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Biomedical subjects

S Goldstein

Publications and source records attributed to S Goldstein.

At least 739 records · Page 41Linked to original sources
PubMedDate not supplied

Progression of heart failure: a role for interstitial fibrosis.

Progressive deterioration of left ventricular (LV) function is a characteristic feature of the heart failure (HF) state. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known but may be related to progressive intrinsic dysfunction, degeneration and loss of viable cardiocytes. In the present study, we tested the hypothesis that accumulation of collagen in the cardiac interstitium (reactive interstitial fibrosis, RIF), known to occur in HF, results in reduced capillary density (CD = capillary/fiber ratio) and increased oxygen diffusion distance (ODD) which can lead to hypoxia and dysfunction of the collagen encircled myocyte. Studies were performed in LV tissue obtained from 10 dogs with chronic HF (LV ejection fraction 26 +/- 1%) produced by multiple sequential intracoronary microembolizations. In each dog, CD and ODD were evaluated in LV regions that manifested severe RIF (volume fraction 16 +/- 2%) and in LV regions of little or no RIF (volume fraction 4 +/- 1%). In regions of severe RIF, CD was significantly decreased compared to regions of no RIF (0.92 +/- 0.02 vs. 1.05 +/- 0.03) (P < 0.003). Similarly, ODD was significantly increased in regions of severe RIF compared to regions of no RIF (15.3 +/- 0.4 vs. 12.2 +/- 0.3 microns) (P < 0.001). These data suggest that in dogs with chronic HF, constituent myocytes of LV regions which manifest severe RIF may be subjected to chronic hypoxia; a condition that can adversely impact the function and viability of the collagen encircled cardiocyte.

Animals↗
PubMedDate not supplied

Comparison of the serum low density lipoprotein and of its apoprotein in the pig, rhesus monkey and baboon with that in man.

The principal form of the serum low density lipoprotein (LDL) in man, baboon, rhesus monkey and pig was isolated by preparative ultracentrifugation in the density interval 1.024-1.045 g/ml. The physicochemical characteristics of pig LDL most closely resembled those of man; thus, electrophoretic studies suggested that both baboon and rhesus LDL have a greater surface charge than that of their human counterpart, and electron-microscopic investigations showed baboon LDL (245 A) to be larger and rhesus LDL (205 A) smaller than those of man (217 A) and pig (228 A). In contrast, the immunological relationship between LDL from the two Old World monkeys and that of man was much closer (80-85% cross-reactivity by micro-immunoprecipitation) than that between pig and man (35% cross-reactivity). The principal difference between pig and human LDL appeared to reside in their protein and carbohydrate moieties. There was a marked resemblance between the protein moieties (apo-LDL) of LDL from the four species. The principal component of each animal apo-LDL was separated by gel-filtration chromatography and amounted to greater than 95% of the total protein; it exhibited a high molecular weight (greater than 250,000) upon SDS-polyacrylamide-gel electrophoresis and was indistinguishable from human apolipoprotein B in amino acid composition. Differences both between the apo-LDL and between the apo-B preparations from the four species, however, were detectable by immunological procedures. Such studies revealed inter-species relationships which were essentially the same as those observed between the respective native LDL preparations. The soluble apolipoproteins, present as minor components (less than 5%) of each apo-LDL, were compared by their electrophoretic mobility in polyacrylamide gel; the pattern seen in baboon and rhesus apo-LDL appeared to be most closely akin to that typical of their human counterpart. It is apparent that many characteristics typical of human serum LDL are found in those of the pig, rhesus monkey and baboon. Moreover, in view of the striking relationship existing between the immunological properties and apo-protein components of the LDL of the two Old World monkeys and that of man, these subhuman primates appear to be highly suitable as animal models for experimental atherosclerosis.

Amino Acids↗
PubMedDate not supplied

The role of antiplatelet therapy in acute coronary syndromes and for secondary prevention following a myocardial infarction.

Acute Coronary Syndromes: Therapy with aspirin is recommended for all patients with acute myocardial ischemic syndromes unless contraindications for its use is present. None of the studies thus far have conclusively established evidence for a selective dose of aspirin. Until conclusive evidence exists, aspirin in doses of 81 mg (children's tablet) to 325 mg (adult tablet) are recommended. Ticlopidine may prove to be an attractive alternate choice in those who cannot take aspirin. According to the ACC/AHA task force recommendations, patients with acute myocardial infarction receiving thrombolytic therapy should receive both heparin and aspirin. Aspirin is to be administered in a dose of 160 mg daily. Heparin can be discontinued after 2 days if the patient's clinical course remains uncomplicated. Aspirin should be continued indefinitely. An alternative strategy in those who cannot take aspirin is to switch to warfarin before hospital discharge with a view toward long-term anticoagulant therapy. Secondary Prevention: Aspirin in a dose of 325 mg daily is recommended for all survivors of an acute myocardial infarction. No benefit derives from the addition of dipyridamole. The role of sulfinpyrazone remains undefined. Warfarin is an effective antithrombotic alternative to aspirin for secondary prevention after a myocardial infarction. However, aspirin is cheaper to administer and follow up when compared with warfarin. From available information, aspirin appears to be an adequate antithrombotic agent in patients who have near-normal left-ventricular function, the elderly, patients with coexisting cerebrovascular or peripheral vascular disease, and those with contraindications for anticoagulants. Warfarin should be preferred in high-risk patients with anterior or apical myocardial infarction, left-ventricular dysfunction with or without a mural thrombus, and those with associated atrial fibrillation. A randomized study assessing aspirin versus warfarin for secondary prevention after myocardial infarction is being initiated to determine the relative efficacy and safety of these drugs in secondary prevention after myocardial infarction.

Angina, Unstable↗
PubMedDate not supplied

Decreased proteolysis and increased amino acid efflux in aging human fibroblasts.

The release of radioactivity was measured following variable times of dual labeling of normal human fibroblasts at early and late passage and late-passage cell strains derived from the progeria and Werner's syndrome of premature aging. In the rapid first phase to 20 min, all 3 late-passage (aged) cells released more acid-soluble radioactivity into the medium than early-passage normal cells in the order Werner's greater than progeria greater than late-passage normal greater than early-passage normal, virtually all of this radioactivity emanating from intracellular material that was acid-soluble after prelabeling (zero time). In the slower second phase from 20 min to 3 h, all 4 cell types showed approximately parallel profiles of release. Following preloading with the non-utilizable amino acid alpha-amino[14C] isobutyric acid, progeria and Werner's cells released radioactivity more rapidly than did early- and late-passage normal cells in that order. In contrast, direct measurements on the net loss of counts from acid-insoluble material, i.e. true proteolysis, revealed that all 3 aged cells degraded proteins of short half-life more slowly but proteins of long half-life were degraded at the same rate as those of young normal cells. The results indicate that aged cells have a reduced proteolytic capacity and increased amino acid efflux. The latter process is probably due to the higher proportion of labeled amino acids in the cell water of aged cells at zero time and possibly increased membrane leakiness. The reason for the decreased proteolysis is not clear but it may relate to the rising proportion of defective proteins, the increased protein content and the loss of replicative capacity in aging cells.

Aging↗
PubMedDate not supplied

Macromolecular synthesis in human fibroblasts at 37 degrees and 42 degrees C during aging in vitro.

A normal strain of human skin fibroblasts was pulse labelled at 42 degrees and 37 degrees C during intervals of the in vitro lifespan with 3H-thymidine, 3H-uridine and 14C-phenylalanine, precursors of DNA, RNA and protein synthesis, respectively. No increased heat lability could be detected in the relative profiles of precursor incorporation at the two temperatures until terminal stages of passage when a minor increase in heat lability appeared in RNA and protein synthesis. Early passage cells, grown in the presence of the substrate analogues, p-fluorophenylalanine or 5-fluorouracil, showed a moderate increase in relative heat lability but comparable patterns were not evident in drug-free cultures, even at terminal stages of passage. Although the results indicate that defects exist in enzyme pathways for macromolecular synthesis at terminal stages of growth and in the presence of analogues, they do not support the hypothesis that such defects are causal to the onset of cellular aging in vitro.

Adult↗
PubMedDate not supplied

Characterization of specific low-density lipoprotein binding sites in human term placental microvillous membranes.

Purified microvillous membranes prepared from normal term human placenta were studied for their ability to bind specifically low-density lipoprotein (LDL). Electron microscopic examination of the membrane preparations revealed essentially microvilli-like structures, and the enzyme analyses a 14-17-fold enrichment in the membrane markers 5'-nucleotidase and alkaline phosphatase. The binding of [125I]LDL was dependent on time, temperature, pH and protein concentration; it was saturable with a low capacity (130.4 +/- 22.2 ng/mg of membrane protein) and presented a high affinity (apparent Ka 6.12 +/- 1.32 micrograms protein per ml). These high-affinity binding sites were specific for LDL (high-density lipoprotein induced less competition than unlabelled LDL) and were sensitive to pronase digestion. Unlike the binding of LDL to other tissues, the [125I]LDL binding to microvillous membranes did not require divalent cations. The presence of specific LDL receptors on the placental microvillous membranes, located at the effective site of exchange between the maternal blood and the placental tissue, supports the concept that human placenta utilizes LDL-cholesterol for its progesterone synthesis.

Female↗
PubMedDate not supplied

Insulin-like growth factor binding protein-3 is overexpressed in senescent and quiescent human fibroblasts.

Cellular insulin-like growth factor binding protein-3 (IGFBP-3) mRNA and IGFBP-3 levels in conditioned medium were consistently higher in cultures of late passage normal (old) fibroblasts and prematurely senescent fibroblasts derived from Werner syndrome (WS) during quiescence induced by serum depletion and during the renewed growth ensuing after serum repletion, compared to cultures of early passage normal (young) fibroblasts. Molar ratios of IGFBP-3/IGF-II were always higher in senescent cultures and maintained a hierarchy of old > WS > young human diploid fibroblasts. Transfection into fibroblasts of the normal full-length IGFBP-3 cDNA in an expression vector resulted in a significant reduction in colony formation compared to cells transfected with an empty expression vector (no cDNA) or with IGFBP-3 cDNA altered by a 273 base pair (bp) deletion. Addition to old and young cultures of recombinant human IGFBP-3 and IGF-I at 1:1 or 5:1 molar ratios inhibited IGF-I-mediated DNA synthesis by approximately 70-80%. These data indicate that IGFBP-3 may play an important role in the quiescent and senescent growth arrest of HDF.

Aging↗
PubMedDate not supplied

Screening for genetic predisposition to mutagens in cancer patients.

Both genetic and environmental factors are known to play an important role in the development of cancer. To determine whether, among individuals who develop cancers, some may have been more susceptible to the mutagenic effects of environmental agents, skin biopsies were taken from 79 cancer patients with different common types of cancers (e.g., lung, breast, bladder, colon, cervix, ovary, brain, vocal cord, uterus, skin, testis, stomach, basal cell carcinoma, leukemia, etc.). Fibroblast cultures have been established from skin explants from nearly all of the patients. The sensitivity of some of these cells as well as a number of other fibroblast strains established from "clinically normal" individuals to a battery of mutagenic agents (e.g., ethylmethane sulfonate, methylmethane sulfonate, ethidium bromide, actinomycin D, mitomycin C, bleomycin, camptothecin), which induce different kinds of DNA damage was examined. For the control group of fibroblasts, a normal range of toxicity for all of the above agents have been established. In contrast to other mutagens for which sensitivity of all of the control cell strains lay within a narrow range, large and interesting differences in sensitivity were observed for ethidium bromide. The fibroblast strains established from fetal tissue were found to be highly resistant to ethidium bromide, whereas fibroblasts from two clinically normal persons exhibited greatly enhanced sensitivity to this agent. The genetic or biochemical basis of increased sensitivity or resistance to ethidium bromide remains to be determined. The sensitivity of cells from 28 cancer patients to a number of the mutagenic agents was also examined. Most of these strains exhibited normal range of sensitivity to the mutagens; however, a few showed small but noticeable differences in sensitivity to specific agents. The fibroblast strains from cancer patients provide a useful resource to examine the genetic and metabolic factors that may be important determinants in cancer susceptibility.

Adolescent↗
PubMedDate not supplied

Identification of gene sequences overexpressed in senescent and Werner syndrome human fibroblasts.

The phenotype of replicative senescence is a dominant trait in human diploid fibroblasts (HDF). Therefore, we have sought to identify overexpressed and/or newly expressed causal genes by constructing and screening a subtracted cDNA library derived from polyA+RNA of prematurely senescent Werner syndrome (WS) HDF. We have identified 15 cDNA clones that are overexpressed in senescent and WS HDF. Among them are six known sequences coding for: acid sphingomyelinase, fibronectin, SPARC, nm23-metastasis suppressor protein, and two translation factors, eIF-2 beta and EF-1 alpha. Among the 10 unknown clones are: S1-5, which encodes a secreted protein containing EGF-like domains and paradoxically stimulates DNA synthesis of young HDF in an autocrine and paracrine manner, S1-3, which encodes a protein containing "zinc finger" domains, suggesting nucleic acid binding properties; S1-15, which shows sequence similarities to human alpha 2-chimerin; and S2-6, which represents a new member of the LIM family of proteins. The other five clones do not have any significant homology to known sequences. Steady-state mRNA levels of all gene sequences thus far studied are elevated in both WS and senescent normal HDF when compared to young HDF, which suggests that senescent and WS HDF enter a final common pathway where multiple gene overexpression may generate diverse antiproliferative mechanisms and pathogenic sequelae.

Adult↗
PubMedDate not supplied

Expression of senescence-induced protein WS3-10 in vivo and in vitro.

In our efforts to characterize cellular senescence we have shown that the mRNA encoding WS3-10 protein is overexpressed in senescent human diploid fibroblasts (HDF) when compared with their younger counterparts, and that forced expression of the WS3-10 cDNA in young HDF results in suppression of calcium-dependent membrane currents, presumably due in part to the presence of a calcium binding domain within the WS3-10 protein. We have now expressed this protein in E. coli and have obtained affinity purified antibodies. Western blot analysis utilizing these antibodies showed that WS3-10 protein is also overexpressed in senescent HDF when compared to young HDF, and in normal fetal lung HDF when compared to SV40-transformed fetal lung HDF. HeLa cells do not express WS3-10 protein. In addition, we looked for WS3-10-related species in a variety of rat tissues. Analysis of WS3-10 immunologically related proteins in rat tissue extracts revealed two WS3-10 homologs, sized 22 kDa and 20 kDa. The latter presumably result from proteolytic removal of the C-terminal end of the 22 kDa polypeptide. The ratio between these polypeptides varies in a tissue-specific manner. Two proteins immunologically related to WS3-10 with sizes of 39 kDa and 91 kDa were present in rat spleen and skeletal muscle, respectively.

Actins↗