Biomedical subjects

A Sherman

Publications and source records attributed to A Sherman.

At least 19 recordsLinked to original sources

PubMed2006

SV40 Pseudovirion gene delivery of a toxin to treat human adenocarcinomas in mice.

SV40 vectors packaged in vitro (pseudovirions) are an efficient delivery system for plasmids up to 17.7 kb, with or without SV40 sequences. A truncated Pseudomonas exotoxin gene (PE38) was delivered into various human cells (HeLa, KB-3-1, human lymphoblastoids, and erythroleukemia cells), in vitro using pseudovirions. The number of viable cells was reduced significantly in the PE38-transduced cells. Human KB adenocarcinomas growing in mice were treated with intratumoral injection of PE38 packaged in vitro, and tumor size decreased significantly. Intraperitoneal treatments were as effective in reducing tumor size as intratumoral treatments. To check the viability of mock- or PE38-treated mice, every 4 days they were weighed, their blood was tested, and various tissues were screened for pathology. All parameters showed that the in vitro-packaged vectors, injected into tumors or intraperitoneally, caused no abnormalities in mice. The combined treatment of doxorubicin with in vitro-packaged PE38 reduced tumor size slightly more than each of the treatments separately. However, the combined treatment did not cause the weight loss seen with doxorubicin alone. These results indicate that SV40 in vitro packaging is an effective system for cancer gene delivery using two different routes of injection and in combination with chemotherapy.

ADP Ribose Transferases↗

PubMed2005

Application of SNPs for assessing biodiversity and phylogeny among yeast strains.

We examined the efficacy of single-nucleotide polymorphism (SNP) markers for the assessment of the phylogeny and biodiversity of Saccharomyces strains. Each of 32 Saccharomyces cerevisiae strains was genotyped at 30 SNP loci discovered by sequence alignment of the S. cerevisiae laboratory strain SK1 to the database sequence of strain S288c. In total, 10 SNPs were selected from each of the following three categories: promoter regions, nonsynonymous and synonymous sites (in open reading frames). The strains in this study included 11 haploid laboratory strains used for genetic studies and 21 diploids. Three non-cerevisiae species of Saccharomyces (sensu stricto) were used as an out-group. A Bayesian clustering-algorithm, Structure, effectively identified four different strain groups: laboratory, wine, other diploids and the non-cerevisiae species. Analysing haploid and diploid strains together caused problems for phylogeny reconstruction, but not for the clustering produced by Structure. The ascertainment bias introduced by the SNP discovery method caused difficulty in the phylogenetic analysis; alternative options are proposed. A smaller data set, comprising only the nine most polymorphic loci, was sufficient to obtain most features of the results.

Biodiversity↗

PubMed2005

Protein interaction of nucleosome assembly protein 1 and casein kinase 2 during desiccation response in the insect-killing nematode Steinernema feltiae IS-6.

The change in gene expression induced by desiccation in the semiarid, entomopathogenic nematode Steinernema feltiae IS-6, includes induction of transcription of a nucleosome assembly protein, NAP1 homolog, and of casein kinase 2 (CK2) genes. Therefore, one of the events during the dehydration response of S. feltiae IS-6 may be transcriptional activation by S. feltiae IS-6 NAP1 homolog (Sf-Nap1), which is regulated by S. feltiae IS-6 CK2 (Sf-CK2). This regulation necessitates physical interaction between the Sf-Nap1 and Sf-CK2 proteins. In the present study we used yeast 2-hybrid analysis to demonstrate physical interaction between the 2 proteins, thus confirming the involvement of a protein interaction-based step in the desiccation response mechanism of S. feltiae IS-6.

Animals↗

PubMed2004

Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy.

BACKGROUND: In a prospective observational study of 42 pregnancies in 39 Caucasian women (age 30 +/- 4 years) with polycystic ovary syndrome (PCOS), we examined effects of metformin on maternal insulin, insulin resistance (IR), insulin secretion (IS), weight gain, development of gestational diabetes (GD), testosterone and plasminogen activator inhibitor activity. We assessed the hypothesis that diet-metformin (MET) lessens the physiological gestational increase in IR and reduces gestational weight gain, thus reducing GD. METHODS: Preconception, in an out-patient clinical research centre, MET 1.5 (eight pregnancies) to 2.55 g/day (34 pregnancies) was started. Women with body mass index <25 or >or=25 kg/m(2) were given a 2000 or 1500 calorie/day, high-protein (26% of calories), low-carbohydrate (44%) diet. Calorie restrictions were dropped after conception. RESULTS: On MET, GD developed in three out of 42 pregnancies (7.1%). Median entry weight (94.5 kg) fell to 82.7 on MET at the last preconception visit (P = 0.0001), fell further to 81.6 during the first trimester, was 83.6 in the second trimester, and 89.1 kg in the third trimester. Median weight gain during pregnancy was 3.5 kg. The median percentage reduction in serum insulin was 40% on MET at the last preconception visit; insulin did not increase in the first or second trimesters (P > 0.05), and rose 10% in the third trimester. The median percentage reduction in HOMA IR was 46% on MET at the last preconception visit; IR did not increase (P > 0.05) in the first, second or third trimesters. HOMA insulin secretion fell 45% on MET at the last preconception visit, did not increase in the first trimester, rose 24% in the second trimester, and rose 109% in the third trimester. Testosterone fell 30% on MET at the last preconception visit (P = 0.01) and then rose 74, 61 and 95% during trimesters 1, 2 and 3; median testosterone during the third trimester did not differ from pre-treatment levels. CONCLUSIONS: By reducing preconception weight, insulin, IR, insulin secretion and testosterone, and by maintaining these insulin-sensitizing effects throughout pregnancy, MET-diet reduces the likelihood of developing GD, and prevents androgen excess for the fetus.

Adult↗

PubMed2004

Child safety education and the world wide web: an evaluation of the content and quality of online resources.

The purpose of this study was to assess the content, quality, and type of internet resources available for safety education. Using 19 search engines with search strings targeting major forms of injury, identified resources were classified by audience group, accessibility, and authorship. Two independent reviewers rated each resource on the basis of its content and a set of quality criteria using a three point scale. Overall, 10 (18.2%) resources were of highest quality, four (7.3%) were intermediate, and 41 (74.5%) were not recommended. Eighteen months after the original search, 67.3% of all resources and 90% of the highest quality resources were still on the internet. This study provides a methodology for evaluating child safety resources on the world wide web and demonstrates that most internet resources for safety education are of dubious quality. A rating system such as the one developed for this study may be used to identify valuable internet materials.

Accident Prevention↗

PubMed2002

Calcium-activated K+ channels of mouse beta-cells are controlled by both store and cytoplasmic Ca2+: experimental and theoretical studies.

A novel calcium-dependent potassium current (K(slow)) that slowly activates in response to a simulated islet burst was identified recently in mouse pancreatic beta-cells (Göpel, S.O., T. Kanno, S. Barg, L. Eliasson, J. Galvanovskis, E. Renström, and P. Rorsman. 1999. J. Gen. Physiol. 114:759-769). K(slow) activation may help terminate the cyclic bursts of Ca(2+)-dependent action potentials that drive Ca(2+) influx and insulin secretion in beta-cells. Here, we report that when [Ca(2+)](i) handling was disrupted by blocking Ca(2+) uptake into the ER with two separate agents reported to block the sarco/endoplasmic calcium ATPase (SERCA), thapsigargin (1-5 microM) or insulin (200 nM), K(slow) was transiently potentiated and then inhibited. K(slow) amplitude could also be inhibited by increasing extracellular glucose concentration from 5 to 10 mM. The biphasic modulation of K(slow) by SERCA blockers could not be explained by a minimal mathematical model in which [Ca(2+)](i) is divided between two compartments, the cytosol and the ER, and K(slow) activation mirrors changes in cytosolic calcium induced by the burst protocol. However, the experimental findings were reproduced by a model in which K(slow) activation is mediated by a localized pool of [Ca(2+)] in a subspace located between the ER and the plasma membrane. In this model, the subspace [Ca(2+)] follows changes in cytosolic [Ca(2+)] but with a gradient that reflects Ca(2+) efflux from the ER. Slow modulation of this gradient as the ER empties and fills may enhance the role of K(slow) and [Ca(2+)] handling in influencing beta-cell electrical activity and insulin secretion.

Action Potentials↗

PubMed2001

From spikers to bursters via coupling: help from heterogeneity.

It has been shown previously that identical spiking cells, incapable of bursting by themselves, may burst under weak diffusive coupling conditions. With stronger coupling, the coupled system reverts to bursting can be recovered by introducing heterogeneity in the model parameters. For a two-cell system, we explain the phenomenon with bifurcation analysis. For larger clusters of coupled cells, we demonstrate by numerical simulation that the phenomenon carries over. In addition, we use a perturbation analysis to deduce the dependence of the heterogeneity parameter used in the bifurcation analysis on the original heterogeneity parameters and the coupling strength. Implications of the phenomenon of emergent bursting are discussed in the context of electrical activity in pancreatic beta cells.

Action Potentials↗

PubMed2001

Measuring in vivo animal soft tissue properties for haptic modeling in surgical simulation.

To provide data for the design of virtual environments and teleoperated systems for surgery, it is necessary to measure tissue properties under both in vivo and ex vivo conditions. The former provides information about tissue behavior in its physiological state, while the latter can provide better control over experimental conditions. We have developed devices to measure tissue properties under extension and indentation, as well as to record instrument-tissue interaction forces. We are creating a web database of data recorded from porcine abdominal tissues.

Abdomen↗

PubMed2000

Channel sharing in pancreatic beta -cells revisited: enhancement of emergent bursting by noise.

Secretion of insulin by electrically coupled populations of pancreatic beta -cells is governed by bursting electrical activity. Isolated beta -cells, however, exhibit atypical bursting or continuous spike activity. We study bursting as an emergent property of the population, focussing on interactions among the subclass of spiking cells. These are modelled by equipping the fast subsystem with a saddle-node-loop bifurcation, which makes it monostable. Such cells can only spike tonically or remain silent when isolated, but can be induced to burst with weak diffusive coupling. With stronger coupling, the cells revert to tonic spiking. We demonstrate that the addition of noise dramatically increases, via a phenomenon like stochastic resonance, the coupling range over which bursting is seen.

Action Potentials↗

PubMed2000

Modeling of membrane excitability in gonadotropin-releasing hormone-secreting hypothalamic neurons regulated by Ca2+-mobilizing and adenylyl cyclase-coupled receptors.

Gonadotropin-releasing hormone (GnRH) secretion from native and immortalized hypothalamic neurons is regulated by endogenous Ca(2+)-mobilizing and adenylyl cyclase (AC)-coupled receptors. Activation of both receptor types leads to an increase in action potential firing frequency and a rise in the intracellular Ca(2+) concentration ([Ca(2+)](i)) and neuropeptide secretion. The stimulatory action of Ca(2+)-mobilizing agonists on voltage-gated Ca(2+) influx is determined by depletion of the intracellular Ca(2+) pool, whereas AC agonist-stimulated Ca(2+) influx occurs independently of stored Ca(2+) and is controlled by cAMP, possibly through cyclic nucleotide-gated channels. Here, experimental records from immortalized GnRH-secreting neurons are simulated with a mathematical model to determine the requirements for generating complex membrane potential (V(m)) and [Ca(2+)](i) responses to Ca(2+)-mobilizing and AC agonists. Included in the model are three pacemaker currents: a store-operated Ca(2+) current (I(SOC)), an SK-type Ca(2+)-activated K(+) current (I(SK)), and an inward current that is modulated by cAMP and [Ca(2+)](i) (I(d)). Spontaneous electrical activity and Ca(2+) signaling in the model are predominantly controlled by I(d), which is activated by cAMP and inhibited by high [Ca(2+)](i). Depletion of the intracellular Ca(2+) pool mimics the receptor-induced activation of I(SOC) and I(SK), leading to an increase in the firing frequency and Ca(2+) influx after a transient cessation of electrical activity. However, increasing the activity of I(d) simulates the experimental response to forskolin-induced activation of AC. Analysis of the behaviors of I(SOC), I(d), and I(SK) in the model reveals the complexity in the interplay of these currents that is necessary to fully account for the experimental results.

Action Potentials↗

PubMed2000

Tk, a new colon tumor-associated antigen resulting from altered O-glycosylation.

Erythrocyte polyagglutination antigens T and Tn are truncated O-glycan chains that are also carcinoma-associated antigens. We investigated whether Tk polyagglutination antigen could similarly be a carcinoma-associated marker and a target of immunotherapy. Monoclonal antibody LM389 was raised against Tk erythrocytes and tested by immunohistochemistry. LM389 strongly reacted with 48% human colorectal carcinomas. Labeling of normal tissues was visible on epithelial cells, mainly digestive, but was confined at a supranuclear level. Expression of the antigen on cloned human carcinoma cells correlated with sialosyl-Tn expression. O-Sialoglycoprotein endopeptidase treatment revealed that on carcinomas and cell lines, the epitope was present on O-glycans. Antibody specificity was determined using synthetic carbohydrates. Direct binding and inhibition studies indicated that LM389 best ligands were terminated by two branched N-acetylglucosamine units. Screening of murine cellular cell lines with LM389 allowed development of an experimental model with Tk-positive and -negative cells in syngeneic BDIX rats. Vaccination of rats with Tk erythrocytes provided a protection against growth of rat Tk-positive, but not of Tk-negative, tumor cells in association with the development of antibodies. Taken together, the results indicate that Tk polyagglutination antigen is a new colorectal carcinoma-associated antigen, absent from the normal cell surface, resulting from alteration of O-glycans biosynthesis and with potential as a target of immunotherapy.

Adenocarcinoma↗

PubMed2000

Amplitude-dependent spike-broadening and enhanced Ca(2+) signaling in GnRH-secreting neurons.

In GnRH-secreting (GT1) neurons, activation of Ca(2+)-mobilizing receptors induces a sustained membrane depolarization that shifts the profile of the action potential (AP) waveform from sharp, high-amplitude to broad, low-amplitude spikes. Here we characterize this shift in the firing pattern and its impact on Ca(2+) influx experimentally by using prerecorded sharp and broad APs as the voltage-clamp command pulse. As a quantitative test of the experimental data, a mathematical model based on the membrane and ionic current properties of GT1 neurons was also used. Both experimental and modeling results indicated that inactivation of the tetrodotoxin-sensitive Na(+) channels by sustained depolarization accounted for a reduction in the amplitude of the spike upstroke. The ensuing decrease in tetraethylammonium-sensitive K(+) current activation slowed membrane repolarization, leading to AP broadening. This change in firing pattern increased the total L-type Ca(2+) current and facilitated AP-driven Ca(2+) entry. The leftward shift in the current-voltage relation of the L-type Ca(2+) channels expressed in GT1 cells allowed the depolarization-induced AP broadening to facilitate Ca(2+) entry despite a decrease in spike amplitude. Thus the gating properties of the L-type Ca(2+) channels expressed in GT1 neurons are suitable for promoting AP-driven Ca(2+) influx in receptor- and non-receptor-depolarized cells.

Animals↗

PubMed2000

The phantom burster model for pancreatic beta-cells.

Pancreatic beta-cells exhibit bursting oscillations with a wide range of periods. Whereas periods in isolated cells are generally either a few seconds or a few minutes, in intact islets of Langerhans they are intermediate (10-60 s). We develop a mathematical model for beta-cell electrical activity capable of generating this wide range of bursting oscillations. Unlike previous models, bursting is driven by the interaction of two slow processes, one with a relatively small time constant (1-5 s) and the other with a much larger time constant (1-2 min). Bursting on the intermediate time scale is generated without need for a slow process having an intermediate time constant, hence phantom bursting. The model suggests that isolated cells exhibiting a fast pattern may nonetheless possess slower processes that can be brought out by injecting suitable exogenous currents. Guided by this, we devise an experimental protocol using the dynamic clamp technique that reliably elicits islet-like, medium period oscillations from isolated cells. Finally, we show that strong electrical coupling between a fast burster and a slow burster can produce synchronized medium bursting, suggesting that islets may be composed of cells that are intrinsically either fast or slow, with few or none that are intrinsically medium.

Animals↗

PubMed2000

Religious faith and spirituality in substance abuse recovery: determining the mental health benefits.

Recently, mental health professionals have begun examining the potential value of religious faith and spirituality in the lives of individuals suffering from a variety of acute and chronic illnesses. This study explored the relation between religious faith, spirituality, and mental health outcomes in 236 individuals recovering from substance abuse. We found that recovering individuals tend to report high levels of religious faith and religious affiliation, but choose to rate themselves as being more spiritual than religious. Results also indicate that among recovering individuals, higher levels of religious faith and spirituality were associated with a more optimistic life orientation, greater perceived social support, higher resilience to stress, and lower levels of anxiety. This represents the largest self-report study to date examining the relation between religious faith, spirituality, and mental health outcomes among individuals recovering from substance abuse.

Adult↗

PubMed2000

An integrated model of group treatment for cancer patients.

Considerable evidence suggests that group interventions are a valuable resource for cancer patients, but few conceptual frameworks are available to guide decisions about which approaches might be most useful for which patients at what phases of illness. This article presents an integrative treatment model for group services. It describes different group interventions geared toward patients at different phases of illness to accommodate the shifting needs and concerns that evolve over the course of the disease. Recommendations are offered concerning further research and model development.

Female↗

PubMed2000

Comparative efficacy and potency of long-term therapy with glipizide or glyburide in patients with type 2 diabetes mellitus.

BACKGROUND: Long-term studies on the comparative efficacy and relative potency of glipizide and glyburide are sparse and controversial. METHODS: In a randomized prospective trial, we compared the effectiveness and relative potency of glipizide and glyburide over a 15-month period in 18 patients with type 2 diabetes mellitus (DM2) (9 on glyburide and 9 on glipizide) who were unresponsive to diet therapy. Glycemic control was assessed using 4 methods: 1) quarterly fasting plasma glucose (FPG), and 2-hour postprandial plasma glucose after a standard breakfast; 2) insulin and glucose response to Sustacal (test meal) challenge every 3 to 6 months; 3) quarterly hemoglobin A1c; and 4) intravenous glucose tolerance testing every 6 months to measure first and second phase insulin secretion. Patient characteristics were similar in each treatment group. RESULTS: Similar doses of glipizide (11 mg/day) or glyburide (10 mg/day) resulted in comparable reduction of FPG and hemoglobin A1c and increase in first phase insulin response to intravenous glucose tolerance testing. There was greater reduction in FPG and 2-hour postprandial plasma glucose with glipizide than with glyburide in 6 months. Contrary to the Physicians' Desk Reference, but consistent with another short-term study, our long-term study demonstrated that glipizide and glyburide are equipotent at similar doses in controlling hyperglycemia in DM2. CONCLUSIONS: Glipizide and glyburide are effective in controlling hyperglycemia with similar doses in DM2. Glipizide exhibits greater reduction in FPG and 2PPG at 6 months. Additional studies are needed to validate equipotency of these drugs.

Adult↗

PubMed2000

Dynamical complexity and temporal plasticity in pancreatic beta-cells.

We discuss some of the biological and mathematical issues involved in understanding and modelling the bursting electrical activity in pancreatic beta-cells. These issues include single-cell versus islet behaviour, parameter heterogeneity, channel noise, the effects of hormones, neurotransmitters, and ions, and multiple slow biophysical processes. Some of the key experimental and modelling studies are described, and some of the major open questions are discussed.

Acetylcholine↗

PubMed2000

Graphically-enabled integration of bioinformatics tools allowing parallel execution.

Rapid analysis of large amounts of genomic data is of great biological as well as medical interest. This type of analysis will greatly benefit from the ability to rapidly assemble a set of related analysis programs and to exploit the power of parallel computing. TurboGenomics, which is a software package currently in its alpha-testing phase, allows integration of heterogeneous software components to be done graphically. In addition, the tool is capable of making the integrated components run in parallel. To demonstrate these abilities, we use the tool to develop a Web-based application that allows integrated access to a set of large-scale sequence data analysis programs used by a transposon-insertion based yeast genome project. We also contrast the differences in building such an application with and without using the TurboGenomics software.

Computational Biology↗