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Biomedical subjects

C Patterson

Publications and source records attributed to C Patterson.

At least 127 records · Page 7Linked to original sources
PubMed1996

Suppression of interleukin-1beta-induced nitric-oxide synthase promoter/enhancer activity by transforming growth factor-beta1 in vascular smooth muscle cells. Evidence for mechanisms other than NF-kappaB.

Nitric-oxide synthases (NOS) utilize L-arginine to produce NO, a potent vasodilator that contributes to the regulation of vascular tone. We demonstrated previously that transforming growth factor (TGF)-beta1 down-regulates inducible NOS after its induction by interleukin (IL)-1beta by decreasing the rate of inducible NOS gene transcription. In the present study we transfected reporter plasmids containing various lengths of the inducible NOS 5'-flanking region into primary cultured rat aortic smooth muscle cells and stimulated the cells with IL-1beta or vehicle. IL-1beta increased the activity of the plasmid containing -1485 to +31 of the inducible NOS gene by more than 10-fold, indicating the presence of IL-1beta-responsive elements. Further deletion analysis revealed that a construct containing -234 to +31 of the inducible NOS gene contained the majority of promoter/enhancer activity after IL-1beta stimulation. Mutation of the NF-kappaB site within this region partially reduced IL-1beta-inducible activity; however, a large portion of activity remained independent of the NF-kappaB site. TGF-beta1 suppressed promoter/enhancer activity after IL-1beta stimulation, and this suppression was complete in the construct with a mutated NF-kappaB site. In addition, TGF-beta1 did not decrease the binding of nuclear proteins to the NF-kappaB site. These data suggest that the ability of TGF-beta1 to suppress inducible NOS promoter/enhancer activity occurs through a site(s) other than the NF-kappaB motif in vascular smooth muscle cells.

Animals↗
PubMed1996

Arrest of endotoxin-induced hypotension by transforming growth factor beta1.

Septic shock is a cytokine-mediated process typically caused by a severe underlying infection. Toxins generated by the infecting organism trigger a cascade of events leading to hypotension, to multiple organ system failure, and frequently to death. Beyond supportive care, no effective therapy is available for the treatment of septic shock. Nitric oxide (NO) is a potent vasodilator generated late in the sepsis pathway leading to hypotension; therefore, NO represents a potential target for therapy. We have previously demonstrated that transforming growth factor (TGF) beta1 inhibits inducible NO synthase (iNOS) mRNA and NO production in vascular smooth muscle cells after its induction by cytokines critical in the sepsis cascade. Thus, we hypothesized that TGF-beta1 may inhibit iNOS gene expression in vivo and be beneficial in the treatment of septic shock. In a conscious rat model of septic shock produced by Salmonella typhosa lipopolysaccharide (LPS), TGF-beta1 markedly reduced iNOS mRNA and protein levels in several organs. In contrast, TGF-beta1 did not decrease endothelium-derived constitutive NOS mRNA in organs of rats receiving LPS. We also performed studies in anesthetized rats to evaluate the effect of TGF-beta1 on the hemodynamic compromise of septic shock; after an initial 25% decrease in mean arterial pressure, TGF-beta1 arrested LPS-induced hypotension and decreased mortality. A decrease in iNOS mRNA and protein levels in vascular smooth muscle cells was demonstrated by in situ hybridization and NADPH diaphorase staining in rats treated with TGF-beta1. Thus these studies suggest that TGF-beta1 inhibits iNOS in vivo and that TGF-beta1 may be of future benefit in the therapy of septic shock.

Animals↗
PubMed1996

Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells.

Pyrrolidinedithiocarbamate (PDTC) and N-acetylcysteine (NAC) have been used as antioxidants to prevent apoptosis in lymphocytes, neurons, and vascular endothelial cells. We report here that PDTC and NAC induce apoptosis in rat and human smooth muscle cells. In rat aortic smooth muscle cells, PDTC induced cell shrinkage, chromatin condensation, and DNA strand breaks consistent with apoptosis. In addition, overexpression of Bcl-2 suppressed vascular smooth muscle cell death caused by PDTC and NAC. The viability of rat aortic smooth muscle cells decreased within 3 h of treatment with PDTC and was reduced to 30% at 12 h. The effect of PDTC and NAC on smooth muscle cells was not species specific because PDTC and NAC both caused dose-dependent reductions in viability in rat and human aortic smooth muscle cells. In contrast, neither PDTC nor NAC reduced viability in human aortic endothelial cells. The use of antioxidants to induce apoptosis in vascular smooth muscle cells may help prevent their proliferation in arteriosclerotic lesions.

Acetylcysteine↗
PubMed1996

Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism?

OBJECTIVE: To determine if health-related quality of life (HRQL) in patients of middle age and older with elevated thyroid-stimulating hormone (TSH) and normal total thyroid hormone levels-subclinical hypothyroidism-improves with L-thyroxine replacement therapy. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Outpatient clinic. PATIENTS: Thirty-seven patients with subclinical hypothyroidism, most with symptoms consistent with hypothyroidism, over 55 years of age. INTERVENTIONS: Placebo or L-thyroxine replacement therapy to achieve normal TSH level. MEASUREMENTS AND MAIN RESULTS: Disease-specific and general HRQL, cognitive function, bone mineral density, lipid levels. The mean daily dose of L-thyroxine replacement in the active group was 68 +/- 21 micrograms. TSH decreased by 8.6 mIU/L (95% confidence interval [CI] 4.1 to 13.1) and T4 increased by 27.9 nmol/L (95% CI 14.8 to 41.2). There was a statistically significant improvement in a composite psychometric memory score in treated versus control patients; all other outcomes showed similar findings in the two groups. Although confidence intervals for most measures did not exclude an important improvement in HRQL with thyroid replacement, no measure of symptoms or HRQL either showed clinically important trends in favor of treatment, or approached conventional levels of statistical significance. CONCLUSIONS: In middle-aged and older patients with elevated TSH and normal T4, it may not be harmful to follow biochemical and clinical status even in the presence of nonspecific symptoms potentially associated with hypothyroidism.

Aged↗
PubMed1996

An assessment of intraoperative radiotherapy.

An assessment of intraoperative radiotherapy (IORT) was undertaken to inform a decision on whether this technology should be introduced into the state of New South Wales. On the basis of a literature review, IORT appeared to be essentially an experimental technology, with limited data to demonstrate its comparative advantage over other treatments. Introduction of a dedicated IORT facility was technically feasible, but there appeared to be major uncertainties regarding selection and referral of suitable patients on a state-wide basis. The results of the assessment suggested that introduction of an IORT facility might have limited advantage for routine health services. A decision was subsequently taken not to support the introduction of this technology.

Combined Modality Therapy↗
PubMed1996

Enhanced expression of vascular endothelial growth factor in human SaOS-2 osteoblast-like cells and murine osteoblasts induced by insulin-like growth factor I.

Formation of new capillaries, a critical component of tissue growth and repair, is a recognized process in the development, formation, and remodeling of bone. Vascular endothelial growth factor (VEGF), a potent angiogenic factor with specific mitogenic actions on endothelial cells, is produced in a regulated manner by many cell types, including osteoblasts. The aim of the present investigation was to test the hypothesis that insulin-like growth factor I (IGF-I), a known osteogenic factor, modulates VEGF expression in osteoblasts. In human SaOS-2 osteoblast-like cells, 10 nM IGF-I increased the abundance of VEGF messenger RNA (mRNA) by 4-fold above the control value at 2h, and the elevated levels of mRNA returned to near basal by 8 h. IGF-I stimulated VEGF mRNA levels at IGF-I concentrations as low as 1-2 nM. The stability of VEGF mRNA was not increased after IGF-I treatment, and actinomycin D abrogated the enhanced expression of VEGF mRNA by IGF-I, indicating that the action of IGF-I was probably mediated by a transcriptional mechanism. The induction of VEGF mRNA by IGF-I in SaOS-2 cells was associated with an increase in immunoreactive VEGF protein, as detected by immunoblot analysis. IGF-I also increased the expression of VEGF mRNA in primary murine osteoblasts, which confirmed that the actions of IGF-I were not unique to SaOS-2 cells. We conclude that IGF-I enhances osteoblast synthesis of VEGF, which may then act locally on endothelium to stimulate angiogenesis, an essential component of bone growth and remodeling.

Animals↗
PubMed1995

Cloning and functional analysis of the promoter for KDR/flk-1, a receptor for vascular endothelial growth factor.

KDR/flk-1 is one of two receptors for vascular endothelial growth factor, a potent angiogenic peptide. KDR/flk-1 is an early marker for endothelial cell progenitors, and its expression is restricted to endothelial cells in vivo. To investigate the molecular mechanisms regulating expression of KDR/flk-1, we cloned and characterized the promoter of the human KDR/flk-1 gene. The transcription start site was localized by primer extension and ribonuclease protection to a nucleotide 303 base pairs (bp) 5' of the initiation methionine codon. The 5'-flanking sequence is rich in G and C residues and contains five Sp1 elements but no TATA consensus sequence. By reporter gene transfection experiments, we found that approximately 4 kilobases of KDR/flk-1 5'-flanking sequence directed high level luciferase activity in bovine aortic endothelial cells; further deletion analysis revealed positive regulatory elements between bp -225 to -164, -95 to -77, -77 to -60, and +105 to +127. Mutation of an atypical GATA sequence between bp +105 and +127 did not affect promoter activity, suggesting that GATA elements are not essential for the high level promoter activity of this gene. Consistent with endothelial cell-restricted expression of KDR/flk-1 mRNA, we found that the 4-kilobase flanking sequence directed high level promoter activity in endothelial cells but not in other cell types. To our knowledge this is the first report characterizing the KDR/flk-1 promoter. Understanding the KDR/flk-1 promoter will allow us to investigate endothelial cell-specific gene regulation and to uncover methods for targeting gene delivery specifically to endothelial cells.

Animals↗
PubMed1995

Vitamin A deficiency in non-vitamin-supplemented patients with AIDS: a cross-sectional study.

The prevalence of vitamin A deficiency and its association with dietary retinol intake in patients with AIDS was assessed in a cross-sectional study. Sixty eligible patients with AIDS provided serum samples that were analyzed for retinol content. Exclusion criteria included current use of vitamin supplements (57% of the 140 willing to participate) and pregnancy (none). Past dietary intake was determined using a standardized food intake frequency questionnaire. The prevalence of hyporetinemia was 22%. This was a 241-fold greater prevalence than that of a representative sample of the U.S. population, after adjusting for age and sex. There was a positive association between serum retinol status and dietary intake, but 27% of those with adequate intake had serum retinol levels below the normal range. These findings suggest that regardless of intake, patients with AIDS may represent a population at considerable risk of vitamin A deficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells.

Vascular endothelial growth factor (VEGF) is a potent and specific mitogen for vascular endothelial cells and promotes neovascularization in vivo. To determine whether interleukin-1 beta (IL-1 beta), which is present in atherosclerotic lesions, induces VEGF gene expression in vascular smooth muscle cells, we performed RNA blot analysis on rat aortic smooth muscle cells (RASMC) with a rat VEGF cDNA probe. IL-1 beta increased VEGF mRNA levels in RASMC in a time- and dose-dependent manner. As little as 0.1 ng/ml IL-1 beta increased VEGF mRNA levels by 2-fold and 10 ng/ml IL-1 beta increased VEGF mRNA by 4-fold. We also measured the half-life of VEGF mRNA and performed nuclear run-on experiments before and after addition of IL-1 beta to see if IL-1 beta increased VEGF mRNA levels by stabilizing the mRNA or by increasing its rate of transcription. The normal, 2-h half-life of VEGF mRNA in RASMC was lengthened to 3.2 h (60%) by IL-1 beta, and IL-1 beta increased the rate of VEGF gene transcription by 2.1-fold. In immunoblot experiments with an antibody specific for VEGF, we found that IL-1 beta increased VEGF protein levels in RASMC by 3.3-fold. Together these data indicate that IL-1 beta induces VEGF gene expression in smooth muscle cells. This IL-1 beta-induced expression of VEGF may accelerate the progression of atherosclerotic lesions by promoting the development of new blood vessels.

Animals↗
PubMed1995

Variation by age group and seasonality at diagnosis of childhood IDDM in Europe. The EURODIAB ACE Study Group.

Recent data provided by the EURODIAB ACE study group have confirmed wide variation in the incidence of insulin-dependent diabetes mellitus (IDDM) across Europe. The aim of this report is to compare age-specific incidence and seasonality at clinical onset of IDDM between study regions. Using a uniform methodology, the EURODIAB ACE framework ascertained 3,168 newly-diagnosed cases of IDDM in children under the age of 15 years during 1989-1990. Eighteen percent of the cases were age 0-4 years at diagnosis, 34% were age 5-9 years and 48% were age 10-14 years. Poisson regression analysis suggested that there were highly significant statistical differences in incidence between the three age groups and between the 24 regions. Although incidence rates in the 0-4 year and 5-9 year age groups varied from region to region in a similar fashion, the pattern of variation in the older age group was different. Seasonality of diagnosis conformed to a sinusoidal model with a peak occurring in winter, a feature which was consistently observed in both sexes and in all age groups. However, a statistically significant heterogeneity in the seasonal distribution was present among regions, those in Scandinavia showing the smallest relative amplitude. The first insulin injection was given the same day or the day after diagnosis in 93% of the cases for whom data were available.

Adolescent↗
PubMed1995

Linkage between sexual orientation and chromosome Xq28 in males but not in females.

We have extended our analysis of the role of the long arm of the X chromosome (Xq28) in sexual orientation by DNA linkage analyses of two newly ascertained series of families that contained either two gay brothers or two lesbian sisters as well as heterosexual siblings. Linkage between the Xq28 markers and sexual orientation was detected for the gay male families but not for the lesbian families or for families that failed to meet defined inclusion criteria for the study of sex-linked sexual orientation. Our results corroborate the previously reported linkage between Xq28 and male homosexuality in selected kinships and suggest that this region contains a locus that influences individual variations in sexual orientation in men but not in women.

Base Sequence↗
PubMed1995

Congestive heart failure due to reversible cardiomyopathy in patients with hyperthyroidism.

The authors describe the clinical characteristics and response to therapy of seven patients with hyperthyroidism, dilated cardiomyopathy, and low-output cardiac failure. All patients (4 women and 3 men, age 47 +/- 4 years, mean +/- standard error of the mean) were admitted with the primary diagnosis of congestive heart failure. The cause of hyperthyroidism was Graves' disease in six patients, and toxic multinodular goiter in one. On admission, the mean serum T4 was 21 +/- 1 microgram/dL and mean serum T3:411 +/- 77 ng/mL, and serum thyroid-stimulating hormone was suppressed ( < 0.03 microU/mL) in all patients. Two-dimensional echocardiogram showed biventricular or four chamber dilatation and impaired left ventricular performance. Therapy of heart failure and hyperthyroidism resulted in rapid clinical improvement. During follow-up (5 months to 9 years), left ventricular ejection fraction improved from a mean of 28% to a mean ejection fraction of 55% (P < 0.01). Resolution of dilated cardiomyopathy with normalization of systolic function was achieved in five patients, and improvement from severe to mild left ventricular dysfunction was observed in two patients. We conclude that some patients with hyperthyroidism may have a reversible form of dilated cardiomyopathy and "low-output failure." Assessment of thyroid hormone status in patients with heart failure might permit the identification of patients with dilated cardiomyopathy and thyrotoxicosis who are likely to have reversible cardia dysfunction.

Adult↗
PubMed1995

The ATF site mediates downregulation of the cyclin A gene during contact inhibition in vascular endothelial cells.

Contact inhibition mediates monolayer formation and withdrawal from the cell cycle in vascular endothelial cells. In studying the cyclins--key regulators of the cell cycle--in bovine aortic endothelial cells (BAEC), we found that levels of cyclin A mRNA decreased in confluent BAEC despite the presence of 10% fetal calf serum. We then transfected into BAEC a series of plasmids containing various lengths of the human cyclin A 5' flanking sequence and the luciferase gene. Plasmids containing 3,200, 516, 406, 266, or 133 bp of the human cyclin A promoter directed high luciferase activity in growing but not confluent BAEC. In contrast, a plasmid containing 23 bp of the cyclin A promoter was associated with a 65-fold reduction in activity in growing BAEC, and the promoter activities of this plasmid were identical in both growing and confluent BAEC. Mutation of the activating transcription factor (ATF) consensus sequence at bp -80 to -73 of the cyclin A promoter decreased its activity, indicating the critical role of the ATF site. We identified by gel mobility shift analysis protein complexes that bound to the ATF site in nuclear extracts from growing but not confluent BAEC and identified (with antibodies) ATF-1 as a binding protein in nuclear extracts from growing cells. Also, ATF-1 mRNA levels decreased in confluent BAEC. Taken together, these data suggest that the ATF site and its cognate binding proteins play an important role in the downregulation of cyclin A gene expression during contact inhibition.

Activating Transcription Factor 1↗
PubMed1995

Disappearance of cyclin A correlates with permanent withdrawal of cardiomyocytes from the cell cycle in human and rat hearts.

The regulated expression of cyclins controls the cell cycle. Because cardiomyocytes in adult mammals withdraw permanently from the cell cycle and thus cannot regenerate after injury, we examined cyclin expression during development by comparing cyclin A-E mRNA levels in fetal and adult human hearts. Cyclin B mRNA was detectable in adult hearts, although at a level markedly lower than that in fetal hearts. Levels of cyclin C, D1, D2, D3, and E mRNA were essentially identical in the two groups. In contrast, cyclin A mRNA was undetectable in adult hearts whereas cyclin A mRNA and protein were readily detectable in fetal hearts and cardiomyocytes, respectively. We then measured cyclin A mRNA and protein levels in rat hearts at four stages of development (fetal and 2, 14, and 28 d). Cyclin A mRNA and protein levels decreased quickly after birth (to 37% at day 2) and became undetectable within 14 d, an observation consistent with reports that cardiomyocytes stop replicating in rats by the second to third postnatal week. This disappearance of cyclin A gene expression in human and rat hearts at the time cardiomyocytes become terminally differentiated suggests that cyclin A downregulation is important in the permanent withdrawal of cardiomyocytes from the cell cycle.

Adult↗
PubMed1994

Health service provision in rural and remote areas: a needs analysis.

OBJECTIVES: To assess the health service needs of rural and remote populations and to examine the relationship between these needs as obtained from available data and as perceived by community general practitioners (GPs) and other health providers. DESIGN: Existing census and research data were used to study the Huon and Channel health district of South-East Tasmania. Primary data collection consisted of structured interviews with medical practitioners and community representatives. RESULTS: Serious health problems are widespread in rural and remote areas as a result of socioeconomic conditions arising from economic recession and unemployment and pre-existing lifestyle and cultural attitudes towards health, low educational levels, isolation and lack of transport. General practice and primary health care provision follow urbanisation and decrease with increasing distance from a major rural centre, as do the incidence of poverty and worsening health problems. CONCLUSIONS: Most primary health care in rural and remote areas is provided by GPs, with curative services predominating. The health service patterns conform to lower socioeconomic patterns in that preventive health is given in low priority. Preventive health programs should tie in with curative health service provision, making use of the resources already available within the communities. The primary role taken by rural GPs in health service provision demands that they take a pivotal role in preventive health service delivery.

Adult↗