Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy

Autoantibodies to the M-type phospholipase A(2) receptor (PLA(2)R) are sensitive and specific for idiopathic membranous nephropathy. The anti-B cell agent rituximab is a promising therapy for this disease, but biomarkers of early response to treatment currently do not exist. Here, we investigated whether levels of anti-PLA(2)R correlate with the immunological activity of membranous nephropathy, potentially exhibiting a more rapid response to treatment than clinical parameters such as proteinuria. We measured the amount of anti-PLA(2)R using Western blot immunoassay in serial serum samples from a total of 35 patients treated with rituximab for membranous nephropathy in two distinct cohorts. Pretreatment samples from 25 of 35 (71%) patients contained anti-PLA(2)R, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 12 months after rituximab. Those who demonstrated this immunologic response fared better clinically: 59% and 88% attained complete or partial remission by 12 and 24 months, respectively, compared with 0% and 33% among those with persistent anti-PLA(2)R levels. Changes in antibody levels preceded changes in proteinuria. One subject who relapsed during follow-up had a concomitant return of anti-PLA(2)R. In summary, measuring anti-PLA(2)R levels by immunoassay may be a method to follow and predict response to treatment with rituximab in membranous nephropathy.     

Statement of Ethics in Neurosurgery of the World Federation of Neurosurgical Societies

This Statement of Ethics in Neurosurgery was developed by the Committee for Ethics and Medico-Legal Affairs of the World Federation of Neurosurgical Societies to help neurosurgeons resolve problems in the treatment of individual patients and meet obligations to the larger society. This document is intended as a framework rather than a set of rules. It cannot cover every situation and should be used with flexibility. However, it is our intent that the fundamental principles enunciated here should serve as a guide in the day-to-day practice of neurosurgery.     

Vitamin D and Selenium in a Thyroid Eye Disease Population in Texas

There is growing evidence of thyroid eye disease association with nutritional deficiencies including selenium and vitamin D. We conducted a retrospective chart review of all patients with clinical diagnosis of TED seen at our clinic from 2016 to 2017. Thirty-five patients met inclusion criteria and had serum 25-hydroxyvitamin D levels available, and 19 had selenium levels available. 7/35 (20%) patients had vitamin D deficiency, and 11 (31%) had vitamin D insufficiency, but none had selenium deficiency. Although both selenium and vitamin D supplementation have been recommended for TED, further investigation is necessary to justify supplementation for patients with TED.     

Gum Ghatti--a pharmaceutical excipient: development, evaluation and optimization of sustained release mucoadhesive matrix tablets of domperidone

The objective of this study was to extend the GI residence time of the dosage form and to control the release of domperidone using directly compressible sustained release mucoadhesive matrix (SRMM) tablets. A 2-factor centre composite design (CCD) was employed to study the influence of independent variables like gum ghatti (GG) (X1) and hydroxylpropylmethyl cellulose K 15M (HPMC K 15M) (X2) on dependent variable like mucoadhesive strength, tensile strength, release exponent (n), t50 (time for 50% drug release), rel(10 h) (release after 10 h) and rel(18 h) (release after 18 h). Tablets were prepared by direct compression technology and evaluated for tablet parametric test (drug assay, diameter, thickness, hardness and tensile strength), mucoadhesive strength (using texture analyzer) and in vitro drug release studies. The tensile strength and mucoadhesive strength were found to be increased from 0.665 +/- 0.1 to 1.591 +/- 0.1 MN/cm2 (Z1 to Z9) and 10.789 +/- 0.985 to 50.924 +/- 1.150 N (Z1 to Z9), respectively. The release kinetics follows first order and Hixson Crowell equation indicating drug release following combination of diffusion and erosion. The n varies between 0.834 and 1.273, indicating release mechanism shifts from non fickian (anomalous release) to super case II, which depict that drug follows multiple drug release mechanism. The t50 time was found to increase from 5 +/- 0.12 to 11.4 +/- 0.14 h (Z1 to Z9) and release after 10 and 18 h decreases with increasing concentration of both polymers concluding with release controlling potential of polymers. The accelerated stability studies were performed on optimized formulation as per ICH guideline and the result showed that there was no significant change in tensile strength, mucoadhesive strength and drug assay.     

MIDG-Emerging grid technologies for multi-site preclinical molecular imaging research communities

Purpose  

Molecular imaging is the visualization and identification of specific molecules in anatomy for insight into metabolic pathways, tissue consistency, and tracing of solute transport mechanisms. This paper presents the Molecular Imaging Data Grid (MIDG) which utilizes emerging grid technologies in preclinical molecular imaging to facilitate data sharing and discovery between preclinical molecular imaging facilities and their collaborating investigator institutions to expedite translational sciences research. Grid-enabled archiving, management, and distribution of animal-model imaging datasets help preclinical investigators to monitor, access and share their imaging data remotely, and promote preclinical imaging facilities to share published imaging datasets as resources for new investigators.     

Repeated hemoglobin A1C ordering in the VA Health System

Background

Hemoglobin A1c (HbA1c) is used to assess glycemic control in patients with diabetes. While underuse of HbA1c testing has been well studied, potential overuse is poorly characterized.

Methods

Our objective was to examine the frequency of HbA1c testing in an integrated delivery system. We conducted a retrospective study of administrative data of 130,538 patients with newly diagnosed diabetes receiving care in the Veterans Administration Healthcare System during 2006 and 2007 (mean age 64.1 years, 97.3% male). Our main outcome measures were the proportion of patients receiving repeat HbA1c testing within 30 and 90 days and the proportion of patients receiving more than 4 repeat tests within 12 months of their initial HbA1c.

Results

Overall 8.4% of patients (N = 11,003) received at least one repeat HbA1c within 30 days of their initial test and 30.8% (N = 40,162) within 90 days. A significantly higher proportion of patients with poor diabetes control received a repeat test within 30 days (14.7%) than patients with intermediate control (9.1%) or good control (6.8%) (P < 0.01). Overall, 4.2% of patients (N = 5,468) received more than 4 repeat HbA1c tests and 0.4% received more than 6 (N = 479). In logistic regression models, receipt of more than 4 repeat HbA1c tests was more common among patients age 50-70 years (compared to younger and older patients), whites (compared to blacks and Hispanics), and patients manifesting complications of diabetes (P < 0.01 for all).

Conclusion

Repeat HbA1c testing appears to occur somewhat more frequently than is warranted.     

Tyrosine phosphorylated c-Cbl regulates platelet functional responses mediated by outside-in signaling

c-Cbl protein functions as an E3 ligase and scaffolding protein, where 3 residues, Y700, Y731, and Y774, upon phosphorylation, have been shown to initiate several signaling cascades. In this study, we investigated the role of these phospho-tyrosine residues in the platelet functional responses after integrin engagement. We observed that c-Cbl Y700, Y731 and Y774 undergo phosphorylation upon platelet adhesion to immobilized fibrinogen, which was inhibited in the presence of PP2, a pan-src family kinase (SFK) inhibitor, suggesting that c-Cbl is phosphorylated downstream of SFKs. However, OXSI-2, a Syk inhibitor, significantly reduced c-Cbl phosphorylation at residues Y774 and Y700, without affecting Y731 phosphorylation. Interestingly, PP2 inhibited both platelet-spreading on fibrinogen as well as clot retraction, whereas OXSI-2 blocked only platelet-spreading, suggesting a differential role of these tyrosine residues. The physiologic role of c-Cbl and Y731 was studied using platelets from c-Cbl KO and c-Cbl(YF/YF) knock-in mice. c-Cbl KO and c-Cbl(YF/YF) platelets had a significantly reduced spreading over immobilized fibrinogen. Furthermore, clot retraction with c-Cbl KO and c-Cbl(YF/YF) platelets was drastically delayed. These results indicate that c-Cbl and particularly its phosphorylated residue Y731 plays an important role in platelet outside-in signaling contributing to platelet-spreading and clot retraction.     

Left ventricular twist mechanics in hypertrophic cardiomyopathy assessed by three-dimensional speckle tracking echocardiography

Left ventricular (LV) twist represents a phenomenon that links systolic contraction with diastolic relaxation and plays a major role in cardiac physiology; thus, the study of twist mechanics is of particular interest in hypertrophic cardiomyopathy (HC). Three-dimensional speckle tracking echocardiography (3D-STE) has the potential to overcome the limitations of 2-dimensional imaging and provide a greater understanding of LV twist in HC. We aimed to examine LV twist mechanics in HC using 3D-STE. Echocardiograms from subjects with a diagnosis of HC were examined for 3D-STE analysis. Age- and gender-matched healthy subjects were tested as a control group. Forty patients with HC (age 37 ± 16 years; 42.5% women) and 40 control subjects (age 35 ± 10 years; 42.5% women) were examined. Compared with the controls, the patients with HC showed increased peak LV twist (16.5 ± 4.7° vs 12.0 ± 3.9°, p <0.001) mainly because of increased apical rotation of those with LV outflow tract obstruction (obstruction, 12.7 ± 4.4° vs nonobstruction, 9.7 ± 2.8°, p = 0.02). In addition, the patients with HC displayed onset of torsion recoil occurring closer to the aortic valve closure (94 ± 6% vs 85 ± 6%, p <0.001; time normalized by the length of systole), limited completion of untwist during early diastole (31 ± 12% vs 62 ± 15%, p <0.001), and delayed peak untwist velocity (22 ± 7% vs 13 ± 9%, p <0.001; time normalized by the length of diastole). In conclusion, the evaluation of twist mechanics using 3D-STE provides novel insight regarding alterations in LV mechanics in patients with HC. Elucidating the characteristics of the wringing motion of the heart might help to broaden the understanding of the hyperdynamic contraction and impaired relaxation observed in these patients.