Treatment of severe infectious purpura in children with human plasma from donors immunized with Escherichia coli J5: a prospective double-blind study. J5 study Group.

To evaluate the efficacy of anti-J5 serum in the treatment of severe infectious purpura, 73 children were randomized to receive either anti-J5 (40) or control (33) plasma. Age, blood pressure, and biologic risk factors were similar in both groups. At admission, however, tumor necrosis factor serum concentrations were 974 +/- 173 pg/ml compared with 473 +/- 85 pg/ml (P = .023) and interleukin-6 serum concentrations were 129 +/- 45 compared with 19 +/- 5 ng/ml (P = .005) in the control and treated groups, respectively. The duration of shock and the occurrence of complications were similar in both groups. The mortality rate was 36% in the control group and 25% in the treated group (P = .317; odds ratio, 0.76; 95% confidence interval, 0.46-1.26). This trend disappeared after correction for unbalances in risk factors at randomization using a logistic regression model. These results suggest that anti-j5 plasma did not affect the course or mortality of severe infectious purpura in children.

Replacement of (R)-methadone by a double dose of (R,S)-methadone in addicts: interindividual variability of the (R)/(S) ratios and evidence of adaptive changes in methadone pharmacokinetics.

METHODS: Twenty-two patients receiving (R)-methadone maintenance treatment were switched to a double dose of (R,S)-methadone: blood samples were collected before and after the change, and the concentrations of the enantiomers were measured. In the second period, during racemic methadone treatment, important interindividual variability in the stereoselective disposition of the enantiomers of methadone was measured, with (R)/(S) ratios ranging from 0.63 to 2.40. This point should be taken into account particularly with respect to therapeutic drug monitoring of racemic methadone. RESULTS: A significant decrease P < 0.005 in the mean serum concentration/dose ratios of the active (R)-enantiomer before and after the change was measured (mean 3.97 and 3.33). CONCLUSION: Although of small amplitude (16%), this decrease confirms previously described adaptive changes in methadone pharmacokinetics during racemic methadone maintenance treatment and may necessitate, in some patients, a dose adjustment.

Therapy of tungiasis: a double-blinded randomized controlled trial with oral ivermectin

Tungiasis is an ectoparasitosis causing considerable pathology in endemic areas. Standard therapy consists of removing the embedded parasite with a sterile needle. There is no effective chemotherapy at hand. To fill this gap, a double-blinded randomized controlled trial with oral ivermectin was conducted. A total of 54 individuals (27 in the placebo group, 27 in the ivermectin group) was followed up for seven days. They presented a total of 192 lesions. Patients received either ivermectin (300 µg/kg body weight at a single dose, repeated after 24 h) or placebo. Outcome measures included the clinical stage of lesion, presence of erythema, pain, itching, signs of viability of the parasite, and total lysis of flea. The ratio of fleas with total lysis per total number of fleas was slightly higher in the ivermectin group; however, this difference was not statistically significant. There was no significant difference in any of the other outcome measures between the treatment and the placebo group. The results show that oral ivermectin is without any clinically significant efficacy against embedded sand fleas at the dose given.

Three new species of Isospora Schneider, 1881 (Apicomplexa: Eimeriidae) from the double-collared seed eater, Sporophila caerulescens (Passeriformes: Emberizidae), from Eastern Brazil

Three isosporan species are described from the double-collared seedeater, Sporophila caerulescens from Eastern Brazil. Isospora sporophilae n. sp. oocysts spherical to subspherical; oocyst wall bi-layered, smooth, inner layer colorless to pale yellowish, 21.6 × 20.9 (19.20-23.20 × 18.40-22.60) µm, shape-index 1.03 ± 0.02 (1-1.10), with no micropyle or oocyst residuum. Polar bodies splinter-like or comma-like. Sporocysts ovoidal, 15.2 × 10.6 (17.40-12.80 × 12.60-8.40) µm, shape-index 1.43 ± 0.14 (1.17-1.81), with knob-like Stieda body and residuum. Large crystalloid body in the center of the sporocyst. Isospora flausinoi n. sp. oocysts spherical to subspherical, oocyst wall bi-layered, smooth, colorless, 17.30 x 16.53 (14-20 × 13.60-20) µm, shape-index 1.05 ± 0.04 (1-1.21). Micropyle and oocyst residuum absent; presence of a large polar body. Sporocyst piriform, 14.88 x 10.70 (11.80-18 × 8-12.40) µm, shape-index 1.40 ± 0.18 (1.07-1.77), with smooth, thin, single-layered wall. Sporocyst with rounded Stieda body with no substieda body, and residuum composed of granular material. Isospora teixeirafilhoi n. sp. oocysts spherical to subspherical, oocyst wall bi-layered, smooth, colorless, 17.41 x 16.81 (15.60 19.40 × 14.20-18.80) µm. Shape-index 1.04 ± 0.08 (1-1.12). Micropyle and oocyst residuum absent; presence of a small double-lobuled polar body. Sporocyst ovoid, 11.74 × 8.12 (9-14.20 × 6.20-9.40) µm. Shape-index 1.46 ± 0.23 (1.06-1.88). Sporocyst with knob-like Stieda body, no sub-Stieda body and residuum composed of granular material.

Mycobacterium avium restriction fragment lenght polymorphism-IS IS1245 and the simple double repetitive element polymerase chain reaction typing method to screen genetic diversity in Brazilian strains

Simple double repetitive element polymerase chain reaction (MaDRE-PCR) and Pvu II-IS1245 restriction fragment length polymorphism (RFLP) typing methods were used to type 41 Mycobacterium avium isolates obtained from 14 Aids inpatients and 10 environment and animals specimens identified among 53 mycobacteria isolated from 237 food, chicken, and pig. All environmental and animals strains showed orphan patterns by both methods. By MaDRE-PCR four patients, with multiple isolates, showed different patterns, suggesting polyclonal infection that was confirmed by RFLP in two of them. This first evaluation of MaDRE-PCR on Brazilian M. avium strains demonstrated that the method seems to be useful as simple and less expensive typing method for screening genetic diversity in M. avium strains on selected epidemiological studies, although with limitation on analysis identical patterns except for one band.

An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States. METHODS: This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function. RESULTS: Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (-0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score -5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events. CONCLUSION: Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registry NCT00333866).

Individual monitoring of medical staff working in interventional radiology in Switzerland using double dosimetry

Physicians who frequently perform fluoroscopic examinations are exposed to high intensity radiation fields. The exposure monitoring is performed with a regular personal dosimeter under the apron in order to estimate the effective dose. However, large parts of the body are not protected by the apron (e.g. arms, head). Therefore, it is recommended to wear a supplemental dosimeter over the apron to obtain a better representative estimate of the effective dose. The over-apron dosimeter can also be used to estimate the eye lens dose. The goal of this study was to investigate the relevance of double dosimetry in interventional radiology. First the calibration procedure of the dosimeters placed over the apron was tested. Then, results of double dosimetry during the last five years were analyzed. We found that the personal dose equivalent measured over a lead apron was underestimated by ∼20% to ∼40% for X-ray beam qualities used in radiology. Measurements made over five-year period confirm that the use of a single under-apron dosimeter is inadequate for personnel monitoring. Relatively high skin dose (>10 mSv/month) would have remained undetected without a second dosimeter placed on the apron.

Adalimumab in Severe and Acute Sciatica (ASAS) : a multicentre, randomized, double-blind, placebo-controlled trial : 1240

Background Based on several experimental results and on a preliminary study, a trial was undertaken to assess the efficacy of adalimumab, a TNF-α inhibitor, in patients with radicular pain due to lumbar disc herniation. Methods A multicentre, double-blind, randomised controlled trial was conducted between May 2005 and December 2007 in Switzerland. Patients with acute (< 12 weeks) and severe (Oswestry Disability index > 50) radicular leg pain and imaging-confirmed lumbar disc herniation were randomised to receive as adjuvant therapy either two subcutaneous injections of adalimumab (40 mg) at 7 days interval or matching placebo. The primary outcome was leg pain, which was recorded every day for 10 days and at 6-weeks and 6- months based on a visual analogue scale (0 to 100). Results Of the 265 patients screened, 61 were enrolled (adalimumab= 31) and 4 were lost to follow-up. Over time, the evolution of leg pain was more favourable in the adalimumab group than in the placebo group (p<0.001). However, the effect size was relatively small and at last follow-up the difference was 13.8 (CI95% -11.5 - 39.0). In the adalimumab group twice as many patients fulfilled the criteria for "responders" and for "low residual disease impact" ( p<0.05) and fewer surgical discectomies were performed (6 versus 13, p=0.04). Conclusion The addition of a short course of adalimumab to the treatment regimen of patients suffering from acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.

TLR3 as a biomarker for the therapeutic efficacy of double-stranded RNA in breast cancer.

The discovery of a targeted therapeutic compound along with its companion predictive biomarker is a major goal of clinical development for a personalized anticancer therapy to date. Here we present evidence of the predictive value of TLR3 expression by tumor cells for the efficacy of Poly (A:U) dsRNA in 194 breast cancer patients enrolled in a randomized clinical trial. Adjuvant treatment with double-stranded RNA (dsRNA) was associated with a significant decrease in the risk of metastatic relapse in TLR3 positive but not in TLR3-negative breast cancers. Moreover, we show the functional relevance of TLR3 expression by human tumor cells for the antitumor effects mediated by dsRNA in several preclinical mouse models carried out in immunocompromised animals. These 2 independent lines of evidence relied upon the generation of a novel tool, an anti-TLR3 antibody (40F9.6) validated for routine detection of TLR3 expression on paraffin-embedded tissues. Altogether, these data suggest that dsRNA mediates its therapeutic effect through TLR3 expressed on tumor cells, and could therefore represent an effective targeted treatment in patients with TLR3-positive cancers.

Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase. DISCUSSION: Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.