Laser capture microdissection: molecular analysis of tissue.
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Cell Separation↗
Biomedical subjects
S Goldstein
Publications and source records attributed to S Goldstein.
Clinical studies on beta blockers and heart failure preceding the MERIT-HF Trial. Metoprolol CR/XL Randomized Intervention Trial in Heart Failure.
With greater understanding of the impact of neuroendocrine stimulation on the adverse outcomes of heart failure, especially lethal arrhythmias and sudden cardiac death, focus has returned to the potential benefits of beta-adrenergic blockade. In patients with myocardial infarction and left ventricular (LV) dysfunction, particularly those prone to life-threatening arrhythmias, beta-blocker therapy has been associated with a lower incidence of arrhythmias and improved survival. Even in the absence of angiotensin-converting enzyme (ACE) inhibition, beta blockade has improved cardiac function and LV contractility in nonischemic heart failure, leading to a decrease in LV end-diastolic pressure and improved clinical status. Both the Metoprolol in Dilated Cardiomyopathy (MDC) trial and the Cardiac Insufficiency Bisoprolol Study (CIBIS) found beta blockade to be associated with decreased mortality rates in patients with nonischemic heart failure. Of the 3 large randomized mortality trials now under way, the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) is specifically designed to investigate the effects of beta blockade on total mortality when used as an adjunct to ACE inhibition in patients with ischemic or nonischemic heart failure. Unresolved issues to be addressed include whether: (1) beta-blocker therapy in heart failure can improve survival and/or reduce the incidence of sudden cardiac death; (2) beta blockade is equally effective in ischemic and nonischemic heart failure; (3) any specific beta blocker may be better tolerated initially and cause fewer adverse effects; and (4) all beta blockers result in improved exercise tolerance and quality of life.
Adrenergic beta-Antagonists↗
Immunohistochemical studies on Waf1p21, p16, pRb and p53 in human esophageal carcinomas and neighboring epithelia from a high-risk area in northern China.
To better understand the roles of p53 and cell cycle-regulating protein alterations in human esophageal carcinogenesis, we investigated immunohistochemically the distribution patterns of Waf1p21, pRb, p16 and p53 in 22 cases of surgically resected esophageal cancer as well as in the neighboring non-cancerous squamous epithelia. Waf1p21 protein was detected in 13 of the 20 cases of well-differentiated squamous-cell carcinoma (SCC), where the Waf1p21-positive cells were located mainly in the interior layers of the cancer nests. Conversely, p53-positive cells were found mostly in the peripheral layers. Cells containing both Waf1p21- and p53-positive immunostaining were not observed in a double-immunostaining experiment. p16 was detected in both the nucleus and cytoplasm in 3 of the 22 cases of SCC. All of these p16-positive cancers showed an absence of pRb immunostaining; this result is consistent with the idea that expression of p16 is regulated negatively by pRb. Eleven of the 22 esophageal SCCs (50%) showed extensive pRb immunostaining cells, and the remaining 11 cases displayed a few pRb-positive cells or an absence of pRb immunostaining. In a majority of the morphologically normal squamous-cell epithelia samples, immunostaining of Waf1p21 and pRb was found in most of the cells in the parabasal layers (proliferation compartment), where PCNA-positive cells also resided. In the pre-cancerous lesions, Waf1p21 and pRb were detected in cells surrounding the top of the lesioned region, p16-positive cells were scattered in the basal cell hyperplastic and dysplastic lesions and p53-positive cells existed in 2 distinct patterns: "scattered" and "focal".
Carcinoma, Squamous Cell↗
Abnormalities of cardiocytes in regions bordering fibrous scars of dogs with heart failure.
Progressive deterioration of left ventricular function is a characteristic feature of the heart failure state and is often speculated to result from ongoing loss of viable myocytes. We previously showed that in dogs with chronic heart failure, cardiocyte death through apoptosis occurs in the border region of fibrous scars (old infarcts). In the present study we examined the structural integrity of cardiocytes in regions bordering fibrous scars using transmission electron microscopy. Morphometric studies were performed using left ventricular tissue obtained from ten dogs with chronic heart failure produced by intracoronary microembolizations. Mitochondrial number increased significantly with proximity to the scar, while mitochondrial size decreased leading to a gradual decrease in mitochondrial volume fraction. Severe injury to mitochondria was present in only 5% of organelles in myocytes far from the scar but increased markedly to 28-41% in myocytes adjacent to or incorporated within the scar. Similarly, severe myofibrillar abnormalities were present in only 3% of myocytes that were far from the scar but increased significantly to 12-73% in myocytes adjacent to or incorporated within the scar. These results indicate that in dogs with chronic heart failure, constituent myocytes of left ventricular regions bordering fibrous scars manifest heterogeneity in the extent of degeneration. The extent of degeneration is greatest in myocytes closest to the scar and least in myocytes far from the scar. We postulate that this wavefront of myocyte degeneration is a dynamic process that may lead to progressive expansion of the scar through loss of viable myocytes and ultimately may contribute, in part, to the progressive left ventricular dysfunction that characterizes the heart failure state.
Animals↗
Regulation of a novel gene encoding a lysyl oxidase-related protein in cellular adhesion and senescence.
We report here a novel cDNA clone with a predicted protein sequence similar to lysyl oxidase. This full-length cDNA clone of 3432 base pairs (WS9-14) was isolated from human fibroblasts on the basis of its overexpression in senescent cells. It encodes an 87-kDa polypeptide, whose protein is a member of the scavenger receptor cysteine-rich family, because it contains four scavenger receptor cysteine-rich domains that are found in several secreted or cell surface proteins. The WS9-14 protein has a 48% identity with both lysyl oxidase and lysyl oxidase-like protein at a region corresponding to exons 2-6, implying the existence of a lysyl oxidase gene family. The pattern of WS9-14 gene expression by fibroblasts parallels pro-collagen I-alpha1 expression. Its mRNA level is induced by transforming growth factor beta-1 and indomethacin and inhibited by phorbol ester and retinoic acid. WS9-14 is abundantly expressed in all tumor cell lines examined that attach to culture dishes but not in cell lines that grow in suspension and is also up-regulated in senescent fibroblasts. These results suggest that WS9-14 gene encodes an extracellular protein that may be specifically involved in cell adhesion and senescence.
3T3 Cells↗
Acute reversibility of pulmonary hypertension predicts neither long-term hemodynamic response nor outcome in patients awaiting heart transplantation.
For transplant wait-list patients with end-stage congestive heart failure, reversibility of pulmonary hypertension tested with acute administration of vasodilators is a prerequisite to listing for transplantation. We have shown that the magnitude of the initial pulmonary vasodilatory response to nitroprusside predicts neither the extent of the long-term hemodynamic response nor the subsequent need for transplantation versus clinical improvement and removal from transplant consideration.
Antihypertensive Agents↗
Indirect oxidation of ferrocyanide by peroxynitrite--evidence against the formation of hydroxyl radicals.
Thermodynamic calculations by different assumptions for arriving to the standard entropy of the formation of peroxynitrite anion in water lead to opposite conclusions considering the feasibility of the homolysis of ONOOH to .OH and .NO2 (Koppenol et al. (1992). Chem. Res. Toxicol. 5, 834-832; Merenyi (1997). The First International Conference on the Chemistry and Biology of Peroxynitrite). Nevertheless, the formation of hydroxyl radicals is not guaranteed even if it is feasible on thermodynamic grounds. To test the role of hydroxyl radicals during the isomerization of ONOOH, the indirect oxidation of ferrocyanide by peroxynitrite was studied in the presence of formate ions and methanol, where all the relevant rate constants of the primary and secondary reactions involving hydroxyl radicals are known. The oxidation rates were unaffected by these scavengers, while the decrease in the oxidation yields was not correlated with the known rate constants of these scavengers with hydroxyl radicals. It is concluded that the indirect oxidation of ferrocyanide by peroxynitrite takes place through an unidentified intermediate (ONOOH*), which is not a cage of .OH and .NO2.
Air↗
Effects of warfarin on markers of hypercoagulability in patients with heart failure.
Heart failure is associated with a hypercoagulable state. A single-center, randomized, double-blind, placebo-controlled trial was performed to test the hypothesis that warfarin will modify a hypercoagulable state in heart failure. This study included 76 patients with heart failure. At baseline, patients had evidence for a hypercoagulable state with elevated plasma levels of thrombin/antithrombin III (TAT) complexes (3.4 +/- 2.0 ng/ml), prothrombin fragment F1 + 2 (1.5 +/- 0.9 nmol/L), and D-dimers (630 +/- 401 ng/ml). Warfarin therapy (international normalized ratio [INR] 2.7 +/- 1.3) significantly decreased plasma levels of TAT complexes (p < 0.002), F1 + 2 (p < 0.001), and D-dimers (p < 0.001) when compared with baseline values at 1, 2, and 3 months of therapy. In contrast, patients receiving placebo had persistent elevation of TAT complexes (p = not significant [NS]), F1 + 2 (p = NS), and D-dimers (p = NS) during follow-up at 1, 2, and 3 months. The two treatment groups followed different trends over time for all three markers (p < 0.001). The effect of low-intensity warfarin (INR 1.3 +/- 0.08) versus moderate-intensity warfarin (INR 2.3 +/- 1.1 ) on markers of hypercoagulability was evaluated in 14 patients. When compared with baseline, low-intensity warfarin administration decreased plasma levels of TAT complexes (p = NS), F1 + 2 (p = 0.05), and D-dimers (p = 0.04). In these patients F1 + 2 was further reduced with moderate-intensity warfarin (p < 0.001). Our findings suggest that a hypercoagulable state in heart failure can be modified by warfarin therapy.
Adult↗
Impact of carvedilol on mortality and cardiovascular morbidity in patients with chronic heart failure.
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Journal Article↗
Beta-blocking drugs and coronary heart disease.
Since the development of beta-adrenergic blocking agents over 30 years ago, they have been established as an important therapeutic modality in the treatment of coronary heart disease. This article reviews the role of beta-blockers in the treatment of hypertension, angina, acute myocardial infarction, and heart failure. A number of multicenter studies indicate that beta-blockers have an important effect in decreasing morbidity and mortality in patients with hypertension and appear to have a relatively increased importance in elderly patients with hypertension. Although their long-term effects on the mortality of angina pectoris have not been fully investigated, investigations indicate that, compared with other drugs, beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris. The largest use of these drugs has been examined in the treatment of acute myocardial infarction. Two major trials, the Norwegian Timolol Trial and the Beta Blocker Heart Attack Trial, confirm the long-term benefit in patients following acute myocardial infarction. Their use in heart failure is under close investigation following a series of preliminary studies suggesting they may decrease mortality risk. Although the tolerability of these drugs has been questioned, careful examination of clinical trials indicate that they are relatively well tolerated. These observations emphasize the importance of beta-adrenergic blocking agents in hypertension, angina, and acute myocardial infarction and speak to a wider clinical use of these drugs.
Adrenergic beta-Antagonists↗
Human CD4+ cells transfected with IL-16 cDNA are resistant to HIV-1 infection: inhibition of mRNA expression.
Interleukin-16 (IL-16) is secreted by activated CD8+ T lymphocytes and acts on CD4+ T lymphocytes, monocytes and eosinophils. Recently, the C-terminal 130-amino acid portion of IL-16 was shown to suppress HIV-1 replication in vitro. To explore the potential of human IL-16 for gene therapy, this portion was transfected into HIV-1-susceptible CD4+ jurkat cells by means of a mammalian expression vector. The stable transfectants synthesized and secreted IL-16 protein. The expression of IL-16 did not alter growth rate and CD4 expression; however, HIV replication was inhibited by as much as 99%. Furthermore, during the initial phase of the infection, equal amounts of HIV-1 proviral DNA were found in cells transfected with IL-16 and with vector alone. In contrast, the 2-kilobase HIV-1 transcripts were markedly reduced and the 4-kb and 9-kb transcripts were undetectable in the cells transfected with IL-16. These findings indicate that IL-16-mediated inhibition of HIV-1 is not at the level of viral entry or reverse transcription, but at messenger RNA expression.
Blotting, Northern↗
Girls with ADHD.
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Attention Deficit Disorder with Hyperactivity↗
The extent of early viral replication is a critical determinant of the natural history of simian immunodeficiency virus infection.
Different patterns of viral replication correlate with the natural history of disease progression in humans and macaques infected with human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), respectively. However, the viral and host factors influencing these patterns of viral replication in vivo are poorly understood. We intensively studied viral replication in macaques receiving identical inocula of SIV. Marked differences in viral replication patterns were apparent within the first week following inoculation, a time prior to the development of measurable specific immune effector responses to viral antigens. Plasma viral RNA levels measured on day 7 postinoculation correlated with levels measured in the postacute phase of infection. Differences in the susceptibility of host cells from different animals to in vitro SIV infection correlated with the permissiveness of the animals for early in vivo viral replication and hence with the postacute set point level of plasma viremia. These results suggest that host factors that exert their effects prior to full development of specific immune responses are critical in establishing the in vivo viral replication pattern and associated clinical course in subjects infected with SIV and, by extension, with HIV-1.
Animals↗
A molecularly cloned, pathogenic, neutralization-resistant simian immunodeficiency virus, SIVsmE543-3.
An infectious molecular clone of simian immunodeficiency virus SIVsm was derived from a biological isolate obtained late in disease from an immunodeficient rhesus macaque (E543) with SIV-induced encephalitis. The molecularly cloned virus, SIVsmE543-3, replicated well in macaque peripheral blood mononuclear cells and monocyte-derived macrophages and resisted neutralization by heterologous sera which broadly neutralized genetically diverse SIV variants in vitro. SIVsmE543-3 was infectious and induced AIDS when inoculated intravenously into pig-tailed macaques (Macaca nemestrina). Two of four infected macaques developed no measurable SIV-specific antibody and succumbed to a wasting syndrome and SIV-induced meningoencephalitis by 14 and 33 weeks postinfection. The other two macaques developed antibodies reactive in Western blot and virus neutralization assays. One macaque was sacrificed at 1 year postinoculation, and the survivor has evidence of immunodeficiency, characterized by persistently low CD4 lymphocyte subsets in the peripheral blood. Plasma samples from these latter animals neutralized SIVsmE543-3 but with much lower efficiency than neutralization of other related SIV strains, confirming the difficulty by which this molecularly cloned virus is neutralized in vitro. SIVsmE543-3 will provide a valuable reagent for studying SIV-induced encephalitis, mapping determinants of neutralization, and determining the in vivo significance of resistance to neutralization in vitro.
Amino Acid Sequence↗
Bacteraemia during direct laryngoscopy and endotracheal intubation: a study using a multiple culture, large volume technique.
Bacteraemia secondary to orotracheal intubation has been reported to occur in 0-5.3% of patients. Bacteraemia detection is dependent upon several factors including the volume of blood per culture and the number of cultures. Prior studies used small volumes of blood and one or two cultures, and may therefore have underestimated the incidence of bacteraemia. Sixty-two adult patients who underwent direct laryngoscopy and endotracheal intubation were studied. Baseline blood cultures were sterile in all patients. After intubation, four blood cultures were obtained in ten minutes, with 10 ml being evenly divided between aerobic and anaerobic media. Two patients (3.2%) became bacteraemic. This is a lower incidence than occurs in association with other procedures for which The American Heart Association does not recommend administration of prophylactic antibiotics. Therefore, prophylactic antibiotics are not recommended prior to direct laryngoscopy. However, when a prophylactic antibiotic is administered prior to surgery, it would be best to administer the antibiotic prior to direct laryngoscopy and intubation.
Adult↗
Sudden cardiac death in ischemic heart disease.
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Adrenergic beta-Antagonists↗
Evaluating community radio as a medium for health messages in Alexandra.
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Adolescent↗
Migration, fertility, and state policy in Hubei Province, China.
Despite China's one-child family planning policy, the nation experienced a slight rise in the birth rate in the mid-1980s. Many observers attributed this rise to the heightened fertility of those rural-to-urban migrants who moved without a change in registration (temporary migrants), presumably to avoid the surveillance of family planning programs at origin and destination. Using a sequential logit analysis with life-history data from a 1988 survey of Hubei Province, we test this possibility by comparing nonmigrants, permanent migrants, and temporary migrants. While changing family planning policies have a strong impact on timing of first birth and on the likelihood of higher-order births, migrants generally do not have more children than nonmigrants. In fact, migration tends to lower the propensity to have a child. More specifically, the fertility of temporary migrants does not differ significantly from that of other women.
Adolescent↗