Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.     

Prevalence of autoantibodies in the course of Gaucher disease type 1: A multicenter study comparing Gaucher disease patients to healthy subjects

Objectives

Type 1 Gaucher disease may be related to the presence of autoantibodies. Their clinical significance is questioned.Primary endpoint was to compare the prevalence of autoantibodies in type 1 Gaucher disease patients with healthy subjects, seeking correlations with autoimmune characteristics. Secondary endpoints were to determine whether patients with autoantibodies reported autoimmunity-related symptoms and if genotype, splenectomy or treatment influenced autoantibodies presence.

Field assessment of generic antiretroviral drugs: a prospective cohort study in Cameroon

OBJECTIVE: To assess the effectiveness of generic anti-retroviral drugs in terms of survival and virological and immunological responses, as well as their tolerability and the emergence of viral resistance. METHODS: A total of 109 HIV-1-infected patients were enrolled in a prospective cohort study in Yaoundé, Cameroon. Available generic drugs were a fixed-dose combination (FDC) of zidovudine (ZDV) and lamivudine (3TC), an FDC of 3TC, stavudine (d4T) and nevirapine (NVP), and individual formulations of ZDV, 3TC and NVP. RESULTS: At baseline, the median CD4 cell count was 150/mm3 [interquartile range (IQR) 61-223] and median viral load was 5.4 log10 copies/ml (IQR 4.8-5.6); 78% of patients received ZDV/3TC/NVP and 22% received 3TC/d4T/NVP. Median follow-up was 16 months (IQR 11-23). The survival probability was high (0.92 at 12 months); plasma viral load declined by a median of 3.3 log10 copies/ml and 86.9% of the intention-to-treat population had viral load <400 copies/ml at 12 months; CD4 count had increased by a median of 106 cells/mm3 at 12 months; drug resistance rarely emerged (incidence rate 3.2 per 100 person-years); and the treatments were reasonably well-tolerated (incidence rate of severe adverse effects 7.8 per 100 person-years). CONCLUSION: Together with previous pharmacological and clinical studies, this prospective study suggests that these generic antiretroviral drugs can be used in developing countries.     

Ultrasonography and detection of subclinical joints and tendons involvements in Systemic Lupus erythematosus (SLE) patients: A cross-sectional multicenter study

Objectives

The aims of this study in SLE population were (1) to describe ultrasonography (US) joint abnormalities, (2) to estimate the reliability of clinical swollen joint count (C-SJC) and SLEDAI (C-SLEDAI) versus US-SJC and US-SLEDAI scores, (3) to highlight specific patterns of lupus patients with Power Doppler (PD) abnormalities.

Mutation in the Hepatitis E Virus Polymerase and Outcome of Ribavirin Therapy

Hepatitis E virus (HEV) can lead to chronic infection in solid-organ transplant patients. Ribavirin is efficient for treatment of chronically infected patients. Recently, the1634R mutation in the HEV polymerase has been associated with treatment failure. However, it is unclear if this mutation can be used as a prognostic marker of treatment outcome. We studied the prevalence of the 1634R mutation in the HEV polymerase of patients starting ribavirin therapy, the influence of the 1634R variants on the viral response, the frequency of the 1634R mutation in patients whose treatment failed, and its impact on ribavirin retreatment. We analyzed pretreatment samples from 63 solid-organ transplant patients with chronic hepatitis E using deep sequencing; 42 patients had a sustained virologic response (SVR), and 21 were non-SVR patients. We detected the 1634R variant by deep sequencing in 36.5% (23/63) of the patients (proportions, 1.3 to 100%). The 1634R variant was detected in 31.0% (13/42) of baseline plasma samples from patients with SVR and in 47.6% (10/21) in the other patients (P = 0.2). The presence of this mutation did not influence the initial decrease in viral RNA. Lastly, a second prolonged ribavirin treatment led to SVR in 70% of the patients who initially did not have SVR, despite the presence of the 1634R variant. We conclude that the presence of the 1634R variant at ribavirin initiation does not lead to absolute ribavirin resistance. Although its proportion increased in patients whose treatment failed, the presence of the 1634R variant did not compromise the response to a second ribavirin treatment.     

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats. 4. Aztreonam

The aim of this study was to determine aztreonam (ATM) membrane permeability using Calu-3 cells and its plasma and pulmonary epithelial lining fluid (ELF) pharmacokinetics in rats after intratracheal nebulization and intravenous administration (15 mg · kg⁻¹). ATM exhibits low Calu-3 permeability (0.07 ± 0.02 × 10⁻⁶ cm · s⁻¹), and a high area under the ELF/unbound plasma concentration time curve between 0 and infinity (AUC_ELF/AUC_u,plasma) ratio of 1,069 was observed after nebulization in rats. These results confirm that ATM is a low-permeability molecule and a good candidate for nebulization.     

The effect of kinesio tape on neuromuscular activity of peroneus longus

Background: Functional ankle instability is the result of sensorimotor or structural deficits. The commonly used kinesio tape (KT) is supposed to have a positive influence on sensorimotor functions. Methods: Eight women and two men (mean ± SD, age 24.4 ± 3.3 years) with functional ankle instability with recurrent ankle sprains ran downhill on a treadmill (3.3 m/s and a negative slope of 5°). The first trial was without KT, the second with KT on the peroneus longus (PL) muscle. Neuromuscular activity was measured using surface electromyography for 15 seconds. Sensation of giving way was assessed with a visual analog scale (VAS). Comparisons were made between measurements with and without KT using the Wilcoxon rank sum test. The level of significance was set at P ≤ 0.05. Results: None of the chosen parameters for preactivation, reflex activation, or total activation showed statistically significant differences between the two trials (P > 0.05). The mean values for the sensation of giving way were lower with KT (VAS, median 1.2, range 0–2.8) than without (VAS, median 1.8, range 0–3.9), but did not reach statistical significance (P = 0.102) or clinical relevance. Conclusion: KT in participants with functional ankle instability (FAI) seems to have no effect on the neuromuscular activity of PL and sensation of giving way during downhill running.     

Done or Almost Done? Improving OSCE Checklists to Better Capture Performance in Progress Tests

Construct: The impact of using nonbinary checklists for scoring residents from different levels of training participating in objective structured clinical examination (OSCE) progress tests was explored. Background: OSCE progress tests typically employ similar rating instruments as traditional OSCEs. However, progress tests differ from other assessment modalities because learners from different stages of training participate in the same examination, which can pose challenges when deciding how to assign scores. In an attempt to better capture performance, nonbinary checklists were introduced in two OSCE progress tests. The purposes of this study were (a) to identify differences in the use of checklist options (e.g., done satisfactorily, attempted, or not done) by task type, (b) to analyze the impact of different scoring methods using nonbinary checklists for two OSCE progress tests (nonprocedural and procedural) for Internal Medicine residents, and (c) to determine which scoring method is better suited for a given task. Approach: A retrospective analysis examined differences in scores (n = 119) for two OSCE progress tests (procedural and nonprocedural). Scoring methods (hawk, dove, and hybrid) varied in stringency in how they awarded marks for nonbinary checklist items that were rated as done satisfactorily, attempted, or not done. Difficulty, reliability (internal consistency), item-total correlations and pass rates were compared for each OSCE using the three scoring methods. Results: Mean OSCE scores were highest using the dove method and lowest using the hawk method. The hawk method resulted in higher item-total correlations for most stations, but there were differences by task type. Overall score reliability calculated using the three methods did not differ significantly. Pass–fail status differed as a function of scoring methods and exam type, with the hawk and hybrid methods resulting in higher failure rates for the nonprocedural OSCE and the dove method resulting in a higher failure rate for the procedural OSCE. Conclusion: The use of different scoring methods for nonbinary OSCE checklists resulted in differences in mean scores and pass–fail status. The results varied with procedural and nonprocedural OSCEs.     

Home trials of a speech synthesizer in severe dysarthria: patterns of use, satisfaction and utility of word prediction.

OBJECTIVE: The aim of this study was to evaluate a speech synthesizer with respect to patterns of use and satisfaction, during a 2-month trial at home, and the usefulness of the word prediction function. DESIGN: Prospective study. PARTICIPANTS: Of the 24 patients with severe dysarthria recruited, 10 completed the study. Five patients had cerebral palsy, 3 amyotrophic lateral sclerosis, one locked-in syndrome, and one anoxic brain damage. Mean age was 32 (standard deviation 21) years (range 9-66 years). METHODS: Each participant received 10 hours of training with the device (Dialo) and then used it at home for 2 months. The main outcome measures were: level of use recorded by the device, Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST) satisfaction score (maximum = 5), and time needed to take dictations of standard-dictionary and personal-dictionary words with and without word prediction. RESULTS: Level of use varied widely across participants. Overall satisfaction at the end of the home trial was high, with a mean QUEST score of 3.4 (SD 1) and was related to the level of use of the device. Level of satisfaction at the end of the training session could not predict the level of use at home. No significant differences were found in dictation-taking times with and without word prediction. However, 6 of the 10 patients took dictation faster with than without word prediction. CONCLUSION: This study provides the first evidence supporting the benefits of a speech synthesizer used at home for several weeks. Word prediction is useful for some patients even if increase in dictation speed did not reach significance.