SummaryBackgroundKCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.MethodsIn this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.Findings90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol [55·2–77·1]) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol [35·5–47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol [41·0–56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2–10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5–24·0] vs 4·1 years [1·3–10·2]; p=0·0005). Initial improvement was noted following transfer to sulfo...
-Peripheral vascular resistance has a major impact on arterial blood pressure levels. Endothelial C-type natriuretic peptide (CNP) participates in the local regulation of vascular tone but the target cells remain controversial. The cGMP-producing guanylyl cyclase-B (GC-B) receptor for CNP is expressed in vascular smooth muscle cells (VSMC). However, whereas endothelial cell-specific CNP knockout mice are hypertensive, mice with deletion of GC-B in VSMC have unaltered blood pressure. -We analyzed whether the vasodilating response to CNP changes along the vascular tree, i.e. whether the GC-B receptor is expressed in microvascular types of cells. Mice with a floxed GC-B () gene were interbred with or lines to develop mice lacking GC-B in endothelial cells or in precapillary arteriolar SMC and capillary pericytes. Intravital microscopy, (non)invasive hemodynamics, fluorescence energy transfer studies of pericyte's cAMP levels and renal physiology were combined to dissect whether and how CNP/GC-B/cGMP signaling modulates microcirculatory tone and blood pressure. -Intravital microscopy studies revealed that the vasodilatatory effect of CNP increases towards small-diameter arterioles and capillaries. Consistently, CNP did not prevent endothelin-1-induced acute constrictions of proximal arterioles but fully reversed endothelin effects in precapillary arterioles and capillaries. Here, the GC-B receptor is expressed both in endothelial and mural cells, i.e. in pericytes. Notably, the vasodilatatory effects of CNP were preserved in mice with endothelial GC-B deletion but abolished in mice lacking GC-B in microcirculatory SMC and pericytes. CNP, via GC-B/cGMP signaling modulates two signaling cascades in pericytes: it activates cGMP-dependent protein kinase I to phosphorylate downstream targets such as the cytoskeleton-associated vasodilator activated phosphoprotein; and it inhibits phosphodiesterase 3A, thereby enhancing pericyte's cAMP levels. Ultimately these pathways prevent endothelin-induced increases of pericyte calcium levels and pericyte contraction. Mice with deletion of GC-B in microcirculatory SMC and pericytes have elevated peripheral resistance and chronic arterial hypertension without a change in renal function. -Our studies indicate that endothelial CNP regulates distal arteriolar and capillary blood flow. CNP-induced GC-B/cGMP signaling in microvascular SMC and pericytes is essential for the maintenance of normal microvascular resistance and blood pressure.
Sclerosing encapsulating peritonitis, a rare cause of bowel obstruction, was described as a complication associated with peritoneal dialysis which is much feared because of its severity. The authors report a case where radiological findings in association with clinical symptoms have allowed for a noninvasive diagnosis of sclerosing encapsulating peritonitis, emphasizing the high sensitivity and specificity of computed tomography to demonstrate the characteristic findings of such a condition.
BACKGROUND: EGFRvIII, a constitutively active EGFR deletion driver mutation, is associated with poor long-term survival in glioblastoma (GB). The investigational vaccine rindopepimut consists of an EGFRvIII-specific peptide sequence conjugated to keyhole limpet hemocyanin (KLH), delivered intradermally with GM-CSF. Three phase II studies in newly diagnosed, resected, EGFRvIII+ GB demonstrated encouraging progression-free survival (PFS), overall survival (OS) and safety. METHODS: In the Phase II "ReACT" study, 73 bevacizumab (BV)-naïve pts in 1st or 2nd relapse with EGFRvIII+ GB were randomized 1:1 to BV plus double-blinded injection of rindopepimut or control (KLH). Endpoints: 6-month PFS (PFS6; primary; target a ¼ 0.2 by 1-sided chi-square test), objective response rate (ORR), PFS, OS and safety. RESULTS: Primary rindopepimut toxicity is Grade 1-2 injection site reaction. For rindopepimut + BV vs. KLH + BV (per centralized review; RANO criteria): PFS6 ¼ 28% (10/36) vs. 16% (6/37) (p ¼ 0.116); ORR ¼ 30% (9/30) vs. 18% (6/34). Cessation of steroids . 2 months: 44% (8/18) vs 21% (4/19), .6 months: 33% (6/18) vs. 0. Median (95% CI) OS ¼ 11.6 (10.0, 16.2) vs. 9.3 (7.1, 11.3) months (HR ¼ 0.57 [0.33, 0.98], p ¼ 0.039). 9 vs 6 pts remain in follow-up; 6 vs. 2 are progression-free. OS analyses adjusted for various prognostic factors consistently favor rindopepimut. Rindopepimut induced robust anti-EGFRvIII titers (1:12,800-1:6,553,600) in 80% of pts. Antibodies, predominantly IgG1 isotype, mediate killing of EGFRvIII+ tumor cells through ADCC and CDCC in vitro. Within the rindopepimut arm, peak titer (≥1:12,800 at any time) and rapid titer generation (≥1:12,800 by Day 57) were associated with prolonged OS (HR ¼ 0.16, p ¼ ,0.0001 and HR ¼ 0.59, p ¼ 0.182, respectively). Evaluation of humoral response quality, HLA typing vs. outcome, and survival follow-up continue. In an additional cohort of BV-exposed pts (n ¼ 53), four pts experienced objective tumor response. CONCLUSIONS: Rindopepimut induces potent EGFRvIII-specific immune response and tumor regression, and appears to significantly prolong survival when administered with BV, in pts with relapsed GB.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.