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Biomedical subjects

M A Moskowitz

Publications and source records attributed to M A Moskowitz.

At least 37 records · Page 2Linked to original sources

Fellowship training and career outcomes for primary care physician-faculty.

PURPOSE: To examine associations between fellowship training and career outcomes among primary care physician-faculty. METHOD: A total of 821 full-time primary care physician-faculty from 24 representative U.S. medical schools were surveyed using a self-administered questionnaire. Primary outcomes were recent grant submissions and funding, career referred publications, rank, and salary. Findings were adjusted for demographic and professional characteristics. RESULTS: Of the 500 respondents, 234 of the physician-faculty had completed a fellowship and 266 had not. Fellowship-trained physician-faculty were more than four times as likely to have submitted a grant proposal and to have had a grant funded (both p < 0.0001) than were physician-faculty without fellowship training. They were also more likely to have had any refereed publications (OR 3.8, p < 0.0001) and to have achieved senior academic rank (OR = 1.9, p = 0.02). Among those with fellowship experience, the amount of research training was important. Those with at least one year of research experience in their fellowship program had more grant proposal submissions (OR = 1.9, p = 0.02), more grants funded (OR = 2.9, p = 0.0003), more publications (OR = 2.4, p = 0.02), and higher academic ranks (OR 2.3, p = 0.03) than did those with less research training. Salaries were similar in every comparison. CONCLUSION: Fellowship-trained primary care physician-faculty were more productive researchers and were more likely to have achieved senior academic rank than were their no-fellowship-trained peers. Even among physician-faculty with fellowship experience, more research training was associated with higher productivity and rank. Salaries were not affected by training experience.

Faculty, Medical↗

Dynamic imaging of cerebral blood flow using laser speckle.

A method for dynamic, high-resolution cerebral blood flow (CBF) imaging is presented in this article. By illuminating the cortex with laser light and imaging the resulting speckle pattern, relative CBF images with tens of microns spatial and millisecond temporal resolution are obtained. The regional CBF changes measured with the speckle technique are validated through direct comparison with conventional laser-Doppler measurements. Using this method, dynamic images of the relative CBF changes during focal cerebral ischemia and cortical spreading depression were obtained along with electrophysiologic recordings. Upon middle cerebral artery (MCA) occlusion, the speckle technique yielded high-resolution images of the residual CBF gradient encompassing the ischemic core, penumbra, oligemic, and normally perfused tissues over a 6 x 4 mm cortical area. Successive speckle images demonstrated a further decrease in residual CBF indicating an expansion of the ischemic zone with finely delineated borders. Dynamic CBF images during cortical spreading depression revealed a 2 to 3 mm area of increased CBF (160% to 250%) that propagated with a velocity of 2 to 3 mm/min. This technique is easy to implement and can be used to monitor the spatial and temporal evolution of CBF changes with high resolution in studies of cerebral pathophysiology.

Animals↗

Evaluating diagnosis-based case-mix measures: how well do they apply to the VA population?

BACKGROUND: Diagnosis-based case-mix measures are increasingly used for provider profiling, resource allocation, and capitation rate setting. Measures developed in one setting may not adequately capture the disease burden in other settings. OBJECTIVES: To examine the feasibility of adapting two such measures, Adjusted Clinical Groups (ACGs) and Diagnostic Cost Groups (DCGs), to the Department of Veterans Affairs (VA) population. RESEARCH DESIGN: A 60% random sample of veterans who used health care services during FY 1997 was obtained from VA inpatient and outpatient administrative databases. A split-sample technique was used to obtain a 40% sample (n = 1,046,803) for development and a 20% sample (n = 524,461) for validation. METHODS: Concurrent ACG and DCG risk adjustment models, using 1997 diagnoses and demographics to predict FY 1997 utilization (ambulatory provider encounters, and service days-the sum of a patient's inpatient and outpatient visit days), were fitted and cross-validated. RESULTS: Patients were classified into groupings that indicated a population with multiple psychiatric and medical diseases. Model R-squares explained between 6% and 32% of the variation in service utilization. Although reparameterized models did better in predicting utilization than models with external weights, none of the models was adequate in characterizing the entire population. For predicting service days, DCGs were superior to ACGs in most categories, whereas ACGs did better at discriminating among veterans who had the lowest utilization. CONCLUSIONS: Although "off-the-shelf" case-mix measures perform moderately well when applied to another setting, modifications may be required to accurately characterize a population's disease burden with respect to the resource needs of all patients.

Aged↗

Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice.

BACKGROUND AND PURPOSE: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) lower serum cholesterol and decrease the incidence of stroke and cardiovascular disease. There is growing evidence that statins exert some of their beneficial effects independent of cholesterol lowering. Indeed, we have previously demonstrated that chronic simvastatin administration upregulates endothelial nitric oxide synthase (eNOS), resulting in more functional protein, augmentation of cerebral blood flow, and neuroprotection in a murine model of cerebral ischemia. In this report we examined whether another member of the statin family shared these effects and whether eNOS upregulation is sustained with longer treatment. METHODS: Mevastatin (2 mg/kg or 20 mg/kg per day) was administered to 18- to 22-g male mice for 7, 14, or 28 days before 2-hour middle cerebral artery occlusion with the use of the filament model (n=9 to 12). Neurological deficits and cerebral infarct volumes were assessed at 24 hours. Arterial blood pressure and gases, relative cerebral blood flow, and blood cholesterol levels were monitored in a subset of animals (n=5). Absolute cerebral blood flow was measured by the [(14)C]iodoamphetamine indicator fractionation technique (n=6). eNOS mRNA and protein levels were determined. RESULTS: Mevastatin increased levels of eNOS mRNA and protein, reduced infarct size, and improved neurological deficits in a dose- and time-dependent manner. Greatest protection was seen with 14- and 28-day high-dose treatment (26% and 37% infarct reduction, respectively). Cholesterol levels were reduced only after 28 days of treatment and did not correlate with infarct reduction. Baseline absolute cerebral blood flow was 30% higher after 14-day high-dose treatment. CONCLUSIONS: Chronic prophylactic treatment with mevastatin upregulated eNOS and augmented cerebral blood flow. These changes occurred in the absence of changes in serum cholesterol levels, were sustained for up to 1 month of treatment, and resulted in neuroprotection after middle cerebral artery occlusion.

Animals↗

Attitudes toward colorectal cancer screening tests.

OBJECTIVE: To examine patient and physician preferences in regard to 5 colorectal cancer screening alternatives endorsed by a 1997 expert panel, determine the impact of patient and physician values regarding certain test features on screening preference, and assess physicians' perceptions of patients' values. DESIGN: Cross-sectional survey. SETTING: A general internal medicine practice at an academic medical center in 1998. PARTICIPANTS: Patients (N=217; 76% response rate) and physicians (N=39; 87% response rate) at the study setting. MEASUREMENTS AND MAIN RESULTS: Patients preferred fecal occult blood testing (43%) or colonoscopy (40%). In patients for whom accuracy was the most important test feature, colonoscopy (62%) was the preferred screening method. Patients for whom invasive test features were more important preferred fecal occult blood testing (76%; P <.001). Patients and physicians were similar in their values regarding the various test features. However, there was a significant difference between physicians' perceptions of which test features were important to patients compared with the patients' actual responses (P <.001). The largest discrepancy was for accuracy (patient actual 54% vs physician opinion 15%) and discomfort (patient actual 15% vs physician opinion 64%). CONCLUSIONS: Patients have distinct preferences for colorectal cancer screening tests that are associated with the importance placed on certain test features. Physicians incorrectly perceive those factors that are important to patients. Physicians should incorporate patient values in regard to certain test features when discussing colorectal cancer screening with their patients and when eliciting their screening preferences.

Adult↗

Fas receptor and neuronal cell death after spinal cord ischemia.

Cell death from spinal cord injury is mediated in part by apoptotic mechanisms involving downstream caspases (e.g., caspase-3). Upstream mechanisms may involve other caspases such as procaspase-8, a 55 kDa apical caspase, which we found constitutively expressed within spinal cord neurons along with Fas. As early as 1.5 hr after transient ischemia, activated caspase-8 (p18) and caspase-8 mRNA appeared within neurons in intermediate gray matter and in medial ventral horn. We also detected evidence for an increase in death receptor complex by co-immunoprecipitation using Fas and anti-procaspase-8 after ischemia. At early time points, Fas and p18 were co-expressed within individual neurons, as were activated caspase-8 and caspase-3. Moreover, we detected p18 in cells before procaspase-3 cleavage product (p20), suggesting sequential activation. The appearance of cytosolic cytochrome c and gelsolin cleavage after ischemia was consistent with mitochondrial release and caspase-3 activation, respectively. Numerous terminal deoxynucleotidyl transferase-mediated DNA nick end-labeling-positive neurons contained p18 or p20 (65 and 80%, respectively), thereby supporting the idea that cells undergoing cell death contain both processed caspases. Our data are consistent with the idea that transient spinal cord ischemia induces the formation of a death-inducing signaling complex, which may participate in caspase-8 activation and sequential caspase-3 cleavage. Death receptors as well as downstream caspases may be useful therapeutic targets for limiting the death of cells in spinal cord.

Animals↗

Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury.

Matrix metalloproteinases (MMPs) belong to a class of extracellular proteinases responsible for maintaining and remodeling the extracellular matrix. In addition to multiple functions in normal physiology, abnormal MMP expression and activity may also participate in the pathophysiology of cerebral disease. Here, we show that MMP-9 (gelatinase B; EC.3.4.24.35) contributes to the pathophysiology of traumatic brain injury. After controlled cortical impact in mice, MMP-9 was increased in traumatized brain. Total MMP-9 levels at 24 hr were significantly increased as measured by a substrate cleavage assay. Zymograms showed that MMP-9 was elevated as early as 3 hr after traumatic brain injury, reaching a maximum at approximately 24 hr. Increased MMP-9 levels persisted for up to 1 week. Western blot analysis indicated increased profiles of MMP-9 expression that corresponded with the zymographic data. Knock-out mice deficient in MMP-9 gene expression were compared with wild-type littermates in terms of morphological and motor outcomes after trauma. Motor outcomes were measured at 1, 2, and 7 d after traumatic brain injury by the use of a rotarod device. MMP-9 knock-out mice had less motor deficits than wild-type mice. At 7 d, traumatic brain lesion volumes on Nissl-stained histological sections were significantly smaller in MMP-9 knock-out mice. These data demonstrate that MMP-9 contributes to the pathophysiology of traumatic brain injury and suggest that interruption of the MMP proteolytic cascade may be a possible therapeutic approach for preventing the secondary progression of damage after brain trauma.

Analysis of Variance↗

Hyperbaric oxygenation induced tolerance against focal cerebral ischemia in mice is strain dependent.

SV129 or C57BL/6 mice were exposed to hyperbaric oxygenation (HBO, 5 days, 1 h every day, 100% O(2) at 3 atm absolute). One day after the 5th HBO session focal cerebral ischemia was induced. In SV129 mice, HBO induced tolerance against permanent focal cerebral ischemia (n=42, mean infarct volume reduction 27%, P=0.001), but not against transient (30 or 60 min) focal cerebral ischemia. In the C57BL/6 strain of mice, HBO did not induce tolerance against focal cerebral ischemia, even when the duration of ischemia or the HBO protocol were modified. For the first time we demonstrate that HBO can induce tolerance to focal cerebral ischemia, but this effect is strain dependent.

Animals↗

Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions.

Caspase-11, a member of the murine caspase family, has been shown to be an upstream activator of caspase-1 in regulating cytokine maturation. We demonstrate here that in addition to its defect in cytokine maturation, caspase-11-deficient mice have a reduced number of apoptotic cells and a defect in caspase-3 activation after middle cerebral artery occlusion (MCAO), a mouse model of stroke. Recombinant procaspase-11 can autoprocess itself in vitro. Purified active recombinant caspase-11 cleaves and activates procaspase-3 very efficiently. Using a positional scanning combinatorial library method, we found that the optimal cleavage site of caspase-11 was (I/L/V/P)EHD, similar to that of upstream caspases such as caspase-8 and -9. Our results suggest that caspase-11 is a critical initiator caspase responsible for the activation of caspase-3, as well as caspase-1 under certain pathological conditions.

Animals↗

DNA methyltransferase contributes to delayed ischemic brain injury.

DNA methylation is important for controlling the profile of gene expression and is catalyzed by DNA methyltransferase (MTase), an enzyme that is abundant in brain. Because significant DNA damage and alterations in gene expression develop as a consequence of cerebral ischemia, we measured MTase activity in vitro and DNA methylation in vivo after mild focal brain ischemia. After 30 min middle cerebral artery occlusion (MCAo) and reperfusion, MTase catalytic activity and the 190 kDa band on immunoblot did not change over time. However, [(3)H]methyl-group incorporation into DNA increased significantly in wild-type mice after reperfusion, but not in mutant mice heterozygous for a DNA methyltransferase gene deletion (Dnmt(S/+)). Dnmt(S/+) mice were resistant to mild ischemic damage, suggesting that increased DNA methylation is associated with augmented brain injury after MCA occlusion. Consistent with this formulation, treatment with the MTase inhibitor 5-aza-2'-deoxycytidine and the deacetylation inhibitor trichostatin A conferred stroke protection in wild-type mice. In contrast to mild stroke, however, DNA methylation was not enhanced, and reduced dnmt gene expression was not protective in an ischemia model of excitotoxic/necrotic cell death. In conclusion, our results demonstrate that MTase activity contributes to poor tissue outcome after mild ischemic brain injury.

Animals↗

Cocaine activation discriminates dopaminergic projections by temporal response: an fMRI study in Rat.

We applied a sensitive new functional magnetic resonance imaging technique to identify the pattern and determinants of cocaine-induced brain activation in drug-naive rats. At doses greater than 0.1 mg/kg iv, cocaine produced robust activation throughout cortex with the largest magnitude increase in frontal neocortex. Additionally, we detected selective activation within dopamine-innervated subcortical regions including dorsomedial and ventrolateral striatum, nucleus accumbens region, and dorsal thalamus. Although dose response was similar among activated regions, temporal response differentiated regions along distinct anatomical boundaries with basal ganglia and limbic cortical structures, reaching maximum activation later than frontal neocortex. Pharmacological specificity was demonstrated by blocking cocaine-induced activation with SCH-23390, a selective D1 antagonist. Our data demonstrate the utility of fMRI to identify spatiotemporal patterns of cocaine-induced brain activation and implicate D1 dopaminergic mechanisms in acute cocaine action.

Animals↗

Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the alpha1A subunit of P/Q type calcium channels.

The P/Q type voltage-gated Ca2+ channels are involved in membrane excitability and Ca2+-dependent neurotransmitter release within the CNS. Mutations in the CacnalA gene encoding the alpha1A subunit of the P/Q type Ca2+ channel have recently been reported in tottering mice and a more severely affected allele, leaner. Here we show using in vivo cortical microdialysis that evoked increases of extracellular glutamate levels are markedly attenuated in both mutants upon KCl-induced depolarization compared with wild-type mice. Tottering and leaner mice also show a 10-fold resistance to cortical spreading depression induced by cortical electrical stimulation or KCl application to the pial surface. A slower transcortical propagation speed and failure to sustain regenerative spread of the depolarizing wave were more pronounced in leaner neocortex. Both signaling defects appeared unrelated to the developmental history of repeated cortical spike-wave discharges, since neither were observed in the stargazer mouse, a Ca2+ channel gamma2 subunit mutant with a similar seizure phenotype. These data demonstrate two cortical excitability defects revealed by prolonged depolarization in cerebral networks expressing mutant P/Q type Ca2+ channels, and are the first to identify a gene linked to a spreading depression phenotype.

Animals↗

Intensive care unit use and mortality in the elderly.

OBJECTIVE: To examine utilization and outcomes of intensive care unit (ICU) use for the elderly in the United States. DESIGN: We used 1992 data from the Health Care Financing Administration to examine ICU utilization and mortality by age and admission reason for hospitalizations of elderly Medicare beneficiaries. MAIN RESULTS: Use of the ICU was least likely for the oldest elderly overall (85+ years, 21.1% of admissions involved ICU; 75-84 years, 27.9%; 65-74 years, 29.7%), but more likely during surgical admissions. Eighty-three percent of the Medicare patients who received intensive care survived at least 90 days. Of the oldest elderly, 74% survived. Even among the 10% most expensive ICU hospitalizations, 77% of all patients and 62% of those 85 years and older survived at least 90 days. CONCLUSIONS: The likelihood of ICU use among these elderly decreased with age, especially among those 85 years or older. Diagnostic mix importantly influenced ICU use by age. The great majority of the elderly, including those 85 years and older and those receiving the most expensive ICU care, survived at least 90 days.

Aged↗

The impact of leaving against medical advice on hospital resource utilization.

OBJECTIVE: To assess the effect of hospital discharge against medical advice (AMA) on the interpretation of charges and length of stay attributable to alcoholism. DESIGN: Retrospective cohort. Three analytic strategies assessed the effect of having an alcohol-related diagnosis (ARD) on risk-adjusted utilization in multivariate regressions. Strategy 1 did not adjust for leaving AMA, strategy 2 adjusted for leaving AMA, and strategy 3 restricted the sample by excluding AMA discharges. SETTING: Acute care hospitals. PATIENTS: We studied 23,198 pneumonia hospitalizations in a statewide administrative database. MEASUREMENTS AND MAIN RESULTS: Among these admissions, 3.6% had an ARD, and 1.2% left AMA. In strategy 1 an ARD accounted for a $1,293 increase in risk-adjusted charges for a hospitalization compared with cases without an ARD ( p =.012). ARD-attributable increases of $1,659 ( p =.002) and $1,664 ( p =. 002) in strategies 2 and 3 respectively, represent significant 28% and 29% increases compared with strategy 1. Similarly, using strategy 1 an ARD accounted for a 0.6-day increase in risk-adjusted length of stay over cases without an ARD ( p =.188). An increase of 1 day was seen using both strategies 2 and 3 ( p =.044 and p =.027, respectively), representing significant 67% increases attributable to ARDs compared with strategy 1. CONCLUSIONS: Discharge AMA affects the interpretation of the relation between alcoholism and utilization. The ARD-attributable utilization was greater when analyses adjusted for or excluded AMA cases. Not accounting for leaving AMA resulted in an underestimation of the impact of alcoholism on resource utilization.

Aged↗

Increased susceptibility to ischemia-induced brain damage in transgenic mice overexpressing a dominant negative form of SHP2.

Cell culture studies have established SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) as an important factor in growth factor and cytokine-activated signaling pathways. However, the significance of SHP2 in the mammalian central nervous system (CNS) is not known since early embryonic lethality occurs in shp2 null mice. To bypass this embryonic lethality, transgenic animals containing a catalytically inactive mutant of SHP2 (SHP2-CS) under the control of a nestin intron II/thymidine kinase minimal promoter were generated. In the developing CNS of these animals, although high-level transgene expression was detected in the neuroepithelium, there was no obvious abnormality in progenitor cell proliferation or migration. In the adult brain, high-level transgene expression was detected in the subventricular zone, rostral migratory stream, dentate gyrus of hippocampus, and cerebellum. Because SHP2 function is likely important in cell survival pathways, we used a focal cerebral ischemia model to examined whether SHP2 is important during CNS injury. Ischemia-induced damage and neuronal death was found to be significantly greater in nestin-SHP2-CS mice than in wild-type littermates. These findings indicate that SHP2 is a required factor in signaling pathway(s) important for neuronal survival.

Animals↗

Specialty choices, compensation, and career satisfaction of underrepresented minority faculty in academic medicine.

PURPOSE: Despite efforts to increase the numbers of underrepresented minorities (URMs), only 3.9% of medical school faculty are URMs. The authors compared the specialty choices, compensation, and career satisfaction of minority faculty with those of their majority counterparts to determine whether there were differences that might affect the recruitment and retention of minority faculty. METHOD: In 1995, the authors mailed a self-administered survey to a stratified random sample of 3,013 eligible full-time salaried faculty in 24 randomly selected medical schools. Those schools, which had at least 200 faculty, did not include the Puerto Rican or historically black medical schools. RESULTS: Of the eligible faculty surveyed, 1,807 (60%) responded; 1,463 were majority faculty, 195 were URM faculty, and 149 were other-minority faculty. Similar proportions of the three groups were in the primary care specialties. Only 11% of the URM respondents were in basic science departments. There was no significant difference in adjusted mean compensation between majority, URM, and other-minority faculty. However, URM faculty were significantly less satisfied with their careers (adjusted scores: 60 versus > 65; p = .001) and more often considered leaving academic medicine within five years (58% versus < 45%). CONCLUSION: Given the demographic changes of the U.S. population, these issues should be addressed by deans and department heads in order to enhance recruitment and facilitate retention of URM faculty in academic medicine.

Data Collection↗

Ischemic brain damage in mice after selectively modifying BDNF or NT4 gene expression.

The neurotrophins and the tyrosine kinase (Trk) B receptor may play a protective role in the pathophysiology of cerebral ischemia. In this study, the authors investigated whether reducing endogenous expression of TrkB-binding neurotrophins modifies the susceptibility to ischemic injury after 1-hour middle cerebral artery occlusion followed by 23 hours of reperfusion in a filament middle cerebral artery occlusion model. Mice lacking both alleles for neurotrophin-4 (nt4-/-) or deficient in a single allele for brain-derived neurotrophic factor (bdnf+/-) exhibited larger cerebral infarcts compared to wild-type inbred 129/SVjae mice (68% and 91%, respectively, compared to controls). Moreover, lesions were larger (21%) in nt4-/- mice after permanent middle cerebral artery occlusion. Hence, expression of both NT4 and BDNF, and by inference the TrkB receptor, confers resistance to ischemic injury.

Animals↗

Evidence for apoptosis after intercerebral hemorrhage in rat striatum.

The overall hypothesis that cell death after intracerebral hemorrhage is mediated in part by apoptotic mechanisms was tested. Intracerebral hemorrhage was induced in rats using stereotactic infusions of 0.5 U of collagenase (1-microL volume) into the striatum. After 24 hours, large numbers of TUNEL-positive stained cells with morphologies suggestive of apoptosis were present in the center and periphery of the hemorrhage. Double staining with Nissl and immunocytochemical labeling with antibodies against neuronal nuclei and glial fibrillary acidic protein suggested that these TUNEL-positive cells were mostly neurons and astrocytes. Electrophoresis of hemorrhagic brain extracts showed evidence of DNA laddering into approximately 200-bp fragments. Western blots showed cleavage of the cytosolic caspase substrate gelsolin. The density of TUNEL-positive cells at 24 and 48 hours after hemorrhage was significantly reduced by treatment with the broad-spectrum caspase inhibitor zVADfmk. It was unlikely that apoptotic changes were due to neurotoxicity of injected collagenase because TUNEL-positive cells and DNA laddering were also obtained in an alternative model of hemorrhage where autologous blood was infused into the striatum. Furthermore, equivalent doses of collagenase did not induce cell death in primary neuronal cultures. These results provide initial evidence that apoptotic mechanisms may mediate some of the injury in brain after intracerebral hemorrhage.

Amino Acid Chloromethyl Ketones↗