Factors influencing insulin secretion from encapsulated islets

Adequate regulation of glucose levels by a microencapsulated pancreatic islet graft requires a minute-to-minute regulation of blood glucose. To design such a transplant, it is mandatory to have sufficient insight in factors influencing the kinetics of insulin secretion by encapsulated islets. The present study investigates factors influencing the glucose-induced insulin response of encapsulated islets in vitro. We applied static incubations and did the following observations. (i) Small islets (90-120 gm) showed a similar instead of a lower glucose-induced insulin response, suggesting that inclusion of only small islets, which are associated with lower protrusion and failing rates, has no consequences for the functional performance of the graft. (ii) A capsule diameter of 800 mum showed identical rather than lower glucose-induced insulin responses as smaller, 500-mum capsules. (iii) Capsule membranes constructed with a conventional permeability interfered with diffusion of insulin, as illustrated by a lower response of islets in capsules with a 10-min poly-L-lysine (PLL) membrane than islets in capsules with a 5-min PLL membrane. (iv) Irrespective of the tested porosity, the capsules provided sufficient immunoprotection because the 10-min PLL membranes did block diffusion of the cytokines IL-1beta (17 kDa) and TNF-alpha (70 kDa) while the 5-min PLL membranes interfered with the diffusion of the vast majority of the cytokines. We conclude that capsules containing small islets (90-120 gm) and a membrane with a lower permeability than routinely applied is preferred in order to obtain a graft with adequate glucose-induced insulin responses

Дисплазия желудочно-кишечного тракта

Рассмотрены возможности прижизненного (дооперационного) изучения состояния слизистой оболочки желудочно−кишечного тракта, дисплазия его эпителия как один из факторов риска возникновения злокачественного образования.Розглянуто можливості прижиттєвого (доопераційного) вивчення стану слизової оболонки шлунково−кишкового тракту, дисплазію його епітелію як один із факторів ризику виникнення злоякісного утворення.The capabilities of vital (preoperative) examination of the state of the gastrointestinal mucosa, epithelial dysplasia as one of the risk factors of malignancy were analyzed

Neonatal Gram Negative and Candida Sepsis Survival and Neurodevelopmental Outcome at the Corrected Age of 24 Months

Objectives: To evaluate the long term neurodevelopmental outcome of premature infants exposed to either gram- negative sepsis (GNS) or neonatal Candida sepsis (NCS), and to compare their outcome with premature infants without sepsis. Methods: Historical cohort study in a population of infants born at <30 weeks gestation and admitted to the Neonatal Intensive Care Unit (NICU) of the Academic Medical Center in Amsterdam during the period 1997-2007. Outcome of infants exposed to GNS or NCS and 120 randomly chosen uncomplicated controls (UC) from the same NICU were compared. Clinical data during hospitalization and neurodevelopmental outcome data (clinical neurological status; Bayley -test results and vision/hearing test results) at the corrected age of 24 months were collected. An association model with sepsis as the central determinant of either good or adverse outcome (death or severe developmental delay) was made, corrected for confounders using multiple logistic regression analysis. Results: Of 1362 patients, 55 suffered from GNS and 29 suffered from NCS; cumulative incidence 4.2% and 2.2%, respectively. During the follow-up period the mortality rate was 34% for both GNS and NCS and 5% for UC. The adjusted Odds Ratio (OR) [95% CI] for adverse outcome in the GNS group compared to the NCS group was 1.4 [0.4-4.9]. The adjusted ORs [95% CI] for adverse outcome in the GNS and NCS groups compared to the UC group were 4.8 [1.5-15.9] and 3.2 [0.7-14.7], respectively. Conclusions: We found no statistically significant difference in outcome at the corrected age of 24 months between neonatal GNS and NCS cases. Suffering from either gram -negative or Candida sepsis increased the odds for adverse outcome compared with an uncomplicated neonatal period

The relationship, structure and profiles of schizophrenia measurements: a post-hoc analysis of the baseline measures from a randomized clinical trial

<p>Background</p> <p>To fully assess the various dimensions affected by schizophrenia, clinical trials often include multiple scales measuring various symptom profiles, cognition, quality of life, subjective well-being, and functional impairment. In this exploratory study, we characterized the relationships among six clinical, functional, cognitive, and quality-of-life measures, identifying a parsimonious set of measurements.</p> <p>Methods</p> <p>We used baseline data from a randomized, multicenter study of patients diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder who were experiencing an acute symptom exacerbation (n = 628) to examine the relationship among several outcome measures. These measures included the Positive and Negative Syndrome Scale (PANSS), Montgomery-Asberg Depression Rating Scale (MADRS), Brief Assessment of Cognition in Schizophrenia Symbol Coding Test, Subjective Well-being Under Neuroleptics Scale Short Form (SWN-K), Schizophrenia Objective Functioning Instrument (SOFI), and Quality of Life Scale (QLS). Three analytic approaches were used: 1) path analysis; 2) factor analysis; and 3) categorical latent variable analysis. In the optimal path model, the SWN-K was selected as the final outcome, while the SOFI mediated the effect of the exogenous variables (PANSS, MADRS) on the QLS.</p> <p>Results</p> <p>The overall model explained 47% of variance in QLS and 17% of the variance in SOFI, but only 15% in SWN-K. Factor analysis suggested four factors: "Functioning," "Daily Living," "Depression," and "Psychopathology." A strong positive correlation was observed between the SOFI and QLS (r = 0.669), and both the QLS and SOFI loaded on the "Functioning" factor, suggesting redundancy between these scales. The measurement profiles from the categorical latent variable analysis showed significant variation in functioning and quality of life despite similar levels of psychopathology.</p> <p>Conclusions</p> <p>Researchers should consider collecting PANSS, SOFI, and SWN-K in their trials. This would allow a broad spectrum of assessments that would have the ability to capture a wide range of treatment outcomes and allow for a rich characterization of the subgroups involved. Additional research is needed to identify the critical cognitive measures.</p> <p>Trials registration</p> <p>Clinical trials registration: Predicting Response to Risperidone Treatment Through Identification of Early-onset of Antipsychotic Drug Action in Schizophrenia</p> <p>ClinicalTrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00337662">NCT00337662</a>; <url>http://www.clinicaltrials.gov/</url></p

Detailed Kinetics of the Direct Allo-Response in Human Liver Transplant Recipients: New Insights from an Optimized Assay

Conventional assays for quantification of allo-reactive T-cell precursor frequencies (PF) are relatively insensitive. We present a robust assay for quantification of PF of T-cells with direct donor-specificity, and establish the kinetics of circulating donor-specific T cells after liver transplantation (LTx). B cells from donor splenocytes were differentiated into professional antigen-presenting cells by CD40-engagement (CD40-B cells). CFSE-labelled PBMC from LTx-recipients obtained before and at several time points after LTx, were stimulated with donor-derived or 3rd party CD40-B cells. PF of donor-specific T cells were calculated from CFSE-dilution patterns, and intracellular IFN-γ was determined after re-stimulation with CD40-B cells. Compared to splenocytes, stimulations with CD40-B cells resulted in 3 to 5-fold higher responding T-cell PF. Memory and naïve T-cell subsets responded equally to allogeneic CD40-B cell stimulation. Donor-specific CD4+ and CD8+ T-cell PF ranged from 0.5 to 19% (median: 5.2%). One week after LTx, PF of circulating donor-specific CD4+ and CD8+ T cells increased significantly, while only a minor increase in numbers of T cells reacting to 3rd party allo-antigens was observed. One year after LTx numbers of CD4+ and CD8+ T cells reacting to donor antigens, as well as those reacting to 3rd party allo-antigens, were slightly lower compared to pre-transplant values. Moreover, CD4+ and CD8+ T cells responding to donor-derived, as well as those reacting to 3rd party CD40-B cells, produced less IFN-γ. In conclusion, our alternative approach enables detection of allo-reactive human T cells at high frequencies, and after application we conclude that donor-specific T-cell PF increase immediately after LTx. However, no evidence for a specific loss of circulating T-cells recognizing donor allo-antigens via the direct pathway up to 1 year after LTx was obtained, underscoring the relative insensitiveness of previous assays

Evaluation of the drug solubility and rush ageing on drug release performance of various model drugs from the modified release polyethylene oxide matrix tablets

Hydrophilic matrix systems are currently some of the most widely used drug delivery systems for controlled-release oral dosage forms. Amongst a variety of polymers, polyethylene oxide (PEO) is considered an important material used in pharmaceutical formulations. As PEO is sensitive to thermal oxidation, it is susceptible to free radical oxidative attack. The aim of this study was to investigate the stability of PEO based formulations containing different model drugs with different water solubility, namely propranolol HCl, theophylline and zonisamide. Both polyox matrices 750 and 303 grade were used as model carriers for the manufacture of tablets stored at 40 °C. The results of the present study suggest that the drug release from the matrix was affected by the length of storage conditions, solubility of drugs and the molecular weight of the polymers. Generally, increased drug release rates were prevalent in soluble drug formulations (propranolol) when stored at the elevated temperature (40 °C). In contrast, it was not observed with semi soluble (theophylline) and poorly soluble (zonisamide) drugs especially when formulated with PEO 303 polymer. This indicates that the main parameters controlling the drug release from fresh polyox matrices are the solubility of the drug in the dissolution medium and the molecular weight of the polymer. DSC traces indicated that that there was a big difference in the enthalpy and melting points of fresh and aged PEO samples containing propranolol, whereas the melting point of the aged polyox samples containing theophylline and zonisamide was unaffected

Podocyte specific knock out of selenoproteins does not enhance nephropathy in streptozotocin diabetic C57BL/6 mice

<p>Abstract</p> <p>Background</p> <p>Selenoproteins contain selenocysteine (Sec), commonly considered the 21^stgenetically encoded amino acid. Many selenoproteins, such as the glutathione peroxidases and thioredoxin reductases, protect cells against oxidative stress by functioning as antioxidants and/or through their roles in the maintenance of intracellular redox balance. Since oxidative stress has been implicated in the pathogenesis of diabetic nephropathy, we hypothesized that selenoproteins protect against this complication of diabetes.</p> <p>Methods</p> <p>C57BL/6 mice that have a podocyte-specific inability to incorporate Sec into proteins (denoted in this paper as PodoTrsp^-/-) and control mice were made diabetic by intraperitoneal injection of streptozotocin, or were injected with vehicle. Blood glucose, body weight, microalbuminuria, glomerular mesangial matrix expansion, and immunohistochemical markers of oxidative stress were assessed.</p> <p>Results</p> <p>After 3 and 6 months of diabetes, control and PodoTrsp^-/-mice had similar levels of blood glucose. There were no differences in urinary albumin/creatinine ratios. Periodic acid-Schiff staining to examine mesangial matrix expansion also demonstrated no difference between control and PodoTrsp^-/-mice after 6 months of diabetes, and there were no differences in immunohistochemical stainings for nitrotyrosine or NAD(P)H dehydrogenase, quinone 1.</p> <p>Conclusion</p> <p>Loss of podocyte selenoproteins in streptozotocin diabetic C57BL/6 mice does not lead to increased oxidative stress as assessed by nitrotyrosine and NAD(P)H dehydrogenase, quinone 1 immunostaining, nor does it lead to worsening nephropathy.</p

Quantum dynamics in strong fluctuating fields

A large number of multifaceted quantum transport processes in molecular systems and physical nanosystems can be treated in terms of quantum relaxation processes which couple to one or several fluctuating environments. A thermal equilibrium environment can conveniently be modelled by a thermal bath of harmonic oscillators. An archetype situation provides a two-state dissipative quantum dynamics, commonly known under the label of a spin-boson dynamics. An interesting and nontrivial physical situation emerges, however, when the quantum dynamics evolves far away from thermal equilibrium. This occurs, for example, when a charge transferring medium possesses nonequilibrium degrees of freedom, or when a strong time-dependent control field is applied externally. Accordingly, certain parameters of underlying quantum subsystem acquire stochastic character. Herein, we review the general theoretical framework which is based on the method of projector operators, yielding the quantum master equations for systems that are exposed to strong external fields. This allows one to investigate on a common basis the influence of nonequilibrium fluctuations and periodic electrical fields on quantum transport processes. Most importantly, such strong fluctuating fields induce a whole variety of nonlinear and nonequilibrium phenomena. A characteristic feature of such dynamics is the absence of thermal (quantum) detailed balance.Comment: review article, Advances in Physics (2005), in pres

State pension funds and corporate social responsibility: do beneficiaries’ political values influence funds’ investment decisions?

This study explores the underlying drivers of US public pension funds’ tendency to tilt their portfolios towards companies with stronger corporate social responsibility (CSR). Studying the equity holdings of large, internally-managed US state pension funds, we find evidence that the political leaning of their beneficiaries and political pressures by state politicians affect funds’ investment decisions. State pension funds from states with Democratic-leaning beneficiaries tilt their portfolios more strongly towards companies that perform well on CSR issues, and this tendency is intensified when the state government is dominated by Democratic state politicians. Moreover, we find that funds which tilt their portfolios towards companies with superior CSR scores generate a slightly higher return compared with their counterparts. Overall, our findings indicate that funds align their investment choices with the financial and non-financial interests of their beneficiaries when deciding whether to incorporate CSR into their equity allocations

Lipidomics Reveals Multiple Pathway Effects of a Multi-Components Preparation on Lipid Biochemistry in ApoE*3Leiden.CETP Mice

Background: Causes and consequences of the complex changes in lipids occurring in the metabolic syndrome are only partly understood. Several interconnected processes are deteriorating, which implies that multi-target approaches might be more successful than strategies based on a limited number of surrogate markers. Preparations from Chinese Medicine (CM) systems have been handed down with documented clinical features similar as metabolic syndrome, which might help developing new intervention for metabolic syndrome. The progress in systems biology and specific animal models created possibilities to assess the effects of such preparations. Here we report the plasma and liver lipidomics results of the intervention effects of a preparation SUB885C in apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) mice. SUB885C was developed according to the principles of CM for treatment of metabolic syndrome. The cannabinoid receptor type 1 blocker rimonabant was included as a general control for the evaluation of weight and metabolic responses. Methodology/Principal Findings: ApoE*3Leiden.CETP mice with mild hypercholesterolemia were divided into SUB885C-, rimonabant- and non-treated control groups. SUB885C caused no weight loss, but significantly reduced plasma cholesterol (-49%, p <0.001), CETP levels (-31%,