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Biomedical subjects

D L Martin

Publications and source records attributed to D L Martin.

At least 37 records · Page 2Linked to original sources
PubMed1998

Physicians' practices and opinions regarding prenatal screening for human immunodeficiency virus and other sexually transmitted diseases.

BACKGROUND AND OBJECTIVES: Early prenatal diagnosis of sexually transmitted diseases (STDs), particularly human immunodeficiency virus (HIV), is critical for maternal and infant health. We conducted a survey to assess physicians' prenatal STD screening practices and opinions. STUDY DESIGN: A random sample of obstetricians and family physicians was selected from the Minnesota Medical Association directory to complete a standardized telephone survey. RESULTS: Eighty-three (86%) of 96 eligible obstetricians and 94 (95%) of 99 eligible family physicians completed the survey. Nearly all physicians recommend universal prenatal screening for syphilis (97%) and hepatitis B (99%); fewer physicians recommend prenatal screening for HIV (43%), chlamydia (26%), and gonorrhea (24%). Adjusting for physicians' specialty, female physicians were more likely than male physicians to recommend universal prenatal HIV screening (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.1-4.2). Adjusting for physicians' ages, physicians with more than 20% uninsured/Medical Assistance patients were more likely than other physicians to recommend prenatal gonorrhea screening (OR = 3.1; 95% CI = 1.4-6.8); similar factors were associated with chlamydia screening. Although 89% of physicians supported universal prenatal HIV counseling and voluntary screening, the median percentage of prenatal patients screened for HIV was only 10%. CONCLUSIONS: Most physicians reported routinely screening prenatal patients for syphilis and hepatitis B. Although many physicians agreed with recommendations for universal prenatal HIV screening, their reported screening practices varied considerably from this approach.

Adult↗
PubMed1998

Are GAD65 and GAD67 associated with specific pools of GABA in brain?

Brain contains at least two pools of gamma-aminobutyric acid (GABA), the transmitter pool and the so-called metabolic pool. To a large extent these pools may reflect the presence of GABA in different intracellular compartments, as immunocytochemical studies show that GABA is not localized mainly in terminals but is distributed throughout neurons. An interesting issue is the extent to which the two major forms of glutamate decarboxylase (GAD65 and GAD67) are specialized to synthesize GABA for these pools. Although GAD65 and GAD67 differ significantly in several characteristics, they also have substantial similarities and interactions, and the presence of individual forms of GAD in certain cell types is consistent with the idea that GAD65 and GAD67 can each synthesize GABA for both pools. Substantial progress has been made in understanding the regulatory properties of GAD, but the available data provide little indication of how differences between the forms might enable each to serve the demands for GABA synthesis in a specific pool.

Amino Acid Sequence↗
PubMed1997

Disposition and metabolism of the sulfonylurea oncolytic agent LY295501 in mouse, rat, and monkey.

The disposition and metabolism of LY295501 was studied in mice, rats, and monkeys. This novel diaryl sulfonylurea oncolytic agent is structurally related to sulofenur and shows excellent activity in a broad range of mouse antitumor models. The compound is well absorbed, giving plasma concentrations greater than 200 micrograms/ml after oral doses of 30-100 mg/kg, where it appears to be completely bound (> 99.9%) to plasma proteins. The high degree of protein binding may be a factor in its relatively long half-life, which ranges from about 8 hr in rats and 15 hr in mice to 50 hr in monkeys. While more material was excreted in feces than in urine from mice and rats given single oral doses of [14C]LY295501, urine was the major route of elimination in monkeys. Three major metabolites-all formed via oxidation of the saturated part of the benzodihydrofuran moiety-were characterized in the urine of mice, rats, and monkeys. It is interesting that two of these metabolites are derived from opening of this saturated ring, an unusual metabolic process which represents a significant part of the metabolism of LY295501. As with sulofenur, metabolites of 3,4-dichloroaniline formed after metabolic cleavage of the sulfonylurea linkage were also found in urine. Unlike sulofenur, these do not seem to have major toxicological significance, but their formation does explain the minor methemoglobinemia observed in toxicology studies of LY295501. Even though only trace amounts of LY295501 were found in urine, LY295501 is the predominant drug-related material in plasma, along with small amounts of other, relatively nonpolar, metabolites.

Animals↗
PubMed1996

Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus.

The excitatory, glutamatergic granule cells of the hippocampal dentate gyrus are presumed to play central roles in normal learning and memory, and in the genesis of spontaneous seizure discharges that originate within the temporal lobe. In localizing the two GABA-producing forms of glutamate decarboxylase (GAD65 and GAD67) in the normal hippocampus as a prelude to experimental epilepsy studies, we unexpectedly discovered that, in addition to its presence in hippocampal nonprincipal cells, GAD67-like immunoreactivity (LI) was present in the excitatory axons (the mossy fibers) of normal dentate granule cells of rats, mice, and the monkey Macaca nemestrina. Using improved immunocytochemical methods, we were also able to detect GABA-LI in normal granule cell somata and processes. Conversely, GAD65-LI was undetectable in normal granule cells. Perforant pathway stimulation for 24 hours, which evoked population spikes and epileptiform discharges in both dentate granule cells and hippocampal pyramidal neurons, induced GAD65-, GAD67-, and GABA-LI only in granule cells. Despite prolonged excitation, normally GAD- and GABA-negative dentate hilar neurons and hippocampal pyramidal cells remained immunonegative. Induced granule cell GAD65-, GAD67-, and GABA-LI remained elevated above control immunoreactivity for at least 4 days after the end of stimulation. Pre-embedding immunocytochemical electron microscopy confirmed that GAD67- and GABA-LI were induced selectively within granule cells; granule cell layer glia and endothelial cells were GAD- and GABA-immunonegative. In situ hybridization after stimulation revealed a similarly selective induction of GAD65 and GAD67 mRNA in dentate granule cells. Neurochemical analysis of the microdissected dentate gyrus and area CA1 determined whether changes in GAD- and GABA-LI reflect changes in the concentrations of chemically identified GAD and GABA. Stimulation for 24 hours increased GAD67 and GABA concentrations sixfold in the dentate gyrus, and decreased the concentrations of the GABA precursors glutamate and glutamine. No significant change in GAD65 concentration was detected in the microdissected dentate gyrus despite the induction of GAD65-LI. The concentrations of GAD65, GAD67, GABA, glutamate and glutamine in area CA1 were not significantly different from control concentrations. These results indicate that dentate granule cells normally contain two "fast-acting" amino acid neurotransmitters, one excitatory and one inhibitory, and may therefore produce both excitatory and inhibitory effects. Although the physiological role of granule cell GABA is unknown, the discovery of both basal and activity-dependent GAD and GABA expression in glutamatergic dentate granule cells may have fundamental implications for physiological plasticity presumed to underlie normal learning and memory. Furthermore, the induction of granule cell GAD and GABA by afferent excitation may constitute a mechanism by which epileptic seizures trigger compensatory interictal network inhibition or GABA-mediated neurotrophic effects.

Animals↗
PubMed1996

Glutamine stimulates gamma-aminobutyric acid synthesis in synaptosomes but other putative astrocyte-to-neuron shuttle substrates do not.

GABAergic neurons require a supply of precursor glutamate for gamma-aminobutyric acid (GABA) synthesis to maintain their GABA levels. Because neurons lack the anaplerotic enzymes necessary for net synthesis of glutamate from glucose, they depend on astrocytes to supply compounds that can be metabolized to glutamate and ultimately used for GABA production. To test the effect of putative astrocytic shuttle metabolites on GABA synthesis, we used synaptosomes prepared from substantia nigra, an area rich in GABAergic terminals. The low number of glutamatergic endings in the nigral preparation allows a more accurate measurement of glutamate present in GABAergic endings. GABA synthesis by nigral synaptosomes was stimulated 3.1-fold when 500 microM glutamine was added to the incubation medium. Glutamate amounts also increased. In contrast, the possible precursor metabolites. 2-oxoglutarate (2-OG), malate and citrate, failed to stimulate GABA synthesis over the rate observed with control medium. Unlike malate and citrate. 2-OG reduced the decline in total glutamate observed when synaptosomes were incubated in control. In contrast to glutamine the production of synaptosomal glutamate from 2-OG, malate, and citrate is not great enough to stimulate GABA synthesis.

Amino Acids↗
PubMed1996

Comparison of coronal sphenoidal versus standard anteroposterior temporal montage in the EEG recording of temporal lobe seizures.

Chronic sphenoidal electrodes were developed to facilitate the recording and localization of temporal lobe seizures during long term monitoring. Many reports demonstrate their utility in displaying temporal interictal epileptiform activity, but there have been few direct comparisons of sphenoidal electrodes and surface temporal recordings actually. We compared simultaneous portions of 74 EEG recordings of temporal lobe seizures (from 42 patients), with one portion including sphenoidal electrodes in a coronal montage and one with a standard anterior posterior temporal montage. Separated tracings were reviewed by readers blinded to the other portion of the tracing. The coronal sphenoidal montage allowed recognition of temporal lobe seizures inapparent with standard surface temporal electrodes in 19% of seizures and led to an earlier identification (usually by > or = 5 s) of the onset in 70% of seizures. Indwelling, flexible sphenoidal electrodes assist in ambulatory recording of temporal lobe seizures, both in demonstrating the presence of seizures and in determining the localization and time of seizure onset.

Electrodes↗
PubMed1996

Heteromers of glutamate decarboxylase isoforms occur in rat cerebellum.

The subunit structure of brain glutamate decarboxylase in cerebellum was investigated by using gel electrophoresis and antisera that specifically recognize the individual isoforms of brain glutamate decarboxylase (termed GAD65 and GAD67). The antisera were prepared against peptides that corresponded to amino acid sequences specific to each isoform. Each antiserum reacted specifically with the appropriate peptide in an ELISA and with the appropriate form of GAD on immunoblots. Nondenaturing gradient gel electrophoresis indicated that GAD is principally multimeric with monomeric forms comprising < 3% of the total. Immunoprecipitation and immunoaffinity chromatography experiments were performed with antisera W624 and W883, which were prepared against peptides specific to GAD65 and GAD67, respectively. Immunoprecipitates prepared from cerebellar supernatants with W624 contained both GAD65 and GAD67, whereas some GAD67 was left in the supernatant. In a similar manner, immunoprecipitates prepared with W883 contained both GAD65 and GAD67, whereas some GAD65 remained in the supernatant. In addition, immunoaffinity columns prepared with either W624 or W883 retained both GAD65 and GAD67 even after extensive washing. These results are consistent with the presence of heteromultimers of GAD65 and GAD67 in cerebellum in addition to homomers of each form.

Amino Acid Sequence↗
PubMed1995

Repeated administration of gamma-vinylGABA reduces rat brain glutamine synthetase activity.

The glutamine cycle has been proposed as a pathway in which glutamine synthesized in glia provides substrate for synthesis of the neurotransmitters glutamate and GABA as they are lost from neurons. To test whether GABA may regulate this pathway, the effect of elevated GABA on the glial enzyme glutamine synthetase was examined in rat brain. Repeated subcutaneous injections of the antiepileptic GABA transaminase inhibitor gamma-vinylGABA at a dose of 150 mg/kg per day for 21 days reduced glutamine synthetase activity by 36% in the cortex and 22% in the cerebellum. At 30 mg/kg per day, glutamine synthetase activity was reduced by 9.5% in the cortex but unchanged in the cerebellum. The reductions were brain specific because the skeletal muscle and liver enzymes were unaffected by gamma-vinylGABA administration. Amino acid analysis of the cortex from gamma-vinylGABA-treated rats demonstrated a 270% increase in GABA levels after 150 mg/kg but no change after 30 mg/kg. GABA levels and glutamine synthetase activity were inversely correlated. The 150 mg/kg dose significantly lowered cortical glutamine and glutamate levels. The decline in brain glutamine synthetase activity with chronic gamma-vinylGABA administration developed gradually over time and may be due to the slow turnover of this enzyme in vivo.

Amino Acids↗
PubMed1994

Acetylcholine receptor agonists stimulate [3H]taurine release from rat sympathetic ganglia.

The endogenous taurine content, and the uptake and release of [3H]taurine were examined using the rat superior cervical ganglion. Taurine was found to be one of the most abundant amino acids in the superior cervical ganglion, and the superior cervical ganglion took up [3H]taurine from the incubation medium. Carbachol stimulated the release of [3H]taurine in a concentration-dependent manner with an EC50 of 26 microM and maximal stimulation at 100 microM. The nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium stimulated release with the same potency but with greater efficacy than carbachol. The nicotinic receptor antagonist hexamethonium (1 mM) inhibited carbachol-stimulated release by 74%. (+/-)-Muscarine stimulated release with an EC50 of 8 microM but with a maximal effect of only 32% of that produced by 100 microM carbachol. Oxotremorine, another muscarinic receptor agonist, was ineffective, even at 1 mM. The muscarinic receptor antagonist atropine inhibited carbachol-stimulated release by 30% at 10 microM. These results show that [3H]taurine release from rat superior cervical ganglion can be stimulated by cholinergic receptor agonists. Release is mediated predominantly by a nicotinic receptor and partially by a muscarinic receptor.

Amino Acids↗
PubMed1994

The level of GAD67 protein is highly sensitive to small increases in intraneuronal gamma-aminobutyric acid levels.

Increases (> 2.5-fold) in GABA levels in rat brain lead to a large decrease in the level of the 67-kDa form of glutamate decarboxylase (GAD67) through a mechanism involving either a change in GAD67 protein stability or a change in GAD67 mRNA translation. In the present study, brain levels of GABA were manipulated by treating rats with various doses of gamma-vinyl-gamma-aminobutyric acid (GVG), and the dependence of total GAD activity and levels of GAD67 and GAD65 protein on the levels of GABA was analyzed. Initial studies showed that both GABA and GAD67 protein levels reached new steady-state levels after two to four daily injections; GABA increased 1.5- (30 mg of GVG/kg) and fourfold (150 mg of GVG/kg), and GAD67 protein content decreased by 30 and 70%. To assess the sensitivity of GAD67 to GABA, rats were injected with eight different doses of GVG (15-150 mg/kg) for 5 days. With increasing doses of GVG, we observed a gradual increase in both whole-tissue and synaptosomal GABA levels and a gradual decrease in GAD67 protein and GAD activity. The levels of GAD65 remained constant at all GVG doses. GAD67 was remarkably sensitive to GABA. The synaptosomal GAD67 level decreased approximately 12% and the whole-neuron GAD67 level decreased approximately 3% for each 1% increase in nerve terminal GABA content when it was close to its physiological level. Our results clearly demonstrate that GAD67 is tightly controlled by intraneuronal GABA, and we suggest that this regulatory mechanism has important implications for the physiological regulation of GABAergic function in the mammalian brain.

Aminocaproates↗
PubMed1993

Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides.

A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N-terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 +/- 4%) is the highest reported for any peptidic renin inhibitor.

Animals↗
PubMed1993

Coxsackievirus B4 alters pancreatic glutamate decarboxylase expression in mice soon after infection.

The 64,000-M(r) (64K) islet autoantigen, which is considered to be a target protein of beta cell destruction in insulin-dependent diabetes mellitus (IDDM), has recently been identified as the enzyme glutamic acid decarboxylase (GAD). We reported a two- to three-fold increased expression of the antigen in islets of diabetes-susceptible mice following infection with a diabetogenic strain of Coxsackievirus B4 (CB4) at 72-h postinfection (p.i.), a time point of active virus replication in the islets. Most of the infected animals subsequently developed 64K autoantibodies and hyperglycemia. Since the infection increases 64K expression, we have analysed immunoreactive GAD expression with a panel of peptide antisera and two widely-used polyclonal antisera against GAD, and measured GAD activity in the brain, pancreas and islets of these mice. Two isoforms, GAD65 and GAD67, are detected in these tissues from non-infected mice. Both GADs are also present in the infected mice brain at 72 h p.i.; however, their islets contain about three-fold more GAD65, and essentially no detectable GAD67. GAD activity is significantly higher in the brain compared with whole pancreas or islets, and islet GAD activity is higher than pancreas GAD activity. The infection significantly reduces islet GAD activity, but not brain GAD activity. CB4-induced abnormalities in islet GAD expression may play a role in virus-induced diabetes.

Animals↗
PubMed1993

Beta-adrenergic-agonist stimulated taurine release from astroglial cells is modulated by extracellular [K+] and osmolarity.

Astroglial cells are known to release taurine in response to stimulation by a variety of stimuli including beta-adrenergic receptor agonists such as isoproterenol (IPR). The effects of changing osmolarity and extracellular [K+] on IPR-stimulated taurine release were studied with LRM55 cells, a continuous astroglial cell line. IPR-stimulated taurine release decreased almost 8% for each 1% increase in osmolarity, indicating that IPR-stimulated release is highly regulated by the osmolarity of the medium. IPR-stimulated taurine release was greatly enhanced when external [K+] was increased isosmotically by substituting KCl for NaCl but was strongly suppressed when external [K+] was increased hyperosmotically by adding KCl to the medium. Both IPR-stimulated and K(+)-stimulated taurine release depended on external [Cl-]; IPR-stimulated release declined approximately in parallel to K(+)-stimulated release as [Cl-] in the medium was reduced. The high sensitivity of IPR-stimulated release to factors that change cell volume (osmolarity, external [K+], external [Cl-]) is consistent with the idea that IPR, elevated [K+], and reduced osmolarity all elicit taurine release via a single tension-controlled mechanism.

Adrenergic beta-Agonists↗