Immunophenotypic changes and clinical outcome in B-cell lymphomas treated with rituximab.

Rituximab is a chimeric monoclonal antibody that recognizes the CD20 antigen and is used to treat B-cell non-Hodgkin lymphoma (B-NHL). Few studies have been published examining the use of antibody panels to evaluate B-NHL treated with rituximab. The authors performed a retrospective analysis of immunophenotypic changes and clinical outcome in 18 patients with B-NHL following rituximab therapy. The intensity of CD20 expression was evaluated by flow cytometry and/or immunohistochemistry, before and after rituximab therapy; the latter samples were taken 5 to 12 months after initiating rituximab therapy (median 7 months). Nine of the 18 patients (50%) achieved complete or partial clinical remission and did not have morphologic evidence of lymphoma in the post-therapy samples. The other nine patients (50%) had persistent disease. Two patterns of CD20 expression were noted in the post-therapy samples: unchanged expression of CD20 in neoplastic cells (4/9 cases) and loss of or a significant decrease in detected CD20 expression in neoplastic cells (5/9 cases). These results show that in many cases of B-NHL persisting after rituximab therapy, CD20 expression decreases or is lost, raising the possibility of deletion or expression modulation of the CD20 gene in neoplastic cells. This study also underscores the importance of using a panel of antibodies to evaluate rituximab-treated B-NHL.     

Endoscopic third ventriculostomy versus ventriculoperitoneal shunt in pediatric and adult population: a systematic review and meta-analysis

Neurosurgical Review - Treatment options for hydrocephalus include endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS). Some ambiguity remains regarding indications, safety,...     

Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection

BackgroundDeveloping a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.MethodsUsing 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.ResultsAn exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell–mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature’s negative predictive value was 90.6% and its positive predictive value was 77.8%.ConclusionsOur findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.     

Eye trauma during the 2011 Egyptian revolution

Background

Cairo university hospitals are at the heart of Cairo with close proximity to Tahrir (Liberation) square and had received the vast majority of casualties during the Egyptian revolution. The aim of this study was to analyze the eye injuries during the uprising.

Design

Retrospective cohort study.

Methods

Data were obtained from patients’ paper records, interview with treating ophthalmologists, and whenever possible patients were interviewed and examined. An electronic medical template had been specially developed for recording these data. Main outcome measures were the flow of patients and their demographics, diagnoses, visual acuities pre and post interventions, investigations and management. Whenever required results were compared at 95 % confidence interval.

Results

There were 184 patients (mean age 27.3?±?9.6 years) with 195 injured eyes of whom 96.7 % were males and 11 patients had both eyes injured. Seventy seven percent of patients had been admitted within 24 h of injury. Open globe injuries comprised 87 % of the eyes of which 147 eyes received 259 imaging investigations. The presenting visual acuities were worse than 3/60 in 72.5 % of eyes which were even worse post interventions and that was significantly dependent on the presenting vision. Wound repair was the primary intervention in 85 % of eyes while 50 % of the secondary interventions were vitrectomies.

Conclusions

Presenting visual acuity is a valid prognostic factor in the setting of mass eye casualty. Management of open globe injuries continues to pose difficult challenges especially bilateral ones.     

Normative Reference Values and Validity for the 30-Second Chair-Stand Test in Healthy Young Adults

BackgroundClinicians often use physical performance tests (PPT) to measure performance measures in sports since they are easy to administer, portable, and cost-efficient. However, PPT often lack good or known psychometric properties. Perhaps, the 30-second chair-stand test (30CST) would be a good functional test in athletic populations as it has been shown to demonstrate good psychometric properties in older adults.Hypothesis/PurposeThe purpose of this study was to determine normative values for and concurrent, convergent and discriminative validity of 30CST for healthy young adults aged 19-35 years.Study DesignCross-sectionalMethodsEighty-one participants completed this study. All participants performed two trials of 30CST, 5-times sit-to-stand (5xSTS), and lateral step-up test (LSUT). Investigators used the International Physical Activity Questionnaire Leisure Domain (LD-IPAQ) to divide participants into insufficiently or sufficiently active groups based on the weekly metabolic equivalent of task per the Physical Activity Guidelines for Americans.ResultsParticipants (Mean + SD age, 25.1 ± 3.4 years; body height, 1.71 ± 0.09 m; body mass, 72.6 ± 16.1 kg; females 47) performed an average of 33.0±5.4 30CST repetitions. The 30CST performance was negatively associated with 5xSTS (r=-0.79 p=0.01) and positively associated with LSUT performances (r=0.51, p=0.01) when using Pearson correlations. In addition, the sufficiently active group performed significantly greater 30CST repetitions than the insufficiently active group (mean difference = 2.5; p=0.04).ConclusionsIn addition to finding a reference value for 30CST performance in young adults, investigators found that the 30CST displayed concurrent and convergent validity in assessing functional lower extremity (LE) muscle strength and discriminated between those with sufficient and insufficient physical activity levels. Training and rehabilitation professionals could use the 30CST for testing functional LE muscle strength for athletes in pre-season or during rehabilitation. Future investigators should perform studies to determine if 30CST predicts sport performance.Level of EvidenceLevel 2     

Investigation of the Renal Protective Effect of Combined Dietary Polyphenols in Streptozotocin-Induced Diabetic Aged Rats

Natural polyphenols are widely reported to have a large range of pharmacological properties, especially antioxidant activities and free radical scavenging capacities. In this study, we investigate the effects of naringin, chlorogenic acid, and quercetin mixtures (NCQ) on renal fibrosis in streptozotocin (STZ)-induced diabetic aged rats and its underlying mechanisms for ten consecutive weeks. The oxidative defense system in the kidneys of treated rats was found to be improved. Several biomarkers were investigated including the blood urea nitrogen, creatinine, and uric acid. Moreover, antioxidant parameters were evaluated and we found that superoxide dismutase, catalase, glutathione peroxidase, Na⁺-K⁺-ATPase activities, the nitric oxide production, the protein carbonyl, the advanced oxidation protein products, lipid peroxidation, and reduced glutathione levels were all significantly balanced and close to control values. In addition, NCQ restored renal injuries and fibrosis as assessed by histological method and molecular biology investigation of the matrix metalloproteinase, the transforming growth factor-beta TGF-β, the tumor necrosis factor TNFα, and p53 expression. Our study proposes the NCQ combination as potential plant-derived bioactive compounds to prevent diabetic nephropathy.     

Isoniazid Mediates the CYP2B6*6 Genotype-Dependent Interaction between Efavirenz and Antituberculosis Drug Therapy through Mechanism-Based Inactivation of CYP2A6

Efavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with the CYP2B6*6/*6 genotype (but not the CYP2B6*1/*1 genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction. In vitro studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [K_i] = 368 μM) and pyrazinamide (K_i = 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [K_I] = 30 μM; maximal rate constant of inactivation [k_inact] = 0.023 min⁻¹) and recombinant CYP2A6 (K_I = 15 μM; k_inact = 0.024 min⁻¹) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or CYP2B6*6 genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.