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Biomedical subjects

J Schwartz

Publications and source records attributed to J Schwartz.

At least 199 records · Page 11Linked to original sources
PubMed1996

Short term effects of urban air pollution on respiratory health in Milan, Italy, 1980-89.

STUDY OBJECTIVE: To investigate the association between daily urban air pollution and acute effects on respiratory health. STUDY DESIGN: Time series analysis following the procedure defined in the APHEA protocol. SETTING: City of Milan, Italy, from 1980-89. Two air pollutants, total suspended particulates (TSP) and sulphur dioxide (SO2), and two health outcomes, deaths and hospital admissions were considered. The last was analysed according to two age groups. SUBJECTS: Daily deaths and general hospital admissions for respiratory causes in residents who died in Milan or were admitted to local hospitals in that city. MAIN RESULTS: There was an increased risk of respiratory death and of hospital admission associated with increased concentrations of SO2 and TSP. The relative risks were similar for both pollutants, and were higher for respiratory deaths than for hospital admissions. No changes in relation to season were seen in the SO2 effect on respiratory deaths, but there was a suggestion of a higher effect on hospital admissions in the cool months. The seasonal pattern of the TSP effect was inconsistent: for mortality it was higher in the warm period while for hospital admissions it seemed to be higher in the cool months. This last result might be due to chance, although some role could have been played by the hospital admission data on all general admissions for respiratory causes (ICD-9: 460-519) as these are a much less specific end point. CONCLUSION: In Milan, a positive association was found between the daily SO2 or TSP concentrations and the number of deaths or hospital admissions for respiratory causes. This confirms results from other European and North American cities.

Acute Disease↗
PubMed1996

Molecular mechanism of growth hormone action.

Although the ability of growth hormone (GH) to stimulate body growth and regulate metabolism has been recognized for many years, only recently has insight been gained into the molecular mechanisms by which binding of GH to its receptor (GHR) elicits its diverse effects. This review provides an overview of what is currently known about the molecular mechanisms of GH action. The model presented is one in which GH binding to two GHRs causes dimerization of GHR, activation of the GHR-associated JAK2 tyrosine kinase, and tyrosyl phosphorylation of both JAK2 and GHR. These events recruit and/or activate a variety of signaling molecules, including MAP kinases, insulin receptor substrates, phosphatidylinositol 3' phosphate kinase, diacylglycerol, protein kinase C, intracellular calcium, and Stat transcription factors. These signaling molecules contribute to the GH-induced changes in enzymatic activity, transport function, and gene expression that ultimately culminate in changes in growth and metabolism.

Animals↗
PubMed1996

The determinants of pulmonary diffusing capacity in a national sample of U.S. adults.

Racial and gender differences in single-breath pulmonary diffusing capacity for carbon monoxide (DLCO) have previously received little attention. Between 1971 and 1975, the first National Health and Nutrition Examination Survey determined DLCO for 4,439 adults ages 25 to 74 residing in the United States, including 2,345 women and 438 blacks. The large sample permitted an evaluation of interactions and nonlinear relationships with DLCO, and its association with biomarkers of inflammation. In a model with separate race, sex, and smoking status intercepts, positive associations with FVC, height, weight, hemoglobin concentration, and negative associations with age and neutrophil count explained 59% of the variation in DLCO. In women, the decline in DLCO with age was much less than in men, but after age 47 the decline with age approached that seen in men. Blacks had lower DLCO levels (-1.96 ml/min/mm Hg, 95% confidence interval [CI] -0.77 to -3.14) with or without adjustment for FVC, but the changes in DLCO with age and height were similar in both races. Former smokers had lower DLCO (-1.13 ml/min/mm Hg, 95% CI -1.57 to -0.69), but this reduction was fully explained by the number of pack-years smoked. In current smokers, cigarettes per day and pack-years were predictive of DLCO even after control for FVC and controlling for these variables fully explained the difference in DLCO between never and current smokers. Peripheral neutrophil count, a biomarker of inflammation, was associated with reduced DLCO. Thus, substantial sex and race differences exist for DLCO within the general United States population.

Adult↗
PubMed1996

Adrenocorticotropin secretion by fetal sheep anterior and intermediate lobe pituitary cells in vitro: effects of gestation and adrenalectomy.

Immunoreactive (ir) ACTH is present in the fetal sheep intermediate lobe (IL) as well as the anterior pituitary (AP). It is not clear whether fetal IL cells can secrete irACTH and if gestational age and glucocorticoids influence the secretion of ACTH from these tissues in a similar fashion. Therefore, we examined the control of irACTH secretion by IL cells, whether the responsiveness of AP and IL cells to arginine vasopressin (AVP) and CRH changes during gestation, and whether withdrawal of adrenal steroids by adrenalectomy influences AP and IL responses. Cultured pituitary cells were studied from intact fetuses at an immature (n = 5; 108 +/- 5 days) and a mature (n = 8; 139 +/- 0 days) stage, from mature fetuses 3 weeks after bilateral adrenalectomy (n = 6), and from neonatal lambs within 16 h of birth (n = 6). Secretion of irACTH was determined by RIA of incubation medium obtained during 3-h exposure of cells to vehicle, AVP, CRH, or both. In all cases, IL cells secreted measurable irACTH. The IL cells of immature fetuses responded to CRH (133 +/- 8% increase over basal secretion), AVP (52 +/- 6%), and CRH plus AVP (244 +/- 8%). In contrast, IL cells from mature fetuses responded only to CRH (160 +/- 20%) or CRH plus AVP (259 +/- 44%), as did cells from mature adrenalectomized fetuses (CRH, 356 +/- 70%; CRH plus AVP, 627 +/- 100%). Secretion from neonatal IL cells was not significantly increased above basal rates by CRH and/or AVP. The AP cells from immature fetuses responded significantly to CRH (406 +/- 16%), AVP (114 +/- 8%), and CRH plus AVP (559 +/- 38%), whereas cells from mature fetuses responded only to AVP (249 +/- 40%) or to CRH plus AVP (570 +/- 146%). In AP cells from mature adrenalectomized fetuses, the response pattern resembled that of immature intact fetal sheep (CRH, 429 +/- 76%; AVP, 146 +/- 15%; CRH plus AVP, 541 +/- 94%). Neonatal AP cells responded to CRH (196 +/- 25%), AVP (442 +/- 71%), and CRH plus AVP (646 +/- 93%). Further characterization of IL cells (n = 6 fetal and 2 neonatal) indicated that they were inhibited by dopamine (basal ACTH secretion decreased by 25 +/- 4%; ACTH secretory response to CRH decreased by 32 +/- 10%). These results show that fetal neurointermediate lobe cells secrete irACTH under basal and stimulated conditions. Moreover, the pattern of response of AP and neurointermediate lobe cells to secretagogues is influenced by gestational age and, possibly, cortisol.

Adrenalectomy↗
PubMed1996

The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH.

GH has been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2 and the Src homology 2 domain-containing transcription factors Stats (signal transducers and activators of transcription) 1, 3, and 5. The present work investigates the role of GHR and JAK2 in the activation of Stats 1, 3, and 5 by GH. The ability of GH to stimulate the tyrosyl phosphorylation of these Stats was assessed in Chinese hamster ovary (CHO) cells expressing truncated and mutated GHR. GH was observed to stimulate tyrosyl phosphorylation of Stats 1, 3, and 5 in CHO cells expressing GHRs that bind JAK2 [GHR1-638 (full-length) and GHR1-454 (lacks approximately half of the cytoplasmic domain)] but not in CHO cells expressing GHR that do not bind JAK2 (GHR1-318 or GHR1-294). GH-dependent tyrosyl phosphorylation of Stat5, but not Stats 1 or 3, was reduced in CHO cells expressing GHR1-454. GH-dependent tyrosyl phosphorylation of Stats 3 and 5 was severely reduced and undetectable for Stat1 in cells expressing GHR1-454 in which tyrosines 333 and 338 (the only tyrosines phosphorylated within 1-454) are mutated to phenylalanine (GHR1-454Y333, 338F). However, GH-dependent phosphorylation of Stats 1, 3, and 5 was observed in cells expressing full-length GHR in which tyrosines 333 and 338 are mutated to phenylalanine (GHR1-638Y333, 338F) GH, whose receptor lacks previously defined Stat1- or Stat3-binding sites, was found in 3T3-F442A fibroblasts and 2fTGH-GHR cells to stimulate tyrosyl phosphorylation of JAK2 to a substantially greater extent than, and JAK1 to a similar extent as, leukemia inhibitory factor (LIF) and/or interferon gamma (IFN gamma), ligands whose receptors contains Stat3- and Stat1-binding sites and activate Stat3 and Stat1, respectively, better than GH. These findings suggest that: 1) JAK2 is required for GH-dependent phosphorylation of Stats 1, 3, and 5; 2) tyrosines 333 and/or 338 are required for maximal tyrosyl phosphorylation of Stats 1, 3, and 5; 3) Stat5 binds to a phosphorylated tyrosine(s) within amino acids 454-638 in addition to tyrosines 333 and/or 338; 4) GH stimulates tyrosyl phosphorylation of JAK1 in addition to JAK2 with JAK2 having a much greater response; 5) some Stat3 and Stat5 (and possibly Stat1) may bind to nonphosphorylated amino acids in GHR or to phosphorylated tyrosines in proteins that bind to GHR (e.g. JAK22) to be maximally activated; and 6) if JAK2, which contains Stat3-binding motifs, does serve as a docking site for some Stat proteins, Stat-JAK2 binding is likely to be more important for GH than LIF or IFN gamma in 3T3-F442A cells since GH induces 15 times more tyrosyl-phosphorylated JAK2 than LIF or IFN gamma.

Animals↗
PubMed1996

Compound word effects differ in reading, on-line naming, and delayed naming tasks.

Bimorphemic compound words (e.g., blueberry), bimorphemic suffixed words (e.g., ceaseless), and monomorphemic controls (e.g., arthritis) were read in neutral sentence contexts in Experiment 1. The main result revealed longer first fixation durations on compound words than on control and suffixed words. Different effects emerged when naming tasks were used. An on-line naming task revealed substantially shorter naming latencies for compound words than for control and suffixed words. Naming latencies for compound and control words were equivalent in a delayed naming task. These results indicate that on-line naming latencies and word-viewing durations may yield diverging results. They also suggest that activation of constituent words of compound words occurs independently from the specification of conventional word meanings.

Adult↗
PubMed1996

Case report: post-transfusion purpura.

Post-transfusion purpura (PTP) is a rare disorder characterized by the abrupt onset of severe thrombocytopenia following a blood transfusion. We describe a case of PTP in a patient treated with plasmapheresis, noting that this is an uncommon but treatable disease entity.

Aged↗
PubMed1996

Is daily mortality associated specifically with fine particles?

Recent epidemiologic studies have consistently reported increased daily mortality associated with exposures to particulate air pollution. Currently, particulate mass is measured as particles smaller than 10 microns (PM10). Fine (PM2.5) and coarse (PM10-PM2.5) mass and sulfate particle concentrations were measured in six eastern U.S. cities for eight years, and aerosol acidity concentrations were measured for approximately one year. Daily mortality for these metropolitan areas was combined with particulate air pollution and weather measurements. City-specific associations with each measure of particle pollution were estimated by Poisson regression, adjusting for time trends and weather by nonparametric methods. Combined effect estimates were calculated as the inverse variance weighted mean of the city-specific estimates. PM10, PM2.5, and SO4= were each significantly associated with increased daily mortality, while no associations were found with coarse mass nor with aerosol acidity (H+) concentrations. The strongest association was found with PM2.5. A 10 micrograms/m3 increase in two-day mean PM2.5 was associated with a 1.5% (95% CI 1.1% to 1.9%) increase in total daily mortality. Somewhat larger increases were found for deaths caused by chronic obstructive pulmonary disease (+3.3%) and by ischemic heart disease (+2.1%). These data suggest that increased daily mortality is specifically associated with particle mass constituents found in the aerodynamic diameter size range under 2.5 microns, that is, with combustion-related particles.

Air Pollution↗
PubMed1995

Novel tricyclic inhibitors of farnesyl protein transferase. Biochemical characterization and inhibition of Ras modification in transfected Cos cells.

Ras protooncogenes encode 21-kDa membrane-associated guanine nucleotide-binding proteins, which play a critical role in control of cellular proliferation and differentiation. Oncogenic, activated forms of Ras proteins are associated with a broad range of human cancers. The elucidation of the post-translational modifications that occur at the carboxyl terminus of Ras and the demonstration that farnesylation of Ras by farnesyl protein transferase is essential for Ras-induced cellular transformation has opened up a new and promising approach to the development of anti-Ras therapeutics. We report here a novel series of potent farnesyl protein transferase (FPT) inhibitors, represented by SCH 44342. This compound inhibits both rat brain and recombinant human FPT with an IC50 of approximately 250 nM, while it is only weakly active against rat brain geranylgeranyl protein transferase-1 (IC50 > 114 microM). FPT inhibition has been observed using both Ha-Ras protein and Ki-Ras-derived peptide substrates in two different assay formats. SCH 44342 and its analogs also inhibit farnesylation of Ras in Cos cells transiently expressing [Val12]Ha-Ras with IC50 values in the low micromolar range. At these concentrations they do not inhibit sterol biosynthesis or geranylgeranylation of protein. In addition, we observed that Cos cells undergo pronounced morphological changes upon overexpression of [Val12]activated forms of Ha-Ras containing COOH-terminal sequences allowing farnesylation (CVLS) or geranylgeranylation (CVLL) but not upon overexpression of activated Ras lacking the isoprenylated Cys (SVLS). Ras-induced morphological changes can be partially reverted with lovastatin. Importantly, SCH 44342 can block morphological changes induced by [Val12]Ha-Ras-CVLS but not [Val12]Ha-Ras-CVLL. Recently, a number of other FPT inhibitors have been reported. Most of the compounds reported to have cell-based activity are peptidomimetic analogs of the CAAX substrate. Our FPT inhibitors are novel in that although they compete with Ras protein in kinetic experiments they are entirely nonpeptidic in nature, they do not have oxidizable sulfhydryl functions, and they are active in cells at low micromolar concentrations.

Alkyl and Aryl Transferases↗
PubMed1995

Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein.

Cytokines and growth factors induce tyrosine phosphorylation of signal transducers and activators of transcription (STATs) that directly activate gene expression. Cells stably transformed by the Src oncogene tyrosine kinase were examined for STAT protein activation. Assays of electrophoretic mobility, DNA-binding specificity, and antigenicity indicated that Stat3 or a closely related STAT family member was constitutively activated by the Src oncoprotein. Induction of this DNA-binding activity was accompanied by tyrosine phosphorylation of Stat3 and correlated with Src transformation. These findings demonstrate that Src can activate STAT signaling pathways and raise the possibility that Stat3 contributes to oncogenesis by Src.

Animals↗
PubMed1995

Air pollution and hospital admissions for cardiovascular disease in Detroit, Michigan.

In the December 1952 smog disaster in London, a substantial increase in mortality was closely associated with the increase in air pollution. Deaths from cardiovascular causes were elevated as well as respiratory deaths. The increase was greatest in the elderly. Hospital admissions were increased for both respiratory and cardiovascular diseases. Since then, many studies have reported associations between lower concentrations of air pollution and daily mortality. Little attention has been paid to the question of hospital admissions for cardiovascular illness, however. This study examined the association between air pollution and cardiovascular hospital admissions for persons aged 65 years and older in the Detroit, Michigan, metropolitan area during the years 1986-1989. After controlling for seasonal and other long-term temporal trends, temperature, and dew point temperature, the particulate matter with an aerodiameter of < or = 10 microns (PM10) was associated with daily admissions for ischemic heart disease (relative risk (RR) = 1.018, 95% confidence interval (CI) 1.005-1.032 for an interquartile range (32 micrograms/m3) increase in pollution). SO2, CO, and ozone made no independent contribution to ischemic heart disease admissions. Both PM10 (RR = 1.024, 95% CI 1.004-1.044) and CO (RR = 1.022, 95% CI 1.010-1.034 for an interquartile range (1.28 ppm) increase in pollution) showed independent associations with heart failure admissions. These results were robust to alternate methods of estimation and weather control.

Aged↗
PubMed1995

A regulatory role for astrocytes in HIV-1 encephalitis. An overexpression of eicosanoids, platelet-activating factor, and tumor necrosis factor-alpha by activated HIV-1-infected monocytes is attenuated by primary human astrocytes.

HIV-1-infected brain macrophages participate in neurologic dysfunction through their continual secretion of neurotoxins. We previously demonstrated that astroglial cells activate HIV-1-infected monocytes to produce such neurotoxic activities. In this study, the mechanism underlying these monocyte secretory activities was unraveled and found dependent on HIV-1's ability to prime monocytes for activation. LPS stimulation of HIV-1-infected monocytes resulted in an overexpression of eicosanoids, platelet-activating factor (PAF), and TNF-alpha. This was dependent on the level of HIV-1 infection and monocyte stimulation. Cell to cell interactions between activated virus-infected monocytes and primary human astrocytes reduced monocyte secretions. The capacity of astrocytes to deactivate monocytes was, notably, TGF-beta independent. Although astrocytes constitutively produced latent TGF-beta 2, HIV-1-infected monocytes neither affected TGF-beta 2 production nor converted it into a bioactive molecule. Furthermore, addition of rTGF-beta 1 or rTGF-beta 2 or its Abs to LPS-stimulated monocyte-astrocyte mixtures had no effect on monokine production. In contrast, addition of rIL-10 to LPS-stimulated monocytes produced a dose-dependent decrease in TNF-alpha. IL-10 mRNAs were detected in monocytes, but not astrocytes, following LPS treatment. These results suggest that macrophage activation, a major component of HIV-1 infection in the brain, precipitates neuronal injury by causing virus-infected cells to synthesize neurotoxins. The neurotoxins produced by monocytes are then regulated by astrocytes. Astrocytes therefore, can play either positive or negative roles for disease depending on prior macrophage activation. These findings begin to unravel the cellular control mechanisms that influence cognitive and motor dysfunctions in HIV-1-infected individuals.

Astrocytes↗
PubMed1995

Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone.

The mechanism by which the binding of growth hormone (GH) to its cell surface receptor elicits changes in gene transcription are largely unknown. The transcription factor Stat1/p91 has been shown to be activated by GH. Here we show that acute phase response factor or Stat3 f1p4an antigenically related protein), is also activated by GH. Stat3 has been implicated in the interleukin-6-dependent induction of acute phase response genes. GH promotes in 3T3-F442A fibroblasts the tyrosyl phosphorylation of a protein immunoprecipitated by antibodies to Stat3. This protein co-migrates with a tyrosyl phosphorylated protein from cells treated with leukemia inhibitory factor, a cytokine known to activate Stat3. Tyrosyl phosphorylated Stat3 is also observed in response to interferon-gamma. Stat3 is present in GH-inducible DNA-binding complexes that bind the sis-inducible element in the c-fos promoter and the acute phase response element in the alpha 2-macroglobulin promoter. The ability of GH to activate both Stat1 and Stat3 (i.e. increase their tyrosyl phosphorylation and ability to bind to DNA) suggests that gene regulation by GH involves multiple Stat proteins. Shared transcription factors among hormones and cytokines that activate JAK kinases provide an explanation for shared responses, while the ability of the different ligands to differentially recruit various Stat family members suggests mechanisms by which specificity in gene regulation could be achieved.

3T3 Cells↗
PubMed1995

Clinical pharmacology of estrogens: cardiovascular actions and cardioprotective benefits of replacement therapy in postmenopausal women.

The use of estrogens in postmenopausal women has been the subject of much controversy regarding hormone formulation, dosage, use in combination with progestins, duration of treatment, and contraindications. Estrogens have been prescribed to relieve menopausal symptoms for more than three decades. The hormones reduce the gynecologic and psychologic changes associated with menopause while inhibiting bone resorption and possibly reducing the risk of cardiovascular disease. Their use however has been complicated by an increased risk of endometrial cancer and possibly breast cancer. The use of estrogens as cardioprotective agents is discussed and the clinical experiences and the possible mechanisms of action are reviewed. The clinical pharmacology of estrogens and the various formulations that are available as monotherapy or in combination with progestins will also be reviewed.

Adult↗