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Biomedical subjects

S Coughlin

Publications and source records attributed to S Coughlin.

At least 19 recordsLinked to original sources
PubMed2006

Defective platelet responsiveness to thrombin and protease-activated receptors agonists in a novel case of gray platelet syndrome: correlation between the platelet defect and the alpha-granule content in the patient and four relatives.

BACKGROUND: We report a novel case of gray platelet syndrome (GPS). A 14-year-old boy had bleeding diathesis, mild thrombocytopenia, giant platelets with severe defect of alpha-granule secretory proteins, myelofibrosis and splenomegaly. METHODS AND RESULTS: Platelet function studies showed a marked reduction of aggregation and Ca(2+) mobilization by thrombin, protease-activated receptor 1 (PAR1)-activating peptide (AP) and PAR4-AP, PAR1 expression at 55% of normal levels, and a more than two hundred fold reduction of in vitro whole-blood thromboxane B(2) (TXB(2)) production. Sequencing of coding regions of the PAR1 gene failed to show abnormalities. This patient was initially classified as a sporadic case of GPS, as electron microscopy failed to identify giant platelets and/or alpha-granule deficiency in his relatives. However, further studies on the father and three other relatives showed a relative lack of platelet alpha-granule proteins by immunofluorescence microscopy, a defective platelet response to PAR4-AP, and severely reduced in vitro whole-blood TXB(2) production. On this basis, we suggest that in this family, GPS was transmitted in a dominant fashion with highly variable penetrance. CONCLUSIONS: Our study suggests that current diagnostic criteria fail to identify some patients with a mild GPS phenotype and that such patients might be identified by the methods cited above. It also better characterizes the pathogenesis of defective platelet responses to thrombin, and raises interesting questions on the correlation between abnormal PAR function and the lack of alpha-granule content in GPS.

Adolescent↗
PubMed2001

Sleep disordered breathing--a new component of syndrome x?

Sleep disordered breathing (SDB) is a complication of obesity estimated to occur in about 4-6% of overweight individuals. These respiratory disturbances during sleep incorporate a number of conditions including snoring, upper airway resistance syndrome and obstructive sleep apnoea syndrome (OSAS). It is thought that as well as having deleterious effects on sleep quality these conditions may also promote cardiovascular and hormonal changes leading to an elevated blood pressure and an increased incidence of cardiovascular morbidity. Evidence reviewed here points to an alteration in sympathovagal balance, baroreceptor sensitivity, insulin resistance and leptin, growth hormone and lipid levels. Whether these changes are a consequence of the associated obesity or the SDB itself remains to be proven.

Cardiovascular Diseases↗
PubMed2001

Population-based estimates of the prevalence of family history of cancer among women.

OBJECTIVE: Family history of cancer is recognized as one of the most important risk factors in predicting personal cancer risk. Nevertheless, there are few published population-based estimates of family history prevalence by age categories. METHODS: We used responses of female controls (n = 4,754) from the population-based Cancer and Steroid Hormone study (1980-1982) to estimate the frequency of family history of various cancers among female relatives. We determined the age- and race-specific prevalence of family history of breast, ovarian, endometrial, and other cancers in first-degree female relatives of women aged 20-54 years. To evaluate changes in reporting family history over time, we also analyzed responses of control women (n = 1,544) from the Women's Interview Study on Health (WISH) (1990-1992) to estimate the prevalence of family history of breast cancer. RESULTS: The prevalence of a first-degree family history of breast, ovarian, endometrial, and cervical cancers was 6.4% (95% CI 5.7-7.1%), 1.1% (0.8-1.4%), 3.5% (3.0-4.0%), and 2.1% (1.7-2.5%), respectively. Among first-degree female relatives, the prevalence of family history of colon, lung, and thyroid cancers was 2.4% (2.1-2.9%), 1.5% (1.2-1.8%), and 0.5% (0.3-0.7%), respectively. The prevalence of family history of breast and colon cancers increased significantly with respondent's age. Similar results for family history of breast cancer were obtained from an analysis of responses from the WISH. CONCLUSIONS: In addition to providing a point of reference for research and health policy, these results may be of interest to providers who care for female patients because of the usefulness of information about family history of cancer for assessing lifetime risk of cancer.

Journal Article↗
PubMed2000

Health care in Hong Kong and mainland China: one country, two systems?

Hong Kong and Mainland China are undertaking health reform following recent economic fluctuations and Hong Kong's transformation to a Special Administrative Region of China in 1997. Despite spending only 4.7% of its Gross Domestic Product on health care, one third as much as in the United States, Hong Kong has developed health statistics comparable to those in leading western nations. In contrast, Mainland China's 3.6% of GDP expenditure on health is associated with health statistics and expenditures similar to those found in most developing countries. Hong Kong has adopted health care financing and organizational health systems that are commonly seen in centrally planned economies, while its economy functions as a highly capitalistic enterprise. In contrast, mainland China has integrated many features of health care systems associated with market economies, while its overall economy is largely centrally planned. In this paper we examine the policy factors associated with these disparate health systems and investigate whether they can be maintained according to the 'one country, two systems' approach that has been adopted by Chinese policy makers.

Cause of Death↗
PubMed2000

UCP-3 expression in skeletal muscle: effects of exercise, hypoxia, and AMP-activated protein kinase.

Uncoupling protein 3 (UCP-3), a member of the mitochondrial transporter superfamily, is expressed primarily in skeletal muscle where it may play a role in altering metabolic function under conditions of fuel depletion caused, for example, by fasting and exercise. Here, we show that treadmill running by rats rapidly (30 min) induces skeletal muscle UCP-3 mRNA expression (sevenfold after 200 min), as do hypoxia and swimming in a comparably rapid and substantial fashion. The expression of the mitochondrial transporters, carnitine palmitoyltransferase 1 and the tricarboxylate carrier, is unaffected under these conditions. Hypoxia and exercise-mediated induction of UCP-3 mRNA result in a corresponding four- to sixfold increase in rat UCP-3 protein. We treated extensor digitorum longus (EDL) muscle with 5'-amino-4-imidazolecarboxamide ribonucleoside (AICAR), a compound that activates AMP-activated protein kinase (AMPK), an enzyme known to be stimulated during exercise and hypoxia. Incubation of rat EDL muscle in vitro for 30 min with 2 mM AICAR causes a threefold increase in UCP-3 mRNA and a 1.5-fold increase of UCP-3 protein compared with untreated muscle. These data are consistent with the notion that activation of AMPK, presumably as a result of fuel depletion, rapidly regulates UCP-3 gene expression.

AMP-Activated Protein Kinases↗
PubMed2000

Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life. PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m(2) (49 patients) or 75 mg/m(2) (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7. 1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P <.001), as was median survival (7.0 v 4.6 months; log-rank test, P =.047). The difference was more significant for docetaxel 75 mg/m(2) patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P =.010; 1-year survival, 37% v 11%; chi(2) test, P =.003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m(2), three of whom died, and in one patient treated with docetaxel 75 mg/m(2). Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m(2), the benefits of docetaxel therapy outweigh the risks.

Adult↗
PubMed1999

Preclinical efficacy of thioxanthone SR271425 against transplanted solid tumors of mouse and human origin.

A highly active and broadly active thioxanthone has been identified: N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthen++ +-4-yl] methylformamide (SR271425, BCN326862, WIN71425). In preclinical testing against a variety of subcutaneously growing solid tumors, the following %T/C and Log10 tumor cell kill (LK) values were obtained: Panc-03 T/C = 0, 5/5 cures; Colon-38 (adv. stage) T/C = 0, 3/5 cures, 4.9 LK; Mam-16/C T/C = 0, 3.5 LK; Mam-17/0 T/C = 0, 2.8 LK; Colon-26 T/C = 0, 1/5 cures, 3.2 LK; Colon-51 T/C = 0, 2.7 LK; Panc-02 T/C = 0, 3.1 LK; B16 Melanoma T/C = 13%, 4.0 LK; Squamous Lung-LC12 (adv. stage) T/C = 14%, 4.9 LK; BG-1 human ovarian T/C = 16%, 1.3 LK; WSU-Brl human breast T/C = 25%, 0.8 LK. The agent was modestly active against doxorubicin (Adr)-resistant solid tumors: Mam-17/AdrT/C =23%, 0.8 LK; and Mam-16/C/Adr T/C = 25%, 1.0 LK, but retained substantial activity against a taxol-resistant tumor: Mam-16/C/taxol T/C = 3%, 2.4 LK. SR271425 was highly active against IV implanted leukemias, L1210 6.3 LK and AML1498 5.3 LK. The agent was equally active both by the IV and oral routes of administration, although requiring approximately 30% higher dose by the oral route. Based on its preclinical antitumor profile, it may be appropriate to evaluate SR271425 in clinical trials.

Animals↗
PubMed1999

Networks of persons with syphilis and at risk for syphilis in Louisiana: evidence of core transmitters.

BACKGROUND AND OBJECTIVES: Differences in sociodemographic attributes and healthcare access may explain differences in regional sexually transmitted disease rates but don't fully explain why syphilis persists disproportionately in certain populations. GOAL OF THIS STUDY: To understand the behavioral epidemiology of syphilis, we conducted a social network analysis of persons with syphilis and their contacts and developed and applied a definition of core transmitters. STUDY DESIGN: We interviewed 10 index persons with primary or secondary untreated syphilis and 80 of their named sexual and social contacts. RESULTS: Fourteen (16%) of 90 interviewed persons met the definition of core transmitters, 9 of whom had past or current syphilis. The other interviewed persons had only moderately risky behaviors. Seventy-eight (42%) of the network sexual contacts were connected directly or indirectly to a core transmitter. CONCLUSION: This analysis suggests that syphilis transmission is maintained by a community with a small percentage of high-risk persons centrally placed amidst a larger group with moderately risky behavior.

Adult↗
PubMed1998

Pregnancy is not associated with the progression of HIV disease in women attending an HIV outpatient program.

The objective of this study was to determine whether pregnancy is associated with an acceleration of human immunodeficiency virus (HIV) disease progression in women who have a pregnancy while HIV infected. A retrospective review of all women aged 15-35 years who attended an HIV outpatient program from January 1989 through August 1995, was undertaken. The 192 women who had a term pregnancy after testing positive for HIV were compared with 164 women who were not pregnant during the same period. The main outcome measures were death, the occurrence of a first acquired immunodeficiency syndrome (AIDS)-defining condition, or a condition indicative of symptomatic HIV. Disease progression was assessed using the Kaplan-Meier method and multivariate proportional hazards models. Compared with nonpregnant women, women with a term pregnancy were significantly more likely to be African-American (88% vs. 78%, p < 0.05), younger than 22 years of age (51 % vs. 11%, p < 0.001), and to have entered the clinic with a higher median CD4 count (519 vs. 433 cells/microl, p < 0.001). After adjusting for entry CD4 count and other factors, pregnancy was not associated with progression to any of the study outcomes. Thus, in women attending a publicly funded clinic, pregnancy does not appear to accelerate the progression of HIV disease.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Bidirectional regulation of uncoupling protein-3 and GLUT-4 mRNA in skeletal muscle by cold.

To elucidate the possible role of the mitochondrial uncoupling protein (UCP)-3 in skeletal muscle as a regulator of adaptive thermogenesis and energy balance, we examined the modulation by cold exposure (5 degrees C) of UCP-3 and glucose transporter isoform GLUT-4 mRNAs in male Sprague-Dawley rats. In skeletal muscle, UCP-3 and GLUT-4 mRNAs increased two- to threefold between 6 and 24 h of cold exposure and then decreased to 50% of the control value after 6 days in the cold. In contrast, skeletal muscle UCP-2 mRNA showed a small increase on day 3 and returned to normal after 6 days. The bidirectional regulation of UCP-3 and GLUT-4 mRNAs in skeletal muscle by cold suggests that UCP-3 may be a major mediator of acute adaptive thermogenesis but then is downregulated, along with GLUT-4, in the chronic state to preserve energy. In contrast, cold exposure caused only transient changes of UCP-2 and GLUT-4 mRNA in heart. These data are consistent with the necessity of the heart to continuously expend energy to maintain blood circulation, regardless of environmental conditions.

Acclimatization↗
PubMed1996

Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway.

BACKGROUND: The Rho-related GTP-binding proteins Cdc42 and Rac1 have been shown to regulate signaling pathways involved in cytoskeletal reorganization and stress-responsive JNK (Jun N-terminal kinase) activation. However, to date, the GTPase targets that mediate these effects have not been identified. PAK defines a growing family of mammalian kinases that are related to yeast Ste20 and are activated in vitro through binding to Cdc42 and Rac1 (PAK: p21 Cdc42-/Rac-activated kinase). Clues to PAK function have come from studies of Ste20, which controls the activity of the yeast mating mitogen-activated protein (MAP) kinase cascade, in response to a heterotrimeric G protein and Cdc42. RESULTS: To initiate studies of mammalian Ste20-related kinases, we identified a novel human PAK isoform, hPAK1. When expressed in yeast, hPAK1 was able to replace Ste20 in the pheromone response pathway. Chemical mutagenesis of a plasmid encoding hPAK1, followed by transformation into yeast, led to the identification of a potent constitutively active hPAK1 with a substitution of a highly conserved amino-acid residue (L107F) in the Cdc42-binding domain. Expression of the hPAK1(L107F) allele in mammalian cells led to specific activation of the Jun N-terminal kinase MAP kinase pathway, but not the mechanistically related extracellular signal-regulated MAP kinase pathway. CONCLUSIONS: These results demonstrate that hPAK1 is a GTPase effector controlling a downstream MAP kinase pathway in mammalian cells, as Ste20 does in yeast. Thus, PAK and Ste20 kinases play key parts in linking extracellular signals from membrane components, such as receptor-associated G proteins and Rho-related GTPases, to nuclear responses, such as transcriptional activation.

Alleles↗
PubMed1994

Topical CTC-96 accelerates wart growth in rabbits infected with cottontail rabbit papillomavirus.

CTC-96, a cobalt containing complex, was tested as a putative topical therapeutic agent for the treatment of papillomavirus-induced tumors in our cottontail rabbit papillomavirus (CRPV)-rabbit model system. Following experimental infection of domestic rabbits with CRPV, CTC-96 was applied to infection sites twice daily, 5 days a week for a total of 8 weeks. Two levels of concentrations of aqueous CTC-96 were compared to placebo control-treated animals. With increasing dose of CTC-96 we observed tumors earlier, larger, and more often across eight infected sites on each animal.

Administration, Topical↗
PubMed1992

Anaesthetic modification of regional myocardial functional adjustments during myocardial ischaemia: halothane vs fentanyl.

During myocardial ischaemia, functional compensation occurs by non-ischaemic regions of the left ventricle (LV). Anaesthetics may affect compensation by altering contractility, metabolism and perfusion. This was studied in dogs anaesthetized with fentanyl (150 micrograms kg-1 loading dose and 100 micrograms kg-1 h-1) or 0.75% and 1.5% halothane and subjected to left anterior descending artery (LAD) occlusion. After 15 min of anterior wall ischaemia, cardiac output, mean arterial pressure and LV maximum dP/dt were diminished in the 1.5% halothane but not in the 0.75% halothane or fentanyl groups. In all groups, stroke volume decreased, LV end-diastolic pressure increased and anterior wall function deteriorated (measured as systolic shortening, peak systolic intramyocardial pressure (IMP), regional wall stroke work (RSW) and slope of preload recruitable stroke work curve (Mw)) with ischaemia. Functional changes in the lateral (non-ischaemic) wall were different between groups. Regional function during occlusion in this area improved with fentanyl (mean (SEM) IMP, RSW and Mw increased by 23 (2)%, 37 (3)% and 69 (7)%, respectively), was relatively well maintained with 0.75% halothane and diminished with 1.5% halothane.

Anesthesia, Inhalation↗
PubMed1987

Mammalian alpha-polymerase: cloning of partial complementary DNA and immunobinding of catalytic subunit in crude homogenate protein blots.

A new polyclonal antibody against the alpha-polymerase catalytic polypeptide was prepared by using homogeneous HeLa cell alpha-polymerase. The antibody neutralized alpha-polymerase activity and was strong and specific for the alpha-polymerase catalytic polypeptide (Mr 183,000) in Western blot analysis of crude extracts of HeLa cells. The antibody was used to screen a cDNA library of newborn rat brain poly(A+) RNA in lambda gt11. A positive phage was identified and plaque purified. This phage, designated lambda pol alpha 1.2, also was found to be positive with an antibody against Drosophila alpha-polymerase. The insert in lambda pol alpha 1.2 (1183 base pairs) contained a poly(A) sequence at the 3' terminus and a short in-phase open reading frame at the 5' terminus. A synthetic oligopeptide (eight amino acids) corresponding to the open reading frame was used to raise antiserum in rabbits. Antibody affinity purified from this serum was found to be immunoreactive against purified alpha-polymerase by enzyme-linked immunosorbent assay and was capable of immunoprecipitating alpha-polymerase. This indicated the lambda pol alpha 1.2 insert encoded an alpha-polymerase epitope and suggested that the cDNA corresponded to an alpha-polymerase mRNA. This was confirmed in hybrid selection experiments using pUC9 containing the cDNA insert and poly(A+) RNA from newborn rat brain; the insert hybridized to mRNA capable of encoding alpha-polymerase catalytic polypeptides. Northern blot analysis of rat brain poly(A+) RNA revealed that this mRNA is approximately 5.4 kilobases.

Amino Acid Sequence↗