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Treatment failure of vaginal trichomoniasis in clinical practice.

We have conducted a retrospective study of treatment failure of Trichomonas vaginalis (TV) infection in a busy, urban genitourinary medicine clinic in Birmingham, UK, between 1998 and 2002. The prevalence of non-response to standard doses of metronidazole without any history of reinfection or nonadherence was 1.7% (28/1603) overall, and has significantly increased from 0.38% in 1999 to 3.5% in 2002 (P = 0.001, chi2 test). There were no associated demographic factors. The majority of patients (53% or 15/28) responded to either a repeat of standard (10/26) or higher oral dose (5/7) of metronidazole. A standardized treatment algorithm using a high dose of metronidazole may be useful in the absence of any new, efficacious non-imidazole-based TV therapy in the clinical management of persistent TV infection.

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The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment.

To demonstrate the result of watchful waiting without specific therapy in unselected children with acute immune thrombocytopenic purpura (ITP). Between May 1992 and October 1999, 55 consecutive children (aged 2 months to 16 years; 28 boys and 27 girls) with acute ITP did not receive intravenously administered immune globulin G (IVIG) or sustained prednisone treatment. Patients with extensive mucosal bleeding were given prednisone, 2 mg/kg/d, for 3 days. In 37 of 55 patients the initial platelet count was <10,000/microL. Ten of these patients had active mucosal bleeding. Five additional patients with bleeding had platelet counts between 10,000 and 20,000/microL. Four patients were given a 3-day course of prednisone. Chronic ITP occurred in 7 (13%) of the patients; 29 patients achieved remission within 6 weeks, and 19 patients, between 6 weeks and 6 months. No life-threatening bleeding occurred, and no patient died. Most children with severe thrombocytopenia do not have active mucosal bleeding. This management approach, which did not administer specific therapy, avoided side effects, reduced cost, and was effective.

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Tolerability of high doses of lercanidipine versus high doses of other dihydropyridines in daily clinical practice: the TOLERANCE Study.

The TOLERANCE study was aimed to compare the tolerability of high doses of lercanidipine (20 mg) with that of other frequently used dihydropyridines (amlodipine 10 mg/nifedipine GITS 60 mg) in the treatment of essential hypertension in daily clinical practice. It was an observational, transversal, multicentre study performed in a Primary Care Setting. A total of 650 evaluable patients with essential hypertension and age > or = 18 years were included. They had been treated with high doses of lercanidipine (n= 446) or amlodipine/nifedipine GITS (n= 204) during at least 1 month and previously with low doses (10 mg, 5 mg, and 30 mg, respectively) of the same drugs. The main objective was to compare the rates of vasodilation-related adverse events between both groups. Rates of signs and symptoms related to vasodilation were significantly higher (P < 0.001) in the amlodipine/nifedipine GITS group (76.8%, CI 95%[70.7; 82.9]) than in lercanidipine group (60.8%, [56.1;65.5]). Blood pressure control (< 140/90 mmHg or <130/80 for diabetics) and type of concomitant antihypertensive medications were similar in both groups. Treatment compliance was good (around 93%) and fairly comparable in both groups. Most adverse events with lercanidipine were mild (74.5% vs. 64% in amlodipine/nifedipine GITS group, P= 0.035) whereas severe adverse event rates did not differ significantly between groups (2.8% vs. 3.6%). In conclusion, treatment with lercanidipine at high doses is associated with a lower rate of adverse events related to vasodilation compared to high doses of amlodipine or nifedipine GITS in clinical practice.

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Efficacy of omeprazole, famotidine, mosapride and teprenone in patients with upper gastrointestinal symptoms: an omeprazole-controlled randomized study (J-FOCUS).

In Japan, treatment guidelines are lacking for patients with upper gastrointestinal symptoms. We aimed to compare the efficacy of different drugs for the treatment of uninvestigated upper gastrointestinal symptoms. This was a randomized, open-label, parallel-group multicenter study. Helicobacter pylori-negative, endoscopically uninvestigated patients ≥ 20 years of age with upper gastrointestinal symptoms of at least moderate severity (Global Overall Symptom score [GOS] ≥ 4 on a 7-point Likert scale) were randomized to treatment with omeprazole (10 mg once daily), famotidine (10 mg twice daily), mosapride (5 mg three times daily) or teprenone (50 mg three times daily). The primary endpoint was sufficient relief of upper gastrointestinal symptoms after 4 weeks of treatment (GOS ≤ 2). UMIN clinical trial registration number: UMIN000005399. Of 471 randomized patients, 454 were included in the full analysis set. After 4 weeks of treatment, sufficient symptom relief was achieved by 66.9% of patients in the omeprazole group, compared with 41.0%, 36.3% and 32.3% in the famotidine, mosapride and teprenone groups, respectively (all, p < 0.001 vs omeprazole). There were no treatment-related adverse events. The favorable efficacy and safety profiles of omeprazole in relieving uninvestigated upper gastrointestinal symptoms support its use as first-line treatment in this patient group in Japan. Patients who show no improvement in symptoms despite PPI use, and those with alarm symptoms (such as vomiting, GI bleeding or acute weight loss) should receive further investigation, including prompt referral for endoscopy. UMIN000005399.

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Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group.

Time to progression (TTP), overall survival, and quality of life (QL) were compared in patients with hormone-resistant prostate cancer (HRPC) treated with prednisone (5 mg orally, four times a day) or flutamide (250 mg orally, three times a day). Symptomatic patients were randomized to receive either prednisone (101 patients) or flutamide (100 patients). Subjective response was assessed based on performance status, the use of analgesics, and the need to apply alternative palliative treatment. Prostate-specific antigen (PSA)-based biochemical response (>or= 50% reduction of baseline PSA) was recorded. At baseline and at 6-week intervals during follow-up, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30. There was no difference between the groups in median TTP (prednisone, 3.4 months; flutamide, 2.3 months) or overall survival (prednisone, 10.6 months; flutamide, 11.2 months). In the prednisone group, 56% of the patients experienced a subjective response, compared with 45% in the flutamide group (P: = .18). The median response duration was 4.8 months for prednisone and 4.2 months for flutamide. A biochemical response was observed in 21% and 23% of the prednisone and flutamide groups, respectively. Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone. The QL assessment parameters favored the use of prednisone with statistically significant differences in pain, fatigue, role functioning, appetite loss, gastrointestinal distress, and overall QL. In symptomatic HRPC, treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response. The QL results favor the use of low-cost prednisone in patients with HRPC.

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Cefuroxime axetil for treatment of uncomplicated gonorrhea.

Oral cefuroxime axetil (1 g) plus probenecid cured 29 of 30 urethral and 6 of 6 rectal gonococcal infections in men; alone the drug cured 22 of 23 urethral and 4 of 6 rectal infections. No toxicity was observed. Cefuroxime axetil alone is effective for urethral gonorrhea in males; rectal gonorrhea probably requires additional probenecid.

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Radiation-induced lung toxicity predictors: Retrospective analysis of 90 patients treated with stereotactic body radiation therapy for stage I non-small-cell lung carcinoma.

The main complication after hypofractionated radiotherapy for lung carcinoma is radiation-induced lung toxicity, which can be divided into radiation pneumonitis (acute toxicity, occurring within 6 months) and lung fibrosis (late toxicity, occurring after 6 months). The literature describes several predictive factors related to the patient, to the tumor (volume, central location), to the dosimetry and to biological factors. This study is a retrospective analysis of 90 patients treated with stereotactic body irradiation for stage I non-small-cell lung carcinoma between December 2010 and May 2015. Radiation pneumonitis was observed in 61.5% of the patients who were mainly asymptomatic (34%). Chronic obstructive pulmonary disease was not predictive of radiation pneumonitis, whereas active smoking was protective. Centrally located tumors were not more likely to result in this complication if the radiation schedule utilized adapted fractionation. In our study, no predictive factor was identified. Whereas the mean lung dose was a predictive factor in 3D radiotherapy, the lung volume irradiated at high doses seemed to be involved in the pathogenesis after hypofractionated radiotherapy. The discovery of predictive factors for radiation pneumonitis is difficult due to the rarity of this complication, especially with an 8×7.5Gy schedule. Radiation pneumonitis seems to be correlated with the volume irradiated at high doses, which is in contrast to the known knowledge about the organs in parallel. This finding leads us to raise the hypothesis that vessel damage, organs in series, occurring during hypofractionated radiotherapy could be responsible for this toxicity.

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Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder.

A series of 237 patients with DSM-III-diagnosed panic disorder, or agoraphobia with panic attacks, received alprazolam as part of the placebo-controlled Cross-National Collaborative Panic Study. After a 1-week drug-free period, alprazolam dosage was titrated upward with the objective of reaching 6.0 mg/d in all patients. At week 3 of treatment, alprazolam plasma levels were significantly correlated with daily dosage (regression slope: 11.7 ng/mL per milligram per day) but with considerable individual variation. Among patients with spontaneous panic attacks, 70% of those with plasma alprazolam levels greater than 20 ng/mL achieved complete remission vs 31% of those with levels less than 20 ng/mL. Situational panic attack remission increased in frequency with increasing plasma levels, but the relationship was not significant. Patient- and physician-rated global improvement and Hamilton Anxiety and Depression Scale score reductions were maximal at 20 to 39 ng/mL, with no further benefit at higher levels. Central nervous system-depressant side effects increased in frequency with higher plasma levels. Between weeks 3 and 8 of treatment, physicians were permitted to adjust dosage (maximum: 10 mg/d) to optimize response. At week 8, the dose-concentration relationship was essentially identical (regression slope: 10.8 ng/mL per milligram per day), but plasma levels were no longer related to efficacy or side effects. Thus, monitoring of plasma alprazolam concentrations may have a clinically useful role during short-term treatment of panic disorder.

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Gabapentin's acute effect on mood profile -- a controlled study on patients with alcohol withdrawal.

Delayed beneficial effects of gabapentin on mood were frequently reported in various patient populations. This is the first controlled study which addressed acute effects of gabapentin on mood. Analysis of the German version of Profile of Mood States (POMS) throughout a randomised placebo-controlled, double-blinded study of gabapentin on acute alcohol withdrawal [Bonnet, U., Banger, M., Leweke, F.M., Specka, M., Müller, B.W., Hashemi, T., Nyhuis, P.W., Kutscher, S., Burtscheidt, W., Gastpar, M. 2003. Treatment of acute alcohol withdrawal with gabapentin -- results from a controlled two-center trial. J Clin Psychopharmacol 23, 514-519]. In addition, subjective severity of alcohol withdrawal was determined by the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA) to control effects of concurrent withdrawal on POMS. Ratings were performed at intake (baseline), day 1 (study medication 400 mg q.i.d.), day 2 (study medication 400 mg q.i.d.) and day 7 (no study medication). Analyses could be performed on 46 out of 59 randomised subjects. Within the first two days of the study, a significant stronger increase in the POMS-vigour subscore occurred in the gabapentin group. A subgroup analysis suggests that gabapentin's effect on vigour largely results from a stronger improvement of vigour in a small group of 11 patients with co-morbid mild depression (according to ICD-10: dysthymia or depressive adjustment disorder). There were no significant differences between the treatment groups regarding the other POMS-subscores (dejection, fatigue, anger) ruling out an overall fast effect on mood. Moreover, ESA-measures were not significantly altered indicating a missing effect of 400 mg gabapentin q.i.d. on acute alcohol withdrawal itself. After tapering off study medication, no more significant differences between gabapentin and placebo group were observed on vigour, strongly suggesting that the initial effect results from a pharmacological gabapentin action. Gabapentin selectively accelerated the improvement of the vigour-subscore of patients with acute alcohol withdrawal within 48 h. This effect was independent from the subjective severity of withdrawal and especially marked in patients with co-morbid mild depression.

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Psychological versus pharmacological treatments of bulimia nervosa: predictors and processes of change.

This article extends the acute outcome findings from a study comparing psychological and pharmacological interventions for bulimia nervosa (B.T. Walsh et al., 1997) by examining 3 additional domains: predictive factors, therapeutic alliance, and time course of change. One hundred twenty women were randomized to cognitive-behavioral therapy (CBT), supportive psychotherapy (SPT) plus antidepressant medication or a placebo, or a medication-alone condition. Results indicate that high baseline frequencies of binge eating and vomiting, as well as a positive history of substance abuse or dependence, are negative prognostic indicators. Although a greater overall therapeutic alliance may increase the likelihood of remission, symptom change over the course of treatment may have as much of an impact on patient ratings of alliance as the reverse. CBT was significantly more rapid than SPT in reducing binge eating and vomiting frequencies.

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Concomitant considerations in long-term antihypertensive treatment.

Even with antihypertensive therapy, the risks in hypertensive patients, especially the incidence of coronary events, cannot be lowered to that of the normotensive population. Therefore, the metabolic effects of long-term therapy on lipid metabolism and the efficacy of antihypertensive drugs to lower blood pressure were studied as possible explanations for this partial therapeutic failure. Hypertensive patients who participated in a long-term trial provided a unique opportunity to observe the effects of long-term treatment and of then discontinuing antihypertensive therapy. During treatment, increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides following hydrochlorothiazide, and increases of LDL-C and triglycerides and a decrease of high-density lipoprotein cholesterol (HDL-C) following atenolol were observed up to 42 months. After 5.2 +/- 1.4 years of randomised antihypertensive treatment, cessation of hydrochlorothiazide led to a decrease of total cholesterol from 6.40 to 5.98 mmol/l and of LDL-C from 4.33 to 3.89 mmol/l. After discontinuation of atenolol, LDL-C decreased from 4.20 to 3.89 mmol/l and triglycerides from 2.21 to 1.91 mmol/l, whereas HDL-C increased from 0.96 to 1.17 mmol/l (all differences significant). Thus the adverse effects of both agents persisted for more than five years and were reversible after medication was discontinued. In recent years titration to the lowest possible dose of antihypertensive agents has been suggested to avoid adverse metabolic alterations and subjective side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

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[Effects of the long-term treatment with losartan and captopril and of the abrupt cessation on circadian blood pressure profile].

The influence of a long-term treatment with losartan (50-100 mg o.d.) and captopril (25-50 mg b.i.d.) followed by the abrupt therapy cessation was studied in an open randomized placebo-controlled parallel group trial. The study was performed on a group of 22 essential (soft to moderate) hypertensive male patients, which entered the trial when a mean daytime diastolic blood pressure was BP > or = 90 Torr. The antihypertensive effect of losartan was more pronounced and homogeneous than the effect of an equivalent dose of captopril. The group-average trough/peak ratios upon the losartan treatment were 61.5 and 61.3% for the systolic and diastolic BP (against 21.2 and 26.9% for captopril), respectively. At the same time, the smoothness index values of the patients treated with losartan and captopril showed no significant difference. Neither treatment with any of the two drugs nor the therapy cessation affected the circadian BP profile or the BP variability. The abrupt termination of the drug administration did not cause a withdrawal syndrome: on the contrary, a significant effect of the captopril and losartan treatment (statistically reliable against the placebo control) persisted for at least four days after the therapy cessation. Taking into account poor homogeneity of the antihypertensive effect of captopril in patients with a stable moderate hypertension treated b.i.d., the drug administration is recommended according to the t.i.d. schedule. In this group of patients, losartan and captopril are probably more expediently administered in combination with other hypertensive drugs.

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[Efficacy of conservative treatment of gastric lymphosarcoma].

To compare efficacy and toxicity of conservative therapy (different programs of polychemotherapy) of gastric lymphosarcoma conducted for the last 10 years in Hematological Research Center of the Russian Academy of Medical Sciences. The study included 63 patients (40 females and 23 males aged 14 to 78 years, mean age 49 years) with primary diagnosis of gastric lymphosarcoma (GL). Of them, 56 (89%) patients had diffuse large B-cell lymphosarcoma (DLBCL) and 7 (11%) had gastric Berkitt's lymphoma (BL). Only detection of t(8;14) with rearrangement of c-myc gene provided accurate diagnosis of gastric BL. By the treatment DLBCL patients were divided into two groups: 44 patients of group 1 received polychemotherapy (PCT) according to CHOP scheme or in combination with radiotherapy and surgical treatment; 12 patients of group 2 were treated according to modified program mNHL-BFM-90, without surgical or radiation treatment. Of 7 patients with gastric BL 5 patients received treatment according to a modified program mNHL-BFM-90 and 2 patients were given CHOP because of DLBCL misdiagnosis without cytogenetic detection of t(8;14). Overall survival in group 1 was 73% in mean follow-up 61 months. The survival depended only on initial factors of poor prognosis (PPF): tumor size over 10 cm, Ann-Arbor stage higher than IE, B-symptoms, elevated level of LDH. Overall survival of 18 gastric DLBCL patients without PPF reached 94%, of 26 patients with PPF - 60%. Lethality due to side effects was 4% (2 patients), primary resistance was 14% (6 patients), recurrence arose in 9% (4 patients). Overall survival in group 2 was 100% in mean remission duration 18 months, was unrelated to PPF (10 of 12 patients) but correlated with high toxicity. 5 BL patients treated with a modified mNHL-BFM-90 program achieved remission (a mean follow-up at present is 1 to 50 months, mean 24 months). 2 BL patients treated with CHOP died for a year. Gastric lymphosarcomas are sensitive to chemotherapy, thereby PCT only is effective in most patients. PPF in gastric DLBCL were responsible for poor outcome in 40% patients in CHOP treatment. The modified program mNHL-BFM-90 can produce up to 100% complete long-term remissions in therapy of gastric lymphosarcoma in adults both in BL and DLBCL patients. A cytogenetic examination of c-myc gene rearrangement is obligatory before initiation of PCT of gastric lymphosarcoma.

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Salbutamol and ipratropium bromide solution in the treatment of bronchospasm in asthmatic children.

The effects of the beta 2-adrenergic agonist salbutamol (0.02 mL/kg of a 0.5% solution) and the cholinergic antagonist ipratropium bromide (2 mL of a 0.025% solution), administered alone or in combination at different doses, were evaluated in 48 asthmatic children using a single-dose, double-blind, crossover design. Spirometric measurements were taken before and 10, 30, 60, 120, 180, 240, 300, and 360 minutes after administration of the drugs. All regimens produced significant bronchodilatation 10 to 30 minutes after administration. The improvement began to decline three to four hours after inhalation, particularly when ipratropium bromide was administered alone. The administration of the salbutamol plus ipratropium combination did not significantly improve pulmonary function values as compared to salbutamol alone. The effects of salbutamol and ipratropium bromide in half-dose or full-dose combinations were indistinguishable. No significant adverse effects on blood pressure or heart rate were observed.

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Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea: a crossover, randomized trial.

No controlled trial has examined the clinical efficacy of antibiotics in small bowel bacterial overgrowth. Ten patients with bacterial overgrowth-related diarrhea underwent the following five 7-day treatment periods: untreated (control period), then placebo, and subsequently, in random order and blinded fashion, norfloxacin (800 mg/day), amoxicillin-clavulanic acid (1500 mg/day), and Saccharomyces boulardii (1500 mg/day). A hydrogen breath test was performed on the first and last day of each period. Daily stool frequency was similar during the control and placebo periods (4.2 +/- 0.6 vs. 3.9 +/- 0.6 [mean +/- SEM], respectively). Norfloxacin and amoxicillin-clavulanic acid led to a significant reduction in daily stool frequency (2.3 +/- 0.4 and 3.0 +/- 0.5, respectively; P < 0.01 vs. placebo period) after 2.0 +/- 1.4 and 1.2 +/- 0.4 days, which was maintained for 6.1 +/- 3.7 and 6.0 +/- 9.6 days, respectively. Breath-expired H(2) volume decreased with norfloxacin (37 +/- 8 to 12 +/- 5 mL per 2 hours; P < 0.01) and amoxicillin-clavulanic acid (24 +/- 6 to 8 +/- 4 mL per 2 hours, respectively; P = 0.01), but H(2) breath test result was negative in only 3 and 5 patients. Norfloxacin and amoxicillin-clavulanic acid are effective in the treatment of bacterial overgrowth-related diarrhea.

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Cyclosporine-drug interactions and the influence of patient age.

Cyclosporine-drug interactions in adult transplant patients and the impact of age were studied. The medical records of transplant patients receiving cyclosporine therapy were identified. Data on patient demographics, cyclosporine dosages, dosage form, blood trough concentrations, clinical laboratory test values, and concurrent medications were collected. One-compartment models for oral and i.v. administration were used to fit cyclosporine concentration data to population pharmacokinetic and statistical models. Nonlinear mixed-effect modeling (NONMEM) software was used. The influence of covariates, including but not limited to concomitant medications and age, on cyclosporine pharmacokinetics was evaluated. The records of 100 patients (36 women and 64 men) were reviewed. A mean +/- S.D. of 9 +/- 2 and 9 +/- 1 medications per day were consumed by patients < 60 and > or = 60 years old, respectively. Mean population pharmacokinetic values of 0.407 L/hr/kg for clearance, 4.0 L/kg for volume of distribution, 31% for bioavailability, and 10.6 hours for half-life were determined on the basis of 569 blood cyclosporine levels. Twelve medications (sertraline, losartan, valsartan, quinine, atorvastatin, simvastatin, pravastatin, fluvastatin, alendronate, digoxin, acyclovir, and oxycodone) with previously unconfirmed pharmacokinetic interactions with cyclosporine were identified as interacting. There was no correlation between age and interactions. Patients taking cyclosporine were at risk for pharmacokinetic drug interactions when cyclosporine was used in combination with sertraline, losartan, valsartan, quinine, atorvastatin, simvastatin, pravastatin, fluvastatin, alendronate, digoxin, acyclovir, and oxycodone. Transplant patients 60-75 years of age had cyclosporine-drug interactions similar to those in younger patients.

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Effects of statin on plaque stability and thrombogenicity in hypercholesterolemic patients with coronary artery disease.

Plaque stability and thrombogenicity contribute to development and clinical expression of atherosclerosis. Experimental studies have shown that lipoproteins or mevalonate regulate matrix metalloproteinase (MMP)-9, tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) expression, providing nonlipid mechanism. We administered simvastatin 20 mg daily during 14 weeks to 32 hypercholesterolemic patients with coronary artery disease. Compared with pretreatment values, simvastatin significantly lowered lipoprotein levels (all P<0.01). Compared with pretreatment values, simvastatin significantly lowered plasma levels of MMP-9, TF, and PAI-1 (P=0.009, P=0.032, and P=0.007, respectively). There were significant inverse correlations between pretreatment MMP-9, TF activity or PAI-1 antigen and the degree of change in those levels after simvastatin (r=-0.793, P<0.001; r=-0.482, P=0.005 and r=-0.590, P<0.001, respectively). Of interest, there were significant correlation between pretreatment or percent changes in MMP-9 levels and pretreatment or percent changes in PAI-1 antigen (r=0.293, P=0.019 and r=0.375, P=0.034, respectively). However, no significant correlations between lipoprotein levels and levels of plaque stability or thrombogenicity markers were determined. Reduction of plaque stability and thrombogenicity markers with statin may contribute to the cardiovascular event reduction and explain the early clinical benefit in clinical trials, independent of lipoprotein changes.

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Antiplatelet effects of a 600 mg loading dose of clopidogrel are not attenuated in patients receiving atorvastatin or simvastatin for at least 4 weeks prior to coronary artery stenting.

To test prospectively whether the antiplatelet effect of a 600 mg loading dose of clopidogrel is attenuated in patients receiving atorvastatin and simvastatin for at least 4 weeks prior to coronary artery stenting. Blood samples were obtained at least 2 h after receiving 100 mg aspirin and 600 mg clopidogrel and prior to coronary stenting from 90 patients without statin therapy and 90 patients with statin (atorvastatin and simvastatin) therapy for at least 4 weeks. Maximal and residual platelet aggregation was evaluated with optical aggregometry in response to ADP (5 and 20 micromol/l). Surface expression of IIb/IIIa (CD61) and P-selectin (CD62) was assessed with whole blood flow-cytometry at baseline and following stimulation (5 and 20 micromol/l ADP). Inhibition of ADP-induced platelet aggregation was not impaired in the presence of concomitant statin therapy. Moreover, patients with and without statin therapy did not differ in respect to all flow-cytometric parameters obtained. The antiplatelet effect of a high, 600 mg loading dose of clopidogrel is not diminished in patients receiving atorvastatin and simvastatin for at least 4 weeks prior to coronary stenting.

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BOXIT-A Randomised Phase III Placebo-controlled Trial Evaluating the Addition of Celecoxib to Standard Treatment of Transitional Cell Carcinoma of the Bladder (CRUK/07/004).

Non-muscle-invasive bladder cancer (NMIBC) has a significant risk of recurrence despite adjuvant intravesical therapy. To determine whether celecoxib, a cyclo-oxygenase 2 inhibitor, reduces the risk of recurrence in NMIBC patients receiving standard treatment. BOXIT (CRUK/07/004, ISRCTN84681538) is a double-blinded, phase III, randomised controlled trial. Patients aged ≥18 yr with intermediate- or high-risk NMIBC were accrued across 51 UK centres between 1 November 2007 and 23 July 2012. Patients were randomised (1:1) to celecoxib 200mg twice daily or placebo for 2 yr. Patients with intermediate-risk NMIBC were recommended to receive six weekly mitomycin C instillations; high-risk NMIBC cases received six weekly bacillus Calmette-Guérin and maintenance therapy. The primary endpoint was time to disease recurrence. Analysis was by intention to treat. A total of 472 patients were randomised (236:236). With median follow-up of 44 mo (interquartile range: 36-57), 3-yr recurrence-free rate (95% confidence interval) was as follows: celecoxib 68% (61-74%) versus placebo 64% (57-70%; hazard ratio [HR] 0.82 [0.60-1.12], p=0.2). There was no difference in high-risk (HR 0.77 [0.52-1.15], p=0.2) or intermediate-risk (HR 0.90 [0.55-1.48], p=0.7) NMIBC. Subgroup analysis suggested that time to recurrence was longer in pT1 NMIBC patients treated with celecoxib compared with those receiving placebo (HR 0.53 [0.30-0.94], interaction test p=0.04). The 3-yr progression rates in high-risk patients were low: 10% (6.5-17%) and 9.7% (6.0-15%) in celecoxib and placebo arms, respectively. Incidence of serious cardiovascular events was higher in celecoxib (5.2%) than in placebo (1.7%) group (difference +3.4% [-0.3% to 7.2%], p=0.07). BOXIT did not show that celecoxib reduces the risk of recurrence in intermediate- or high-risk NMIBC, although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib. Celecoxib was not shown to reduce the risk of recurrence in intermediate- or high-risk non-muscle-invasive bladder cancer (NMIBC), although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib.

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Citalopram modulation of neuronal responses to aversive face emotions: a functional MRI study.

This study investigated the serotonergic modulation of face emotion processing using blood oxygen level-dependent (BOLD) functional MRI. In a placebo-controlled, balanced order design, intravenous citalopram (7.5 mg) was given to 12 male volunteers 60 min before a covert face emotion recognition task. Angry, disgusted and fearful faces produced BOLD signal responses, which were broadly consistent with previous findings. Citalopram enhanced the BOLD signal response in the left posterior insula (together with nonprespecified pulvinar and visual cortex) but attenuated activation in the left amygdala to disgusted faces and right amygdala activation to fearful faces. No citalopram modulation of BOLD responses to angry faces were found. These results suggest that serotonin modulates low-level amygdala activation to aversive stimuli.

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Efficacy and tolerability of combination therapy with valsartan/hydrochlorothiazide in the initial treatment of severe hypertension.

Most patients with severe hypertension are at high risk for cardiovascular events and require prompt blood pressure (BP)-lowering and combination therapy to achieve BP goals. This study evaluated the therapeutic efficacy and tolerability of initial treatment with the combination of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with severe hypertension. This was a 6-week, randomized, double-blind, multicenter, forced titration study that compared initial therapy with the combination of valsartan/HCTZ 160/12.5 mg (force titrated to 160/25 mg after 2 weeks and to 320/25 mg after 4 weeks) to monotherapy with valsartan 160 mg (force titrated to 320 mg after 2 weeks and sham-titrated to 320 mg after 4 weeks). Eligible patients were 18-80 years old with severe essential hypertension (mean sitting diastolic BP > or = 110 mmHg and < 120 mmHg and mean sitting systolic BP > or = 140 mmHg and < 200 mmHg). The Clinical Trial Registry number was NCT00273299. The primary efficacy variable was the rate of BP control (mean sitting BP < 140/90 mmHg) at Week 4. Tolerability was evaluated by monitoring all adverse events, vital signs, and laboratory tests including hematology and biochemistry. A total of 608 patients were randomized to either valsartan/HCTZ (n = 307) or valsartan monotherapy (n = 301). Significantly more patients achieved overall BP control (< 140/90 mmHg) with valsartan/HCTZ compared to monotherapy at Week 4 (primary efficacy variable and timepoint) (39.6% vs. 21.8%; p < 0.0001) and Week 6 (48.2% vs. 27.2%; p < 0.0001). Mean reductions in BP at Week 4 were significantly greater for valsartan/HCTZ (30.8/22.7 mmHg vs. 21.7/17.5 mmHg; p < 0.0001), with further reductions at Week 6. BP control rates were greater with combination therapy as early as Week 2. The overall incidence of adverse events was comparable between the combination therapy (34.9%) and monotherapy (36.7%) treatment groups. A potential limitation of the forced-titration design is that some patients were titrated to higher doses despite having achieved goal BP. This may impact the interpretation of the incidence of dose-dependent adverse events. Initial therapy with valsartan/HCTZ is effective and well tolerated in patients with severe hypertension.

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Efficacy of salmeterol xinafoate powder in children with chronic persistent asthma.

The efficacy and safety of salmeterol powder have not previously been evaluated in children with asthma in the United States. The efficacy and safety of salmeterol powder versus placebo were compared in children between the ages of 4 and 11 years with chronic persistent asthma. A randomized, double-blind, placebo-controlled, parallel group trial was performed at 11 clinical centers. Two hundred seven patients were randomly assigned to receive 50 microg salmeterol powder or placebo (and albuterol as needed) twice daily via a breath-actuated device for 12 weeks. Twelve-hour serial pulmonary function assessments were conducted on day 1 and at week 12. Daily recordings of morning and evening peak expiratory flow (PEF), supplemental albuterol use, asthma symptoms, and nocturnal awakenings were assessed. On day 1 and at week 12, weighted mean percent of predicted PEF (P < .001, day 1 and P=.008, week 12) and weighted mean forced expiratory volume in one second (P < .001, day 1 and week 12) were significantly higher at all timepoints evaluated over the 12-hour postdosing period in patients treated with salmeterol powder compared with placebo. Overall reductions in supplemental albuterol use and mean asthma symptom scores were also significantly greater in children administered salmeterol compared with placebo (P=.004 and P=.006, respectively). The frequency of adverse events was similar in the two treatment groups. Salmeterol powder (50 microg twice daily) is effective and safe in producing bronchodilation and relieving symptoms in children with chronic persistent asthma during 12 weeks of treatment.

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A valved holding chamber does not decrease the bronchodilator activity of budesonide-formoterol combination metered dose inhaler.

Spacers and valved holding chambers (VHCs) were developed to facilitate using pressurized metered dose inhaler (pMDI) by patients who could not coordinate the actions required for successful pMDI use. There is little in vivo evidence about how VHC may affect the bronchodilation from combination drugs in pMDI. This study was to determine the effect, if any, of VHC on the bronchodilating actions of the pMDI budesonide/formoterol combination. Sixteen adult asthmatic subjects with 15% or greater reversibility of forced expiratory volume in one second (FEV-1), 15 minutes after inhaling 180-360 μg of albuterol, participated. The study had a randomized crossover design with each subject using budesonide-formoterol pMDI as described in the product information one timeand on a second occasion using the pMDI with a VHC. Spirometry and impedance osscilometry were measured at baseline and repeatedly over a 12-hour period. This study was approved by IntegReview Institutional Review Board, Austin, TX, USA. The clinical trial number for this study was NCT 009-15538 (http://www.westernskymed.com). The area under the curve of FEV-1, the FEV-1, and the fraction FEV-1/FVC was similar over the 12-hour time frame with both methods. Resistance was not different at any time point. In both procedures, the onset of bronchodilation occurred rapidly within 3 to 5 minutes. In well-trained asthmatic subjects, both tested methods caused equivalent bronchodilation. This suggests a VHC itself has no deleterious effect on the bronchodilator activity in the combined drug. These results may not apply to patients who have coordination problems with the pMDI and further study is indicated.

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Preventing angiographic progression of coronary atherosclerosis with pravastatin.

We conducted a prospective study to investigate the relationship between the decrease of serum lipid levels during pravastatin therapy and changes of coronary angiography parameters in Japanese patients with coronary atherosclerosis. The patients were predominantly male, aged between 18 and 75 years (mean: 58 years), had at least 25% stenosis of one or more major coronary arteries, and had a serum total cholesterol ( TC) level > or = 200 mg/dl (5.18 mM/l). Treatment with pravastatin (10 mg/day) was continued for 3 years. Coronary angiography was performed before and 3 years after the start of pravastatin therapy to assess the relationship between the mean segment diameter (MSD), the minimal lumen diameter (MLD), and the annual changes of percent stenosis and TC levels. of 265 patients who were initially registered, 129 were followed for an average of 35 months. Consequently, second angiograms were only obtained in 68 patients for various reasons, so this group was used for analysis. During pravastatin therapy, the TC level significantly decreased from 239 mg/dl (6.19 mM/l) to 210 mg/dl (5.44 mM/l) (a 12% reduction; p<0.001). In addition, HDL-cholesterol increased by 5% (p=0.007), but the triglyceride level did not show a significant change. Both MSD and MLD were significantly improved on follow-up angiography, increasing from 2.67 mm to 2.76 mm and from 2.09 mm to 2.13 mm, respectively. However, no change of percent stenosis was observed. The mean TC level during treatment did not show any significant correlation with the changes of angiography parameters. However, a significant correlation was observed between the percent reduction of TC and the annual change of MSD (r=-0.272, p=0.027). A similar relationship was also found between the change of MLD and the percent reduction of TC (r=-0.260, p=0.035). In conclusion, the percent decrease of serum cholesterol may be a better indicator of clinical efficacy than the absolute cholesterol level during pravastatin therapy.

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Treatment of end-stage renal disease due to lupus nephritis: comparison of six patients treated with both peritoneal and hemodialysis.

End-stage renal disease (ESRD) is one of the most significant complications of systemic lupus erythematosus (SLE). Previous investigators have evaluated the morbidity and mortality of different renal replacement treatment modalities in these patients. Earlier reports have suggested that the systemic manifestations of SLE diminish, or "burn out," once ESRD occurs. These investigators also suggested that vascular access complications were a significant cause of morbidity and mortality in these patients treated with hemodialysis (HD). A retrospective review of the records of 6 patients with ESRD from lupus nephritis (LN), who received both HD and peritoneal dialysis (PD), was performed to determine if there was a difference in disease activity between treatment modalities, using patients as self-controls. The number of SLE flares was determined by clinical and/or serologic studies, and prednisone dosages compared for each treatment modality. Four of the 6 patients continued to have active SLE after renal replacement therapy was begun. There were no significant differences in the number of SLE flares or prednisone dosages while receiving either treatment modality. While PD eliminates problems associated with vascular access, both HD and PD were effective forms of renal replacement therapy. Most patients in this study continued to have active SLE after commencement of dialysis, with no differences in disease activity noted during HD or PD.

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Nodular gastritis in adults is caused by Helicobacter pylori infection.

A close relationship exists between nodular gastritis and Helicobacter pylori infection in children. The pathogenesis and optimal management of nodular gastritis in adults, however, are unclear. This study describes the clinicopathologic features of nodular gastritis in adults and correlates treatment with outcome. Of 97,262 adult patients who underwent endoscopy, 187 (0.19%) were diagnosed with nodular gastritis, 151 (81%) of whom had dyspepsia. Nodular gastritis predominantly affects young women (49 men and 138 women, mean age, 32.6 years). All 134 patients tested for Helicobacter pylori infection were infected, and 65/66 (98%) had inflammation of both the antrum and the corpus. Twenty-five (13%) had associated lesions (peptic ulcers or cancer). Dyspepsia improved after eradication of Helicobacter pylori infection, but did not improve spontaneously. Nodular gastritis in adults is caused by Helicobacter pylori infection and shows a predilection for females and young adults. Helicobacter pylori eradication decreases symptoms and reduces the risk of peptic ulcers and possibly gastric cancer.

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Serum biomarkers of inflammation and muscle strength among women with systemic lupus erythematosus.

Muscle strength is an important determinant of physical function in women with systemic lupus erythematosus (SLE). Serum biomarkers of inflammation, including interleukin-6 (IL-6) and C-Reactive Protein (CRP), are associated with differences in muscle strength among individuals without rheumatologic disease. We examined whether serum levels of IL-6 and CRP are associated with upper and lower extremity muscle strength among adult women with SLE. One hundred thirty-six women with SLE participated in this cross-sectional study. High-sensitivity CRP was analyzed by nephelometry. IL-6 serum levels were analyzed by high sensitivity enzyme-linked immunosorbent assay. Upper and lower extremity muscle strength were assessed by grip strength and peak torque of knee extension and flexion, respectively. Regression analyses modeled associations of CRP and IL-6 with upper and lower extremity muscle strength controlling for age, SLE duration, physical activity, prednisone use, BMI, plaquenil use, and pain. Higher serum levels of IL-6 and CRP were associated with significantly weaker upper and lower extremity muscle strength even when controlling for covariates. Increased serum IL-6 and CRP are associated with clinically significant differences in upper and lower extremity muscle strength and may be useful in identifying those at risk for weakness and decreased physical function.

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Twenty-four-hour monitoring of intragastric acidity: comparison between lansoprazole 30mg and pantoprazole 40mg.

To date, there is no published study, comparing the effects of lansoprazole and pantoprazole on gastric acid secretion inhibition. The aim of this study, was to compare the effects of these two drugs on 24-h intragastric pH-metry. Twelve healthy volunteers were included in an open, randomized, crossover study. Each subject received lansoprazole 30mg during 7 days followed, after a 14-day wash-out period, by pantoprazole 40 mg for 7 days or vice versa. Intragastric 24-h pH monitoring was performed before the treatment, and then after the first and seventh intake in each treatment period. The decrease in gastric acidity on daytime, night-time and total 24-h periods during both treatments was significantly different from the base value. Significant differences in acid inhibition were found between lansoprazole 30mg and pantoprazole 40 mg during daytime and 24 h after the first intake. After repeated dose regimens, a significant difference was detected between treatment periods but only for pH above 4. After the first dose, the median pH value with lansoprazole was also significantly greater than for pantoprazole. Pantoprazole activity increased significantly from first to seventh intake, in contrast to lansoprazole. Lansoprazole 30 mg was significantly more potent than pantoprazole 40 mg on 24-h pH profiles on the first and seventh days. The antisecretory effect of lansoprazole was maximum after the first intake whereas pantoprazole activity increased significantly between the first and last intake.

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Helicobacter pylori Eradication Prevents Metachronous Gastric Neoplasms after Endoscopic Resection of Gastric Dysplasia.

There is insufficient data about the role of eradication of H. pylori after endoscopic resection (ER) for gastric dysplasia. The aim was to investigate the benefit of H. pylori eradication after ER in patients with gastric dysplasia to prevent metachronous gastric neoplasms. We retrospectively reviewed 1872 patients who underwent ER of gastric dysplasia. We excluded patients with a follow-up period of <2 years or who had not undergone tests for active H. pylori infection. A total of 282 patients were enrolled. The patients were categorized into those without active H. pylori infection (H. pylori-negative group, n = 124), those who successfully underwent H. pylori eradication (eradicated group, n = 122), and those who failed or did not undergo H. pylori eradication (persistent group, n = 36). Metachronous recurrence was diagnosed in 36 patients, including 19 in the H. pylori-negative group, 10 in the eradicated group, and 7 in the persistent group. The cumulative incidence of metachronous recurrence was significantly lower in the H. pylori-eradicated group in comparison with either of the H. pylori-persistent (non-eradicated or failed) groups (p = 0.039). Similarly, the incidence of metachronous recurrence was significantly lower in the H. pylori-eradicated group compared with the H. pylori-negative group (p = 0.041). Successful H. pylori eradication may reduce the development of metachronous gastric neoplasms after ER in patients with gastric dysplasia.

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Comparison of salmefamol and salbutamol in patients with chronic airways obstruction.

1 Inhaled salmefamol, in doses of 100 mug and 200 mug has been compared with inhaled salbutamol, in a dose of 200 mug, and with placebo in patients with airways obstruction. 2 Both salmefamol and salbutamol are potent bronchodilators with a signficantly superior action over placebo at all times up to 8 h after treatment. 3 The mean peak percentage increases in FEV produced by the three active preparations were similar. The decline from peak values was significantly slower with salmefamol than with salbutamol. Neither drug produced tachycardia.

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Salbutamol for transient tachypnea of the newborn.

Transient tachypnea of the newborn is characterized by tachypnea and signs of respiratory distress. Transient tachypnea typically appears within the first two hours of life in term and late preterm newborns. Although transient tachypnea of the newborn is usually a self limited condition, it is associated with wheezing syndromes in late childhood. The rationale for the use of salbutamol (albuterol) for transient tachypnea of the newborn is based on studies showing that β-agonists can accelerate the rate of alveolar fluid clearance. To assess whether salbutamol compared to placebo, no treatment or any other drugs administered to treat transient tachypnea of the newborn, is effective and safe in the treatment of transient tachypnea of the newborn in infants born at 34 weeks' gestational age or more. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 3), MEDLINE (1996 to March 2016), EMBASE (1980 to March 2016) and CINAHL (1982 to March 2016). We applied no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia New Zealand and Pediatric Academic Societies) from 2000 to 2015 and clinical trial registries. Randomized controlled trials, quasi-randomized controlled trials and cluster trials comparing salbutamol versus placebo or no treatment or any other drugs administered to infants born at 34 weeks' gestational age or more and less than three days of age with transient tachypnea of the newborn. For each of the included trials, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical ventilation, duration of mechanical ventilation, etc.) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review were duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical ventilation. Three trials, which included 140 infants, met the inclusion criteria. All three trials compared a nebulized dose of salbutamol with placebo; in one of the three trials newborns were assigned to two different doses of the intervention. We found differences in the duration of oxygen therapy (mean difference (MD) -43.10 hours, 95% confidence interval (CI) -81.60 to -4.60). There were no differences in the need for continuous positive airway pressure (risk ratio (RR) 0.73, 95% CI 0.38 to 1.39; risk difference (RD) -0.15, 95% CI -0.45 to 0.16; 1 study, 46 infants) or the need for mechanical ventilation (RR 1.50, 95% CI 0.06 to 34.79; RD 0.03, 95% CI -0.08 to 0.14; 1 study, 46 infants). Tests for heterogeneity were not applicable for any of the analyses as only one study was included. Among secondary outcomes, we found no differences in terms of duration of hospital stay and tachypnea. The quality of the evidence was very low due to the imprecision of the estimates. One trial is ongoing. At present there is insufficient evidence to determine the efficacy and safety of salbutamol in the management of transient tachypnea of the newborn. The quality of evidence was low due to paucity of included trials, small sample sizes and overall poor methodologic quality.

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Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome.

The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d(3)-leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL(2) cholesterol (P < 0.001), HDL(3) cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome.

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Salbutamol-induced Decrease in Augmentation Index is Related to the Parallel Increase in Heart Rate.

The change in augmentation index following salbutamol inhalation has been applied to evaluate endothelial function. We examined the contribution of salbutamol-induced increase in heart rate to the observed decrease in augmentation index. Haemodynamics were recorded using whole-body impedance cardiography and continuous pulse wave analysis from tonometric radial blood pressure. All subjects (n = 335, mean age 46, body mass index 26, 48% men) were without medications with cardiovascular influences. The effects of salbutamol inhalation (0.4 mg) versus the endothelium-independent agent nitroglycerin resoriblet (0.25 mg) were examined during passive head-up tilt, as the haemodynamic influences of these compounds depend on body position. Salbutamol decreased augmentation index by ~3-4% units in supine and upright positions. Although salbutamol moderately increased cardiac index (+4.5%) and decreased systemic vascular resistance (-8.5%), the significant haemodynamic explanatory factors for decreased augmentation index in multivariate analysis were increased supine heart rate, and increased upright heart rate and decreased ejection duration (p < 0.001 for all, r² = 0.36-0.37). Sublingual nitroglycerin decreased supine and upright augmentation index by ~15% units and ~23% units, respectively. The haemodynamic explanatory factors for these changes in multivariate analysis were increased heart rate, reduced ejection duration and reduced systemic vascular resistance (p ≤ 0.021 for all, r²  = 0.22-0.34). In conclusion, the lowering influence of salbutamol on augmentation index may be largely explained by increased heart rate, suggesting that this effect may not predominantly reflect endothelial function.

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Treatment of primary orbital lymphomas.

We present an overview of the treatment and clinical outcome of 15 orbital lymphomas, carried out in our center from 1993 to 2002. The surgical approach was determined by the location, and type of the lesion. Lateral orbitotomy was performed in five laterally located lesions, a transconjunctival approach in five medial, basal, extra-, intraconal lesions. Pterional intradural and extradural and intradural approaches (three) were used in case of intracranial involvement or location in the apex and optic canal. Two lesions of the lid or extraconal space were operated via eyebrow incision. Ten patients were diagnosed as extranodal marginal zone lymphoma. Diffuse large B-cell lymphoma (DLCL) was encountered in two patients, follicular lymphoma (FCL) in two patients, and diffuse lymphoplasmacytic/lymphoplasmacytoid lymphoma in one patient. All patients except one failed to reveal systemic disease and had a localized orbital lymphoma. Twelve of the patients responded to radiation therapy with usually 40 Gy. Cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy was applied in two patients, once in combination with radiotherapy. Local recurrence was seen in one patient with FCL. Systemic manifestation occurred in one patient with DLCL, undergoing ifosfamide, carboplatin, etoposide chemotherapy with complete remission. The course of orbital non-Hodgkin's lymphoma is variable and requires a multidisciplinary treatment. Therapeutic options include surgical biopsy, radiation therapy, and chemotherapy.

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Calcium antagonists and renal protection from cyclosporine nephrotoxicity: long-term trial in renal transplantation patients.

Cyclosporine (CsA) treatment in solid organ transplantation has represented one of the greatest advances in the past 20 years, reducing acute rejection and increasing long-term survival. However, CsA has an important side effect, producing renal vasoconstriction and systemic hypertension. The main histological findings in the kidney are vascular lesions in the endothelium and smooth muscle cells. On proximal tubule cells, severe atrophy, vacuolization and thickening of the basal membrane can be found. The main mechanisms of vasoconstriction are secondary to endothelium disorders, increasing vasoconstrictor substances like endothelin, thromboxane, free radicals, etc., and reducing vasodilator substances like nitric oxide and prostaglandins. CsA acute nephrotoxicity produces haemodynamic changes with minor histological lesions, which will disappear when the medication is discontinued. Long-term CsA nephrotoxicity has been widely discussed in the literature. For some authors, a limited number of patients can develop end-state renal failure but others did not suffer these complications. Nevertheless, it seems clear that high doses of CsA can produce renal lesion and renal insufficiency, being difficult to evaluate in renal transplant patients because of the frequent association with chronic rejection lesions. Several types of drugs have been used to treat CsA nephrotoxicity in renal transplant patients but calcium antagonists and angiotensin converting enzyme-inhibitors are the most frequently used, especially the former due to their effect on the afferent arteriole vasodilatation, their natriuretic properties and their reducing intracellular calcium. The greatest experience has been with nifedipine, but other drugs like verapamil, diltiazem, amlodipine, felodipine, isradipine, etc., have also been used. Lacidipine, a 1,4-dihydropiridine, has demonstrated a beneficial effect during the short term after renal transplantation, and a multicentre, multinational, double-bind, placebo-controlled clinical trial for the long term currently ongoing.

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Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome.

To evaluate whether the administration of metformin exerts any effects on serum homocysteine (Hcy) levels in patients with polycystic ovary syndrome (PCOS) and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium. A total of 50 patients affected by PCOS, without additional metabolic or cardiovascular diseases, were enrolled in a prospective nonrandomized placebo-controlled double-blind clinical study. They were grouped into two treatment arms that were matched for age and BMI. Patients were treated with a 6-month course of metformin (1,700 mg daily) plus folic acid (400 microg daily; experimental group, n = 25) or placebo (control group, n = 25). Complete hormonal and metabolic patterns, serum Hcy, folate, vitamin B12, endothelin-1 levels, brachial artery diameter at the baseline (BAD-B) and after reactive hyperemia (BAD-RH), flow-mediated dilation, and intima-media thickness in both common carotid arteries were evaluated. After treatment, a significant increase in serum Hcy levels was observed in the control group compared with the baseline values and the experimental group. A beneficial effect was observed in the concentrations of BAD-B, BAD-RH, flow-mediated dilation, intima-media thickness, and serum endothelin-1 in both groups. However, the results were improved more significantly in the experimental group than in the control subjects. Metformin exerts a slight but significant deleterious effect on serum Hcy levels in patients with PCOS, and supplementation with folate is useful to increase the beneficial effect of metformin on the vascular endothelium.

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Helicobacter pylori first-line treatment and rescue option containing levofloxacin in patients allergic to penicillin.

To assess the efficacy and tolerability of Helicobacter pylori first-line treatment (omeprazole-clarithromycin-metronidazole) and second-line rescue option (omeprazole-clarithromycin-levofloxacin) in patients allergic to penicillin. Prospective multicenter study including consecutive patients allergic to penicillin. Therapy regimens: First-line treatment (50 patients): Omeprazole (20mg b.i.d.), clarithromycin (500 mg b.i.d.) and metronidazole (500 mg b.i.d.) for 7 days. Second-line treatment (15 therapy failures out of the aforementioned 50 patients): Omeprazole (20mg b.i.d.), clarithromycin (500 mg b.i.d.) and levofloxacin (500 mg b.i.d.) for 10 days. Negative (13)C-urea breath test 8 weeks after completion of treatment. (1) First-line treatment (omeprazole-clarithromycin-metronidazole): Per-protocol and intention-to-treat eradication rates were 55% (27/49; 95%CI=40-70%) and 54% (27/50; 95%CI=39-69%). Compliance with treatment and follow-up was complete in 98% of cases (one patient was not compliant due to nausea). Adverse events were reported in 5 patients (10%): 4 nausea, 1 diarrhoea. (2) Second-line treatment (omeprazole-clarithromycin-levofloxacin): Per-protocol and intention-to-treat eradication rates were both 73% (11/15; 95%CI=45-92%). Compliance with treatment and follow-up was complete in all the cases. Adverse events were reported in 4 patients (20%), which did not prevent the completion of treatment: Mild nausea (2 patients), and vomiting and myalgias/arthralgias (1 patient). In H. pylori infected patients allergic to penicillin, the generally recommended first-line treatment with omeprazole, clarithromycin and metronidazole has low efficacy for curing the infection. On the other hand, a levofloxacin-containing regimen (together with omeprazole and clarithromycin) represents an encouraging second-line alternative in the presence of penicillin allergy.

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The association between tramadol hydrochloride misuse and other substances use in an adolescent population: Phase I of a prospective survey.

Tramadol hydrochloride is a common prescription pain reliever that is structurally similar to morphine and codeine with its analgesic effects identified as a mu-receptor agonist. Due to its opioid-like stimulant effects, the potential for tramadol misuse is a public health concern. As such, the aim of this investigation is to estimate the prevalence of tramadol misuse in a sample of Iranian adolescents and to assess the relationship between tramadol misuse and other substance use. This is the first phase of a prospective survey examining the prevalence of adolescent smoking status, substances use and related factors in Ilam city, Iran. Grade 10 male and female students (n=2000) were recruited using multistage sampling. Self-administered multiple-choice questionnaires were conducted with data analysed using cross tabulations and logistic regression models. The prevalence of lifetime tramadol misuse was 4.8% (7.6% males; 1.8% females). Adjusted odds ratios and confidence intervals for lifetime tramadol misusers reporting substance use during the past month were 2.2 (1.1-4.4) for alcohol, 5.0 (1.5-21.9) for cannabis, 8.9 (2.7-29.4) for ecstasy, 0.5 (0.03-7.0) for methamphetamine and 2.3 (0.7-7.4) for opium. Tramadol could be a related factor or co-factor for adolescent alcohol, cannabis and ecstasy use. We recommend future longitudinal studies to investigate the possible role of tramadol as a gateway drug in the development of substance abuse.

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The influence of prednisone on the efficacy of docetaxel in men with metastatic castration-resistant prostate cancer.

Prednisone and other corticosteroids can provide palliation and tumor responses in patients with prostate cancer. The combination of docetaxel and prednisone was the first treatment shown to prolong survival in men with metastatic castration-resistant prostate cancer (mCRPC). Since the approval of docetaxel in 2004, additional treatments are available, including abiraterone, which is also administered with prednisone. Therefore, patients are increasingly likely to have prednisone therapy several times throughout their disease course, and the contribution of prednisone to the efficacy of docetaxel is unknown. We conducted a retrospective study of patients with mCPRC treated with docetaxel at our institution between 2004 and 2014. Patients were divided into two cohorts based upon whether prednisone was co-administered with docetaxel. Cohorts were further stratified based upon prior prednisone (with abiraterone) or hydrocortisone (with ketoconazole) use. The primary end point was clinical/radiographic progression-free survival (PFS). The secondary end points were >50% PSA response rate and PSA progression-free survival (PSA PFS). A multivariable Cox regression model was constructed to determine whether prednisone use was independently predictive of PFS. We identified 200 consecutive patients for inclusion in the study: 131 men received docetaxel with prednisone and 69 received docetaxel alone. The docetaxel-prednisone cohort had superior PFS compared with the docetaxel-alone cohort (median PFS: 7.8 vs. 6.2 months, HR 0.68 (95% confidence interval (CI) 0.48-0.97), P=0.03). Prednisone use was associated with a reduced risk of progression on docetaxel in the propensity score-weighted multivariable Cox model (P=0.002). Among abiraterone- or ketoconazole-pretreated patients, no difference in PFS was observed between prednisone-containing and non-prednisone-containing docetaxel regimens (median PFS: 7.1 vs. 6.3 months, HR 0.96 (95% CI 0.59-1.57), P=0.87). The incorporation of prednisone potentially augments the efficacy of docetaxel in patients with mCRPC. We hypothesize that this advantage is limited to patients who have not previously received corticosteroids. Prospective confirmation is needed.

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A multi-centre, randomised, open-label study of atomoxetine compared with standard current therapy in UK children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

To assess the broader efficacy (i.e., improvements in quality of life/functional outcomes) of atomoxetine compared with standard current therapy (SCT) in UK paediatric patients with ADHD and to explore clinician/parent/child perceptions of ADHD. A total of 201 patients with ADHD were randomised into this multi-centre, open-label study to receive atomoxetine (n = 104) or SCT (n = 97) for 10 weeks. Broader efficacy was assessed using the parent-rated Child Health and Illness Profile-Child Edition (CHIP-CE) total (global) t-score. Secondary outcome measures included the five CHIP-CE domains; parent-rated Family Burden of Illness Module (FBIM); investigator-rated ADHD-Rating Scale; investigator-rated Clinical Global Impression (CGI)-Severity/Improvement scales; and child-rated Harter Self-Perception Profile (HSPP). Quality of life of children/adolescents with ADHD was extremely compromised at baseline (CHIP-CE total t-scores: atomoxetine, 23.2 +/- 12.2; SCT, 23.9 +/- 11.0), and improved during the 10-week study for both groups; the CHIP-CE score was statistically significantly higher for patients treated with atomoxetine (38.4 +/- 1.3) compared with SCT (30.8 +/- 1.3) at week 10 (p < 0.001). ADHD-RS, CGI-Severity, and CGI-Improvement scores were significantly different between the groups in favour of atomoxetine (p < 0.001). There was a statistically significant difference between the groups in the HSPP Social Acceptance domain in favour of atomoxetine, but not in the five other HSPP domains or FBIM total score. Atomoxetine was well-tolerated. Results from this open-label trial show that atomoxetine is superior to SCT in addressing broader efficacy and functional outcomes in UK children/adolescents with ADHD. This study contributes to the understanding of broader efficacy in children with ADHD, and is timely in light of recent NICE guidance.

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What is a clinically important level of improvement in symptoms of attention-deficit/hyperactivity disorder?

To compare the desired and actual reduction in scores on a parent reported behaviour rating scale in a naturalistic sample of children and adolescents who had been treated with psychostimulant medication, referenced to global ratings of treatment benefit. Forty-five parents reporting poor global response to psychostimulant treatment, 44 reporting moderate response, and 49 reporting a high response retrospectively completed Conners rating scales describing their child prior to treatment, the child currently, and how the parent hoped the child would be following treatment. Percentage actual improvement in behaviour rating scales from baseline ranged from around 25% for the poor responders to above 50% for the high responders. Desired improvement was above 50%, with no significant difference between the groups on level of expectation. Percentage cut points used to indicate clinical improvement reported in previous controlled trials of psychostimulant medication are probably too low, and could lead to an overestimate of treatment effect. Expectation of treatment benefit is unlikely to contribute to variation in treatment response.

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A retrospective analysis of medication prescription records for determining the levels of compliance and persistence to urate-lowering therapy for the treatment of gout and hyperuricemia in The Netherlands.

Urate-lowering therapy (ULT) is a recommended life-long treatment for gout patients. However, despite these recommendations, recurrent gout attacks are commonly observed in clinical practice. The purpose of this study was to assess the levels of compliance and persistence to ULT in The Netherlands, in order to reflect on the current gout care delivered by health professionals. Anonymous prescription records were obtained from IQVIA's Dutch retrospective longitudinal prescription database, containing ULT dispensing data for allopurinol, febuxostat, and benzbromarone from November 2013 to July 2017. Compliance to ULT was determined by calculating the proportion of days covered (PDC) over 12 months. Persistence over 12 months was evaluated by determining the time to discontinuation, without surpassing a refill gap of > 30 days. Association of PDC and persistence with age, gender, and first prescriber were examined using beta regression- and cox-regression models, respectively. There were 45,654 patients who met the inclusion criteria. Overall, 51.7% of the patients had a ULT coverage of ≥ 80% of the days in 1 year (PDC ≥ 0.80), and 42.7% of the patients were still persistent after 1 year. Men, older patients, and patients whose first prescriber was a rheumatologist were more persistent and had a higher PDC. Our results show that medication adherence to ULT after 1 year is suboptimal, considering that current guidelines recommend ULT as a life-long treatment. Future studies addressing the reasons for treatment cessation and improving treatment adherence seem warranted.

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Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis.

The objective of this article is to evaluate the efficacy and safety of gabapentin enacarbil (GEn) for migraine prophylaxis. In this randomized, double-blind, parallel-group study, patients with International Headache Society-defined migraine who met criteria suggesting the need for prophylactic therapy were randomized 2:1:2:2:1 to one of the following five groups, designated according to target daily dose of study medication during the 20-week treatment period: placebo, GEn 1200 mg, GEn 1800 mg, GEn 2400 mg, or GEn 3000 mg. The intent-to-treat population included 523 patients (n = 128 placebo, n = 66 GEn 1200 mg, n = 134 GEn 1800 mg, n = 133 GEn 2400 mg, n = 62 GEn 3000 mg). No statistically significant difference between active treatment (the average of 1800 mg and 2400 mg treatment groups) and placebo was found for change from baseline in the number of migraine headache days during the last four weeks of treatment prior to taper (the primary endpoint). Results of analyses of the primary endpoint using the per protocol population, analyses using imputation methods different from those of the primary analysis, and nonparametric analyses were consistent with the primary analysis in showing no difference between active treatment and placebo. The pattern of results was similar for the secondary efficacy endpoints. Pharmacokinetic data demonstrate that patients had adequate estimated exposure to GEn. The adverse event profile of GEn was consistent with that in previous studies. GEn did not significantly differ from placebo for migraine headache prophylaxis. A high placebo effect should be considered when interpreting these results.

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Simvastatin therapy in lymphocyte cross-match-positive kidney transplantation candidates.

Recent identification of several mechanisms by which statins decrease recruitment of monocytes and T cells into the arterial wall and inhibit both T-cell and B-cell activation and proliferation in vitro prompted us to study the immunomodulatory effects of statins. In this study, we examined the effect of simvastatin therapy on lymphocyte cross-match positivity in kidney transplantation candidates. Simvastatin therapy (20 mg/d) was administered to 25 patients (18 men, 7 women of mean age 34 +/- 11.7 years who displayed positive lymphocyte cross-matches between July 2002 and October 2004. The etiologies of end-stage renal disease were vesicoureteral reflux (n = 5), urinary stone disease (n = 4), glomerulonephritis (n = 6), amyloidosis secondary to familial Mediterranean fever (n = 1), and unknown (n = 9). The lymphocyte cross-match became negative in 10 patients 4-9 months, and successful kidney transplantation was performed in 6 of them. The serum creatinine levels of these patients ranged between 0.8 and 1.4 mg/dL. Two patients required higher doses, but none suffered from adverse effects. The remaining 4 patients are still undergoing pretransplantation evaluation. Simvastatin therapy seems to be a cost-effective and useful method for lymphocyte cross-match-positive kidney transplantation candidates compared with immunoadsorption or intravenous immunoglobulin use.

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Analysis of dose intensity in doxorubicin-containing adjuvant chemotherapy in stage II and III breast carcinoma.

Three hundred thirty-six patients with stage II or stage III breast cancer were treated on an adjuvant protocol containing fluorouracil, doxorubicin, cyclophosphamide, vincristine, and prednisone (FACVP). Depending on the estrogen-receptor (ER) status, the patients were subdivided to receive maintenance chemotherapy with or without tamoxifen. The administered dose intensity of fluorouracil, doxorubicin, and cyclophosphamide (FAC) (mg/m2/wk) relative to the projected dose intensity (based on planned dose) was computed for each patient. The relative dose intensity of the first six cycles of chemotherapy (RDI6) was compared with disease-free survival (DFS). Of the 299 patients who completed at least six cycles of therapy, 83% received dose intensities within 20% of standard intensity (.8 less than or equal to RDI6 less than or equal to 1.2). The group with the highest dose intensity (RDI6 greater than or equal to 1.13) had the longest DFS, though there was not a clear trend of linear association between dose intensity and DFS after adjustment for prognostic factors (P = .16). The patients who received at least standard dose intensity (RDI6 greater than or equal to 1.0) had longer DFS than those whose therapy did not reach standard intensity (RDI6 less than 1.0). This difference was significant in patients with stage III disease (P = .01). The 37 patients who completed fewer than six cycles of chemotherapy had the shortest DFS (5-year DFS of 48% v 65% in the others). This retrospective analysis, in a heterogeneously treated group of patients, did not show the differences in outcome associated with dose intensity as demonstrated in the earlier studies comparing projected dose intensity of various cyclophosphamide, methotrexate-, and fluorouracil (CMF)-containing adjuvant trials. Improved DFS was noted in the stage III patients receiving higher dose intensity. Our failure to demonstrate the differences in stage II patients may be due to the narrow range of dose intensity in this study or to a difference in the dose-response curves depending on the stage of disease.

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Use of topiramate and risk of glaucoma: a case-control study.

To examine the possible link of acute-onset glaucoma with topiramate. Case-control study. A case-control study was conducted among a cohort of subjects who had visited an ophthalmologist in the Province of British Columbia, Canada from 2000 to 2007. Cases were identified as those newly diagnosed with glaucoma (ICD-9 360). For each case, 5 controls were selected and matched to the cases by age and calendar time using density-based sampling. Crude and adjusted rate ratios (RRs) for current and past use of topiramate were computed. As a sensitivity analysis, the risk of glaucoma with a positive control drug (an oral steroid) and a negative control drug (inhaled albuterol) was also assessed. From the initial cohort of 989 591 subjects, 178 264 cases of glaucoma and 891 320 controls were identified. There was a slight increase in the risk of glaucoma among current users of topiramate (RR = 1.23 [95% confidence interval (CI), 1.09-1.40]). This risk was further elevated among new users of the drug (RR = 1.54 [95% CI, 1.09-2.17]). No increase in the risk of glaucoma requiring drug therapy was observed among current topiramate users (RR = 1.09 [95% CI, 0.80-1.61]). We found an increase in the risk of glaucoma with first-time users of topiramate. Future studies are needed to confirm these findings.

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Role of omeprazole in prevention and treatment of postendoscopic variceal sclerotherapy esophageal complications. Double-blind randomized study.

Endoscopic variceal sclerotherapy-related esophageal complications are quite common. The potential efficacy of omeprazole in the prevention and treatment of postsclerotherapy esophageal complications was evaluated in 47 patients with portal hypertension in randomized, placebo-controlled study. Twenty-one patients in the omeprazole group and 23 patients in the placebo group completed the study. The two treatment groups were similar in regards to the etiology of portal hypertension, Child's class, and clinical characteristics. Esophageal ulcers developed in 16 patients in the omeprazole group (2.43 ulcers/patient) and 18 patients in the placebo group (2.39 ulcers/patient). Most of the ulcers (> 90%) healed within 14 days in each group. Esophageal strictures requiring dilatation developed in two and one patient in the omeprazole and placebo groups, respectively. There was no statistically significant difference in regards to the complication rate between the two groups. We conclude that omeprazole is not effective for the prevention or treatment of postsclerotherapy esophageal complications.

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Genome-wide association of lipid-lowering response to statins in combined study populations.

Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy. Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks), Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks), and Treating to New Targets (10 mg/day atorvastatin, 8 weeks). Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8 x 10(-8)). This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0 x 10(-6)). Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol. Using combined GWA analysis from three clinical trials involving nearly 4,000 individuals treated with simvastatin, pravastatin, or atorvastatin, we have identified SNPs that may be associated with variation in the magnitude of statin-mediated reduction in total and LDL-cholesterol, including one in the CLMN gene for which statistical evidence for association exceeds conventional levels of genome-wide significance. PRINCE and TNT are not registered. CAP is registered at Clinicaltrials.gov NCT00451828.

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[Insomnia and its treatment during the postoperative period].

A total of 108 patients have filled in questionnaires on falling asleep, sleeping, night awakenings and other characteristics. Their answers have been analysed and it was concluded that night sleep of patients especially in the postoperative period was characterized by prolonged period of falling asleep (over 30 min in 50% of patients), reduced duration, in 77% of patients night awakenings have been recorded. The use of analgin (1000 mg) in combination with dimedrol (10 mg), promedol (20 mg) for tramal (100 mg) for normalization of sleep in the postoperative period was of little efficacy. Therapy of night sleep disturbances will improve the patients' condition and enhance the efficacy of management after surgical interventions.

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Carvedilol affects the physiological and behavioral response to smoked cocaine in humans.

The noradrenergic system is implicated in mediating some of the physiological effects of cocaine. The purpose of this study was to investigate whether treatment with an adrenergic blocker, carvedilol, which would be expected to attenuate the physiological effects of cocaine, would also attenuate the subjective and behavioral response to cocaine in humans. Twelve crack cocaine users participated in this double-blind, placebo-controlled outpatient study. Acute treatment with 50 mg of oral carvedilol attenuated the smoked cocaine-induced increases in heart rate, systolic and diastolic blood pressure. The number of cocaine self-administrations was lower under 25 mg carvedilol treatment condition compared with 50 mg carvedilol or placebo treatment conditions. The subjective responses to smoked cocaine deliveries were not affected by carvedilol treatment. These results suggest that acute treatment with carvedilol attenuates the physiological effects of smoked cocaine. The effects of carvedilol on cocaine self-administration need to be studied further.

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The place of diuretic enhanced Doppler sonography in distinguishing between obstructive and non-obstructive hydronephrosis in children.

In an attempt to differentiate obstructive from non-obstructive dilation of the renal collecting system in children, a prospective clinical study was carried out. During duplex Doppler sonography examination in 23 children resistive index (RI) and pulsatility index (PI) and RI ratio values before and after intraverous furasemide administration were compared with the findings obtained with diuretic renogram examination (t(1/2)). Evaluation of the results demonstrated that diuresis RI and PI determination may aid differentiation of severely obstructed renal units from those with slight (equivocal) or no obstruction. Kidneys with severe UPJ obstruction tended to have more elevated RI and PI values than the non-obstructed or equivocally obstructed ones. Again, determination of RIR values for each kidney showed the same elevation in severely obstructed kidneys, while non-obstructive or indeterminately obstructed ones demonstrated statistically insignificant changes.

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Patterns of growth factor usage and febrile neutropenia among older patients with diffuse large B-cell non-Hodgkin lymphoma treated with CHOP or R-CHOP: the Intergroup experience (CALGB 9793; ECOG-SWOG 4494).

Patterns of myeloid growth factor (GF) usage and febrile neutropenia (FN) were examined in patients >60 years of age with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) enrolled on CALGB 9793/ECOG-SWOG 4494, receiving initial therapy with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab + CHOP (R-CHOP). Myeloid GFs were administered to 256/520 (49%) patients. Indications for use were: prevent dose reduction/dose delay (81%, 207/256); treat FN or non-febrile neutropenia (NFN) (19%, 48/256). One or more FN episodes occurred in 41% (212/520) of patients, with FN most often in cycle 1 (38% of episodes). In multivariate analysis, risk factors for FN included age >65 years (odds ratio (OR) = 2.6, 95% CI: [1.4, 4.9]) and anemia (hemoglobin <12 g/dl) (OR =2.2, 95% confidence intervals (CI): [1.4, 3.5]. Myeloid GF use was common in this older DLBCL population receiving CHOP-based therapy, as was FN, especially during cycle one. Risk factors predictive for FN should be used prospectively to identify patients for whom myeloid GFs are best utilized.

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Modern approaches to combining sirolimus with calcineurin inhibitors.

Routine renal transplantation maintenance immunosuppression at the University of Nebraska Medical Center consists of rabbit anti-thymocyte globulin (rATG) induction with early steroid withdrawal followed by maintenance with sirolimus and tacrolimus, a regimen we have used with >900 patients. Induction consists of 6 mg/kg rATG in 4 doses of 1.5 mg/kg each on days 0, 2, 4, and 6. Prednisone is used only in association with rATG administration. Maintenance agents are introduced gradually depending on renal function. Since April 2004, we have been conducting a prospective, randomized trial of this regimen versus 2 modifications: administering the rATG induction dose (6 mg/kg) in a single infusion over 24 hours; and, after 6 months, replacing tacrolimus with mycophenolate mofetil (MMF) in half of the study subjects. This study has shown several benefits of single-dose rATG induction, including significantly improved early graft function with both living and deceased donor kidneys and improved 2- to 12-month function in deceased donor organs (P = .026). Single-dose lymphocyte counts return to baseline sooner (2.2 vs 15.3 years; P < .05) without increased rejection (1 year; 8.5% single vs 12.5% divided; P = NS), and single-dose induction reduces chronic allograft nephropathy at 1 year (P = .05). Preliminary results of replacing tacrolimus with MMF show immediately improved renal function (months 1 and 2; P = .02 and .05; months 1-6, P = .058) without increased rejection.

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Trazodone, a triazolopyridine derivative, in primary depressive disorder.

A double-blind controlled study was conducted to compare the effects of imipramine and placebo with trazodone, a new antidepressant, in 45 hospitalized patients with primary depression. After a three to seven-day baseline period, patients were treated for four weeks. Response was assessed by the Hamilton Psychiatric Scale for Depression, Structured Clinical Interview, Clinical Global Impression, and Global Ward Behavior Scale. The antidepressant effect of trazodone was evident within seven days of treatment and persisted throughout the study. Patients treated with imipramine also improved, but the response was not as great or as rapid as in the trazodone group.

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Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.

Randomised trials have shown that aspirin reduces the short-term risk of recurrent colorectal adenomas in patients with a history of adenomas or cancer, but large trials have shown no effect in primary prevention of colorectal cancer during 10 years' follow-up. However, the delay from the early development of adenoma to presentation with cancer is at least 10 years. We aimed to assess the longer-term effect of aspirin on the incidence of cancers. We studied the effect of aspirin in two large randomised trials with reliable post-trial follow-up for more than 20 years: the British Doctors Aspirin Trial (N=5139, two-thirds allocated 500 mg aspirin for 5 years, a third to open control) and UK-TIA Aspirin Trial (N=2449, two-thirds allocated 300 mg or 1200 mg aspirin for 1-7 years, a third placebo control). We also did a systematic review of all relevant observational studies to establish whether associations were consistent with the results of the randomised trials and, if so, what could be concluded about the likely effects of dose and regularity of aspirin use, other non-steroidal anti-inflammatory drugs (NSAID), and the effect of patient characteristics. In the randomised trials, allocation to aspirin reduced the incidence of colorectal cancer (pooled HR 0.74, 95% CI 0.56-0.97, p=0.02 overall; 0.63, 0.47-0.85, p=0.002 if allocated aspirin for 5 years or more). However, this effect was only seen after a latency of 10 years (years 0-9: 0.92, 0.56-1.49, p=0.73; years 10-19: 0.60, 0.42-0.87, p=0.007), was dependent on duration of scheduled trial treatment and compliance, and was greatest 10-14 years after randomisation in patients who had had scheduled trial treatment of 5 years or more (0.37, 0.20-0.70, p=0.002; 0.26, 0.12-0.56, p=0.0002, if compliant). No significant effect on incidence of non-colorectal cancers was recorded (1.01, 0.88-1.16, p=0.87). In 19 case-control studies (20 815 cases) and 11 cohort studies (1 136 110 individuals), regular use of aspirin or NSAID was consistently associated with a reduced risk of colorectal cancer, especially after use for 10 years or more, with no difference between aspirin and other NSAIDs, or in relation to age, sex, race, or family history, site or aggressiveness of cancer, or any reduction in apparent effect with use for 20 years or more. However, a consistent association was only seen with use of 300 mg or more of aspirin a day, with diminished and inconsistent results for lower or less frequent doses. Use of 300 mg or more of aspirin a day for about 5 years is effective in primary prevention of colorectal cancer in randomised controlled trials, with a latency of about 10 years, which is consistent with findings from observational studies. Long-term follow-up is required from other randomised trials to establish the effects of lower or less frequent doses of aspirin.

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Integrating interacting drugs and genetic variations to improve the predictability of warfarin maintenance dose in Chinese patients.

Compared with genetic factors, drug interactions are largely unexplored in pharmacogenetic studies. This study sought to systematically investigate the effects of VKORC1, STX4A, CYP2C9, CYP4F2, CYP3A4, and GGCX gene polymorphisms and interacting drugs on warfarin maintenance dose. A retrospective study of 845 Chinese patients after heart valve replacement receiving long-term warfarin maintenance therapy was conducted. Thirteen polymorphisms in the six genes were genotyped, and 36 drugs that may interact with warfarin were investigated. Single-nucleotide polymorphism association analysis showed that VKORC1, CYP2C9 and CYP4F2 variations were highly associated with the warfarin maintenance dose. Among 36 drugs that may interact with warfarin, fluconazole, amiodarone, and omeprazole were associated with the requirement for 45.8, 16.7, and 16.7% lower median warfarin dose (all P<0.05 with a false discovery rate <0.05). The final pharmacogenetic equation explained 43.65% of interindividual variation of warfarin maintenance dose with age, body surface area, VKORC1 g.3588G>A, CYP2C9*3, CYP4F2 c.1297G>A, amiodarone, fluconazole, and diltiazem accounting for 1.97, 2.74, 24.12, 3.94, 1.64, 5.92, 2.47, and 0.84% of variation. The present study indicated that VKORC1, CYP4F2, and CYP2C9 genotypes and interacting drugs had a significant impact on the warfarin maintenance dose in Chinese patients with heart valve replacement and demonstrated that integrating interacting drugs can largely improve the predictability of the dose algorithm.

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Comparative effects of carvedilol and metoprolol on regional vascular responses to adrenergic stimuli in normal subjects and patients with chronic heart failure.

Adrenergic receptor blockers used in the treatment of heart failure have distinct receptor affinity profiles. We hypothesized that alpha-adrenergic-blocking effects of carvedilol would limit vasoconstriction in response to adrenergic stimuli when compared with metoprolol. Forearm vascular resistance responses to isometric handgrip and cold pressor test were determined by plethysmography before and during adrenergic receptor blockade in prospective randomized trials. Acute effects were assessed in a crossover trial in normal subjects (single dose of 25 mg carvedilol, 100 mg metoprolol tartrate, and placebo). Chronic effects (25 mg carvedilol BID versus 200 mg extended-release metoprolol succinate daily for 6 months) were assessed in a parallel group trial of chronic heart failure subjects. In normal subjects, carvedilol decreased forearm vascular resistance responses to adrenergic stimuli when compared with metoprolol and placebo (isometric handgrip -3.5 U for carvedilol versus -1.2 U for metoprolol and -2.2 U for placebo, P=0.15; cold pressor test 3.1+/-8.9 U for carvedilol versus 9.0+/-2.7 U for metoprolol and 8.2+/-5.8 U for placebo, P<0.05). In heart failure subjects, vasomotor responses to isometric handgrip and cold pressor test did not differ between treatment groups. Acute administration of carvedilol attenuates the vasoconstriction response to adrenergic stimuli when compared with placebo and metoprolol in normal subjects, whereas chronic administration of carvedilol does not attenuate the vasoconstrictor response to adrenergic stimuli when compared with metoprolol in heart failure subjects. These data suggest that long-term benefits of carvedilol in heart failure are not mediated by alpha-adrenergic blockade.

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Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis.

We performed this meta-analysis to update the clinical evidences on the relation between clopidogrel non-responsiveness and clinical outcomes in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention. An electronic literature search through MEDLINE, EMBASE, Web of Science, and the Cochrane Library and bibliographies of retrieved articles up to January, 2009 was conducted. Studies were included if they had a cohort prospective design, if they analysed clopidogrel responsiveness in CAD patients in relation to death and/or occurrence of adverse coronary events during follow-up, and if they reported an adequate statistical analysis. Fourteen studies, totalling 4,564 CAD patients followed for a time ranging from 14 days to one year, were included. The cumulative analysis reported that residual platelet reactivity despite clopidogrel treatment was significantly associated with an increased risk of death and/or thrombotic recurrences (odds ratio [OR] 5.67, 95% confidence interval [CI] 2.97 to 10.84; p<0.00001). However, four studies contributed to a consistent heterogeneity of the model and evidenced a significant risk of publication bias, so were excluded from the analysis. This exclusion, however, did not influence the overall result, by confirming the increased risk of cardiovascular recurrences for patients with a poor response to clopidogrel treatment (OR 3.58, 95%CI 2.54 to 5.05; p<0.00001). The present updated meta-analysis documents a significant association between residual platelet reactivity under clopidogrel treatment and recurrent cardiovascular events, so suggesting the relevance of ongoing interventional studies aimed at tailoring the antithrombotic therapy in CAD patients.

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Inhaled prostaglandin E1 for treatment of acute lung injury in severe multiple organ failure.

Acute lung injury is characterized by hypoxemia due to pulmonary ventilation/perfusion-mismatching. I.v. administered prostaglandin E1 (PGE1), a vasodilator with a high pulmonary clearance, has been studied in acute lung injury. Inhalation of the vasodilators nitric oxide and prostacyclin improved oxygenation by selective dilation of the pulmonary vasculature in ventilated lung areas. In the present study, PGE1 inhalation was used for treatment of acute lung injury. Fifteen patients with acute lung injury defined as PaO2/fraction of inspired oxygen (FIO2) <160 mm Hg were treated with PGE1 inhalation in addition to standard intensive care. The drug was continuously delivered via a pneumatic nebulizer. Acute physiology and chronic health evaluation system II and multiple organ failure scores were (mean +/- SEM) 33 +/- 2 and 10 +/- 0.3, respectively. Inhaled PGE1 was administered for 103 +/- 17 h at a dose of 41 +/- 2 microg/h. The PaO2/FIO2 ratio increased from 105 +/- 9 to 160 +/- 17 mm Hg (P < 0.05) and to 189 +/- 25 mm Hg (P < 0.05) after 4 h and 24 h, respectively. PGE1 inhalation decreases in mean pulmonary artery pressure and central venous pressure were not statistically significant. Mean arterial pressure, pulmonary capillary wedge pressure, cardiac output, and heart rate remained unchanged. Intensive care unit mortality was 40%. The present data suggest that inhaled PGE1 is an effective therapeutic option for improving oxygenation in patients with acute lung injury. Whether inhaled PGE1 will increase survival in acute lung injury should be investigated in a controlled prospective trial. In patients with severe acute lung injury and multiple organ failure, inhaled prostaglandin E1 improved oxygenation and decreased venous admixture without affecting systemic hemodynamic variables. Controlled clinical trials are warranted.

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[Short- and long-term effects of intensified versus conventional antilipidemic therapy in patients with coronary heart disease. Results from the Lipid-Coronary Artery Disease (L-CAD) Study].

In a prospective, randomized study of patients with acute manifestation of coronary heart disease and hypercholesterolemia (LDL cholesterol >/= 130 </= 250 mg/dl), we compared the effect of an early-initiated, intensified therapy to usual care antilipidemic therapy with respect to coronary lesions and clinical events. Patients were included immediately following acute myocardial infarction and/or PTCA because of severe/instable angina pectoris. The intensified therapy consisted of pravastatin 20-40 mg with addition of colestyramine and/or nicotinic acid, if necessary, to achieve an LDL cholesterol </= 130 mg/dl. In the control group, antilipidemic therapy was left up to the private physician. The group with intensified therapy consisted of 70 patients (LDL cholesterol 179 +/- 27 mg/dl, age 55 +/- 10 years, 81% males), the control group of 56 patients (LDL cholesterol 177 +/- 28 mg/dl, age 58 +/- 11 years, 79% males). Cholesterol was reduced longterm by 28% under intensified therapy, but it remained constant in the control group. Quantitative coronary angiography revealed a mean of increase minimal lumen diameter of 0.05 mm after 6 months with intensified therapy and of 0.13 mm after 24 months. Under conventional therapy, however, it decreased by 0.08 mm after 6 months, and by 0.18 mm after 24 months (p < 0.01). In addition, within 12 months of therapy, significantly (p < 0.01) less cardiovascular clinical events were observed in patients under intensified therapy. After 2 years 43% (n = 22) of the controls, but only 17% (n = 14) of the patients with intensified therapy experienced a major clinical event (p < 0.03), i. e. death, myocardial infarction, necessary coronary intervention, cerebral infarction or new peripheral vascular disease. This study is the first to show that aggressive early - initiated cholesterol-lowering therapy can induce regression and reduce progression of coronary lesions already after 6 months. These changes are accompanied by a significant reduction in clinical events. The results of our study underline the necessity of immediate cholesterol screening and early intensive antilipemic therapy at the latest when of coronary heart disease becomes manifest.

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Bone mineral density in patients with alopecia areata treated with long-term intralesional corticosteroids.

Intralesional corticosteroid injections are a common treatment for patchy alopecia areata, the most prevalent subtype of this autoimmune hair disorder. To date, no studies have examined the potential adverse effects of this therapy on bone mineral density (BMD). In this retrospective, cross-sectional case series, 18 patients with patchy alopecia areata treated at 4- to 8-week intervals with intralesional triamcinolone acetonide for at least 20 months were evaluated for BMD using dual-energy x-ray absorptiometry (DXA). Follow-up DXA measurements were obtained in those with abnormal findings. Nine out of 18 patients (50%) had abnormal DXA results. Patients with the following risk factors were more likely to have abnormal BMD: age older than 50 years, body mass index less than 18.5 kg/m2, lack of weight-bearing exercise, smoking history, postmenopausal status, past stress fracture, family history of osteopenia or osteoporosis, and a cumulative intralesional triamcinolone acetonide dose of greater than 500 mg. Patients with patchy alopecia areata who receive chronic intralesional triamcinolone acetonide therapy should be counseled on preventive measures for osteoporosis and monitored for effects on BMD.

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Comparison of two long-acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.

1 Eight healthy men received two long-acting formulations of metoprolol 200 mg (SA Astra, SR Geigy), conventional metoprolol 200 mg and atenolol 100 mg once daily for 1 week each in balanced, crossover fashion. There was a washout period of at least a week between each phase. 2 On the last day of each phase, post-exercise heart rate was recorded at intervals and compared to pretreatment values. Plasma metoprolol concentrations were measured. 3 The mean AUC was similar after each of the three formulations of metoprolol (relative bioavailability of SA and SR v conventional was 97%) but with SA and SR metoprolol the time to peak was significantly delayed by about 2 h. 4 In comparison to conventional metoprolol only metoprolol SA was associated with significantly higher plasma metoprolol concentrations at the end of a dosing interval (mean values: conventional, 25 ng/ml, SR 37 ng/ml, SA 51 ng/ml). 5 Mean (+/- s.d.) reduction in exercise tachycardia at the end of a dosing interval was significantly greater with atenolol (14.8 +/- 4.5%) and metoprolol SA (13.7 +/- 10.3%) than with metoprolol SR (10 +/- 8.4%) and conventional metoprolol (8.2 +/- 7.1%). 6 The variability in beta-adrenoceptor blockade at 24 h was much greater with each of the three metoprolol formulations than that with atenolol. This was explained by the variability in metoprolol metabolism. 7 Oxidation phenotype testing with debrisoquine showed there were six extensive metabolisers and two poor metabolisers. The AUC, half-life and response to metoprolol at 24 h were much greater in poor metabolisers. Response to atenolol was not influenced by phenotype.

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Comparison of antidepressant classes and the risk and time course of suicide attempts in adults: propensity matched, retrospective cohort study.

Placebo-controlled clinical trials have led to concern over possible increased risk of suicide-related events in some populations exposed to antidepressants. To evaluate the risk of suicide attempts by antidepressant drug class and the presence or absence of depression. A retrospective propensity-matched new-user cohort study was used to compare participants with incident depression classified by antidepressant treatment with each other and with the general population. Among the treated group, the suicide attempt rate peaked in the month prior to diagnosis then decreased steadily over the next 6 months. Among the pharmacologically untreated group, the highest rate was seen in the second month after diagnosis. Cohorts with depression had significantly higher suicide attempt risk than the general population, but the treated group did not differ significantly from the untreated group. Patients on antidepressants did not have significantly higher risk compared with untreated patients. No significant differences were observed for patients treated with individual serotonin-noradrenaline reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) or by class (SSRI v. SNRI cohorts).

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Quadruple therapy compared with dual therapy for eradication of Helicobacter pylori in ulcer patients: results of a randomized prospective single-centre study.

To assess the efficacy and side-effect profile of two currently advocated treatment regimens for eradicating Helicobacter pylori. A randomized, controlled, open, single-centre study. A community hospital in The Netherlands. Seventy-six consecutive patients with (chronic) ulcer disease and biopsy-proven H. pylori infection, but without active ulceration at the time of inclusion. Patients were randomly allocated to 1 week of quadruple therapy with omeprazole, bismuth, tetracycline and metronidazole (group 1) or 2 weeks of dual therapy with omeprazole and amoxicillin (group 2). Group 1 patients were pretreated with omeprazole for 3 days. Cure was confirmed by obtaining 10 endoscopic biopsies for urease testing, histology and culture 6 weeks after treatment. Side-effects were scored on a standard questionnaire. Three patients were lost to follow-up. In the 'intention to treat' analysis 37 (92.5%) of 40 patients in group 1 were cured compared with 20 (55.6%) of 36 patients in group 2 (P < 0.001). The difference in efficacy was 36.9% (95% confidence interval 18.7-55.1%). Side-effects were fewer and milder in group 2, but all patients in both groups were able to complete the course of treatment. Dual therapy is significantly less effective in curing H. pylori infection in peptic ulcer patients than quadruple therapy. No patients were intolerant to either treatment. On the basis of the low efficacy of dual therapy, we believe that this therapy should not be used as a first-line treatment strategy. We confirmed our previous finding that 1 week of quadruple therapy is tolerated well and that it is highly effective against metronidazole-sensitive as well as metronidazole-resistant strains of H. pylori.

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Spontaneous superior ophthalmic vein thrombosis: a rare entity with potentially devastating consequences.

Spontaneous superior ophthalmic vein thrombosis (SOVT) is a rare entity. We describe three patients with spontaneous ophthalmic vein thrombosis, each with various risk factors. A retrospective review of three patients with a diagnosis of superior ophthalmic vein thrombosis. Clinical characteristics, radiographic features, management techniques and outcomes are described. All patients presented with unilateral painful proptosis. Two patients had intact light perception, whereas one patient presented with absent light perception. All patients had identifiable risk factors for thrombosis, which included sickle cell trait, hereditary hemorrhagic telangectasia and colon cancer with recurrent deep vein thrombosis. Anticoagulation was initiated in two patients. Resolution of proptosis was seen in all patients, with no recovery of vision in one patient. Risk factors for spontaneous superior ophthalmic vein thrombosis are multifactorial. MRI and MRV confirm the diagnosis of SOVT. Despite urgent intervention devastating visual loss may occur.

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Loracarbef (LY163892) versus amoxicillin-clavulanate in the treatment of bacterial acute otitis media with effusion.

The efficacy and safety of loracarbef, a new beta-lactam antibiotic, was compared with that of amoxicillin-clavulanate potassium in the treatment of bacterial acute otitis media with effusion. A double-blind format was utilized to administer 10-day, randomized, parallel treatment regimens to patients who were between 6 months and 12 years of age. The most prevalent causative pathogens found in the two treatment groups were Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella (Branhamella) catarrhalis. The percentages of favorable posttherapy clinical responses in evaluable patients were similar for both drugs: 87.3% (124/142) of the loracarbef group, compared with 91.5% (130/142) of the amoxicillin-clavulanate group, showed favorable responses within 72 hours after treatment. Ten to sixteen days after treatment, 68.1% of the loracarbef group, compared with 76.1% of the amoxicillin-clavulanate group, showed favorable responses. More patients in the amoxicillin-clavulanate group reported treatment-emergent events: 46.1% compared with 35.8% in the loracarbef group (p = 0.023). Diarrhea was the most frequently reported event, occurring in 13.3% of the loracarbef group and in 26.3% of the amoxicillin-clavulanate group (p less than 0.001). Vomiting was reported by 5.8% of the loracarbef group and 10.3% of the amoxicillin-clavulanate group (p = 0.072). Loracarbef is comparable in efficacy to amoxicillin-clavulanate in the treatment of bacterial acute otitis media with effusion and has a more desirable safety profile.

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Brain activity in adolescent major depressive disorder before and after fluoxetine treatment.

Major depression in adolescents is a significant public health concern because of its frequency and severity. To examine the neurobiological basis of depression in this population, the authors studied functional activation characteristics of the brain before and after antidepressant treatment in antidepressant-naive depressed adolescents and healthy comparison subjects. Depressed (N=19) and healthy (N=21) adolescents, ages 11 to 18 years, underwent functional MRI assessment while viewing fearful and neutral facial expressions at baseline and again 8 weeks later. The depressed adolescents received 8 weeks of open-label fluoxetine treatment after their baseline scan. Voxel-wise whole brain analyses showed that depressed youths have exaggerated brain activation compared with healthy comparison subjects in multiple regions, including the frontal, temporal, and limbic cortices. The 8 weeks of fluoxetine treatment normalized most of these regions of hyperactivity in the depressed group. Region-of-interest analyses of the areas involved in emotion processing indicated that before treatment, depressed youths had significantly greater activations to fearful relative to neutral facial expressions than did healthy comparison subjects in the amygdala, orbitofrontal cortex, and subgenual anterior cingulate cortex bilaterally. Fluoxetine treatment decreased activations in all three regions, as compared with the repeat scans of healthy comparison subjects. While effective treatments are available, the impact of depression and its treatment on the brain in adolescents is understudied. This study confirms increases in brain activation in untreated depressed adolescents and demonstrates reductions in these aberrant activations with treatment.

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Non-steroidal anti-inflammatory drugs, polygenic risk score and colorectal cancer risk.

The regular use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced colorectal cancer (CRC) risk. To explore whether this association varies according to background polygenic risk for CRC. Data were collected from a large population-based case-control study on CRC in Germany. A polygenic risk score (PRS) based on 140 CRC-related risk loci was used to quantify the genetic risk. The associations of regular use of NSAIDs (≥2times per week for at least 1 year) with CRC risk were estimated in the whole population and in subgroups according to PRS levels using multivariable logistic regression. The impact of NSAIDs on CRC risk was compared to PRS using the 'genetic risk equivalent' (GRE), a recently developed metric for effective risk communication. In total 5129 CRC cases and 4093 controls were included in this analysis. The regular use of NSAIDs (including aspirin) was associated with reduced CRC risk [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.59, 0.74], as was regular use of aspirin only (OR 0.73, 95% CI 0.65, 0.83), without indication of interaction with the PRS (P = 0.10 and 0.22 respectively). The effect of NSAID use was equivalent to the effect of having a 32 percentiles lower PRS (GRE -32, 95% CI -41, -22). The regular use of NSAIDs is associated with greatly reduced CRC risk regardless of individual genetic profile. With an equivalent reduction of relative risk across all polygenic risk groups, absolute risk reduction would be expected to be strongest among those with the highest polygenic risk score.

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Failure of amoxicillin to produce false-positive urine screens for cocaine metabolite.

Amoxicillin has been causally linked in the lay and medical literature to false-positive urine drug screens for cocaine metabolites. An exhaustive search of the peer-reviewed medical literature revealed no data to support this link. We hypothesized that amoxicillin does not cause false-positive urine drug screens for cocaine metabolites. To test this hypothesis, we examined the urine of 33 subjects administered a course of amoxicillin, subjecting the specimens to four common urine screening immunoassays. Thirty-one specimens were negative for the cocaine metabolite, benzoylecgonine (BE), by all four screening methods; two were positive for BE by all four screening methods. Both positive specimens were confirmed by gas chromatography-mass spectrometry (GC-MS) for the presence of BE at > 150 ng/mL. Three specimens that screened negative, but produced absorbance values that were intermediate between negative and positive controls, were submitted for GC-MS analysis; BE was detected in all three specimens at concentrations of 54, 94, and 119 ng/mL. Twenty-eight specimens produced screening results indistinguishable from negative controls. Within the limitations of the study design, we conclude that amoxicillin is unlikely to produce false-positive urine screens for cocaine metabolites.

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Prasugrel versus clopidogrel in patients with ST-segment elevation myocardial infarction according to timing of percutaneous coronary intervention: a TRITON-TIMI 38 subgroup analysis (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38).

This study sought to evaluate the efficacy of prasugrel versus clopidogrel in ST-segment elevation myocardial infarction (STEMI) by the timing of percutaneous coronary intervention (PCI). Treatment strategies and outcomes for patients with STEMI may differ when treated with primary compared with secondary PCI. STEMI patients in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38) were randomized to prasugrel or clopidogrel on presentation if primary PCI was intended or later during secondary PCI. Primary PCI was defined as within 12 h of symptom onset. The primary endpoint was cardiovascular death, myocardial infarction (MI), or stroke. Because periprocedural MI is difficult to assess in the setting of STEMI, we performed analyses excluding these events. Reductions in the primary endpoint with prasugrel versus clopidogrel (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.65 to 0.97; p = 0.022) were consistent between primary and secondary PCI patients at 15 months (HR: 0.89; 95% CI: 0.69 to 1.13 vs. HR: 0.65; 95% CI: 0.46 to 0.93; p interaction = 0.15). However, a tendency toward a difference in treatment effect at 30 days (HR: 0.68; 95% CI: 0.54 to 0.87; p = 0.002) was observed between primary and secondary PCI patients (HR: 0.81; 95% CI: 0.60 to 1.09 vs. HR: 0.51; 95% CI: 0.34 to 0.76; p interaction = 0.06). When periprocedural MI was excluded, the efficacy of prasugrel remained consistent among primary and secondary PCI patients at 30 days (HR: 0.53; 95% CI: 0.34 to 0.81 vs. HR: 0.44; 95% CI: 0.22 to 0.88; p interaction = 0.68) and 15 months (HR: 0.76; 95% CI: 0.56 to 1.03 vs. HR: 0.75; 95% CI: 0.46 to 1.21; p interaction = 0.96). The efficacy of prasugrel versus clopidogrel was consistent irrespective of the timing of PCI, particularly in preventing nonprocedural events. (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; NCT00097591).

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Social judgment processes in hyperactive boys: effects of methylphenidate and comparisons with normal peers.

Although there is consensus that ADHD children have serious social problems, there is little understanding of the mechanisms underlying or accompanying such problems. To examine the possibility of atypical or faulty social reasoning, we presented ADHD and normal boys with a social perception task that entailed evaluating the behaviors of unknown peers. ADHD "judges" participated under both methylphenidate and placebo conditions, and on each occasion they evaluated an unfamiliar ADHD "target" in each medication state. In contrast to placebo, methylphenidate appeared to dampen overall response rates in ADHD judges, but there was no effect on sensitivity to medication-related differences. Regardless of their own medication state, ADHD judges identified more undesirable behaviors in peers on placebo than in those taking methylphenidate. Judges with the most serious behavior problems tended to identify the greatest number of negative behaviors in peers, especially when both judge and target were unmedicated. There were no effects of target medication status on detections of positive behaviors and few differences in detection patterns of ADHD versus normal judges. Discussion focused on the need to distinguish general regulatory from specific social-cognitive processes.

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Efficacy and safety of combined parenteral and oral steroid therapy in Graves' orbitopathy.

Glucocorticoids (GC) are the treatment of choice for moderate-to-severe and active Graves' orbitopathy (GO), but optimal treatment is still . The aim of the present study was to analyze the efficacy and tolerability of combined parenteral GC pulse therapy followed by oral GC in the interpulse period. The study included 50 patients (48 ± 10 years; 37 female) with untreated, active and moderate-to-severe GO. Patients received 500 mg of methylprednisolone in 500 ml of physiologic saline. Infusion was repeated after 48 h and then followed by tapering doses of oral prednisone and the cycle repeated each month for the next 5 months. The cumulative dose was 10.2g.Ophthalmic assessment was performed before and 6 months after start of treatment. Side effects of GC therapy were evaluated and recorded each month. GC showed the greatest effectiveness on soft tissue changes (incorporated in the CAS). Median CAS values decreased from 4.5 to 2 (p>0.001). Improvement was demonstrated in 37 patients (74%), there was no change in 13 patients (26%) and none of the patients presented with deterioration of inflammatory status. Diplopia improved in 21 patients (42%), was unchanged in 28 patients (56%) and deteriorated in 1 patient (2%). Improvement in visual acuity occurred in 36% of patients. At 6 months, 33/50 patients (66%) demonstrated overall treatment response. Response to GC therapy was influenced by CAS, TSHRAb and smoking behavior. The only independent parameter associated with positive treatment response was CAS ≥ 4 (p<0.001). Side effects occurred in 35/50 patients (70%) and the vast majority of them were mild to moderate. During the 6-months follow-up period, 2/33 patients (6%) had relapsing GO. With appropriate selection of patients and careful monitoring during and after treatment, combined parenteral and oral GC therapy is effective and safe.

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Treating hyperlipidemia in African Americans.

The purpose of this paper is to provide information concerning the treatment of hyperlipidemia in African Americans. There is a similar prevalence of hypercholesterolemia in Blacks and Whites, but Blacks have been neglected in most pharmacological studies of hyperlipidemia. Intimal atherosclerotic involvement of the aorta and coronary artery occurs in young Black and White males. Epidemiological studies suggest there is a higher mortality rate due to coronary disease in Blacks vs Whites in the United States. Thirty-four percent of Blacks require a fasting lipid profile and 9% of Black adults aged 20 years or older would require lipid-lowering therapy. However, fewer Blacks (26%) than Whites (47%) are aware of their hypercholesterolemia. Studies with lovastatin and pravastatin show efficacy in the treatment of hypercholesterolemia. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is designed to determine all-cause mortality for subjects receiving pravastatin vs a control group receiving "usual care." Randomized, blinded, prospective trials are needed to assess the impact of hyperlipidemia as a risk factor, and the impact of its reduction in African Americans.

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Bone mineral density and bone microarchitecture after long-term suppressive levothyroxine treatment of differentiated thyroid carcinoma in young adult patients.

Bone mineral density (BMD) seems not to be decreased in young patients given long-term suppressive doses of levothyroxine (LT4), but information regarding the bone microstructure in these patients is lacking. The aim of this study was to determine whether supraphysiologic doses of LT4, initiated during childhood or adolescence for treatment of differentiated thyroid carcinoma (DTC), have any detrimental effects on bone microarchitecture as evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Seventeen patients (27.3 ± 7.1 years old) with DTC with subclinical hyperthyroidism since adolescence and 34 healthy volunteers matched for age, sex, and body mass index were studied by dual-energy X-ray absorptiometry (DXA) to determine the areal BMD at the lumbar spine, hip, and proximal third of the radius. Volumetric BMD and structural parameters of the trabecular and cortical bone were assessed by HR-pQCT of the distal radius and distal tibia. DTC patients were given suppressive doses of LT4 starting at a mean age of 12.6 years, and the mean duration of treatment was 14.2 years. In DTC patients, clinical parameters did not correlate with DXA or HR-pQCT parameters. No differences were found between the patients and controls with respect to BMD and Z scores at any site evaluated by DXA, and no differences were found in the bone microstructure parameters evaluated by HR-pQCT. This cross-sectional study suggests that long-standing suppressive therapy with LT4 during the attainment of peak bone mass may have no significant adverse effects on bone density or microarchitecture.

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Fluoxetine: relationships among dose, response, adverse events, and plasma concentrations in the treatment of depression.

Data from two large, fixed-dose trials support the efficacy of a fixed 20 mg/day dose of fluoxetine in the treatment of depression. Data pooled from these two studies suggest a dose relationship for adverse events during fluoxetine therapy. At a fixed 20 mg/day dose, only nausea and insomnia were reported by a significantly greater percentage of patients (p less than .05) than those treated with placebo. However, at 60 mg/day, nausea, anxiety, dizziness, and insomnia were reported by a significantly greater percentage of patients (p less than .05) than those treated with placebo. The potential relationship of response rate [Hamilton Rating Scale for Depression (HAM-D) total decrease greater than or equal to 50%] to plasma concentrations of fluoxetine, norfluoxetine, and fluoxetine plus norfluoxetine was evaluated in one study which excluded early responders (less than or equal to 3 weeks of therapy). No significant relationship was found. Furthermore, adverse events were not related to plasma concentrations.

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Adverse reactions to subcutaneous immunotherapy in patients with allergic rhinitis, a real-world study.

The efficacy of subcutaneous immunotherapy (SCIT) for allergic rhinitis (AR) have been proven but application is still limited by concerns about the safety. The aims of this study were to investigate the incidence of adverse reactions and to ascertain possible risk factors in patients treated with SCIT in central China. This study retrospectively analyzed the application of SCIT from 2016 to 2018, in 236 patients with AR. After each injection, allergen dosage and details about local reactions (LRs)/systemic reactions (SRs) were recorded. Totaling 236 patients received 5844 injections. The rates of LR were 3.0% per injection and 34.7% per patient, while the rates of SR were 0.48% per injection and 10.6% per patient. 86.9 percent LRs were small. Most SRs were grade 1 (16/57.1%), followed by grade 2 (8/28.6%), grade 3 (4/14.3%). No fatal SRs was recorded. Children, high sensitization and absence of premedication were identified as risk factors for LRs. Recurrent LRs increased the risk of SRs. Premedication could reduce the number and severity of LRs, but not SRs. Dual therapy with antihistamine and montelukast did not provide additional benefit when compared with antihistamine alone. The incidence of SRs was low while LRs were common in SCIT. Children may be prone to develop LRs, while pretreatments could reduce the number and severity of LRs. Recurrent LRs was a risk factor for SRs.

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Salbutamol dry powder inhaler: efficacy, tolerability, and acceptability study.

Dry powder inhaler (DPI) devices are frequently used in children over 5 years of age in order to avoid coordination difficulties often seen with the use of pressurized metered dose inhalers (pMDI). This study assessed the efficacy, tolerability, and acceptability of salbutamol delivered via two delivery systems, in a population of pediatric patients. The primary aim of the study was to investigate the bronchodilator efficacy of a single dose (100 microg) of salbutamol administered via a dry powder inhaler (Clickhaler) compared to a similar dose administered by a pressurized metered dose inhaler via a large-valved holding chamber (VHC) to children with asthma. The study comprised two phases: the first comparator phase, followed by an open 4-week treatment period. Sixty-one children with a mean (SD) age of 11.3 years (2.9) (range, 6-17) and mild or moderate asthma completed the study. The primary efficacy endpoint, forced expiratory volume in 1 sec (FEV1), indicated that there was no clinically or statistically significant difference between the bronchodilator effects of salbutamol delivered via either device, with a maximum posttreatment percentage change in FEV1 (SD) of 12.4% (10.0) and 14.15 (9.3) for Clickhaler and pMDI plus VHC, respectively. Most patients rated the Clickhaler as easy to use (97%) and liked the device (84%). Both treatments were well--tolerated. These results support the suitability of salbutamol Clickhaler as an acceptable, well-tolerated, and effective alternative to a pMDI plus VHC in mild to moderate asthmatic children over age 6 years.

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Zolpidem and restoration of consciousness.

Zolpidem has been reported to cause temporary recovery of consciousness in vegetative and minimally conscious patients, but how often and why this occurs are unknown. The authors aimed to determine the frequency of this phenomenon and whether it can be predicted from demographic and clinical variables. This is a placebo-controlled, double-blind, single-dose, crossover study performed by caregivers and replicated by trained professionals, for naive participants. Four previously identified responders were also studied to further characterize the clinical drug response. Eighty-four participants with traumatic and nontraumatic disorders of consciousness of at least 4 mos' duration were studied. Four "definite responders" were identified, but no demographic or clinical features were predictive of the response. Indicators of a drug response included increased movement, social interaction, command following, attempts at communication, and functional object use; typically lasted 1-2 hrs; and sometimes ended with increased somnolence. Adverse events were more common on zolpidem than placebo, but most were rated as mild. Approximately 5% (4.8%) of the participants responded to zolpidem, but the responders could not be distinguished in advance from the nonresponders. Future research is needed to understand the mechanism of zolpidem in enhancing consciousness and its potential role in treatment and research.

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The effects of a single, intravenous dose of bumetanide versus furosemide in patients with ascites and edema due to alcoholic liver disease.

Ascites with or without edema, secondary to alcoholic liver disease, which had failed to respond to conventional in-hospital medical treatment with thiazides, spironolactone, and salt restriction was treated with a single intravenous dose of 0.5 mg bumetanide or 20 mg furosemide. In this single-blind, randomized, parallel study in 20 men over 18 years of age, significant diuresis and increased excretion of sodium, potassium, and chloride occurred with both drugs. Weight loss was slight but significant within groups but not between drug treatments. Osmolality was significantly decreased after both treatments due to the magnitude of urine volume. Sodium/potassium ratio was significantly increased up to 120 minutes after both treatments. Creatinine excretion and clearance were increased after treatment with bumetanide but not significantly. In the furosemide group, the increase was first significant but after 90 minutes remained decreased. Supine and standing blood pressure and pulse rate changes were negligible. EKG monitoring revealed no abnormalities. No consistent alterations of laboratory tests were identified after treatment, nor were any important clinical adverse responses recognized. A 15-decibel unilateral high-frequency hearing loss was observed following bumetanide treatment in one patient with prior evidence of ear disease.

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Mortality in major affective disorder: relationship to subtype of depression. The Danish University Antidepressant Group.

A total of 219 inpatients with a DSM-III diagnosis of major depression, 150 women and 69 men, were followed prospectively for 3-10 years and mortality was recorded. The patients were previous participants in psychopharmacological multicenter trials, which were carried out for the purpose of comparing the antidepressant effect of newer 5-HT reuptake inhibitors with that of the tricyclic antidepressant drug, clomipramine. The study comprised patients with a total Hamilton Rating Scale for Depression score of > or = 18 and/or a Hamilton subscale score of > or = 9. Diagnostic classification according to the Newcastle I Scale in endogenous and nonendogenous depression was performed. The observed mortality was significantly greater than that expected. The increased mortality was essentially due to suicides and mainly found among women. Patients scored as nonendogenously depressed had a significantly higher suicide rate than endogenously depressed patients. The excess number of suicides in the nonendogenous group largely occurred within the first year of observation. No association was found between response to the antidepressant treatment in the trial and the suicide risk in the first 3 years of observation.

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Efficacy and Safety of Loading Doses With P2Y12-Receptor Antagonists in Patients Without Dual Antiplatelet Therapy Undergoing Elective Coronary Intervention.

European Guidelines on Myocardial Revascularization recommend clopidogrel loading dose added to acetylsalicylic acid in elective percutaneous coronary interventions (PCIs). However, there is few evidence supporting this recommendation and other P2Y12 inhibitors have not been tested in these patients. To evaluate the effectiveness and safety of different loading doses of clopidogrel and ticagrelor in patients without double antiplatelet therapy and stable coronary artery disease (SCAD) undergoing elective PCI. Retrospective study of 147 consecutive patients with SCAD undergoing elective PCI. Loading P2Y12 inhibitor doses evaluated were: clopidogrel 600 mg, clopidogrel 300 mg, clopidogrel 150 mg, and ticagrelor 180 mg. We analyzed the occurrence of major adverse cardiovascular events and periprocedural myocardial infarction. One hundred twenty-five patients were treated with clopidogrel (16 with clopidogrel 150 mg, 7 with clopidogrel 300 mg, and 93 with clopidogrel 600 mg) and 21 with ticagrelor 180 mg at the catheterization laboratory. The ticagrelor group had a significantly lower postprocedural peak of troponin-I (0.7 ± 3.4 vs. 0.3 ± 0.7 ng/mL; P = 0.02). There were no differences between groups in terms of major bleeding and hemoglobin drop after PCI (0.6 ± 0.8 vs. 4 ± 0.6; P = 0.8). The median of follow-up was 17 months (interquartile range 9-32.7). At the end of follow-up, major adverse cardiovascular event rate was not different between groups. In patients without dual antiplatelet therapy undergoing elective PCI, the use of ticagrelor showed lower postprocedural myocardial injury without more bleeding complications.

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[Modification of blood coagulation by antihypertensive therapy? Effect of enalapril and hydrochlorothiazide on blood coagulation parameters in patients with essential hypertension].

An increased tendency of the blood to clot in patients with arterial hypertension is not desirable, since cardiovascular and cerebrovascular sequelae may be aggravated. Recently, activation of coagulation under ACE inhibition with captopril has been described. In an open, randomized study, we compared the influence of enalapril on various coagulation parameters with that of hydrochlorothiazide. In contrast to the latter, we detected no unfavorable influence of enalapril on the coagulation factors investigated. A transient increase in fibrin monomeres was observed in one patient each on enalapril and hydrochlorothiazide.

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Ticagrelor improves peripheral arterial function in patients with a previous acute coronary syndrome.

The novel P2Y12 antagonist ticagrelor inhibits adenosine diphosphate (ADP)-induced platelet aggregation more potently than clopidogrel and reduces the incidence of myocardial infarction and total death in patients with an acute coronary syndrome (ACS). Furthermore, ticagrelor inhibits adenosine reuptake and increases coronary flow reserve during adenosine infusion in man. We wanted to determine whether ticagrelor improves peripheral arterial function in patients with a previous ACS compared to patients treated with aspirin, clopidogrel, or prasugrel. 127 patients with a previous ACS (>3 months to <3 years ago) on maintenance dose of (1) no ADP blocker (n = 35); (2) clopidogrel 75 mg (n = 35); (3) prasugrel 10 mg (n = 32), or (4) ticagrelor 90 mg twice daily (n = 25) were evaluated with peripheral arterial tonometry after forearm ischemia. Ticagrelor improves peripheral arterial function compared to the other groups [(1) controls 1.78 ± 0.53; (2) clopidogrel 1.78 ± 0.45; (3) prasugrel 1.64 ± 0.33, and (4) ticagrelor 2.25 ± 0.54 (means ± SD)] with a significance of p < 0.01 for ticagrelor versus no ADP blocker, p < 0.01 for ticagrelor versus clopidogrel, and p < 0.001 for ticagrelor versus prasugrel. There were fewer patients with endothelial dysfunction (<1.67 reactive hyperemia index) in the ticagrelor group (12%) compared to aspirin (51%), clopidogrel (46%), and prasugrel (53%) (p < 0.01). Treatment with ticagrelor improves peripheral endothelial function compared to no ADP blocker, clopidogrel, or prasugrel treatment.

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Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial.

An echocardiographic substudy of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial was designed to test the ability of losartan to reduce left ventricular (LV) mass more than atenolol. A total of 960 patients with essential hypertension and LV hypertrophy (LVH) on screening ECG were enrolled at centers in 7 countries and studied by echocardiography at baseline and after 1, 2, 3, 4, and 5 years' randomized therapy. Clinical examination and blinded readings of echocardiograms in 457 losartan-treated and 459 atenolol-treated participants with > or =1 follow-up measurement of LV mass index (LVMI) were used in an intention-to-treat analysis. Losartan-based therapy induced greater reduction in LVMI from baseline to the last available study than atenolol with adjustment for baseline LVMI and blood pressure and in-treatment pressure (-21.7+/-21.8 versus -17.7+/-19.6 g/m2; P=0.021). Greater LVMI reduction with losartan was observed in women and men, participants >65 or <65 years of age, and with mild or more severe baseline hypertrophy. The difference between treatment arms in LVH regression was due mainly to reduced concentricity of LV geometry in both groups and lesser increase in LV internal diameter in losartan-treated patients. Antihypertensive treatment with losartan, plus hydrochlorothiazide and other medications when needed for pressure control, resulted in greater LVH regression in patients with ECG LVH than conventional atenolol-based treatment. Thus, angiotensin receptor antagonism by losartan has superior efficacy for reversing LVH, a cardinal manifestation of hypertensive target organ damage.

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Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure.

The aim of this study was to compare the effects on BP and sympathetic activity of chronic treatment with an angiotensin (Ang)-converting enzyme (ACE) inhibitor and an AngII receptor blocker in hypertensive patients with chronic renal failure (CRF). In ten stable hypertensive CRF patients (creatinine clearance, 46 +/- 17 ml/min per 1.73 m(2)), muscle sympathetic nerve activity (MSNA), plasma renin activity (PRA), baroreceptor sensitivity, and 24-h ambulatory BP were measured in the absence of antihypertensive drugs (except diuretics) after 6 wk of enalapril (10 mg orally) and after 6 wk of losartan (100 mg orally). The order of the three phases was randomized. Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced MSNA (from 33 +/- 10 to 27 +/- 13 and 27 +/- 13 bursts/min, respectively; P < 0.05) and average 24-h BP (from 141 +/- 8/93 +/- 8 to 124 +/- 9/79 +/- 8 and 127 +/- 8/81 +/- 9 mmHg; P < 0.01). PRA was not different during the treatments. The change in BP and the change in MSNA during the treatments were correlated (r = 0.70 and r = 0.63, respectively; both P < 0.05). Baroreceptor sensitivity was not affected by the treatments. This is the first study to compare the effects of ACE inhibition and AngII blockade on MSNA. In hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sympathetic hyperactivity in these patients.

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Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response.

Evidence suggests that plasminogen activator inhibitor type 1 gene (SERPINE1) is a stress-related gene and serum plasminogen activator inhibitor type 1 levels are increased in patients with major depressive disorders (MDD). To investigate whether common genetic variation in the SERPINE1 gene is associated with MDD and the therapeutic response to antidepressants, six polymorphisms (rs2227631, rs1799889, rs6092, rs6090, rs2227684 and rs7242) of the SERPINE1 gene were genotyped in 188 Chinese MDD patients and 346 controls. Among the MDD patients, 140 accepted selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressant treatment for 4 weeks with therapeutic evaluation before and after. In single-marker-based analysis, the rs2227684-G and rs7242-T alleles were more frequent in MDD patients than in controls (P=0.010 and 0.010, respectively). The haplotype derived from the rs6090-G, rs2227684-G and rs7242-T polymorphisms was 1.19-fold higher in patients with MDD than in controls (P=0.0038). Haplotype analysis in responders (defined as a 50% reduction of the initial Hamilton score) and nonresponders after 4 weeks of antidepressant treatment showed that the haplotype derived from the rs2227631-G and rs1799889-4G polymorphisms was lower in responders than nonresponders (11.4 vs. 22.4%, P=0.014). Our findings show, for the first time, that SERPINE1 genetic variants may play a role in MDD susceptibility and in the acute therapeutic response to selective serotonin reuptake inhibitors.

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Age and sex inequalities in the prescription of evidence-based pharmacological therapy following an acute coronary syndrome in Portugal: the EURHOBOP study.

To assess the proportion of patients receiving pharmacological therapy for secondary prevention after an acute coronary syndrome (ACS) in Portugal and to identify age and sex inequalities. Retrospective cohort study. We studied 747 episodes of ST-segment elevation myocardial infarction (STEMI) and 1364 of non-ST-segment elevation ACS (NSTE-ACS), within a sample of ACS cases consecutively discharged from 10 Portuguese hospitals, in 2008-2009. We estimated adjusted odds ratios (OR) for the association of age and sex with the use of each pharmacological treatment. In STEMI and NSTE-ACS patients, the proportion of patients discharged with aspirin was 96 and 88%, clopidogrel 91 and 78%, aspirin+clopidogrel 88 and 71%, beta-blockers 80 and 76%, angiotensin-converting enzyme (ACE) inhibitors/ARB 82 and 80%, statins 93 and 90%, 3-drug (aspirin/clopidogrel+beta-blocker+statin) 76 and 69%, and 5-drug treatment (aspirin+clopidogrel+beta-blocker+ACE inhibitor/ARB+statin) 61 and 48%, respectively. Among STEMI patients, those aged ≥80 years were substantially less often discharged with clopidogrel (OR 0.22, 95% confidence interval, CI, 0.08-0.56), aspirin+clopidogrel (OR 0.34, 95% CI 0.15-0.76), beta-blockers (OR 0.39, 95% CI 0.18-0.82), 3-drug (OR 0.41, 95% CI 0.21-0.83), and 5-drug treatments (OR 0.44, 95% CI 0.23-0.83) than those <60 years; women were less likely to be discharged with aspirin+clopidogrel (OR 0.52, 95% CI 0.29-0.91). Among NSTE-ACS patients, those aged ≥80 years were much less likely to be discharged with beta-blockers (OR 0.58, 95% CI 0.36-0.93), statins (OR 0.35, 95% CI 0.19-0.64), and 3-drug treatment (OR 0.47, 95% CI 0.30-0.75); sex had no significant effect on treatment prescription. The vast majority of younger patients were discharged on evidence-based secondary preventive medications, but only half received the 5-drug combination. Recommended therapies were substantially underprescribed in older patients.

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Risk and benefit of dual antiplatelet treatment among non-revascularized myocardial infarction patients in different age groups.

Dual anti-platelet treatment with clopidogrel and aspirin is indicated for most patients after myocardial infarction. We examined the risk/benefit relationship of dual anti-platelet treatment according to age in a nationwide cohort of 30,532 myocardial infarction patients without revascularization. Patients admitted with first-time myocardial infarction in 2002-2010, not undergoing revascularization, were identified from nationwide Danish registers. Dual anti-platelet treatment use was assessed by claimed prescriptions. Stratified into age groups, risk of bleeding, all-cause mortality and a combined endpoint of cardiovascular death, recurrent myocardial infarction and ischaemic stroke was analysed by Cox proportional-hazard models and tested in a propensity-score matched population. A total of 21,302 users and 9230 non-users of dual anti-platelet treatment were included (mean age 67.02 (±13.8) years and 64.7% males). Use of dual anti-platelet treatment decreased with age: 80% (<60 years), 76% (60-69 years), 66% (70-79 years) and 52% (>79 years). We found a reduced risk of cardiovascular death, recurrent myocardial infarction and ischaemic stroke in users <60 years (Hazard ratio (HR) =0.69; 95% confidence interval (CI) 0.59-0.80), 60-69 years (HR=0.64; 95% CI 0.56-0.73), 70-79 years (HR=0.80; 95% CI 0.72-0.89) and >79 years (HR=0.92; 95% CI 0.84-1.01, NS). Risk of bleeding increased with dual anti-platelet treatment use in patients aged <60 years (HR=1.63; 95% CI 1.17-2.26), 60-69 years (HR=1.22; 95% CI 0.97-1.59, NS), 70-79 years (HR=1.42; 95% CI 1.17-1.72) and >79 years (HR=1.46; 95% CI 1.22-1.74). Similar tendencies in all four age groups were found in the propensity-matched population. Dual anti-platelet treatment use was less likely among elderly patients although similar effects regarding both risk and benefit were found in all age groups. Increased focus on initiating dual anti-platelet treatment in elderly, non-invasively treated myocardial infarction patients is warranted.

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Helicobacter pylori eradication in childhood after failure of initial treatment: advantage of quadruple therapy with nifuratel to furazolidone.

Failures of Helicobacter pylori eradication in children are common. To evaluate the efficacy of amoxicillin, bismuth subcitrate and omeprazole and nifuratel or furazolidone for H. pylori eradication in children who failed initial treatment with a standard triple therapy. Seventy-six consecutive H. pylori-positive paediatric out-patients (aged 12-16 years; mean age 13.7 +/- 1.4) with chronic abdominal complaints who had failed one attempt of eradication of H. pylori using metronidazole-containing triple therapy were enrolled. It was an open prospective study. Patients were randomized to receive a 2-week course of bismuth subcitrate (8 mg/kg/day, q.d.s.), amoxicillin (50 mg/kg/day, q.d.s.), with either nifuratel (15 mg/kg/day, q.d.s.) or furazolidone (10 mg/kg/day, q.d.s.), plus omeprazole (0.5 mg/kg, once daily). There were 37 patients in the nifuratel group and 39 in the furazolidone group. Helicobacter pylori was eradicated in 33 of 37 (89%; 95% CI: 74.5-96.9; intention-to-treat) in nifuratel group and in 34 of 39 (87%; 95% CI: 72.5-95.7) in furazolidone group, respectively. Frequency of severe side-effects was greater with furazolidone (21%) than with nifuratel (3%; P = 0.0289). Nitrofuran-containing therapies consisting of a proton-pump inhibitor, amoxicillin and bismuth citrate plus either nifuratel or furazolidone produced good cure rates even among those who had failed prior therapy. Nifuratel is preferred because of the lower frequency of side-effects.

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Intraoperative prediction of cardiac surgery-associated acute kidney injury using urinary biomarkers of cell cycle arrest.

Tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are postoperative urinary biomarkers of renal stress and acute kidney injury (AKI). We conducted this study to test the hypothesis that intraoperative concentrations of urinary [TIMP-2]·[IGFBP7] are associated with postoperative AKI. We measured urinary [TIMP-2]·[IGFBP7] at 8 perioperative timepoints in 400 patients who participated in a randomized controlled trial of atorvastatin for AKI in cardiac surgery. We compared [TIMP-2]·[IGFBP7] between subjects who did and did not develop KDIGO stage 2 or 3 AKI within 48 hours of surgery, adjusted for AKI risk factors. Fourteen patients (3.5%) met the primary endpoint of stage 2 or 3 AKI within 48 hours of surgery, and an additional 77 patients (19.3%) developed stage 1 AKI. Patients who developed stage 2 or 3 AKI displayed bimodal elevations of [TIMP-2]·[IGFBP7], with a first elevation (median, 0.45 [ng/mL]²/1000) intraoperatively and a second elevation (1.45 [ng/mL]²/1000) 6 hours postoperatively. Patients who did not develop AKI did not have any elevations in [TIMP-2]·[IGFBP7]. Each 10-fold increase in intraoperative [TIMP-2]·[IGFBP7] was independently associated with a 290% increase in the odds of stage 2 or 3 AKI (P = .01), and each 10-fold increase in the 6 hours postoperative [TIMP-2]·[IGFBP7] was independently associated with a 650% increase in the odds of stage 2 or 3 AKI (P < .001). The maximum [TIMP-2]·[IGFBP7] between these 2 timepoints provided an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI], 0.73-0.90), 100% sensitivity, and 100% negative predictive value using the >0.3 cutoff to predict stage 2 or 3 AKI. Intraoperative elevations of [TIMP-2]·[IGFBP7] can predict moderate or severe AKI and could provide an opportunity to alter postoperative management to prevent kidney injury.

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Evaluation of Quality of Life, Functioning, Disability, and Work/School Productivity Following Treatment with an Extended-Release Hydrocodone Tablet Formulated with Abuse-Deterrence Technology: A 12-month Open-label Study in Patients with Chronic Pain.

This phase 3 study evaluated quality of life, functioning, and productivity after treatment with extended-release (ER) hydrocodone formulated with CIMA^® Abuse-Deterrence Technology platform. Patients with chronic pain were rolled over from a 12-week placebo-controlled hydrocodone ER study or were newly enrolled. Hydrocodone ER doses were titrated (15 to 90 mg every 12 hours) to an analgesic dose, and patients received up to 52 weeks of open-label treatment. Assessments included Clinician Assessment of Patient Function (CAPF), Patient Assessment of Function (PAF), Brief Pain Inventory-Short Form (BPI-SF), 36-item Short-Form Health Survey (SF-36), Sheehan Disability Scale (SDS), and World Health Organization Health and Work Performance Questionnaire-Short Form (HPQ-SF). Of 330 enrolled patients, 291 composed the full analysis population. By week 4, ≥ 50% of patients showed improvement from baseline in all 5 CAPF domains (general activities, walking, work/daily living, relationships, and enjoyment of life) and 6 of 7 PAF domains (work attendance, work performance, walking, exercise, socializing, and enjoying life). Mean decreases from baseline of 2 to 3 points were noted for BPI-SF pain interference questions from week 4 through endpoint. Mean improvements from baseline to endpoint in SF-36 subscales ranged from 3.3 to 22.3, and SDS scores improved from moderate (4.8 to 5.1) to mild (2.5 to 2.8) disruptions in work/school, social life, and family life. At endpoint, mean HPQ-SF absolute absenteeism scores decreased from 13.6 to 10.0 hours lost/month and absolute presenteeism scores improved from 67.0 to 77.1. Patients receiving hydrocodone ER showed early numeric improvements in functioning that continued throughout this 12-month study.

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Gabapentin therapy improves heart rate variability in diabetic patients with peripheral neuropathy.

Diabetic cardiac neuropathy, which is characterized by reduced heart rate variability (HRV), frequently coexists with peripheral neuropathy. Gabapentin has been used for the treatment of diabetic neuropathy. We aimed to evaluate the possible effect of gabapentin treatment on autonomic function in patients with type 2 diabetes via HRV. Thirty patients with type 2 diabetes mellitus and peripheral neuropathy and 28 age- and sex-matched healthy controls were consecutively registered. Each patient underwent HRV measurements, and diabetic patients were administered gabapentin. After 3 months of gabapentin therapy, HRV parameters were measured again. Baseline HRV parameters were blunted in patients with diabetes mellitus according to the controls [standard deviation of all NN intervals (SDNN, ms): 106.3+/-29.9 vs. 148.8+/-36.5, P=.001; power spectrum of the high-frequency band (HF, ms(2)): 133.6+/-98.3 to 231.4+/-197.6, P=.02; power spectrum of the low-frequency band (LF, ms(2)): 341.8+/-247.8 to 511.5+/-409.4, P=.048; LF/HF ratio: 3.3+/-2.4 to 2.6+/-1.5, P=.33]. After 3 months of treatment with gabapentin, some HRV parameters showed some improvement. SDNN (106.2+/-29.8 to 119.4 +/- 25, P=.016) and HF (133.6+/-98.3 to 167.6+/-118.3, P=.021) increased significantly. LF/HF ratio decreased (from 3.3+/-2.4 to 2.3+/-1.9, P=.039) and LF remained unchanged (341.8+/-247.8 to 352.3+/-228.9, P=.88). Therapeutic doses of gabapentin not only alleviate neuropathic symptoms but also improve cardiac autonomic function in diabetic patients with peripheral neuropathy.

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Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Addition of a delayed-intensification (DI) phase after standard induction/consolidation therapy was previously shown to improve outcome for patients younger than 10 years of age with intermediate-risk acute lymphoblastic leukemia (ALL). The current trial randomized 1204 patients to regimens containing a single DI phase (405 patients), 2 DI phases (DDI) (402 patients), or a single DI phase in conjunction with increased vincristine and prednisone pulses during maintenance (DIVPI) (397 patients). Estimates of event-free survival (EFS) and survival at 6 years are 79% +/- 1% and 89% +/- 1%, respectively. EFS was improved on DDI compared with either DI (log-rank P =.04; Kaplan-Meier [KM] P =.04; relative risk [RR] = 1.38) or DIVPI (log-rank P =.04; KM P =.01; RR = 1.39). There was no difference in EFS for the DI and DIVPI regimens (log-rank P =.96; KM P =.75). Survival estimates at 6 years were 87% (SD = 2%) for DI; 91% (SD = 2%) for DDI; and 90% (SD = 2%) for DIVPI (P =.17). Significant univariate risk factors for the overall cohort included poor day-7 marrow response, black race, and age of at least 5 years. These data demonstrate that DDI improves EFS of patients younger than 10 years of age with intermediate-risk ALL.

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Multivariate analysis of donor-specific versus random transfusion protocols in haploidentical living-related transplants.

A total of 127 haploidentical living-related transplants have been performed at our institution since March 1986. A donor-specific transfusion plus azathioprine protocol was used until July 1988 (n = 74) and a random transfusion (RT) protocol without AZA used thereafter (n = 53) in an effort to decrease risk of recipient sensitization and reduce the burden on the prospective donor. All patients were given cyclosporine 8 mg/kg/day orally beginning 1 week prior to transplantation. Immunosuppression was similar in both groups and consisted of triple induction therapy with prednisone, CsA, and AZA. A positive T cell crossmatch eliminated the potential donor. Seven individuals (9.6%) were sensitized in the DST group and 1 (1.9%) in the RT group, leaving 67 and 52 patients in the two groups of the study, respectively. Groups were similar with respect to age, sex, history of pregnancy in female patients, peak and baseline panel-reactive antibody (PRA), DR match, and prior transplants. The groups differed slightly with respect to AB antigens shared, with an advantage in the RT group. Actuarial graft survival was not statistically significantly different between the two groups, with 2-year graft survival of 95% in the DST and 91% in the RT group (log rank, P = 0.16). Patients in the RT group had significantly more rejection episodes and had them sooner than their counterparts in the DST group. At the end of 1 year, 50% of patients in the DST group had at least 1 rejection episode, compared with 75% of patients in the RT group (P = 0.0008). Multivariate (Poisson) analysis of 10 variables was performed, with an overall model P-value of 0.0001. Only DST (P = 0.0001) and pregnancy (P = 0.015) were significant predictors of rejection episodes, both protective. The difference in rejection episodes and the timing with which they occur has not yet translated into a significant difference in graft survival between DST and RT groups.

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The choice of timing for diuresis renography: the F + 0 method.

To investigate a method of diuresis renography where the radiopharmaceutical and frusemide (diuretic) are given simultaneously, in contrast to conventional renography which involves an intravenous injection with frusemide 20 min after administering the radiopharmaceutical (F + 20) or 15 min before (F - 15), with particular interest in the effect of this change on assessing split renal function and interpreting upper tract drainage dynamics. In a prospective study, 29 patients (18 women and 11 men, mean age 47 years, range 21--86) were assessed. Each patient had two renograms taken over a 48-h period, either by the F + 20 or F - 15, and the F + 0 method: Data for split renal function and drainage curves were obtained in the usual way. Two independent assessments of the drainage curves were obtained and the results compared. The split function assessments were identical (< 5% variation) in all but two patients; 26 of 29 (90%) gave identical conclusions about the drainage curves. The three patients with discrepancies between the studies had either hugely dilated upper tracts or otherwise had multiple complicating factors, e.g. impaired renal function, neuropathic bladder. F + 0 renography has been used in paediatric urological practice before, but there are no comparative studies and no data on its use in adults. This prospective study confirmed that in investigating dilated upper tracts, the F + 0 technique gives similar results to the conventional techniques. The F + 0 method has the potential to reduce the time required to undertake standard F + 20 renography but it may not be useful in evaluating the grossly dilated upper tract, where the F-15 technique has the best record in terms of reducing equivocal results.

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[Necessity and safety of conversion from mycophenolate mofetil to AzA thioprine after renal transplantation].

To investigate the necessity and safety of conversion from mycophenolate mofetil (MMF) to Azathioprine (AzA) in stable renal transplant patients. In a randomised open clinical trial, A total of 87 low-risk renal allograft recipients on triple immunosuppressive therapy (prednisone/MMF/cyclosporine) 6 months after transplantation was randomised into two groups: converted (switching MMF to AzA treatment 6 months after transplantation, n = 42) and control (continued MMF treatment, n = 45). Renal function, acute rejection episodes, side effects and related complications were analysed in each group. The outcome (such as event-free graft survival rate and incidence of acute rejection) of treatment after a 12-months follow-up of patients in two groups was similar. Liver lesion and leukocytopenia, most of which was reversible, occurred more frequently in the converted than in the control group. Under the special economic atmosphere and medical insurance system of our country, the conversion from MMF to AzA in some renal transplant patients was necessary and safe. Further study is needed to evaluate the long-term outcome of this conversion.

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Pharmacokinetics and pharmacodynamics of single oral doses of albuterol and its enantiomers in humans.

Albuterol (INN, salbutamol) is a beta 2-adrenergic receptor agonist widely used in the treatment of asthma. It is administered clinically as a racemic mixture, but only one enantiomer is active (eutomer) while the other (distomer) has been implicated in causing toxicity. This study used a chiral assay to compare the pharmacokinetics and pharmacodynamics of racemic albuterol with its two enantiomers in a three-way crossover of single oral doses in 12 healthy males. The bioavailability of the eutomer was less than that of the distomer after administration of pure enantiomers and racemate. Apart from causing a small increase in plasma potassium, the distomer had no effect on any pharmacodynamic parameter. The eutomer administered alone was significantly more potent than an equivalent dose given as racemate with regard to its effects on heart rate, QTc interval, plasma potassium levels, and plasma glucose levels. Despite this higher potency, the area under the plasma concentration versus time curve for eutomer after administration of pure eutomer was significantly lower than after administration of the racemate. This difference is probably the result of the more efficient metabolism of the eutomer in the absence of the distomer.

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Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial.

Treatment of adults with autoimmune thrombocytopenic purpura (AITP) is based more on individual experience than on results of controlled studies. We compared intravenous immunoglobulin with high-dose methylprednisolone in untreated adults with severe AITP and assessed efficacy of subsequent oral steroids compared with placebo. Primary outcome was number of days with platelet count greater than 50 x 10(9)/L within the first 21 days. We did a randomised multicentre trial based on a 232 design. 122 adults with severe AITP (platelet count < or =20 x 10(9)/L) were randomly assigned to receive either intravenous immunoglobulin or high-dose methylprednisolone on days 1-3 (randomisation A), and then to receive either oral prednisone or placebo (randomisation B) on days 4-21. Analysis was by intention to treat. Six patients were excluded from the analysis. The number of days on which platelet counts were above 50 x 10(9)/L was 18 in 56 patients receiving intravenous immunoglobulin and 14 in 60 receiving high-dose methylprednisolone (p=0.02). Percentage of patients who had platelet counts over 50 x 10(9)/L on days 2 and 5 was 7% and 79%, respectively, in the intravenous immunoglobulin group compared with 2% and 60%, respectively, in the high-dose methylprednisolone group (p=0.04). During the second treatment period, prednisone was more effective than placebo for all short-term endpoints. Patients who received intravenous immunoglobulin and prednisone had platelet count greater than 50 x 10(9)/L for 18.5 days (p=0.005), and those treated with high-dose methylprednisolone and prednisone had this count for 17.5 days. Intravenous immunoglobulin and oral prednisone seems to be more effective than high-dose methylprednisolone and oral prednisone in adults with severe AITP, although the latter treatment is effective and well tolerated.

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Risk of postprocedural intracerebral hemorrhage in patients with ruptured cerebral aneurysms after treatment with antiplatelet agents.

Endovascular treatment of ruptured cerebral aneurysms frequently requires antiplatelet medication to prevent thromboembolism. This might raise concern regarding the risk of postprocedural hemorrhage (pH), e.g. from placement of intracranial probes. We explored the risk of PH associated with standard antiplatelet therapy (sAP: acetylsalicylic acid, and/or clopidogrel) in the context of aneurysmal subarachnoid hemorrhage (aSAH). We retrospectively reviewed a total of 146 consecutive cases with cerebral aneurysms treated between 1/2011-12/2015, and distinguished between minor (0.5 cm³) - 4 cm³) or major (> 4 cm³) PH occurring within four weeks after intervention. A separate analysis included hemorrhages related to placement of intracranial probes and drainages in the subgroup of 99 cases with such surgical interventions (pPH). Clinical outcome was assessed via Glasgow Outcome Scale (GOS) twelve months after aSAH. A total of 49 cases (33.6%) in the overall sample sustained PH, there were 19 cases of pPH. Multifactorial analyses yielded sAP as an independent predictor for minor, but not major PH (p < 0.001 vs. p = 0.829), with comparable results for pPH (p = 0.001 vs. p = 0.184). sAP did not influence the clinical outcome in either group. sAP was associated with a higher rate of minor PH and, more specifically, of minor pPH. However, it was neither accompanied by the occurrence of major hemorrhages nor by unfavorable clinical outcome. Future prospective studies should confirm these observations and hemorrhage risks associated with extended anticoagulation regimes after complex interventions and intra-arterial vasospasm therapy should be explored in order to facilitate interdisciplinary decision-making in aSAH.

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Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized, cross-over study with four antihypertensive drugs (The GENRES Study).

Only a minority of hypertensive individuals is adequately controlled for their hypertension, partially because reliable predictors for efficient antihypertensive drug therapy are lacking. In a prospective, randomized, double-blind, cross-over, placebo-controlled study (The GENRES Study), 208 moderately hypertensive Finnish men (aged 35 to 60 years) were treated for 4 weeks with antihypertensive drugs from four different classes: amlodipine (5 mg), bisoprolol (5 mg), hydrochlorothiazide (25 mg), or losartan (50 mg) daily. Each individual received each of the four monotherapies in a randomized order. Four-week placebo periods were included before and between drug treatment periods. Antihypertensive responses were assessed with 24-h ambulatory and office measurements and analyzed according to age, body mass index, triceps skin fold thickness, waist-to-hip ratio, duration of hypertension, number of previous antihypertensive drugs, number of affected parents, and blood pressure (BP) levels, and profiles during placebo periods. The median BP responses in 24-h ambulatory recordings (systolic/diastolic) were 11/8 mm Hg for bisoprolol, 9/6 mm Hg for losartan, 7/5 mm Hg for amlodipine, and 5/2 mm Hg for hydrochlorothiazide. The highest pairwise within-subject correlations in BP responses were seen for the combinations of bisoprolol-losartan and amlodipine-hydrochlorothiazide. The BP responses to bisoprolol and losartan did not vary according to the variables. Amlodipine and hydrochlorothiazide responses were positively correlated with age, placebo BP level, and lower night-time dipping on placebo. Baseline clinical and BP parameters may be used to predict the efficacy of antihypertensive therapies. The GENRES Study material should provide an excellent platform for future pharmacogenetic analyses of antihypertensive drug responsiveness.

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