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Aims To compare, in a double-blind, randomized, multi-national study, 52- or 78-week treatment with basal insulin peglispro or insulin glargine, added to pre-study oral antihyperglycaemic medications, in insulin-naïve adults with type 2 diabetes. Material and methods The primary outcome was non-inferiority of peglispro to glargine with regard to glycated haemoglobin ( HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients. Results Peglispro was non-inferior to glargine in HbA1c reduction [least-squares ( LS) mean difference: −0.29%, 95% confidence interval ( CI) −0.40, −0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p = .005), more patients achieving HbA1c <7.0% without nocturnal hypoglycaemia [odds ratio ( OR) 2.15 (95% CI 1.60, 2.89); p < .001], greater HbA1c reduction (p < .001), and more patients achieving HbA1c<7.0% [ OR 1.97 (95% CI 1.57, 2.47); p < .001]. Total hypoglycaemia rate and fasting serum glucose did not achieve statistical superiority. At 52 weeks, peglispro-treated patients had higher triglyceride (1.9 vs 1.7 mmol/L). alanine transaminase (34 vs 27 IU/ L), and aspartate transaminase levels (27 vs 24 IU/ L). LS mean liver fat content was unchanged with peglispro at 52 weeks but decreased 3.1% with glargine [difference: 2.6% (0.9, 4.2); p = .002]. More peglispro-treated patients experienced adverse injection site reactions (3.5% vs 0.6%, p < .001). Conclusions Compared with glargine at 52 weeks, peglispro resulted in a statistically superior reduction in HbA1c, more patients achieving HbA1c targets, less nocturnal hypoglycaemia, no improvement in total hypoglycaemia, higher triglyceride levels, higher aminotransferase levels, and more injection site reactions. [ABSTRACT FROM AUTHOR]

We propose a graph-based sweep algorithm for solving the steady-state, monoenergetic discrete ordinates on meshes of high-order (HO) curved mesh elements. Our spatial discretization consists of arbitrarily HO discontinuous Galerkin finite elements using upwinding at mesh element faces. To determine mesh element sweep ordering, we define a directed, weighted graph whose vertices correspond to mesh elements and whose edges correspond to mesh element upwind dependencies. This graph is made acyclic by removing select edges in a way that approximately minimizes the sum of removed edge weights. Once the set of removed edges is determined, transport sweeps are performed by lagging the upwind dependency associated with the removed edges. The proposed algorithm is tested on several two-dimensional and three-dimensional meshes composed of HO curved mesh elements. [ABSTRACT FROM AUTHOR]

Aim: To compare steady state pharmacodynamic and pharmacokinetic profiles of insulin glargine 300U/mL (Gla-300) with insulin degludec 100U/mL (Deg-100) in people with type 1 diabetes., Methods: This single-centre, randomized, double-blind crossover euglycaemic clamp study included two parallel cohorts with fixed once-daily morning dose regimens. For both insulins participants received 0.4 (n=24) or 0.6U/kg/day (n=24), before breakfast, for 8 days prior to the clamp. The main endpoint was within-day variability (fluctuation) of the smoothed glucose infusion rate (GIR) over 24 hours (GIR-smFL 0-24 )., Results: Gla-300 provided 20% less fluctuation of steady state glucose infusion rate profiles than Deg-100 over 24 hours at 0.4U/kg/day (GIR-smFL 0-24 treatment ratio 0.80 [90% confidence interval: 0.66 to 0.96], P=0.047), while at the dose of 0.6U/kg/day the difference between insulins was not statistically significant (treatment ratio 0.96 [0.83 to 1.11], P=0.603). Serum insulin concentrations appeared more evenly distributed with both dose levels of Gla-300 versus the same doses of Deg-100, as assessed by relative 6-hour fractions of the area under the curve within 24 hours. Both insulins provided exposure and activity until 30 hours (end of clamp)., Conclusion: Gla-300 provides less fluctuating steady state pharmacodynamic profiles (i.e. lower within-day variability) and more evenly distributed pharmacokinetic profiles, compared with Deg-100 in a once-daily morning dosing regimen of 0.4U/kg/day., (Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The possibility of a slow post-acylation conformational change during catalysis by cysteine proteinases was investigated by using a new chromogenic substrate, N-acetyl-Phe-Gly methyl thionoester, four natural variants (papain, caricain, actinidin and ficin), and stopped-flow spectral analysis to monitor the pre-steady state formation of the dithioacylenzyme intermediates and their steady state hydrolysis. The predicted reversibility of acylation was demonstrated kinetically for actinidin and ficin, but not for papain or caricain. This difference between actinidin and papain was investigated by modelling using QUANTA and CHARMM. The weaker binding of hydrophobic substrates, including the new thionoester, by actinidin than by papain may not be due to the well-known difference in their S2-subsites, whereby that of actinidin in the free enzyme is shorter due to the presence of Met211. Molecular dynamics simulation suggests that during substrate binding the sidechain of Met211 moves to allow full access of a Phe sidechain to the S2-subsite. The highly anionic surface of actinidin may contribute to the specificity difference between papain and actinidin. During subsequent molecular dynamics simulations the P1 product, methanol, diffuses rapidly (over<8 ps) out of papain and caricain but 'lingers' around the active centre of actinidin. Uniquely in actinidin, an Asp142-Lys145 salt bridge allows formation of a cavity which appears to constrain diffusion of the methanol away from the catalytic site. The cavity then undergoes large scale movements (over 4.8 A) in a highly correlated manner, thus controlling the motions of the methanol molecule. The changes in this cavity that release the methanol might be those deduced kinetically.

The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti-4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell-independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti-4-1BB mAb was given within 1 wk after immunization. Anti-4-1BB inhibition was observed in mice lacking functional CD8(+) T cells, indicating that CD8(+) T cells were not required for the induction of anergy. Analysis of the requirements for the anti-4-1BB-mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti-4-1BB-treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti-4-1BB-treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti-4-1BB-treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti-4-1BB mAbs.

Cultured human umbilical vein endothelial cells (HUVECs) are a valuable model for investigation of endothelial functions, but they enter senescence at low passage. Transfection of early passage HUVECs with the early genes of SV40 greatly extends the replicative potential of these cells, but eventually results in marked changes in growth, morphology, and biochemistry. Here we report a modified approach that appears to have overcome the problem of late passage decline after transfection. Plasmid pX-8 containing the SV40 early genes was transfected into passage four HUVECs. At passage five, these transfectants were cloned by limiting dilution and selected on the basis of both morphological and biochemical resemblance to their untransfected counterparts. Two clones that expressed factor VIII and in which the basal and the tumor necrosis factor-alpha inducible levels of interleukin 6 and endothelial adhesion molecules were normal were chosen. Vimentin and fibronectin distribution in these clones resembled untransfected cells. At passage 25, growth pattern changes were becoming evident, but recloning these late passage clones recovered numerous subclones of normal, cobblestone appearance. Two of these were further characterized and found to resemble their original parental clone by all of the biochemical criteria listed above. These subclones appeared to transform more rapidly than the parental clone, but repeated subcloning again rescued clones with normal morphologies and normal biochemical characteristics. We conclude that periodic recloning may indefinitely perpetuate lines that are useful equivalents of their original counterparts.

The purpose of this study was to determine the efficacy of laparoscopic-assisted vaginal hysterectomy utilising the contact-tip Nd:YAG (Neodymium: Yttrium-Aluminum-Garnet) laser (Surgical Laser Technologies, Oaks, PA). Postoperative activity levels, operative times, blood loss, pain medication use, length of hospital stay, and complications of laparoscopic-assisted vaginal hysterectomy were determined. Sixty-seven women with extensive disease including endometriosis, adenomyosis, adhesions, and multiple fibroids underwent laparoscopic-assisted vaginal hysterectomy (LAVH). The procedures were performed utilising the contact-tip Nd:YAG laser and a laparoscopic linear stapling device. All patients were operated on for a primary diagnosis of pelvic pain and would have required an abdominal approach for surgery due to extensive adhesions, fibroids, or endometriosis. Sixty-eight cases of laparoscopic-assisted vaginal hysterectomy were attempted. In 67 of these cases, the procedure was completed as planned. One case required conversion to abdominal hysterectomy due to extensive adhesions. Average hospital stay after surgery was 2.7 days with a minimum stay of less than one day. The average operating time for the LAVH was 149 minutes with an estimated blood loss of 220 mL and a haemoglobin drop from surgery to day 1 after surgery of 1.9 g. The complication rate was 11.9% with all of the complications occurring in the first 46 cases. By day 14 after surgery, patients reported their activity level at 8.8 on a scale of 1 to 10 with 10 being unlimited activities. By day 21, they reported their activity level at 9.5. The majority of the patients were able to return to work within two weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

The dog heartworm Dirofilaria immitis has been diagnosed by thoracotomy as the etiology of neoplastic-appearing nodules in two patients in the Peoria, Illinois area. This brings the total number of reported cases of human pulmonary dirofilariasis to approximately 81 in the United States. The major concern of this benign disease is that in making the diagnosis the patients undergo the risk of surgery because of the presumed preoperative diagnosis of cancer. Greater awareness of this disease is needed as the geographic distribution of human pulmonary dirofilariasis expands in this country.

Combination therapy for type II (non-insulin-dependent) diabetes mellitus with insulin and sulfonylureas has been a topic of interest since the latter were introduced to clinical use. In recent years, improved understanding of potential complications associated with hyperinsulinemia has led to resurgent interest in alternatives to insulin monotherapy for patients who have failed on a regimen of diet and sulfonylureas. A plethora of clinical trials have reported on the efficacy of oral hypoglycemic agents in limiting insulin requirements while achieving glycemic control in this subset of diabetic patients. However, few studies have been appropriate in both design and duration to provide convincing results. The randomized placebo-controlled double-blind trials that have used a parallel design and study periods of up to 1 yr have uniformly investigated second-generation sulfonylureas and yielded the most reliable information. In all instances, the combination regimen achieved reduction in insulin requirement with varying evidence of a pancreatic effect as the responsible mechanism. This treatment modality is becoming more widely accepted in the effort to achieve optimal glycemic control with minimum risk to the patient.

Peripheral vascular disease is a well-known source of morbidity and potential mortality in diabetic patients. Sixty-five subjects with diabetes were studied in order to describe the contributions of the patient, the physician, and the health care system to the performance of a preventive foot examination. The incidences of foot examination on the day of study (12.3 percent) and during the previous year (49.2 percent) were similar to those found by other investigators. The feet of patients at higher risk for limb amputation were not examined with greater frequency at the clinic, although such patients were more often referred to a podiatrist. The most significant determinants of physician foot examination were patient recall of foot-related education received at the clinic and inter-physician variability. These data suggest that the patient, physician, and clinic routine all play an important role in the success of a foot screening program for patients with diabetes.