study, patients (n = 474) with LDL-C > or =160 mg/dL and < or =240 mg/dL and TG > or =150 mg/dL and <400 mg/dL were treated for 8 weeks with simvastatin 40 mg, rosuvastatin/fenofibric acid 5 mg/135 mg, rosuvastatin/fenofibric acid 10 mg/135 mg, or rosuvastatin/fenofibric acid 20 mg/135 mg. Primary and secondary variables were mean percent changes in LDL-C comparing rosuvastatin/fenofibric acid 20 mg/135 mg with simvastatin 40 mg and rosuvastatin/fenofibric acid 10 mg/135 mg and rosuvastatin/fenofibric acid 5 mg/135 mg with simvastatin 40 mg, respectively. Additional efficacy variables included non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (Apo) B, HDL-C, TG, and high-sensitivity C-reactive protein (hsCRP). Safety was evaluated based on data collected for adverse events (AEs), physical and electrocardiographic examinations, vital sign measurements, and clinical laboratory tests. Significantly greater reductions in LDL-C levels from baseline values were observed with the combination of rosuvastatin/fenofibric acid 20 mg/135 mg (-47.2%, p < 0.001), rosuvastatin/fenofibric acid 10 mg/135 mg (-46.0%, p < 0.001), and rosuvastatin/fenofibric acid 5 mg/135 mg (-38.9%, p = 0.007) than with simvastatin 40 mg (-32.8%). Significant (p < or = 0.04 for all comparisons) improvements in non-HDL-C, ApoB, HDL-C, TG, and hsCRP levels were also observed with each of the rosuvastatin/fenofibric acid doses as compared with simvastatin 40 mg. Treatment-related AEs and discontinuations due to AEs were similar across groups. The incidence of serious AEs was 0% with simvastatin 40 mg, 3.4% with rosuvastatin/fenofibric acid 5 mg/135 mg, 0.8% with rosuvastatin/fenofibric acid 10 mg/135 mg, and 2.5% with rosuvastatin/fenofibric acid 20 mg/135 mg. No cases of rhabdomyolysis or drug-related myopathy were reported. In patients with high LDL-C and TG levels, combination treatment with rosuvastatin/fenofibric acid was well tolerated, and each of the rosuvastatin/fenofibric acid doses produced greater reductions in LDL-C and improvements in other efficacy parameters, compared with simvastatin 40 mg. [Clinical trial is registered at www.clinicaltrials.gov NCT00812955.].

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Bronchodilator responsiveness in normal infants and young children.

Several studies have demonstrated that normal infants exhibit bronchoconstriction after inhalation of nonspecific agonists and that the induced airway narrowing can be reversed by the inhalation of a beta-agonist. However, there are very limited data on baseline airway tone and the airway response to a beta-agonist in this subject population. The purpose of our study was to evaluate in normal infants baseline airway responsiveness to the inhaled beta-agonist, albuterol, using changes in maximal expiratory flows. Forty-one healthy infant volunteers with no history of respiratory disease or recurrent wheezing (ages 5.4 to 141.4 wk) were studied. Maximal expiratory flow- volume curves were obtained at baseline and 10 min after inhalation of albuterol (n = 28) or placebo (n = 13) using a metered-dose inhaler with a spacer. The mean percent change was significantly greater (p < 0.05) in the albuterol versus placebo group for FEV(0.5) (2.2% versus -1.5%), FEF(75%) (10.6% versus -3.1%), and FEF(85%) (12.9% versus 0.5%). Six of 28 albuterol-treated infants demonstrated increases in FEF(75%) greater than two standard deviations from the mean change in FEF(75%) seen in the placebo group. These infants were younger and more frequently exposed to maternal smoking during pregnancy. We conclude that normal healthy infants have overall levels of baseline airway tone that are similar to that reported in adults and older children; however, among the infants we evaluated the response to an inhaled bronchodilator was greatest in the youngest infants and in those exposed to tobacco smoking. airway responsiveness; asthma; tobacco smoke; infant pulmonary function; bronchodilator

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Metabolomics study of COVID-19 patients in four different clinical stages.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the coronavirus strain causing the respiratory pandemic COVID-19 (coronavirus disease 2019). To understand the pathobiology of SARS-CoV-2 in humans it is necessary to unravel the metabolic changes that are produced in the individuals once the infection has taken place. The goal of this work is to provide new information about the altered biomolecule profile and with that the altered biological pathways of patients in different clinical situations due to SARS-CoV-2 infection. This is done via metabolomics using HPLC-QTOF-MS analysis of plasma samples at COVID-diagnose from a total of 145 adult patients, divided into different clinical stages based on their subsequent clinical outcome (25 negative controls (non-COVID); 28 positive patients with asymptomatic disease not requiring hospitalization; 27 positive patients with mild disease defined by a total time in hospital lower than 10 days; 36 positive patients with severe disease defined by a total time in hospital over 20 days and/or admission at the ICU; and 29 positive patients with fatal outcome or deceased). Moreover, follow up samples between 2 and 3 months after hospital discharge were also obtained from the hospitalized patients with mild prognosis. The final goal of this work is to provide biomarkers that can help to better understand how the COVID-19 illness evolves and to predict how a patient could progress based on the metabolites profile of plasma obtained at an early stage of the infection. In the present work, several metabolites were found as potential biomarkers to distinguish between the end-stage and the early-stage (or non-COVID) disease groups. These metabolites are mainly involved in the metabolism of carnitines, ketone bodies, fatty acids, lysophosphatidylcholines/phosphatidylcholines, tryptophan, bile acids and purines, but also omeprazole. In addition, the levels of several of these metabolites decreased to "normal" values at hospital discharge, suggesting some of them as early prognosis biomarkers in COVID-19 at diagnose.

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Skeletal muscle relaxant ingestion.

We retrospectively analyzed 56 consecutive cases involving acute skeletal muscle relaxant exposure that were reported to the Poison Control Center over a 1-year period. The age range was 9 mo to 56 years (mean 18.9 +/- 13.1) with the site of exposure being the primary residence in 54 cases (96.4%). The reasons for inquiry to the Poison Center were reported to be intentional suicide in 26 cases (46.4%), accidental in 21 cases (37.5%), with intentional misuses in 5 cases (8.9%). No deaths were reported. Eighteen cases (32.1%) were reported with co-ingestants (average number of substances taken was 2.7 +/- 0.8). Of these cases 3 patients (16.7%) had major effects with life-threatening symptoms with 6 (33.3%) patients having no symptoms. Of the remaining 38 cases, 17 (44.7%) wer cyclobenzaprine, 6 (15.8%) were methocarbamol, 5 (13.2%) were carisoprodol, 5 (13.2%) were chlorzoxazone, 3 (7.89%) were Baclofen and the remainder were either life-threatening symptoms (2.6%), while 29 (74.3%) had no or minor effects with symptoms that subsided. We conclude that morbidity and mortality are low in pure skeletal muscle relaxant ingestion, however it may be increased in multiple ingestions.

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Preferential pulmonary retention of (S)-albuterol after inhalation of racemic albuterol.

The (R)-enantiomer of racemic albuterol produces bronchodilation, whereas the (S)-enantiomer may increase airway reactivity. After oral or intravenous administration of racemic albuterol, the (R)- enantiomer is metabolized several times faster than the (S)-enantiomer; however, enantiomer disposition after inhaling racemic albuterol with a metered-dose inhaler (MDI) is not known. Accordingly, 10 healthy subjects inhaled racemic albuterol with a MDI alone and with a MDI and holding chamber. We measured plasma levels of unchanged (R)- and (S)-albuterol before and up to 4 h after inhalation of racemic albuterol, and determined the unchanged R/S ratio in urine before and at 0.5, 4, 8, and 24 h later. The disposition of albuterol's enantiomers with a MDI and holding chamber was similar to that with a MDI alone. The area under the curve (AUC) of the plasma levels over time was significantly lower for the (S)- than for the (R)-enantiomer-395.5 +/- 141.0 (SE) versus 882.7 +/- 126.4 ng. ml(-)(1). min (p < 0.05)-indicating preferential retention of (S)-albuterol in the lung. The R/S ratio in urine at 0. 5 h after albuterol was > 1, reflecting the higher plasma level of the (R)-enantiomer. In conclusion, preferential retention of the (S)- compared with the (R)-enantiomer in the lung could lead to accumulation of the (S)-enantiomer after long-term use of racemic albuterol.

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The effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin alone on post-fat load endothelial function in patients with metabolic syndrome: a randomized double-blind crossover trial.

Insulin resistance is associated with postprandial hyperlipidemia and endothelial dysfunction. Patients with metabolic syndrome, characterized by insulin resistance, are at increased cardiovascular risk. The aim of the present study was to investigate whether a similar low-density lipoprotein cholesterol (LDL-c) reduction with combination therapy of low-dose simvastatin and ezetimibe or with high-dose simvastatin alone has similar effects on (post-fat load) endothelial function. Randomized, double blind, crossover trial in 19 male obese patients with metabolic syndrome with high-dose simvastatin 80 mg versus combination therapy of low-dose simvastatin 10 mg with ezetimibe 10 mg. Fasting and post-fat load lipids and endothelial function (brachial artery flow-mediated dilation) were determined. Fasting LDL-c concentrations (2.1 +/- 0.5 mmol/L) and fasting endothelial function (6.9 +/- 0.8 vs. 7.6 +/- 1.2%) were the same after both treatments. Although post-fat load plasma triglycerides concentrations were higher (3.2 +/- 0.4 vs. 2.6 +/- 0.2 mmol x h/L) with combination therapy compared to monotherapy, ApoB particles were comparable (0.9 +/- 3.3 vs. -0.2 +/- 2.3 g x h/L). Combination therapy did not decrease post-fat load endothelial function (7.6 +/- 1.2 vs. 7.7 +/- 1.6%), contrary to high-dose simvastatin monotherapy (6.9 +/- 0.8 vs. 4.3 +/- 0.6%). Combination therapy with low-dose simvastatin and ezetimibe preserved post-fat load endothelial function, contrary to treatment with high-dose simvastatin monotherapy in male metabolic syndrome patients. There were no differences in fasting lipid profiles and endothelial function.

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A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. The Canadian Apheresis Study Group.

Sixty-three patients with crescentic glomerulonephritis (cellular crescents in greater than 50% of glomeruli) were considered for a prospective randomized trial comparing intravenous methylprednisolone, prednisone, and azathioprine with and without plasma exchange. Of 32 patients who fulfilled the inclusion criteria for this study, 16 were randomly assigned to receive drug therapy (control) and 16 to receive plasma exchange as well. The randomization was stratified for initial need of dialysis, and the presence of oliguria and sclerosis. Renal pathology was similar in the two groups of patients. There was no significant difference in the number of patients initially on dialysis who were able to discontinue it during the study (2/7 control v 3/4 plasma exchange), whereas no control but two plasma exchange-treated patients started dialysis during the study. Serum creatinine at randomization was similar in the two groups: 769 +/- 486 mumol/L (8.7 +/- 5.5 mg/dL) in the control group versus 643 +/- 275 mumol/L (7.3 +/- 3.1 mg/dL) in the plasma exchange group. There was no significant difference between the two groups in mean serum creatinine, change in serum creatinine, change in reciprocal, or change in logarithm of serum creatinine at 1, 3, 6, or 12 months following randomization. Power calculation, assuming a 20% difference would be clinically relevant, was 0.94 at 12 months. There was significant morbidity in both groups; there were two deaths within 1 year of randomization, both of pulmonary infection and both in the plasma exchange group. We conclude that plasma exchange offers no additional therapeutic benefit to patients with idiopathic rapidly progressive glomerulonephritis (RPGN) who are not dialysis-dependent at presentation.

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Postoperative chemotherapy and chemohormonal therapy in women with node-positive breast cancer.

Separate trials for premenopausal and postmenopausal (less than or equal to 65 yr of age) patients with node-positive breast carcinoma were initiated by the Eastern Cooperative Oncology Group in 1978 to evaluate adjuvant chemotherapy and chemohormonal therapy approaches. Postoperative patients were stratified by degree of axillary nodal involvement and estrogen receptor (ER) status prior to randomization. Premenopausal patients received 12 monthly cycles of intermittent cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus continuous tamoxifen (CMFPT). Postmenopausal patients received either observation or 12 monthly cycles of CMFPT or CMFP. The median follow-up for the analyzed patients is 54 months for the 553 premenopausal patients and 59 months for the 223 postmenopausal patients. The premenopausal trial has not demonstrated any significant differences between the regimens for either relapse-free or overall survival. The relapse-free survival in the postmenopausal trial has demonstrated a trend for CMFPT over observation (P = .07). Both CMFP and CMFPT are associated with an improved relapse-free survival over observation alone in ER-negative patients (P = .01) and in progesterone receptor-negative patients (P = .01). However, the relapse-free survival advantages have not translated to survival. Side effects were significantly increased with the addition of P to CMF in the premenopausal trial. The addition of T to CMFP was associated with an increased incidence of edema and hot flashes in premenopausal patients; however, the latter was decreased in postmenopausal patients relative to CMFP.(ABSTRACT TRUNCATED AT 250 WORDS)

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[Treatment of post kidney transplantation erythrocytosis (PTE) with ACE inhibitors].

Post kidney transplantation erythrocytosis is a frequent complication in male subjects. In our experience, it occurs in approximately 20% of transplant patients receiving cyclosporine immunosuppression therapy. Twenty-two patients with post kidney transplantation erythrocytosis were treated using ACE-inhibitors (lisinopril) at a dose of 2-5-5 mg/day for a mean period of 15 months. Owing to the onset of collateral effects, 27% of these patients requested the conversion of ACE into angiotensin II receptor antagonists (AII). Twenty out of 22 patients were male (90%). Treatment resulted in a 15% reduction of hematocrit values compared to basal levels, which remained stable over time. No collateral effects were recorded, either for the kidneys or in terms of hypotension. ACE-inhibitors (lisinopril) or alternatively the use of angiotensin II receptor antagonists, like Losartan, at low doses, is an effective and safe treatment for patients developing post-transplantation erythrocytosis (PTE).

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Mycophenolate mofetil treatment for therapy-resistant glomerulopathies.

The management of steroid-resistant glomerulopathies remains a clinical problem. In this trial, we report a clinical observation of 43 patients treated with mycophenolate mofetil (MMF) for steroid-resistant glomerulopathies. All patients underwent renal biopsies, and immunofluorescence and light microscopy examinations were conducted in all cases. All patients had been treated with prednisone at a dose of 1 mg/kg per day for at least 8 weeks. Of the 43 patients, 16 were treated with cyclophosphamide and five were treated with cyclosporine A before MMF started. The primary study outcomes were the change in the urinary protein excretion, serum creatinine, comparing the levels at the start of MMF treatment with those at the end of the MMF treatment period. Changes in renal function were also estimated with Modification of Diet in Renal Failure calculation. Wilcoxon signed-ranks test was used as appropriate to compare data from the start with data at the end of the treatment period. The primary glomerular diseases represented included membranoproliferative glomerulonephritis in 23.2%, membranous glomerulonephritis in 18.6%, IgA nephropathy in 13.9%, focal segmental glomerulosclerosis in 9.3%, lupus nephritis (systemic lupus erythematosus) in 25.6% and pauci-immune glomerulopathy in 9.3% of patients. The mean follow-up time was 28.9+/-12 months. Before MMF treatment, 16 patients (37%) had nephrotic range proteinuria and 11 (26%) had renal insufficiency. The urinary protein before MMF treatment was 3.3+/-2.6 g/dL (0.6-9.6) and decreased significantly to 0.87+/-1.1 g/dL (0-5.5) at the end of the MMF treatment period (P=0.02). During treatment, complete remission was seen in 27 patients, partial remission in 10 patients and MMF failure in six patients. The serum creatinine level decreased significantly from 1.29+/-0.55 mg/dL (0.6-3.0) to 1.14+/-0.38 mg/dL (0.5-2.4) post MMF therapy (P=0.046). Using the four-variable Modification of Diet in Renal Failure formula, the glomerular filtration rate increased from 71.5+/-28 mL/min per 1.73 m2 to 78.1+/-27 mL/min per 1.73 m2 (P=0.021). Renal insufficiency resolved in seven of the 11 (63.6%) patients with renal insufficiency initially, two with membranoproliferative glomerulonephritis, two with membranous glomerulonephritis, one with focal segmental glomerulosclerosis, four with pauci-immune glomerulopathy, two with systemic lupus erythematosus nephritis, and in two patients de novo renal insufficiency developed. In general, MMF was well tolerated, and most of the patients achieved remission and improvement of renal functions. MMF treatment appeared to offer benefits to problematic patients refractory to conventional therapies for glomerulopathies.

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Prolongation of near-normoglycemic remission in black NIDDM subjects with chronic low-dose sulfonylurea treatment.

Microvascular and neuropathic complications of diabetes mellitus can be significantly decreased by long-term, near-normoglycemic regulation in patients with insulin-dependent diabetes mellitus. Prevention or delay of onset of hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) patients should reduce morbidity and mortality from these complications. NIDDM can be nearly normoglycemic when diagnosed by screening before its symptomatic stage or when clinically hyperglycemic NIDDM goes into remission. One potential strategy to delay the onset of hyperglycemia in individuals at high risk is chronic low-dose sulfonylurea therapy. Thirty black NIDDM subjects who recently had developed near-normoglycemia were followed with no treatment or were randomly assigned to a 3-year, double-blind glipizide or placebo treatment. Baseline and follow-up parameters included fasting plasma glucose (FPG), HbA1c, plasma insulin, and glucose responses to an oral glucose tolerance test and insulin action, as determined by the euglycemic insulin clamp. Baseline FPG and HbA1c for all three groups were 107 mg/dl and 4.7%, respectively. Relapse to hyperglycemia was defined as an FPG level > or = 140 mg/dl on several consecutive visits or an FPG level > or = 140 mg/dl and symptoms of hyperglycemia. During the course of the treatment and follow-up, hyperglycemia occurred in 6 of 10 subjects in the no treatment group, 6 of 10 in the placebo group, and 2 of 10 in the glipizide treatment group. Prolongation of near-normoglycemia was significantly (P < 0.05) increased by low-dose (2.5 mg/day) glipizide compared with placebo treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

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Clopidogrel response: head-to-head comparison of different platelet assays to identify clopidogrel non responder patients after coronary stenting.

We investigated the agreement between different platelet tests to identify clopidogrel non response. Biological definition of clopidogrel non response remains controversial. Different platelet tests have been linked with recurrent ischemic events and proposed for daily practice. We prospectively investigated the agreement of platelet tests to isolate clopidogrel non response in patients receiving high 150 mg clopidogrel maintenance dose after coronary stenting. Clopidogrel response was assessed with ADP-induced aggregation (ADP-Ag) (non response if >70%), Platelet reactivity index VASP (PRI VASP) (non response if >50%) and Verify Now Point-of-care assay (VN) (non response if PRU > 240 AU). Seventy consecutive patients were included. The rates of non-responders were respectively: 13% (n = 9) with the ADP-Ag, 39% (n = 27) with the PRI VASP and 33% (n = 23) with the VN. We observed significant correlation between different platelet tests assessing clopidogrel response: r = 0.55 (p < 0.0001) for ADP-Ag and PRI VASP, r = 0.64 (p < 0.0001) for ADP-Ag and VN and r = 0.59 (p < 0.0001) for PRI VASP and VN. However, using the most common thresholds, the agreement between the difference tests was poor: 0.35 for ADP-Ag and PRI VASP, 0.36 for ADP-Ag and VN and 0.46 for PRI VASP and VN. This study showed that assessment of platelet function inhibition by clopidogrel is highly test-specific. Indeed, our results demonstrated a poor agreement between different platelet assays and suggested that identification of clopidogrel non responders is test-dependent.

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Effects of frusemide and hypoxia on the pulmonary vascular bed in man.

Diuretic therapy is conventionally used to treat oedema in patients with hypoxic cor pulmonale. This condition is associated with activation of the renin angiotensin system (RAS) with elevated levels of angiotensin II (ANG II), a potent pulmonary pressor agent. We explored the hypothesis that RAS activation by diuretic therapy might therefore worsen hypoxic pulmonary vasoconstriction via the effects of ANG II on the pulmonary vascular bed. Eight normal volunteers were studied on 2 separate days. They either received 40 mg frusemide daily or placebo for 4 days and were then rendered hypoxaemic, by breathing an N2/O2 mixture for 20 min to achieve an SaO2 of 85-90% adjusted for a further 20 min to achieve an SaO2 of 75-80%. Pulsed wave doppler echocardiography was used to measure mean pulmonary artery pressure, cardiac output and hence pulmonary vascular resistance (PVR). Plasma renin activity (PRA) was significantly (P < 0.01) increased after prior treatment with frusemide compared with placebo at all time points. Prior treatment with frusemide significantly (P < 0.05) increased PVR compared with placebo at baseline: 185 +/- 17 vs 132 +/- 10 dyn s cm-5 at an SaO2 of 85-90%: 291 +/- 18 vs 229 +/- 16 dyn s cm-5 and at SaO2 of 75-80%: 356 +/- 12 vs 296 +/- 17 dyn s cm-5 respectively. However, the delta-PVR response to hypoxaemia was not significantly altered by frusemide compared with placebo. In contrast to its effect on the pulmonary vasculature prior treatment with frusemide did not significantly alter systemic haemodynamic parameters either at baseline or during hypoxia. Thus, prior treatment with frusemide increased baseline pulmonary vascular resistance and significantly augmented the hypoxaemic pulmonary vascular response in additive fashion. It is hypothesised that this effect of frusemide may be due to RAS activation with ANG II mediated pulmonary vasoconstriction.

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Quality of gastric ulcer healing evaluated by endoscopic ultrasonography.

To evaluate the quality of gastric ulcer healing after different antiulcer treatment by endoscopic ultrasonography (EUS). The patients were divided into three groups, and received lansoprazole, amoxicillin and clarithromycin for 1 wk. Then group A took lansoprazole combined with tepreton for 5 wk, group B took lansoprazole and group C took tepreton for 5 wk. Endoscopy and EUS were performed before and 6 wk after medication. There was no significant difference in cumulative healing rate to S stage between the groups (89%, 82% vs 83%, P>0.05). The rate of white scar formation was significantly higher in group A than in groups B and C (67%, 36%, 50%, P<0.05). The average contraction rates of the width of ulcer crater, length of disrupted muscularis propria layer and hypoechoic area were higher in group A than in groups B and C (0.792+/-0.090, 0.660+/-0.105 vs 0.668+/-0.143, P<0.05). The hypoechoic area disappeared in four cases of group A, one of group B and two of group C. The percentage of hypoechoic area disappearance was higher in group A than in the other two groups (44%, 9% vs 17%, P<0.05). Gastric ulcer healing was better in group A. The combined administration of proton-pump inhibitors and mucosal protective agent can improve gastric ulcer healing.

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The impact of smoking cessation on objective and subjective markers of sleep: review, synthesis, and recommendations.

Sleep disturbance is commonly reported as a prominent subjective symptom by quitting smokers. However, little research on this issue has used objective measures of sleep quality. Previous research has relied mainly on retrospective report of sleep disturbance, with few studies investigating sleep during the initial period after quitting tobacco use. Studies that have used objective measurements suggest that sleep fragmentation is a common occurrence during the withdrawal period. In sleep medicine, sleep disturbance is viewed as a consequence of frequent arousals and is now considered to have particularly deleterious daytime consequences, including sleepiness and dysphoric mood. Recent work also indicates that such awakenings affect the cardiovascular system by providing repetitive bursts of sympathetic nervous system activation, possibly contributing to elevated levels of cardiovascular and cerebrovascular morbidity. Pharmacological treatments designed to facilitate smoking cessation are ineffective for sustained abstinence in many smokers, which may be related to sleep disturbance. Indeed, preliminary evidence suggests that the administration of nicotine replacement therapy (NRT) or bupropion can result in disrupted sleep, particularly in women. However, to better understand the role that nicotine withdrawal and bupropion or NRT treatment, independently and in combination, might play in sleep disturbance, it is necessary to develop a better understanding of the nature of the sleep disturbance than can be provided by self-report. This is particularly important for the development of treatment approaches targeted to ameliorate sleep disruption as part of an overall smoking cessation strategy. The present review seeks to report the current state of knowledge based on extant findings and argues for the need to conduct more detailed polysomnographic investigations of the potentially vicious cycle of smoking cessation leading to sleep disturbances that may prove iatrogenic to sustained cessation.

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[Second malignancies following Hodgkin's disease treatment in Tunisia. Retrospective study of 26 cases observed at the institute Salah-Azaïz].

To collect second cancers in patients treated for Hodgkin disease (HD) during adolescence and young adulthood at Salah Azaïz Institute of Tunis. We consider as second cancer all tumours other than HD observed in patients after treatment for HD. Twenty-five patients among 614 treated for HD between 1975 and 1991 developed 26 secondary tumours (4.2%). There were 17 males and eight females (sex ratio 2:1). Mean age at the diagnosis of HD was 32.5 years (12-56). HD was stage II (eight cases), stage III (14) and stage IV in three. The first treatment was combined chemotherapy and radiotherapy in 22 cases and only chemotherapy in three cases (stage IV). Radiotherapy was delivered with Cobalt 60 by large fields. Mean dose was 41.3 Gy (2 Gy/fraction in 21 and 3.3 in one). Chemotherapy was MOPP (13), MOPP and vinblastine (four), MOPP-ABVD (five), ABVD (two) and vinblastine only in one. Mean delay of second tumours was 114.5 months (40-276). There was five acute myeloid leukaemia, two digestive non-Hodgkin lymphomas, five nodal high-grade lymphomas, three breast cancers (one in man associated with thyroid cancer), five lung cancers (three non-small cell and two of small cell type), two gastric tumours and one rectal cancer, one synovialosarcoma of the knee and one malignant Schwannoma of the neck. Median survival was 12.5 months (2-48). Twenty-one patients died and four are still alive with 8, 12, 24 and 48 months of follow-up. Second cancer risk after treatment for HD is not low. Risk factors and preventive strategies are discussed.

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Efficacy of gabapentin in the treatment of SUNCT syndrome.

This study was designed to evaluate the efficacy of gabapentin (GBP) in the treatment of SUNCT syndrome on a relatively large sample of Persian patients. Eight patients with SUNCT syndrome underwent a 4-week, open-label, daily treatment of 600-900 mg GBP. The frequency, intensity and duration of attacks were compared before and after the trial. After 4 weeks of treatment, intensity, duration and frequency of headaches were significantly (P < 0.05) reduced. In addition, five patients (62.5%) were completely relieved from headaches, and in the other three patients the mean intensity, frequency and duration of headaches were decreased notably. In this study, GBP was well tolerated and no unfavourable side-effects were reported. After the end of the trial all patients continued the medication, and after 3 months none reported undesired side-effects or return of the headaches to the pre-treatment status. Our patients had a significant response to GBP, and considering other case reports on the effectiveness of GBP in the treatment of SUNCT syndrome, we propose that, taking into account the good side-effect profile and lack of interactions of GBP, this drug could be considered as an option for the treatment of SUNCT.

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Changes in use of valproate and other mood stabilizers for patients with schizophrenia from 1994 to 1998.

The study describes changes over time in the adjunctive use of valproate and other mood stabilizers-lithium, carbamazepine, and gabapentin--among hospitalized psychiatric patients with a diagnosis of schizophrenia. For each calendar year from 1994 through 1998, data were drawn from a database containing clinical and drug prescription information for every inpatient in the adult civil facilities of the New York State Office of Mental Health. In 1994 a total of 26.2 percent of inpatients diagnosed as having schizophrenia received a mood stabilizer, compared with 43.4 percent in 1998. In 1994 lithium was the most commonly prescribed mood stabilizer, for 13.2 percent of patients, followed by valproate, for 12.3 percent. In 1998 valproate was the most commonly prescribed, for 35 percent of patients, followed by lithium, for 11.3 percent. On average, patients received valproate for about two-thirds of their hospital stay, at a mean dose of 1,520 mg per day. The adjunctive use of valproate nearly tripled from 1994 to 1998 among patients with a diagnosis of schizophrenia. Valproate has become the most commonly prescribed mood stabilizer for this population, despite the paucity of evidence in the literature for efficacy in this use. Controlled clinical trials are needed to examine the adjunctive use of mood stabilizers, in particular valproate, among patients with schizophrenia.

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Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate.

The objective of this study was to compare the efficacy of a combination of allopurinol (AL) and low-dose meglumine antimoniate (MA) with standard-dose MA in cutaneous leishmaniasis caused by Leishmania major. An open, controlled study was performed. Seventy-two patients were randomly selected from volunteers with cutaneous leishmaniasis living in a hyperendemic area. Exclusion criteria included pregnancy, nursing vs. gestation, age less than 5 years, and duration of disease of more than 4 months. Each patient received MA (60 mg/kg/day) or AL (20 mg/kg/day) plus low-dose MA (30 mg/kg/day) for 20 days, and was followed up for 30 days after cessation of treatment. The study was completed as planned in 66 patients. Complete healing occurred in 74.2% of patients in the MA group and in 80.6% of patients in the MA + AL group. No difference was found between the two groups with respect to side-effects. The combination of AL and MA increases the anti-leishmanial effects of antimoniate. In this study, it was confirmed that low-dose MA plus AL is as effective as high-dose MA in the treatment of cutaneous leishmaniasis caused by L. major.

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Vasculitis of the gastrointestinal tract in chronic periaortitis.

The term "chronic periaortitis" (CP), proposed by Mitchinson in 1984, comprises 3 main entities: idiopathic retroperitoneal fibrosis (IRF), inflammatory abdominal aortic aneurysms (IAAAs), and perianeurysmal retroperitoneal fibrosis (PRF).The presence of constitutional symptoms, high acute-phase reactants, positive autoantibodies, and associated autoimmune diseases suggests a systemic inflammatory process. Histopathologic findings show vasculitis with fibrinoid necrosis involving the aortic vasa vasorum as well as the small and medium retroperitoneal vessels.We reviewed the medical records of 608 patients with a diagnosis of vasculitis involving the gastrointestinal (GI) tract at the Mayo Clinic between January 1996 and December 2007. Only patients with biopsy-proven or typical angiographic findings of vasculitis localized to the GI tract were included.Five patients were identified with evidence of CP (1 patient with PRF, 1 with IRF, and 3 with IAAAs). Three patients were men, and the median age at diagnosis was 49 years. The diagnosis of GI vasculitis and CP was made simultaneously in 4 patients. At the time of onset, all patients had abdominal pain and constitutional manifestations; the median erythrocyte sedimentation rate was 62.5 mm/1 h (range, 20-86 mm/1 h). All patients had evidence of mesenteric vasculitis at angiography. Three patients also had associated renal artery stenoses. Abdominal computed tomography showed spleen infarcts in 2 patients, bowel wall thickening in 1, and liver infarction in 1. Two patients underwent surgical intervention for acute abdomen; there was histologic evidence of small bowel infarcts and infarction of the spleen and liver in 1. Oral prednisone was administered to all 5 patients (median starting dose, 60 mg/d; range, 25-80 mg/d). Three patients also received immunosuppressive agents, 1 tamoxifen, and 1 anti-tumor necrosis factor therapy. All patients had at least 1 relapse or recurrence of vasculitis, but at last visit, GI vasculitis and CP were in remission in all 5 patients.This study provides evidence that GI manifestations due to mesenteric vasculitis may be associated with CP. Vasculitic involvement of the renal arteries is also frequently present in these patients. Aggressive immunosuppressive treatment should be promptly initiated to forestall abdominal complications. These findings reinforce the hypothesis that a vasculitic process plays an important role in the pathogenesis of CP.

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Use of prazosin in management of hypertension in patients with chronic renal failure and in renal transplant recipients.

Prazosin was used in combination with other antihypertensive drugs in the successful management of hypertension in seven patients with chronic renal failure and six renal transplant recipients, also with chronic renal failure. The addition of small doses of prazosin (mean 3 mg/day) to the antihypertensive regimen produced significant falls in systolic and diastolic blood pressures in both the lying and standing positions. The standing blood pressures were significantly lower than the lying blood pressures during prazosin treatment. Neither the mean blood urea concentrations nor the mean plasma creatinine concentrations changed significantly during prazosin administration. Chromium-51 edetic acid clearances did not change significantly during prazosin treatment in the seven patients in whom it was measured. Severe symptomatic postural hypotension occurred in one patient a week after starting prazosin 3 mg/day. This hypotensive episode was associated with a transient and reversible deterioration in renal function. Another patient developed a rash while on prazosin but it was probably related to propranolol rather than prazosin. Prazosin is thus an effective antihypertensive drug in patients with chronic renal failure, and it may be used with a variety of other drugs. It should be used cautiously, however, since patients with chronic renal failure may respond to small doses, and significant postural falls in blood pressure may result. There was no evidence that the use of prazosin resulted in progressive deterioration in the residual renal function of the patients with chronic renal failure.

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Addition of metronidazole to omeprazole/amoxycillin dual therapy increases the rate of Helicobacter pylori eradication: a double-blind, randomized trial.

To compare the efficacy, safety and tolerability of an omeprazole/amoxycillin (OA) dual therapy Helicobacter pylori eradication regimen with an omeprazole/amoxycillin/metronidazole (OAM) triple therapy regimen. In this double-blind trial, conducted in 19 hospitals, 119 patients with symptomatic duodenal ulcer disease were randomized to receive either 14 days treatment with omeprazole 40 mg daily, amoxycillin 500 mg t.d.s. and placebo followed by a further 14 days' treatment with omeprazole 20 mg daily (n = 59) or 14 days treatment with omeprazole 40 mg daily, amoxycillin 500 mg t.d.s., and metronidazole 400 mg t.d.s., followed by a further 14 days' treatment with omeprazole 20 mg daily (n = 60). H. pylori status was assessed by 13C-urea breath test at entry and at 4 weeks post-treatment. H. pylori infection was eradicated in 46% of the OA treated patients and in 92% of the OAM treated patients, a mean difference of 46% (P < 0.0001, 95% CI for the difference: +30 to +62). In only one patient was the duodenal ulcer not endoscopically healed after 4 weeks of treatment (OA 100%; OAM 98% healed). There were no significant differences in speed of symptom relief or improvement in symptoms between the two groups. Both regimens were well tolerated, with 96% of patients completing the course, and only one patient withdrawing due to an adverse event. The only side-effect with a significantly higher incidence in the OAM group was diarrhoea, which occurred in 36% of patients compared to 16% of patients in the OA group (P < 0.05). A regimen consisting of omeprazole 40 mg daily, amoxycillin 500 mg t.d.s. and metronidazole 400 mg t.d.s. for 14 days gives an appreciably higher H. pylori eradication rate than omeprazole and amoxycillin alone, with acceptable tolerability.

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[Primary non-Hodgkin's lymphoma of the nasal cavity at early stage: long-term treatment outcomes and prognostic analyses of 108 cases].

Primary non-Hodgkin's lymphoma (NHL) of the nasal cavity has unique clinicopathologic features, and optimal treatment regimen remains unclear. This study was to summarize the clinical features, treatment outcomes, and prognostic factors of primary NHL of the nasal cavity at early stage. Records of 108 patients with primary NHL of the nasal cavity, consecutively treated at Cancer Center, Sun Yat-sen University from Jun. 1990 to Sep. 2004, were reviewed. All diagnoses were confirmed with pathology and immunochemistry. Seven cases were of B-cell phenotype. Survival prognostic factors were analyzed by Kaplan-Meier method and Cox regression model with SPSS12.0 software. Median follow-up time for survived patients was 41 months. The overall complete remission (CR) rate after primary treatment was 67.6%, and CR rates were 80.2% for the patients received radiochemotherapy and 29.6% for the patients received chemotherapy alone. There were evidences indicating systemic relapse in 33 (30.6%) patients. With regard to the control of local, regional, and systemic failure, radiochemotherapy was better than chemotherapy alone. The 5-year overall survival rate was 50.0% for all patients. Both univariate analysis and multivariate analysis showed that pre-treatment history of more than 3 months, primary lesion limited in the nasal cavity, CR after primary treatment, and radiochemotherapy were favorable prognostic factors. Nasal cavity is frequently involved by peripheral T- and NK-cell lymphomas. Pre-treatment history of disease, extent of primary lesion involvement, and response to the primary treatment may be independent prognostic factors.

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Diffuse biliary tract injury after orthotopic liver transplantation.

An unusual type of diffuse biliary tract injury after liver transplantation that is characterized by multiple intrahepatic biliary strictures, ductal dilatations, fluid collections, or intrahepatic abscesses has been identified. Over a 5-year period, a total of 10 patients (2%) developed diffuse intrahepatic biliary injury with established vascular patency and no obvious source for their biliary tract pathology. All patients received livers preserved in University of Wisconsin solution with a mean preservation time of 16 hours. This biliary tract injury was associated with the presence of severe preservation injury and Roux limb biliary reconstruction. Of the 10 patients, 5 were treated nonoperatively with multiple stricture dilations and stent placements, 3 underwent retransplantation, 1 was treated operatively with hepaticojejunostomy, and 1 died of sepsis. This study suggests that this complication appears to be related to preservation injury and that the etiology may be ischemic in origin.

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Quinapril versus lisinopril in the treatment of essential hypertension in elderly patients with low blood renin.

The aim of the study was to evaluate efficacy and tolerability of quinapril 20 mg once-a-day versus lisinopril 20 mg, in the treatment of old patients suffering from essential mild or moderate hypertension and presenting low levels of plasmarenin. It was a cross-over study with open treatments randomly assigned. Ten patients were treated, 6 females and 4 males, with average age of 67.1 years +/- 7.1. Two wash-out periods with placebo were scheduled, each lasting one week before the onset of active therapy; each treatment period lasted 21 days. Blood pressure controls (including the 24 hours monitoring) were done at basal time, after seven days and at the end of each treatment. Results show the efficacy and the safety of both the drugs and a more effective and constant control of hypertension by Quinapril was confirmed.

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Somatostatin and D cells in patients with gastritis in the course of Helicobacter pylori eradication: a six-month, follow-up study.

As well as causing chronic gastritis, Helicobacter pylori predisposes patients to peptic ulcer disease and gastric cancer, and induces gastric functional disorders. The aim of our study was to investigate the effects of H. pylori eradication therapy on the morphological and functional recovery of gastric antral and corpus D cells in patients with chronic gastritis during 6 months of follow-up. Forty consecutive, dyspeptic patients referred for endoscopy (31 with H. pylori infection and nine controls; mean age 49 years; 17 men, 23 women) entered the study. All patients had histological signs of gastritis but no signs of peptic ulcer or gastric cancer. Antrum (n=8) and corpus (n=6) biopsy specimens were collected for routine histology, radioimmunoassay tissue somatostatin levels, immunohistochemistry and electron microscopy, prior to and 6 months after therapy. Basal plasma somatostatin levels were determined prior to eradication, plus 6 weeks and 6 months after therapy. Eradication therapy consisted of amoxicillin, metronidazole and omeprazole. Basal somatostatin plasma values in antral and corpus tissue were lower in infected patients than in the H. pylori-negative controls at the beginning of the study. A significant increase occurred after successful eradication therapy, together with an increase in the number of D cells in both regions. Changes in the D-cell ultrastructure in antral and corpus mucosa after eradication therapy suggest an increase in somatostatin synthesis and secretion. The structural and functional restoration of D cells following eradication therapy indicates possible recovery of the diseased mucosa.

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Ambulatory consolidation chemotherapy for acute myeloid leukemia with antibacterial prophylaxis is associated with frequent bacteremia and the emergence of fluoroquinolone resistant E. Coli.

Ambulatory consolidation chemotherapy for acute myeloid leukemia (AML) is frequently associated with bloodstream infections but the spectrum of bacterial pathogens in this setting has not been well-described. We evaluated the emergence of bacteremias and their respective antibiotic susceptibility patterns in AML patients receiving ambulatory-based consolidation therapy. Following achievement of complete remission, 207 patients received the first cycle (C1), and 195 the second cycle (C2), of consolidation on an ambulatory basis. Antimicrobial prophylaxis consisted of ciprofloxacin, amoxicillin and fluconazole. There were significantly more positive blood cultures for E. coli in C2 as compared to C1 (10 vs. 1, p=0.0045); all E. coli strains for which susceptibility testing was performed demonstrated resistance to ciprofloxacin. In patients under age 60 there was a significantly higher rate of Streptococccus spp. bacteremia in C2 vs. C1; despite amoxicillin prophylaxis all Streptococcus isolates in C2 were sensitive to penicillin. Patients with Staphylococcus bacteremia in C1 had significantly higher rates of Staphylococcus bacteremia in C2 (p=0.009, OR=8.6). For AML patients undergoing outpatient-based intensive consolidation chemotherapy with antibiotic prophylaxis, the second cycle is associated with higher rates of ciprofloxacin resistant E. coli, penicillin-sensitive Streptococcus bacteremias and recurrent Staphylococcus infections.

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NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland.

To evaluate the risk of first myocardial infarction (MI) associated with the use of various non-steroidal anti-inflammatory drugs (NSAIDs) in the general population. We conducted a population-based matched case-control study over the years 2000-3 in outpatient residents of Finland. In the nationwide Hospital Discharge Register 33 309 persons with first time MI were identified. A total of 138 949 controls individually matched for age, gender, hospital catchment area, and index day were selected from the Population Register. For combined NSAIDs, the adjusted odds ratio for the risk of first MI with current use was 1.40 (95% CI, 1.33-1.48). The risk was similar for conventional (1.34; 1.26-1.43), semi-selective (etodolac, nabumetone, nimesulide, and meloxicam) (1.50; 1.32-1.71), and cyclo-oxygenase-2 (COX-2) selective NSAIDs (rofecoxib, celecoxib, valdecoxib, and etoricoxib) (1.31; 1.13-1.50). Age of current user did not consistently modify the risk. No NSAID was associated with an MI-protective effect. All durations from 1 to 180 days of conventional NSAIDs and from 31 to 90 days duration of COX-2 selective NSAIDs were associated with an elevated risk of MI. Current use of all NSAIDs is associated with a modest risk of first time MI.

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Individual sulfonylureas and serious hypoglycemia in older people.

To compare the risk of serious hypoglycemia associated with the use of individual sulfonylureas in older people. A retrospective cohort study. The Tennessee Medicaid Program. A total of 13,963 Medicaid enrollees, aged 65 years or older, who were prescribed one of six sulfonylureas from 1985 to 1989. Hospitalization, emergency room admission, or death associated with neuroglycopenic or autonomic symptoms, myocardial infarction, stroke, or injury, with a concomitant blood glucose determination of less than 2.8 mmol/L (50 mg/dL). We identified 255 persons with a first episode of serious hypoglycemia during 20,715 person-years of sulfonylurea use. The crude rate (per 1000 person-years) of serious hypoglycemia was highest in glyburide users, 16.6 (95% confidence interval [CI], 13.2 to 19.9 and lowest among users of tolbutamide, 3.5 (95% CI, 1.2 to 5.9). Users of tolbutamide, tolazamide, and glipizide had lower risks of serious hypoglycemia than users of chlorpropamide, whereas the risk of serious hypoglycemia among glyburide users did not differ from that of chlorpropamide users. Among second generation sulfonylureas, the adjusted relative risk of severe hypoglycemia among glyburide users, compared with glipizide users, was 1.9 (95% CI, 1.2 to 2.9). An increased risk of serious hypoglycemia associated with use of glyburide compared with glipizide occurred in all strata, including those defined by gender, race, nursing home residence, dose, and duration of use. Significant differences in risk of serious hypoglycemia were observed among users of individual agents. This may be explained by duration, timing, or potency of hypoglycemic action. These data confirm previous findings that chlorpropamide use is associated with high risk of hypoglycemia and indicate that among second generation sulfonylureas, glipizide is less associated with hypoglycemia than is glyburide. More information comparing the effectiveness of glycemic control among individual sulfonylureas is needed to assist prescribers in selecting a specific agent for use in clinical practice.

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Effect of metformin pretreatment on pregnancy outcome of in vitro matured oocytes retrieved from women with polycystic ovary syndrome.

To determine the effect of metformin pretreatment on in vitro maturation (IVM) in the patients with clomiphene citrate-resistant polycystic ovary syndrome. Prospective randomized study. University affiliated hospital. Fifty-six women with clomiphene citrate-resistant polycystic ovary syndrome underwent 70 cycles of IVM treatment. Metformin was administered at a dose of 500 mg twice per day for 12 weeks before IVM treatment. The number of immature oocytes, oocyte maturation, fertilization, cleavage, high-quality embryo, and clinical pregnancy rates. A significantly higher high-quality embryo rate (37.8%) was obtained in the metformin-treated group compared with the control group (24.3%). Accordingly, the clinical pregnancy and implantation rates were significantly higher in the metformin-treated group (38.2% and 15.3%) than the control group (16.7% and 6.2%). Pretreatment with metformin improves IVM outcome in terms of embryo quality and clinical pregnancy rate as well as implantation rate.

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Stress Hyperglycemia and Prognosis of Minor Ischemic Stroke and Transient Ischemic Attack: The CHANCE Study (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events).

We aimed to determine the association between stress hyperglycemia and risk of new stroke in patients with a minor ischemic stroke or transient ischemic attack. A subgroup of 3026 consecutive patients from 73 prespecified sites of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) were analyzed. Stress hyperglycemia was measured by glucose/glycated albumin (GA) ratio. Glucose/GA ratio was calculated by fasting plasma glucose divided by GA and categorized into 4 even groups according to the quartiles. The primary outcome was a new stroke (ischemic or hemorrhagic) at 90 days. We assessed the association between glucose/GA ratio and risk of stroke by multivariable Cox regression models adjusted for potential covariates. Among 3026 patients included, a total of 299 (9.9%) new stroke occurred at 3 months. Compared with patients with the lowest quartile, patients with the highest quartile of glucose/GA ratio was associated with an increased risk of stroke at 3 months after adjusted for potential covariates (12.0% versus 9.2%; adjusted hazard ratio, 1.46; 95% confidence interval, 1.06-2.01). Similar results were observed after further adjusted for fasting plasma glucose. We also observed that higher level of glucose/GA ratio was associated with an increased risk of stroke with a threshold of 0.29 using a Cox regression model with restricted cubic spline. Stress hyperglycemia, measured by glucose/GA ratio, was associated with an increased risk of stroke in patients with a minor ischemic stroke or transient ischemic attack. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

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Prospective comparison of periprocedural coagulation markers among uninterrupted anticoagulants for atrial fibrillation ablation.

The difference in coagulation state during the periprocedural period of atrial fibrillation (AF) ablation among patients with uninterrupted anticoagulation has not been fully elucidated. The purpose of this study was to compare periprocedural trends in coagulation markers among patients on uninterrupted anticoagulation for AF ablation. In total, 275 consecutive patients who underwent AF ablation were evaluated. These patients were divided according to the anticoagulant they received into the dabigatran group (DG) (n = 64); rivaroxaban group (RG) (n = 62); apixaban group (AG) (n = 60); edoxaban group (EG) (n = 59); and warfarin group (WG) (n = 30). The trends in coagulation markers and the rate of silent stroke (SS) confirmed by postoperative magnetic resonance imaging were evaluated. The fibrin monomer complex (FMC) level on postoperative day 1 and the prothrombin fragment 1+2 (PF1+2) levels on the operative day and postoperative day 1 were higher in DG than in the other groups (P <.05, <.001, and <.001, respectively). The incidence of SS in DG (17%) was significantly higher than in RG (6%), AG (3%, EG (7%), or WG (4%) (P <.05). Dabigatran use independently predicted the occurrence of SS (odds ratio 4.12; 95% confidence interval 1.37-12.7; P <.05). FMC and PF1+2 levels during the periprocedural period of AF ablation were higher in DG than in the other groups. Dabigatran use independently predicted the occurrence of SS.

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