IntroductionThe shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with ...diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone.Research design and methodsThis is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed <10 years who underwent 2-hour 75 g OGTT at baseline as part of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Insulin sensitivity (homeostasis model of insulin sensitivity, HOMA2-S) and β-cell function (early, late, and total incremental insulin and C peptide responses adjusted for HOMA2-S) were calculated. Glucose curve shape was classified as monophasic, biphasic, or continuous rise.ResultsThe monophasic profile was the most common (67.8% monophasic, 5.5% biphasic, 26.7% continuous rise). The monophasic subgroup was younger, more likely male and white, and had higher body mass index (BMI), while the continuous rise subgroup was more likely female and African American/black. HOMA2-S and fasting glucose did not differ among the subgroups. The biphasic subgroup had the highest early, late, and total insulin and C peptide responses (all p<0.05 vs monophasic and continuous rise). Compared with the monophasic subgroup, the continuous rise subgroup had similar early insulin (p=0.3) and C peptide (p=0.6) responses but lower late insulin (p<0.001) and total insulin (p=0.008) and C peptide (p<0.001) responses.ConclusionsBased on the large multiethnic GRADE cohort, sex, race, age, and BMI were found to be important determinants of the shape of the glucose response curve. A pattern of a continuously rising glucose at 2 hours reflected reduced β-cell function and may portend increased glycemic failure rates.Trial registration numberNCT01794143.
Phytoecdysteroids such as 20-hydroxyecdysone (20HE) are nutritional supplements marketed as enhancers of lean body mass. In this study the impact of 20HE ingestion on protein kinase B/Akt-mechanistic ...target of rapamycin complex 1 signaling in the skeletal muscle and liver of male rats was found to be limited. Bioavailability of 20HE, whether consumed alone or with leucine, also remained low at all doses ingested. Additional work is necessary to clarify 20HE mechanism of action in vivo.
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DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Scientific background: Activated macrophages, present in excess during natural inflammatory responses, bear the potential to kill and eradicate cancer cells. Efranat has developed cancer ...immunotherapy based on macrophage activation using a plasma protein designated EF-022, a modified Vitamin D Binding Protein Macrophage Activator.
Methods: We performed an open label single-center phase I study in patients diagnosed with inoperable, recurrent or metastatic malignant solid tumors, deemed incurable, and who have failed to respond to standard therapy or for whom no standard therapy is available. The dose-escalation study was comprised of three cohorts, each receiving intramuscular (IM) injections of EF-022, once weekly for two cycles of treatment. Each cycle consisted of 4 weekly injections. Three dose levels were evaluated: 100 ng, 500ng and 1000ng. Patients were followed for up to 12 months from the start of treatment. The primary study objectives were to determine the safety and tolerability and to define the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Blood and tissue biopsies were obtained for pharmacodynamics evaluation.
Results: 12 patients with solid tumors have been enrolled. Median age = 65; male: female = 5:7. Among 12 treated patients, the most frequent drug related adverse events were flu like symptoms and rash and were mostly grade 1 or 2; no serious adverse events (SAE) related to study drug were observed. No DLTs were observed. CT imaging performed at 8 weeks showed stable disease (SD) in 5/12 patients (cholangiocarcinoma, H&N cancer, esophageal-gastric cancer, ovarian cancer and liposarcoma). 11 patients completed 57 days of treatment and 1 patient left the study after 1st cycle of treatment (29 days). Significant reduction in Tregs (CD4+CD127-CD25+) levels and increase in M1/M2 monocyte (CD14+HLA+ /CD16+CD163+) ratio in the blood was detected in most of the patients. In patients demonstrating SD an increase in the M1/M2 macrophage ratio (CD68+CD163-/ CD68+CD163+) was found at the tumor site.
Conclusions: Treatment with EF-022 has an acceptable safety profile and resulted in disease stabilization in 42% of patients. Pharmacodynamics markers suggest a reduction of Tregs and increase of the M1/M2 ratio. These findings are being further explored in a dose expansion cohort.
ClinicalTrials.gov Identifier: NCT02052492
Citation Format: Talia Golan, Raanan Berger, Aliza Ackerstein, Steve Raskin, Alexander M. Lesokhin, David Sidransky, Mark L. Levitt, Hana Gadassi, Uri Yogev, Michal Shahar. A phase 1 open label, dose-escalation trial evaluating the safety and tolerability of EF-022, macrophage activator, in subjects with advanced solid malignancies. abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B30.
Contour processing is a fundamental task in many fields, such as Photogrammetry, Meteorology, and Geographic Information Science. Contours, usually extracted from raster images or triangulated ...meshes, greatly benefit from a smoothing postprocessing phase. In the case of triangulated meshes, unsmoothed contours look angular, and disclose the edges of the underlying mesh. Attempts to smooth contours individually by using splines may cause crossings among nearby contours, clearly misrepresenting the data. To partially reduce this problem, previous studies propose to use the underlying mesh at aiding the contour smoothing process. The algorithm proposed herein builds on previous work to guarantee, for the first time, non-crossing smooth contours that are continuous in the first derivative. We formally prove our claims and present experimental results to show that, in addition, our algorithm outputs less than half the control points produced by previous approaches. Further work is proposed for achieving higher degrees of smoothness.
Percutaneous acetabuloplasty (PA) is a promising treatment for painful metastatic lesions of the acetabulum. Four patients were treated with injection of the bone cement polymethylmethacrylate ...directly into the lesion. After the procedure, all four patients had improvement or relief of their pain and were able to resume weight-bearing activities. The procedure was well tolerated by each patient without morbidity. PA appears to be a reasonable palliative procedure for painful and fragile hips associated with metastatic bone disease.
HD 172189 is a spectroscopic eclipsing binary system with a rapidly-rotating pulsating δ Scuti component. It is also a member of the open cluster IC 4756. These combined characteristics make it an ...excellent laboratory for asteroseismic studies. To date, HD 172189 has been analysed in detail photometrically but not spectroscopically. For this reason we have compiled a set of spectroscopic data to determine the absolute and atmospheric parameters of the components. We determined the radial velocities (RV) of both components using four different techniques. We disentangled the binary spectra using KOREL, and performed the first abundance analysis on both disentangled spectra. By combining the spectroscopic results and the photometric data, we obtained the component masses, 1.8 and 1.7 $M_{\odot}$, and radii, 4.0 and 2.4 $R_{\odot}$, for inclination $i = 73.2^{\circ}$, eccentricity $e = 0.28$, and orbital period $\Pi = 5.70198$ days. Effective temperatures of 7600 K and 8100 K were also determined. The measured $v \sin i$ are 78 and 74 km s-1, respectively, giving rotational periods of 2.50 and 1.55 days for the components. The abundance analysis shows Fe/H = –0.28 for the primary (pulsating) star, consistent with observations of IC 4756. We also present an assessment of the different analysis techniques used to obtain the RVs and the global parameters.
Summary
Niemann–Pick disease type C (NPC) is an autosomal recessive neurovisceral lysosomal lipid storage disorder that leads to variable symptoms that include cognitive decline, ataxia, dystonia, ...cataplexy, vertical supranuclear gaze palsy, and seizures. Currently, there is no specific treatment for NPC other than palliative care. Substrate reduction therapy represents a potential strategy for treating this debilitating neurodegenerative disorder. Miglustat (Zavesca) is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyses the first step in the biosynthesis of most glycosphingolipids. Miglustat has pharmacokinetic properties that allow it to cross the blood–brain barrier, thus making it a potential therapeutic agent for treating neurological symptoms in NPC patients. We present here a case report of a Brazilian child treated with miglustat. Before treatment, the patient presented with difficulties walking and swallowing, slurred speech, moderate cognitive impairments, ataxia, ptosis, and vertical supranuclear ophthalmoplegia. On a disability scale, the patient obtained a score of 15 before treatment and 8 after treatment. Following 12 months of treatment, the patient remained stable with improvements in speech, ptosis, ophthalmoplegia, ataxia, hypotonia and seizures. The Child Behavior Checklist (CBCL) was used to assess psychopathological, behavioural and social problems before and after treatment. The CBCL showed that indices for depression, affective and attention problems were all in the normal range following treatment. Thus, for this individual miglustat was an effective, well-tolerated and efficacious medication for treatment of NPC symptoms. Follow-up maintenance studies are vital to establish whether both the efficacy and safety of miglustat persist with time.
ABSTRACT
Objective. To assess the safety of duloxetine at a fixed‐dose of 60 mg twice daily (BID) for up to 52 weeks, and compare duloxetine with routine care in the management of patients with ...diabetic peripheral neuropathic pain (DPNP).
Design and Interventions. Patients who completed a 13‐week, randomized, double‐blind, placebo‐controlled acute therapy period were randomly reassigned in a 2:1 ratio to therapy with duloxetine 60 mg BID (N = 197) or routine care (N = 96) for an additional 52 weeks.
Patients. The trial included outpatients ≥18 years of age diagnosed with moderate to severe DPNP caused by type 1 or type 2 diabetes.
Results. Fourteen patients discontinued due to adverse events or death (11 5.6% duloxetine‐ and 3 3.1% routine care‐treated patients). There were no significant therapy‐group differences observed for patients with ≥1 serious adverse event. In total, 110 (55.8%) duloxetine‐ and 47 (49%) routine care‐treated patients had ≥1 treatment‐emergent adverse event (TEAE). The TEAE with a significant therapy‐group difference, with patients in the duloxetine therapy group experiencing a higher percentage of events, was asthenia (11 5.6% duloxetine‐ vs no routine care‐treated patients). Duloxetine did not appear to adversely affect lipid profiles, or nerve or eye function. There were no significant therapy‐group differences observed in mean change in systolic blood pressure, weight, or electrocardiogram parameters. Significant therapy‐group differences were observed in favor of duloxetine in the SF‐36 physical component summary score, and subscale scores of physical functioning, bodily pain, mental health, and vitality.
Conclusions. The results of this study provide support for the use of duloxetine in the long‐term management of DPNP.
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