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Biomedical subjects

M A Moskowitz

Publications and source records attributed to M A Moskowitz.

At least 91 records · Page 5Linked to original sources
PubMed1998

Inadequate management of blood pressure in a hypertensive population.

BACKGROUND: Many patients with hypertension have inadequate control of their blood pressure. Improving the treatment of hypertension requires an understanding of the ways in which physicians manage this condition and a means of assessing the efficacy of this care. METHODS: We examined the care of 800 hypertensive men at five Department of Veterans Affairs sites in New England over a two-year period. Their mean (+/-SD) age was 65.5+/-9.1 years, and the average duration of hypertension was 12.6+/-5.3 years. We used recursive partitioning to assess the probability that antihypertensive therapy would be increased at a given clinic visit using several variables. We then used these predictions to define the intensity of treatment for each patient during the study period, and we examined the associations between the intensity of treatment and the degree of control of blood pressure. RESULTS: Approximately 40 percent of the patients had a blood pressure of > or =160/90 mm Hg despite an average of more than six hypertension-related visits per year. Increases in therapy occurred during 6.7 percent of visits. Characteristics associated with an increase in antihypertensive therapy included increased levels of both systolic and diastolic blood pressure at that visit (but not previous visits), a previous change in therapy, the presence of coronary artery disease, and a scheduled visit. Patients who had more intensive therapy had significantly (P<0.01) better control of blood pressure. During the two-year period, systolic blood pressure declined by 6.3 mm Hg among patients with the most intensive treatment, but increased by 4.8 mm Hg among the patients with the least intensive treatment. CONCLUSIONS: In a selected population of older men, blood pressure was poorly controlled in many. Those who received more intensive medical therapy had better control. Many physicians are not aggressive enough in their approach to hypertension.

Aged↗
PubMed1998

Putative 5-ht5 receptors: localization in the mouse CNS and lack of effect in the inhibition of dural protein extravasation.

Putative 5-ht5 receptor binding sites were visualized by in vitro autoradiography using [125I]LSD (in the presence of clozapine and spiperone) or [3H]5-carboxamidotryptamine (in the presence 8-OH-DPAT, GR127935 and spiperone). Under these conditions, no [3H]5-carboxamidotryptamine labeling was detected in the brain of mice lacking the gene encoding the putative 5-ht5a receptor (knockout mice), whereas intermediate densities of binding sites were seen in the olfactory bulb and neocortex of wild-type mice. [125I]LSD labeled the same areas as [3H]5-carboxamidotryptamine in wild-type mice. High densities of [125I]LSD binding sites were observed in the medial habenula of wild type and knockout mice. 5-CT competed for [125I]LSD binding sites with an affinity of 2 nM in the olfactory bulb and neocortex of wild-type mice and an affinity of 30 nM in the habenula of knockout mice, suggesting that habenular labeling might be accounted for by putative 5-ht5b receptors. In the presence of 5'-guanylylimidodiphosphate, 5-CT displaced [125I]LSD from putative 5-ht5a and 5-ht5b sites with a 6-times and 3-times lower affinity, respectively, suggesting that both receptor subtypes are coupled to G proteins in brain. We also studied the inhibitory effect of 5-CT on dural neurogenic inflammation in knockout mice. In wild type mice, 3 ng/kg 5-CT inhibited dural protein extravasation by 60%. A similar effect was observed in knockout mice, even in the presence of the 5-HT1B receptor antagonist GR127935. These results suggest that the inhibitory effects of 5-CT are not mediated by a site with the characteristics of the putative 5-ht5 receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Attenuated neurotransmitter release and spreading depression-like depolarizations after focal ischemia in mutant mice with disrupted type I nitric oxide synthase gene.

Nitric oxide (NO) plays a complex role in the pathophysiology of cerebral ischemia. In this study, mutant mice with disrupted type I (neuronal) NO synthase (nNOS) were compared with wild-type littermates after permanent focal ischemia. Cerebral blood flow in the central and peripheral zones of the ischemic distribution were measured with laser doppler flowmetry. Simultaneously, microdialysis electrodes were used to measure extracellular amino acid concentrations and DC potential in these same locations. Blood flow was reduced to <25 and 60% of baseline levels in the central and peripheral zones, respectively; there were no differences in nNOS mutants versus wild-type mice. Within the central ischemic zone, DC potentials rapidly shifted to -20 mV in all mice. In the ischemic periphery, spreading depression (SD)-like waves of depolarization were observed. SD-like events were significantly fewer in the nNOS mutant mice. Concurrent with these hemodynamic and electrophysiological perturbations, extracellular elevations in amino acids occurred after ischemia. There were no detectable differences between wild-type and mutant mice in the ischemic periphery. However, in the central zone of ischemia, elevations in glutamate and GABA were significantly lower in the nNOS mutants. Twenty-four hour infarct volumes in the nNOS mutant mice were significantly smaller than in their wild-type littermates. Overall, the number of SD-like depolarizations and the integrated efflux of glutamate were significantly correlated with infarct size. These results suggest that NO derived from the nNOS isoform contributes to tissue damage after focal ischemia by amplifying excitotoxic amino acid release in the core and deleterious waves of SD-like depolarizations in the periphery.

Alanine↗
PubMed1998

Relation of family responsibilities and gender to the productivity and career satisfaction of medical faculty.

BACKGROUND: Studies have found that female faculty publish less, have slower career progress, and generally have a more difficult time in academic careers than male faculty. The relation of family (dependent) responsibilities to gender and academic productivity is unclear. OBJECTIVE: To describe dependent responsibilities by gender and to identify their relation to the aspirations, goals, rate of progress, academic productivity, and career satisfaction of male and female medical school faculty. DESIGN: 177-item survey questionnaire. SETTING: 24 randomly selected medical schools in the contiguous United States. PARTICIPANTS: 1979 respondents from a probability sample of full-time academic medical school faculty. MEASUREMENTS: The main end point for measuring academic productivity was the total number of publications in refereed journals. Perceived career progress and career satisfaction were assessed by using Likert scales. RESULTS: For both male and female faculty, more than 90% of time devoted to family responsibilities was spent on child care. Among faculty with children, women had greater obstacles to academic careers and less institutional support, including research funding from their institutions (46% compared with 57%; P < 0.001) and secretarial support (0.68 full-time equivalents compared with 0.83 full-time equivalents; P = 0.003), than men. Compared with men with children, women with children had fewer publications (18.3 compared with 29.3; P < 0.001), slower self-perceived career progress (2.6 compared with 3.1; P < 0.001), and lower career satisfaction (5.9 compared with 6.6; P < 0.001). However, no significant differences between the sexes were seen for faculty without children. CONCLUSIONS: Compared with female faculty without children and compared with men, female faculty with children face major obstacles in academic careers. Some of these obstacles can be easily modified (for example, by eliminating after-hours meetings and creating part-time career tracks). Medical schools should address these obstacles and provide support for faculty with children.

Adult↗
PubMed1998

Minority faculty and academic rank in medicine.

CONTEXT: Previous studies have found that fewer minority medical school faculty hold senior professorial ranks than do majority faculty and may not be promoted as rapidly. OBJECTIVE: To determine whether minority faculty were as likely as majority faculty to have attained senior rank (associate professor or full professor) after adjusting for other factors that typically influence promotion. DESIGN: A self-administered mailed survey of US medical school faculty using the Association of American Medical Colleges database. The sample was stratified by department, graduation cohort, and sex. PARTICIPANTS: A stratified random sample of 3013 full-time faculty at 24 representative US medical schools. All underrepresented minority faculty at these schools were sampled. MAIN OUTCOME MEASURE: Attainment of senior academic rank (associate professor or full professor). RESULTS: Of 3013 faculty surveyed, 1807 (60.0%) responded, including 1463 white (81.0%), 154 black (8.5%), 136 Asian (7.5%), and 54 Hispanic (3.0%). Overall, 980 faculty (54%) had attained senior academic rank, including 47 (30.5%) of 154 black faculty, 59 (43.4%) of 136 Asian faculty, 22 (40.8%) of 54 Hispanic faculty, and 852 (58.3%) of 1463 white faculty. White faculty had significantly more first-authored and total peer-reviewed publications than the other groups. After adjusting for the medical school, department, years as medical school faculty, number of peer-reviewed publications, receipt of research grant funding, proportion of time in clinical activities, sex, and tenure status, we found that the odds ratios of holding senior rank relative to white faculty were 0.33 (95% confidence interval [CI], 0.17-0.63) for black faculty, 0.36 (95% CI, 0.12-1.08) for Hispanic faculty, and 0.58 (95% CI, 0.30-1.12) for Asian faculty. CONCLUSIONS: Minority faculty were less likely than white faculty to hold senior academic rank. This finding was not explained by potential confounders such as years as a faculty member or measures of academic productivity.

Career Mobility↗
PubMed1998

Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase.

The treatment of ischemic strokes is limited to prophylactic agents that block the coagulation cascade. Here, we show that cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, protect against cerebral injury by a previously unidentified mechanism involving the selective up-regulation of endothelial NO synthase (eNOS). Prophylactic treatment with HMG-CoA reductase inhibitors augments cerebral blood flow, reduces cerebral infarct size, and improves neurological function in normocholesterolemic mice. The up-regulation of eNOS by HMG-CoA reductase inhibitors is not associated with changes in serum cholesterol levels, but is reversed by cotreatment with L-mevalonate and by the downstream isoprenoid, geranylgeranyl pyrophosphate and not by farnesyl pyrophosphate. The blood flow and neuroprotective effects of HMG-CoA reductase inhibitors are completely absent in eNOS-deficient mice, indicating that enhanced eNOS activity by HMG-CoA reductase inhibitors is the predominant if not the only mechanism by which these agents protect against cerebral injury. Our results suggest that HMG-CoA reductase inhibitors provide a prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia.

Animals↗
PubMed1998

Protective effects of 5-iodo-6-amino-1,2-benzopyrone, an inhibitor of poly(ADP-ribose) synthetase against peroxynitrite-induced glial damage and stroke development.

Peroxynitrite triggers DNA single-strand breakage, which activates the nuclear enzyme poly(ADP-ribose) synthetase (PARS). Activation of PARS depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, resulting in cell necrosis. Here, we demonstrate that inhibition of PARS with the novel, potent PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) protects against peroxynitrite-induced cell death (as measured by measurement of mitochondrial respiration and release of lactate dehydrogenase) in C6 glioma cells in vitro, and in a murine stroke model in vivo. Inhibition of PARS with INH2BP may represent a novel approach for the experimental therapy of stroke.

Animals↗
PubMed1998

Role of peroxynitrite and neuronal nitric oxide synthase in the activation of poly(ADP-ribose) synthetase in a murine model of cerebral ischemia-reperfusion.

Poly(ADP-ribose) synthetase (PARS) activation, a downstream event of nitric oxide (NO) neurotoxicity has been implicated in cerebral reperfusion injury. The aim of our study was to identify the trigger of PARS activation during stroke. Formation of poly(ADP-ribose) profoundly increased in the early phase of reperfusion. Poly(ADP-ribose) formation was attenuated in mice deficient for neuronal NO synthase (nNOS). We next tested in glioma cells whether NO, or peroxynitrite (a cytotoxic oxidant formed from NO and superoxide) is the actual trigger of PARS activation. Peroxynitrite, but not various NO donors, activated PARS and suppressed cellular viability in a PARS-dependent fashion. Thus, nNOS is responsible for PARS activation in stroke. PARS activation, however, is not a direct result of NO production, but it occurs via peroxynitrite formation.

Animals↗
PubMed1998

Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia.

We examined the expression, activation, and cellular localization of caspase-3 (CPP32) using immunohistochemistry, immunoblots, and cleavage of the fluorogenic substrate N-benzyloxycarbonyl-Asp-Glu-Val-Asp-7-amino-4-trifluoromethyl coumarin (zDEVD-afc) in adult mouse brain after temporary (2 hr) middle cerebral artery occlusion produced by filament insertion into the carotid artery. Immunoreactive caspase-3p32 but not its cleavage product caspase-3p20 was constitutively expressed in neurons throughout brain and was most prominent in neuronal perikarya within piriform cortex. Caspase-like enzyme activity was elevated in brain homogenate 0-3 hr after reperfusion and reached a peak within 30 to 60 min. Caspase-3p20 immunoreactivity became prominent in neuronal perikarya within the middle cerebral artery territory at the time of reperfusion and on immunoblots 1-12 hr later. DNA laddering (agarose gels) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL)-stained cells were detected 6-24 hr after reperfusion. At 12-24 hr, immunoreactive p20 was visualized in TUNEL-positive cells, a finding also observed in apoptotic mouse cerebellar granule cells on postnatal day 5. Together, these observations suggest the existence of a time-dependent evolution of ischemic injury characterized by the close correspondence between caspase-like enzyme activation and an associated increase in immunoreactive product (caspase-3p20) beginning at or before reperfusion and followed several hours later by morphological and biochemical features of apoptosis.

Age Factors↗
PubMed1998

Defects in regulation of apoptosis in caspase-2-deficient mice.

During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Mammography use helps to explain differences in breast cancer stage at diagnosis between older black and white women.

BACKGROUND: Older black women are less likely to undergo mammography and are more often given a diagnosis of advanced-stage breast cancer than older white women. OBJECTIVE: To investigate the extent to which previous mammography explains observed differences in cancer stage at diagnosis between older black and white women with breast cancer. DESIGN: Retrospective cohort study using the Linked Medicare-Tumor Registry Database. SETTING: Population-based data from three geographic areas of the United States included in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program (Connecticut; metropolitan Atlanta, Georgia; and Seattle-Puget Sound, Washington). PARTICIPANTS: Black and white women 67 years of age and older in whom breast cancer was diagnosed between 1987 and 1989. MEASUREMENTS: Medicare claims were used to classify women according to mammography use in the 2 years before diagnosis as nonusers (no previous mammography), regular users (> or =2 mammographies done at least 10 months apart), or peri-diagnosis users (mammography done only within 3 months before diagnosis). Information on mammography use was linked with SEER data to determine cancer stage at diagnosis. Stage was classified as early (in situ or local) or late (regional or distant). RESULTS: Black women were more likely to not undergo mammography (odds ratio [OR], 3.00 [95% CI, 2.41 to 3.75]) and to be given a diagnosis of late-stage disease (OR, 2.49 [CI, 1.59 to 3.92]) than white women. When women were stratified by previous mammography use, the black-white difference in cancer stage occurred only among nonusers (adjusted OR, 2.54 [CI, 1.37 to 4.71]). Among regular users, cancer was diagnosed in black and white women at similar stages (adjusted OR, 1.34 [CI, 0.40 to 4.51]). In logistic modeling, previous mammography alone explained about 30% of the excess late-stage disease in black women. In a separate model, previous mammography explained 12% of the excess late-stage disease among black women after adjustment for sociodemographic and comorbidity information. CONCLUSION: Differences in breast cancer stage at diagnosis between older black and white women are related to previous mammography use. Increased regular use of mammography may result in a shift toward earlier-stage disease at diagnosis and narrow the observed differences in stage at diagnosis between older black and white women.

Black or African American↗
PubMed1998

Perfusion-weighted imaging defects during spontaneous migrainous aura.

Perfusion- and diffusion-weighted magnetic resonance imaging was performed during spontaneous visual auras in four migraineurs. Alterations in relative cerebral blood flow (16-53% decrease), cerebral blood volume (6-33% decrease), and tissue mean transit time (10-54% increase) were observed in the gray matter of occipital cortex contralateral to the affected visual hemifield. No changes in the apparent diffusion coefficient were observed either while the patients were symptomatic or after resolution of the visual symptoms but before the onset of headache. Functional magnetic resonance imaging can be a useful noninvasive tool to study hemodynamic changes during spontaneous attacks of migraine with aura.

Adult↗
PubMed1998

Measurement of changes in cerebral blood volume in spontaneously hypertensive rats following L-arginine infusion using dynamic susceptibility contrast MRI.

To understand whether the NO-dependent vasodilator L-arginine was effective upon a chronically hypertensive cerebral capillary endothelium, dynamic susceptibility contrast MRI was used to measure the relative cerebral blood volume (rCBV) changes in nonischemic spontaneously hypertensive rats (SHRs). rCBV was measured in 11 rats at 4.7 T using fast gradient echo imaging with intravenous injection of Gd-DTPA. Images were acquired before, immediately after, and up to 90 min after the infusion of 300 mg/kg L-arginine (n = 7) or of an equivalent volume of saline (n = 4). L-arginine increased rCBV in cortex beginning 10 min after infusion and reached significance after 30 min (P < 0.01), reached a peak of 1.24 +/- 0.06 (mean +/- SEM) times pre-injection level after 50 min, and was sustained throughout the 90 min observation period. In contrast, the rCBV in the deeper gray matter (striatum) showed no statistically significant change over the 90 min observation period. While this is consistent with previous studies showing that L-arginine infusion can directly modulate vascular tone and cerebral hemodynamics, it demonstrates that the effect is present only in cortex, and that it can occur also in the setting of a disturbed capillary endothelium.

Animals↗
PubMed1998

[Apoptosis and ischemic infarct].

Apoptosis and programmed cell death have attracted major scientific interest during the last few years. Apoptosis can be differentiated from necrosis by means of morphological, biochemical, molecular and pharmacological parameters. Several molecular pathways leading to apoptosis have been elucidated over the last few years. Apoptosis is not only important for physiological cell turnover, but also plays a role in many pathological processes. Recently, a number of laboratories have found evidence of apoptotic cell death in cerebral ischemia in animal models. Quantitatively, apoptosis seems to be important in the border zone of the infarction, the so-called penumbra. Since parts of the apoptotic cascade can be inhibited, pharmacological treatment seems feasible. The so-called caspase inhibitors are promising therapeutic agents for the treatment of acute stroke and may be administered with other neuroprotective medications in humans in the near future.

Animals↗
PubMed1998

The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis.

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonist (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-i mine hydrogen maleate (MK-801) was examined on c-fos-like immunoreactivity (c-fos-LI) in urethane-anesthetized Sprague-Dawley rats using a polyclonal antibody. C-fos, an indicator of neuronal activation, was assessed within the trigeminal nucleus caudalis (TNC), area postrema. lateral reticular and solitary tract nuclei 2 h after intracisternal injection of capsaicin. C-fos-positive cells were counted at three representative levels corresponding to obex, -2.05 mm and -6.45 mm in 18 tissue sections (50 microm). A weighted average was obtained reflecting total brainstem expression within lamina I, II of TNC using a recently validated method. Capsaicin (0.1, 1, 5, 10 and 15 nmol) caused a dose-dependent labeling of cells in lamina I, II at obex similar to that previously reported after intracisternal blood or carrageenin administration in rats and guinea pigs. MK-801 (0.3, 1 and 3 mg/kg) administered i.p. 30 min before capsaicin (5 nmol in 100 microl artificial CSF) reduced significantly and dose-dependently (12%, 36% and 47%, respectively) the c-fos-LI cells in TNC at each level from rostral to caudal but not in solitary tract, area postrema and lateral reticular nuclei, and for unexplained reasons, increased c-fos-LI within the inferior olive. These results suggest that NMDA receptors provide a potential therapeutic target for cephalic pain (e.g. migraine) due to trigeminovascular activation from meningeal afferents.

Animals↗
PubMed1998

The protein tyrosine phosphatase SHP-2 is expressed in glial and neuronal progenitor cells, postmitotic neurons and reactive astrocytes.

In this study we examined the distribution and developmental profile of the src homology 2 (SH2) domain-containing protein tyrosine phosphatase SHP-2 in the mouse brain. We found that SHP-2 is present in both mitotically active and postmitotic cells in the forebrains of embryonic day 12 (E12) mice. In a developmental study extending from embryonic day 12 to adulthood, Western blotting analysis demonstrated equivalent levels of SHP-2 protein at all of the ages examined. Expression of SHP-2 paralleled the level of enzymatic activity at the different developmental periods. In the adult brain SHP-2 was restricted to diverse classes of neurons, while the majority of glial cells did not express detectable levels of protein. However, reactive astrocytes in response to an ischemic brain injury showed SHP-2 immunolabelling. Our data suggest that SHP-2 may play a role in pathways of neuronal and glial progenitor cells, in a broad spectrum of neuronal responses in the adult brain and in the gliotic response to the injury.

Animals↗