Biomedical subjects

M A Moskowitz

Publications and source records attributed to M A Moskowitz.

At least 55 records · Page 3Linked to original sources

PubMed2000

Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment.

Nitric oxide, a product of nitric oxide synthase activity, relaxes vascular smooth muscle and elevates brain blood flow. We evaluated the importance of eNOS to cerebral blood flow augmentation after L-arginine infusion and increases in flow after eNOS upregulation in SV-129 mice. Blood flow was measured by laser-Doppler flowmetry before and after L-arginine infusion (450 mg/kg during a 15-minute period) or measured by 14C-iodoamphetamine indicator fractionation or 14C-iodoantipyrine tissue equilibration techniques. rCBF increased by 26% (laser Doppler flowmetry) after L-arginine infusion but did not change in mutant mice deficient in eNOS expression. After eNOS upregulation by chronic simvastatin treatment (2 mg/kg subcutaneously, daily for 14 days), L-arginine amplified and sustained the hyperemia (38%) and increased absolute brain blood flow from 86 +/- 7 to 119 +/- 10 mL/100 g per minute. Furthermore, pretreatment with simvastatin enhanced blood flow within ischemic brain tissue after middle cerebral artery occlusion. Together, these findings suggest that eNOS activity is critical for blood flow augmentation during acute L-arginine infusion, and chronic eNOS upregulation combined with L-arginine administration provides a novel strategy to elevate cerebral blood flow in the normal and ischemic brain.

Animals↗

PubMed2000

Is all perfusion-weighted magnetic resonance imaging for stroke equal? The temporal evolution of multiple hemodynamic parameters after focal ischemia in rats correlated with evidence of infarction.

Although perfusion-weighted imaging techniques are increasingly used to study stroke, no particular hemodynamic variable has emerged as a standard marker for accumulated ischemic damage. To better characterize the hemodynamic signature of infarction. the authors have assessed the severity and temporal evolution of ischemic hemodynamics in a middle cerebral artery occlusion model in the rat. Cerebral blood flow (CBF) and total and microvascular cerebral blood volume (CBV) changes were measured with arterial spin labeling and steady-state susceptibility contrast magnetic resonance imaging (MRI), respectively, and analyzed in regions corresponding to infarcted and spared ipsilateral tissue, based on 2,3,5-triphenyltetrazolium chloride histology sections after 24 hours ischemia. Spin echo susceptibility contrast was used to measure microvascular-weighted CBV, which had a maximum sensitivity for vessels with radii between 4 and 30 microm. Serial measurements between 1 and 3 hours after occlusion showed no change in CBF (22 +/- 20% of contralateral, mean +/- SD) or in total CBV (78 +/- 13% of contralateral) in regions destined to infarct. However, microvascular CBV progressively declined from 72 +/- 5% to 64 +/- 11% (P < 0.01) during this same period. Microvascular CBV changes with time were entirely due to decreases in subcortical infarcted zones (from 73 +/- 9% to 57 +/- 14%. P < 0.001) without changes in the cortical infarcted territory. The hemodynamic variables showed differences in magnitude and temporal response, and these changes varied based on histologic outcome and brain architecture. Such factors should be considered when designing imaging studies for human stroke.

Animals↗

PubMed2000

The challenges of diagnosing erectile dysfunction in the primary care setting.

Erectile dysfunction is present in approximately half of all men between the ages of 40 and 70. Patients are often reluctant to discuss this problem with their practitioner; therefore, unless the practitioner is able to initiate the discussion, the diagnosis will not be made and successful treatment will not be started. Primary care practitioners have previously received little training in taking the sexual history of their patients. In addition, primary care practitioners are under increasing pressure to see more and more patients in less and less time. Erectile dysfunction is a condition that is relatively easy to diagnose using history, physical examination, and laboratory tests at the disposal of the primary care practitioner. Although referral to an urologist may be necessary, most patients can be successfully treated in the primary care setting.

Erectile Dysfunction↗

PubMed2000

Mammography use, breast cancer stage at diagnosis, and survival among older women.

BACKGROUND: Women age 65 years and older account for most newly diagnosed breast cancers and deaths from breast cancer. Yet, older women are least likely to undergo mammography, perhaps because mammography's value is less well demonstrated in older women. OBJECTIVE: To investigate the relationship between prior mammography use, cancer stage at diagnosis, and breast cancer mortality among older women with breast cancer. DESIGN: Retrospective cohort study using the Linked Medicare-Tumor Registry Database. SETTING: Population-based data from three geographic areas included in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. PARTICIPANTS: Women aged 67 and older diagnosed with a first primary breast cancer, from 1987 to 1993, residing in Connecticut, metropolitan Atlanta, Georgia, or Seattle-Puget Sound, Washington. MEASUREMENTS: Medicare claims were reviewed and women were classified according to their mammography use during the 2 years before diagnosis: nonusers (no prior mammograms), regular users (at least two mammograms at least 10 months apart), or peri-diagnosis users (only mammogram(s) within 3 months before diagnosis). Mammography utilization was linked with SEER data to determine stage at diagnosis and cause of death. Our main outcome variables were (1) stage at diagnosis, classified as early (in situ/Stage I) or late (Stage II or greater), and (2) breast cancer mortality, measured from diagnosis until death from breast cancer or end of the follow-up period (December 31, 1994). RESULTS: Older women who were nonusers of mammography were diagnosed with breast cancer at Stage II or greater more often than regular users (adjusted odds ratio (OR), 3.12; 95% confidence interval (CI), 2.74-3.58). This association was present within each age group studied. Nonusers of mammography were at significantly greater risk of dying from their breast cancer than regular users for all women (adjusted hazard ratio (HR), 3.38; 95% CI, 2.65-4.32) and for women within each age group. Even assuming a lead time of 1.25 years, nonusers of mammography continued to be at increased risk of dying from breast cancer. Our findings remained significant for all women and for the two youngest age groups (67-74 years, 75-85 years), although the benefit was no longer statistically significant for the oldest women (85 years and older). CONCLUSIONS: Older women who undergo regular mammography are diagnosed with an earlier stage of disease and are less likely to die from their disease. These data support the use of regular mammography in older women and suggest that mammography can reduce breast cancer mortality in older women, even for women age 85 and older.

Aged↗

PubMed2000

Gender differences in the treatment of cerebrovascular disease.

OBJECTIVE: Previous studies have shown that women receive fewer invasive procedures for the treatment of coronary artery disease than men, but gender differences in cerebrovascular disease have not been well studied. Our objective was to explore differences in the treatment of stroke between men and women. DESIGN: Secondary database analyses. STUDY PARTICIPANTS: We examined the use of carotid endarterectomy in a nationally representative sample of Medicare enrollees aged 65 to 84, hospitalized for a principal diagnosis of stroke in 1992, the "all strokes group". We also studied a subgroup of patients, the "carotid disease subgroup", admitted with a principal diagnosis of precerebral arterial occlusion and stenosis or transient cerebral ischemia. MEASUREMENTS: We determined rates of carotid endarterectomy for the all strokes group within gender and age groups and calculated corresponding female-to-male relative risks (RR) and 95% confidence intervals (CI). We also performed similar analyses for the carotid disease subgroup. We then used logistic regression to estimate the relative risk of use of carotid endarterectomy for women, controlling for age and comorbidity. RESULTS: The all-strokes group consisted of 3,356 women and 2,927 men, of whom 1,009 women and 990 men were in the carotid disease subgroup. The overall age-adjusted female-to-male relative risk of undergoing carotid endarterectomy for those aged 65 to 84 was 0.69 (95% CI, 0.64-0.74) in the all strokes group and 0.77 (95% CI, 0.72-0.82) in the carotid disease subgroup. In both analyses, the RR became more pronounced with increasing age. In the all strokes group, for example, the RR was 0.80 (0.70-0.92) for those aged 65 to 69 and 0.39 (0.32-0.48) for those aged 80 to 84. The RR for the all strokes group remained similar in magnitude even after controlling for comorbidity (RR, 0.63 and 95% CI, 0.59-0.70). CONCLUSION: We conclude that women hospitalized for strokes undergo fewer carotid endarterectomies than men. Further studies are needed to examine the reasons for and implications of this gender difference.

Aged↗

PubMed2000

Spinal cord ischemia. Development of a model in the mouse.

BACKGROUND AND PURPOSE: Spinal cord ischemia with resulting paraplegia is a devastating complication of thoracoabdominal aortic surgery. Experimental models of spinal cord ischemia have been developed in primate, dog, pig, rabbit, and rat with variable reproducibility, but none has been developed in mouse. Because genetically engineered mice have become important to examine the impact of specific genes in ischemic pathophysiology, we sought to develop a reproducible mouse model of spinal cord ischemia. METHODS: C57BL/6NCrlBR mice were subjected to cross-clamping of the aortic arch, left subclavian artery, and internal mammary artery for 9 minutes (group A; n=8) or 11 minutes (group B; n=29) followed by reperfusion for 24 or 48 hours. Mean distal arterial blood pressure (left femoral artery) and lumbar (L1) spinal cord blood flow (laser-Doppler flowmetry) were measured for the duration of the procedure. The arterial blood supply of the spinal cord was visualized by intravascular perfusion of carbon black ink. We evaluated motor function in the hind limbs at 0, 1, 3, 6, and 24 hours after reperfusion using a rating scale of 0 (normal function) to 6 (total absence of movement). Spinal cord histopathology was evaluated after 24 and 48 hours of reperfusion by Luxol fast blue-hematoxylin and eosin. RESULTS: The vascular anatomy of the mouse and human spinal cord appeared similar in that blood was supplied by 1 anterior and 2 posterior spinal arteries and heterosegmental radicular arteries. During combined occlusion of aortic arch and left subclavian artery, mean distal arterial blood pressure dropped to 10+/-5 mm Hg, and spinal cord blood flow at the L1 level decreased to 27+/-7% of baseline. All animals recovered from anesthesia with acute paraplegia. Animals in the 9-minute group (group A) showed steady recovery of hind limb function over the ensuing 24 hours, whereas the majority (80%) in the 11-minute group (group B) remained paralyzed with maximum deficit throughout the postoperative period. Mortality was 0% and 21% in groups A and B, respectively. Maximal ischemic damage was observed at the lower thoracic and higher lumbar spinal levels in both groups. In group A (9 minutes), tissue damage was mild, affecting predominantly dorsal horns and intermediate gray matter, whereas ventral horns were minimally involved. All mice in group B (11 minutes) showed extensive gray matter lesions particularly involving dorsal horns and intermediate areas; in ventral horns, >50% of motor neurons died. White matter lesions were present in the most severely damaged cords only. CONCLUSIONS: Spinal cord ischemia caused by aortic arch plus left subclavian artery cross-clamping provides a mouse model useful for the study of spinal cord injury and of potential relevance to the complications following thoracoabdominal aortic surgery in humans.

Animals↗

PubMed2000

Neuroprotection mediated by changes in the endothelial actin cytoskeleton.

Cerebral blood flow is regulated by endothelium-derived nitric oxide (NO), and endothelial NO synthase-deficient (eNOS-deficient; eNOS(-/-)) mice develop larger cerebral infarctions following middle cerebral artery (MCA) occlusion. We report that disruption of Rho-mediated endothelial actin cytoskeleton leads to the upregulation of eNOS expression and reduces the severity of cerebral ischemia following MCA occlusion. Mice treated with the Rho inhibitor Clostridium botulinum C3 transferase (10 microgram/d) or the actin cytoskeleton disrupter cytochalasin D (1 mg/kg) showed a two- to fourfold increase in vascular eNOS expression and activity. This increase in eNOS expression was not due to increases in eNOS gene transcription, but to prolongation of eNOS mRNA half-life from 10 +/- 3 hours to 24 +/- 4 hours. Indeed, endothelial cells overexpressing a dominant-negative Rho mutant (N19RhoA) exhibited decreased actin stress fiber formation and increased eNOS expression. Inhibition of vascular Rho guanosine-5'-triphosphate binding activity by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin increased cerebral blood flow to ischemic regions of the brain, and mice treated with simvastatin, C3 transferase, or cytochalasin D showed smaller cerebral infarctions following MCA occlusion. No neuroprotection was observed with these agents in eNOS(-/-) mice. These findings suggest that therapies which target the endothelial actin cytoskeleton may have beneficial effects in ischemic stroke.

Actins↗

PubMed2000

[New method for evaluating the effects of neuroprotective therapy in the hemodynamic penumbra].

Recently, we established a novel temporal correlation mapping (TCM) technique in combination with high-resolution functional computed tomography (CT) scanning to analyze the temporal changes in bolus transit dynamics of iodinated contrast agents in focal cerebral ischemia. Based on changes in the temporal dynamics of blood flow, we defined a new kind of penumbra and core in focal ischemia: the hemodynamic penumbra and hemodynamic core. We visualized for the first time a larger hemodynamic core and smaller hemodynamic penumbra in endothelial NOS knockout mice than in wild type mice early after focal ischemia by using the TCM analysis technique. In addition, neuroprotective effects of the water-soluble AMPA receptor antagonist YM872 were for the first time observed in the hemodynamic penumbra after focal ischemia. In conclusion, early TCM analysis could be used to directly and quantitatively evaluate the effects of neuroprotective therapy and the evolution of neuronal damage in the hemodynamic penumbra.

Animals↗

PubMed2000

Central and peripheral mechanisms of migraine.

Central (cortex and upper brainstem) and peripheral (trigeminovascular) mechanisms are involved in the pathophysiology of migraine. We propose that unknown migraine triggers initiate depolarization of cortical neurons followed concomitantly by a transient increase in blood flow. This transient hyperemia spreads at a rate of 3-6 mm/min followed by hypoperfusion which is more long-lasting. Through unknown mechanisms (probably chemical), we hypothesize that this wave activates or sensitizes trigeminovascular axons which is a consequence of neuropeptide release and neurogenic inflammation. Orthodromic conduction along trigeminovascular fibers transmits information centrally via the trigeminal caudalis and other brainstem nuclei to higher cortical structures for registration and modulation of nociceptive information.

Central Nervous System↗

PubMed2000

Experimental models of migraine.

Experimental models have been developed to study various aspects of migraine. Here we describe the most commonly used models--mostly animal models--which led to the development of a pathophysiological concept of migraine. We focus on activation studies of the trigeminovascular system, the sphenopalatine ganglion, the superior sagittal sinus, the dura mater as well as blood vessels. The most common consequences of activation are noted and include protein extravasation, neuropeptide release, rCBF and diameter changes, c-fos expression and electrical neuronal activity. In addition, we briefly summarize the results of cortical spreading depression studies, as they relate to the human migraine aura. These models will continue to be useful to elucidate migraine pathophysiology and explore drug mechanisms.

Animals↗

PubMed1999

A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice.

Extracellular adenosine critically modulates ischemic brain injury, at least in part through activation of the A(1) adenosine receptor. However, the role played by the A(2A) receptor has been obscured by intrinsic limitations of A(2A) adenosinergic agents. To overcome these pharmacological limitations, we explored the consequences of deleting the A(2A) adenosine receptor on brain damage after transient focal ischemia. Cerebral morphology, as well as vascular and physiological measures (before, during, and after ischemia) did not differ between A(2A) receptor knock-out and wild-type littermates. The volume of cerebral infarction, as well as the associated neurological deficit induced by transient filament occlusion of the middle cerebral artery, were significantly attenuated in A(2A) receptor knock-out mice. This neuroprotective phenotype of A(2A) receptor-deficient mice was observed in different genetic backgrounds, confirming A(2A) receptor disruption as its cause. Together with complimentary pharmacological studies, these data suggest that A(2A) receptors play a prominent role in the development of ischemic injury within brain and demonstrate the potential for anatomical and functional neuroprotection against stroke by A(2A) receptor antagonists.

Aging↗

PubMed1999

MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia.

The MEK1 (MAP kinase/ERK kinase)/ERK (extracellular-signal-responsive kinase) pathway has been implicated in cell growth and differentiation [Seger, R. & Krebs, E. G. (1995) FASEB J. 9, 726-735]. Here we show that the MEK/ERK pathway is activated during focal cerebral ischemia and may play a role in inducing damage. Treatment of mice 30 min before ischemia with the MEK1-specific inhibitor PD98059 [Alessi, D. R., Cuenda, A., Cohen, P. , Dudley, D. T. & Saltiel, A. R. (1995) J. Biol. Chem. 270, 27489-27494] reduces focal infarct volume at 22 hr after ischemia by 55% after transient occlusion of the middle cerebral artery. This is accompanied by a reduction in phospho-ERK1/2 immunohistochemical staining. MEK1 inhibition also results in reduced brain damage 72 hr after ischemia, with focal infarct volume reduced by 36%. This study indicates that the MEK1/ERK pathway contributes to brain injury during focal cerebral ischemia and that PD98059, a MEK1-specific antagonist, is a potent neuroprotective agent.

Animals↗

PubMed1999

Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage.

Nitric oxide (NO) is a new intercellular messenger that occurs naturally in the brain without causing overt toxicity. Yet, NO has been implicated as a mediator of cell death in cell death. One explanation is that ischemia causes overproduction of NO, allowing it to react with superoxide to form the potent oxidant peroxynitrite. To address this question, we used immunohistochemistry for citrulline, a marker for NO synthase activity, and 3-nitrotyrosine, a marker for peroxynitrite formation, in mice subjected to reversible middle cerebral artery occlusion. We show that ischemia triggers a marked augmentation in citrulline immunoreactivity but more so in the peri-infarct than the infarcted tissue. This increase is attributable to the activation of a large population (approximately 80%) of the neuronal isoform of NO synthase (nNOS) that is catalytically inactive during basal conditions, indicating a tight regulation of physiological NO production in the brain. In contrast, 3-nitrotyrosine immunoreactivity is restricted to the infarcted tissue and is not present in the peri-infarct tissue. In nNOS(Delta/Delta) mice, known to be protected against ischemia, no 3-nitrotyrosine immunoreactivity is detected. Our findings provide a cellular localization for nNOS activation in association with ischemic stroke and establish that NO is not likely a direct neurotoxin, whereas its conversion to peroxynitrite is associated with cell death.

Animals↗

PubMed1999

Both 5-HT1B and 5-HT1F receptors modulate c-fos expression within rat trigeminal nucleus caudalis.

A possible mechanism of action of antimigraine drugs such as sumatriptan is inhibition of the trigeminovascular pathway. Sumatriptan's effects might be mediated by 5-HT1B, 5-HT1D or 5-HT1F receptors. To establish the relative importance of these subtypes, we compared the effects of sumatriptan with those of a selective 5-HT1F receptor agonist (LY 344864) on c-fos protein expression in the trigeminal nucleus caudalis. c-fos expression was induced in urethane-anaesthetized rats by intracisternal capsaicin administration. Sumatriptan and LY 344864 decreased the number of capsaicin-induced c-fos-like immunoreactive cells within trigeminal nucleus caudalis (ID50 = 0.04 and 0.6 mg kg(-1)). The effect of sumatriptan, but not of LY 344864, was prevented by pretreatment with the antagonist SDZ 21-009, which displays high affinity for rat 5-HT1B receptors. LY 344864 appears to attenuate c-fos-like immunoreactivity via 5-HT1F receptors, while sumatriptan acts via 5-HT1B receptors. The fact that activation of 5-HT1F receptors is sufficient to modulate the activity of the trigeminal system suggests that this receptor may be a target for antimigraine drugs with improved safety profile.

Adrenergic beta-Antagonists↗

PubMed1999

Investigation of the early response to rat forepaw stimulation.

The role of relative cerebral blood volume (rCBV) in the early response of blood oxygenation level-dependent (BOLD) signal following sensory stimulation was assessed. Magnetic resonance imaging (MRI) measurements of rCBV and BOLD signal as a function of time (t) were compared with relative cerebral blood flow (rCBF) obtained by laser doppler flowmetry during a repeated epoch of rat forepaw stimulation in which 6 sec of electrical stimulation followed 54 sec of rest. rCBF(t) exceeded rCBV(t) in somatosensory cortex at all time points and reached a maximal increase (60%) during a 6 sec stimulation that was much higher than maximal rCBV (10%). An initial dip was not observed in BOLD signal, which showed a delay with respect to rCBF that was roughly consistent with the cerebral blood transit time.

Animals↗

PubMed1999

MRI measurement of the temporal evolution of relative CMRO(2) during rat forepaw stimulation.

This study reports the first measurement of the relative cerebral metabolic rate of oxygen utilization (rCMRO(2)) during functional brain activation with sufficient temporal resolution to address the dynamics of blood oxygen level-dependent (BOLD) MRI signal. During rat forepaw stimulation, rCMRO(2) was determined in somatosensory cortex at 3-sec intervals, using a model of BOLD signal and measurements of the change in BOLD transverse relaxation rate, the resting state BOLD transverse relaxation rate, relative cerebral blood flow (rCBF), and relative cerebral blood volume (rCBV). Average percentage changes from 10 to 30 sec after onset of forepaw stimulation for rCBF, rCBV, rCMRO(2), and BOLD relaxation rate were 62 +/- 16, 17 +/- 2, 19 +/- 17, and -26 +/- 12, respectively. A poststimulus undershoot in BOLD signal was quantitatively attributed to the temporal mismatch between changes in blood flow and volume, and not to the role of oxygen metabolism. Magn Reson Med 42:944-951, 1999.

Animals↗

PubMed1999

Caspases as treatment targets in stroke and neurodegenerative diseases.

Apoptosis is one of the most exciting and intensely investigated areas of biology and medicine today. Cysteine proteases called caspases serve as the executioners of apoptosis, a form of cell suicide. Hypoxic/ischemic cell death proceeds in part, by apoptosis, particularly within the periinfarct zone or ischemic penumbra. During ischemia, activated caspases dismantle the cell by cleaving multiple substrates including cytoskeletal proteins and enzymes essential for cell repair. Strategies that inhibit caspase activity block cell death in experimental models of mild ischemia, and preserve neurological function. The therapeutic window for caspase inhibition is substantially longer than for glutamate receptor antagonists, and treatment combinations with both classes of drugs decrease ischemic injury and expand the treatment window synergistically. Hence, the caspases are now recognized as novel therapeutic targets for central nervous system diseases in which cell death is prominent. This article will review the evidence and the potential importance of caspase inhibition to cerebral ischemia and briefly summarize an emerging body of data implicating caspases in cell death accompanying neurodegenerative disorders.

Apoptosis↗

PubMed1999

Does the survival advantage of nonwhite dialysis patients persist after case mix adjustment?

PURPOSE: Nonwhite dialysis patients survive longer than white patients; however, their clinical characteristics differ. We examined whether case mix differences explain the apparent survival advantage of nonwhite dialysis patients. SUBJECTS AND METHODS: We performed a prospective cohort study using data from the US Renal Data System Case Mix Severity Study that included 4,797 randomly selected dialysis patients 20 years of age and older who were followed up for up to 6 years. Demographic, comorbidity, laboratory, nutritional, and functional status data were obtained. Multivariable proportional hazards models adjusted for case mix differences between nonwhite and white dialysis patients. Additional analyses examined the effects of differences in transplantation rates, withdrawal from dialysis rates, and treatment modality selection. RESULTS: Unadjusted survival rates of black, Native American, and Asian or Pacific Islander dialysis patients were similar, and better than that for white dialysis patients. Relative to whites, the unadjusted relative risk (RR) for mortality among nonwhite patients was 0.64 (95% confidence interval [CI]: 0.58 to 0.70). Adjustment for case mix reduced, but did not eliminate, the survival advantage associated with nonwhite race (RR = 0.78, CI: 0.71 to 0.86). Adjustment for differences in transplantation rates (RR = 0.83, CI: 0.75 to 0.91), withdrawal from dialysis rates (RR = 0.81, CI: 0.73 to 0.90), and initial treatment modality (RR = 0.79, CI: 0.71 to 0.87) did not explain the lower mortality among nonwhites. CONCLUSIONS: A survival advantage for nonwhite dialysis patients persists after case mix adjustment. Future studies should explore additional physiologic and socioeconomic factors that might explain this difference.

Adult↗