Combination therapy with rituximab, low-dose cyclophosphamide, and prednisone for idiopathic membranous nephropathy: a case series

BACKGROUND: Membranous nephropathy is a common cause of the nephrotic syndrome. Treatment with standard regimens fails to induce complete remission in most patients. We evaluated the efficacy of combination therapy with rituximab, low-dose, oral cyclophosphamide, and an accelerated prednisone taper (RCP) for the treatment of idiopathic membranous nephropathy. METHODS: We analyzed 15 consecutive patients with idiopathic membranous nephropathy treated with RCP at Massachusetts General Hospital. Seven patients (47%) received RCP as initial therapy, and the other eight patients (53%) received RCP for relapsing or refractory disease. All patients had at least 1 year of follow-up. The co-primary outcomes were attainment of partial and complete remission. Partial remission was defined as a urinary protein to creatinine ratio (UPCR) < 3 g/g and a 50% reduction from baseline. Complete remission was defined as a UPCR < 0.3 g/g. Secondary outcomes were serious adverse events and the change in proteinuria, serum creatinine, serum albumin, cholesterol, triglycerides, and immunoglobulin G levels after 1 year of treatment. RESULTS: Over a median follow-up time of 37 (IQR, 34-44) months, 100% of patients achieved partial remission and 93% of patients achieved complete remission at a median time of 2 and 13 months, respectively. After 1 year of treatment, median (IQR) UPCR declined from 8.2 (6.6-11.1) to 0.3 (0.2-0.7) g/g (P < 0.001). Three serious adverse events occurred over 51 patient years. No patients died or progressed to ESKD. CONCLUSIONS: Treatment of idiopathic membranous nephropathy with RCP resulted in high rates of complete remission. Larger studies evaluating this regimen are warranted

Technology Development for the Constellation-X Spectroscopy X-Ray Telescope

The Constellation-X Spectroscopy X-ray Telescope (SXT) is a large diameter, high throughput, grazing incidence imaging mirror system, designed to perform high sensitivity spectroscopy of cosmic X-ray sources in the 0.2-10.0 keV band. The baseline effective area requirement is -3 m# at 1 keV. The system-level angular-resolution requirement is a 15-arcseconds half-power diameter, with a 5-arcsecond goal. The effective area is attained through a modular design, involving the nesting of many confocal, thin-walled Wolter I mirror segments. Considerable progress has been made in developing thin, thermally formed, glass mirror substrates that meet or better the angular-resolution requirement. Several approaches to mounting and aligning reflector segments into a mirror system are under investigation. We report here on the progress of the SXT technology development program toward reaching the performance goals

Effects of Placental Transfusion on Neonatal and 18 Month Outcomes in Preterm Infants: A Randomized Controlled Trial

Objective: To assess the effect of delayed cord clamping (DCC) vs immediate cord clamping (ICC) on intraventricular hemorrhage (IVH), late onset sepsis (LOS), and 18-month motor outcomes in preterm infants. Study Design: Women (n = 208) in labor with singleton fetuses (\u3c32 weeks gestation) were randomized to either DCC (30-45 seconds) or ICC (\u3c10 seconds). The primary outcomes were IVH, LOS, and motor outcomes at 18-22 months corrected age. Intention-to-treat was used for primary analyses. Results: Cord clamping time was 32 ± 16 (DCC) vs 6.6 ± 6 (ICC) seconds. Infants in the DCC and ICC groups weighed 1203 ± 352 and 1136 ± 350 g and mean gestational age was 28.3 ± 2 and 28.4 ± 2 weeks, respectively. There were no differences in rates of IVH or LOS between groups. At 18-22 months, DCC was protective against motor scores below 85 on the Bayley Scales of Infant Development, Third Edition (OR 0.32, 95% CI 0.10-0.90, P = .03). There were more women with preeclampsia in the ICC group (37% vs 22%, P = .02) and more women in the DCC group with premature rupture of membranes/preterm labor (54% vs 75%, P = .002). Preeclampsia halved the risk of IVH (OR 0.50, 95% CI 0.2-1.0) and premature rupture of membranes/preterm labor doubled the risk of IVH (OR 2.0, 95% CI 1.2-4.3). Conclusions: Although DCC did not alter the incidence of IVH or LOS in preterm infants, it improved motor function at 18-22 months corrected age

The hsp56 immunophilin component of steroid receptor heterocomplexes: Could this be the elusive nuclear localization signal-binding protein?

In many cells, the glucocorticoid receptor undergoes rapid steroid-mediated translocation from the cytoplasm to the nucleus, and this receptor is an excellent model for studying the mechanism of targeted protein movement through the cytoplasm. For such unidirectional movement to occur, the receptor must attach to a retrograde movement system in a manner that involves the nuclear localization signal. It is improbable that such attachment occurs via a direct protein-protein interaction between the receptor and the movement system; rather, one or more linker proteins are likely to be involved. As with other steroid receptors, the glucocorticoid receptor is associated with several other proteins in a heterocomplex. Two of these receptor-associated proteins are the heat shock proteins hsp90 and hsp56, and a third heat shock protein, hsp70, is required for assembly of the receptor heterocomplex. The hormone binding domain of the steroid receptors determines the interaction with both hsp90 and hsp70. Hsp56 is known to bind to hsp90, but its potential site, or sites, of interaction with the receptor are undefined. Hsp56 has recently been cloned and demonstrated to be an immunophilin of the FK506/rapamycin binding class. The immunophilins have peptidyl-prolyl isomerase activity but their cellular functions are unknown. Herein, we review the literature on the hsp56 immunophilin component of the receptor heterocomplex and present a rationale for hsp56 being the protein that determines the direction of receptor movement via a direct protein-protein interaction with the nuclear localization signal.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30603/1/0000240.pd

Prospective screening for postoperative deep venous thrombosis in patients undergoing infrainguinal revascularization

AbstractPurpose: The incidence of deep venous thrombosis (DVT) in patients undergoing infrainguinal bypass graft procedures has not been well documented, and the need for routine prophylaxis remains controversial. The purpose of this study was to prospectively evaluate the risk of postoperative DVT complicating infrainguinal revascularization. Methods: Seventy-four patients undergoing infrainguinal bypass graft procedures during a 12-month period were prospectively screened for DVT. Bilateral lower extremity venous duplex scan imaging was performed preoperatively and within 1 week and 6 weeks, postoperatively. Routine DVT prophylaxis was not used, with anticoagulation reserved for specific indications. Results: Of the 74 patients screened, three patients (4.1%) had DVT identified on preoperative venous duplex scan imaging and were excluded from the study. Of the remaining 71 patients enrolled, only two patients (2.8%) had postoperative DVT. Postoperative DVT was ipsilateral to the bypass graft extremity in both patients, with involvement of the peroneal vein in one patient and the femoral vein in the other. Although routine prophylaxis was not used, 18 of these patients (25%) were anticoagulated for other indications, with DVT occurring in one patient (5.6%). Of the remaining 53 patients who did not receive postoperative anticoagulation, only one patient (1.8%) had DVT. Conclusions: According to this prospective study, the risk of postoperative DVT in patients undergoing infrainguinal revascularization is low. Routine prophylaxis is not recommended, with postoperative anticoagulation reserved for specific indications. (J Vasc Surg 2000;32:669-75.

Recurrence of chronic venous ulcers on the basis of clinical, etiologic, anatomic, and pathophysiologic criteria and air plethysmography

AbstractIntroduction: Leg ulcers associated with chronic venous insufficiency (CVI) frequently recur after healing. The risk of recurrence has not been well defined for patients in different anatomic and hemodynamic groups. We reviewed the risk of ulcer recurrence on the basis of clinical, etiologic, anatomic, and pathophysiologic criteria and hemodynamic characteristics of the affected limb as assessed with air plethysmography (APG). Methods: Ninety-nine limbs with class 6 CVI were assessed clinically and with standing duplex ultrasound scanning and APG for the definition of clinical, etiologic, anatomic, and pathophysiologic criteria. Leg ulcers were treated with high-pressure compression protocols. Surgical correction of venous abnormalities was offered to patients with appropriate conditions. After ulcer healing, the limbs were placed in compressive garments and followed at 6-month intervals for ulcer recurrence. Results: The mean patient age was 54.3 years, and 46% of the patients were female. Corrective venous surgery was performed in 37 limbs. The mean follow-up time for all 99 limbs was 28 months. The ulcer recurrence rate with life table was 37% ± 6% at 3 years and 48% ± 10% at 5 years. The patients who underwent venous surgery had a significantly lower recurrence rate (27% ± 9% at 48 months) than did those patients who had not undergone surgery (67% ± 8% at 48 months; P =.005). The patients with deep venous insufficiency (DVI; n=51) had significantly higher recurrence rates (66% ± 8% at 48 months) than did the patients without DVI (n = 48; 29% ± 9% at 48 months; P =.006). This difference was significant even after accounting for the effects of surgery (P =.03).The hazard ratio of ulcer recurrence increases by 14% for every unit increase in the venous filling index (VFI; P =.001). This remains significant even after accounting for the effects of surgery (P =.001). The combination of DVI and a VFI of more than 4 mL/s yields a risk of ulcer recurrence of 43% ± 9% at 1 year and 60% ± 10% at 2 years. Conclusion: Leg ulcers associated with CVI have a high rate of recurrence. Ulcer recurrence is significantly increased in patients with DVI and in patients who do not have venous abnormalities corrected surgically. The VFI obtained from APG is useful in the prediction of increased risk for recurrence, particularly in association with anatomic data. (J Vasc Surg 2002;35:723-8.

Leucine-enriched protein feeding does not impair exercise-induced free fatty acid availability and lipid oxidation: beneficial implications for training in carbohydrate-restricted states

Given that the enhanced oxidative adaptations observed when training in carbohydrate (CHO) restricted states are potentially regulated through free fatty acid (FFA) mediated signalling and that leucine rich protein elevates muscle protein synthesis, the present study aimed to test the hypothesis that leucine enriched protein feeding enhances circulating leucine concentration but does not impair FFA availability nor whole body lipid oxidation 56 during exercise. Nine males cycled for 2 h at 70% VO2peak when fasted (PLACEBO) or having consumed a whey protein solution (WHEY) or a leucine enriched whey protein gel (GEL), administered as 22 g 1 hour pre-exercise, 11 g/h during and 22 g thirty minutes post-exercise. Total leucine administration was 14.4 g and 6.3 in GEL and WHEY, respectively. Mean plasma leucine concentrations were elevated in GEL (P= 0.001) compared 60 with WHEY and PLACEBO (375 ± 100, 272 ± 51, 146 ± 14 μmol.L-1 respectively). No differences (P= 0.153) in plasma FFA (WHEY 0.53 ± 0.30, GEL 0.45 ± 0.25, PLACEBO 0.65 ± 0.30, mmol.L-1) or whole body lipid oxidation during exercise (WHEY 0.37 ± 0.26, GEL 0.36 ± 0.24, PLACEBO 0.34 ± 0.24 g/min) were apparent between trials, despite elevated (P= 0.001) insulin in WHEY and GEL compared with PLACEBO (38 ± 16, 35 ± 16, 22 ± 11 pmol.L-1 respectively). We conclude that leucine enriched protein feeding does not impair FFA availability nor whole body lipid oxidation during exercise, thus having practical applications for athletes who deliberately train in CHO restricted states to promote skeletal muscle adaptations

Lack of Association of Two Common Polymorphisms rs2910164 and rs11614913 with Susceptibility to Hepatocellular Carcinoma: A Meta-Analysis

BACKGROUND: Single nucleotide polymorphisms (SNPs) in microRNA-coding genes may participate in the process of carcinogenesis by altering the expression of tumor-related microRNAs. It has been suggested that two common SNPs rs2910164 in miR-146a and rs11614913 in miR-196a2 are associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. In the present study, we performed a meta-analysis to systematically summarize the possible association between the two SNPs and the risk for HCC. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a search of case-control studies on the associations of SNPs rs2910164 and/or rs11614913 with susceptibility to HCC in PubMed, EMBASE, ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library and Chinese National Knowledge Infrastructure databases. Data from eligible studies were extracted for meta-analysis. HCC risk associated with the two polymorphisms was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). 5 studies on rs2910164 and 4 studies on rs11614913 were included in our meta-analysis. Our results showed that neither allele frequency nor genotype distribution of the two polymorphisms was associated with risk for HCC in all genetic models. Similarly, subgroup analysis in Chinese population showed no association between the two SNPs and the susceptibility to HCC. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that two common SNPs rs2910164 and rs11614913 are not associated with the risk of HCC. Well-designed studies with larger sample size and more ethnic groups are required to further validate the results