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Biomedical subjects

S Thomas

Publications and source records attributed to S Thomas.

At least 217 records · Page 12Linked to original sources
PubMed1999

Influence of surgeon's experience on speech outcome in cleft lip and palate.

Relation between the number of cases treated and outcome, particularly in low-incidence anomalies, are difficult to identify and rectify. We show clear advantages in speech outcomes for children born with a cleft lip and palate who are operated on by surgeons who do large numbers of these procedures.

Child↗
PubMed1999

Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles.

It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.

Administration, Oral↗
PubMed1999

Oral contraceptives and myocardial infarction: results of the MICA case-control study.

OBJECTIVES: To determine the association between myocardial infarction and use of different types of oral contraception in young women. DESIGN: Community based case-control study. Data from interviews and general practice records. SETTING: England, Scotland, and Wales. PARTICIPANTS: Cases (n=448) were recruited from women aged between 16 and 44 who had suffered an incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n=1728) were women without a diagnosis of myocardial infarction matched for age and general practice. MAIN OUTCOME MEASURES: Odds ratios for myocardial infarction in current users of all combined oral contraceptives stratified by their progestagen content compared with non-users; current users of third generation versus second generation oral contraceptives. RESULTS: The adjusted odds ratio for myocardial infarction was 1.40 (95% confidence interval 0.78 to 2. 52) for all combined oral contraceptive users, 1.10 (0.52 to 2.30) for second generation users, and 1.96 (0.87 to 4.39) for third generation users. Subgroup analysis by progestagen content did not show any significant difference from 1, and there was no effect of duration of use. The adjusted odds ratio for third generation users versus second generation users was 1.78 (0.66 to 4.83). 87% of cases were not exposed to an oral contraceptive, and 88% had clinical cardiovascular risk factors or were smokers, or both. Smoking was strongly associated with myocardial infarction: adjusted odds ratio 12.5 (7.29 to 21.5) for smoking 20 or more cigarettes a day. CONCLUSIONS: There was no significant association between the use of oral contraceptives and myocardial infarction. The modest and non-significant point estimates for this association have wide confidence intervals. There was no significant difference between second and third generation products.

Adolescent↗
PubMed1999

Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling.

Paxillin is a focal adhesion adaptor protein involved in the integration of growth factor- and adhesion-mediated signal transduction pathways. Repeats of a leucine-rich sequence named paxillin LD motifs (Brown M.C., M.S. Curtis, and C.E. Turner. 1998. Nature Struct. Biol. 5:677-678) have been implicated in paxillin binding to focal adhesion kinase (FAK) and vinculin. Here we demonstrate that the individual paxillin LD motifs function as discrete and selective protein binding interfaces. A novel scaffolding function is described for paxillin LD4 in the binding of a complex of proteins containing active p21 GTPase-activated kinase (PAK), Nck, and the guanine nucleotide exchange factor, PIX. The association of this complex with paxillin is mediated by a new 95-kD protein, p95PKL (paxillin-kinase linker), which binds directly to paxillin LD4 and PIX. This protein complex also binds to Hic-5, suggesting a conservation of LD function across the paxillin superfamily. Cloning of p95PKL revealed a multidomain protein containing an NH2-terminal ARF-GAP domain, three ankyrin-like repeats, a potential calcium-binding EF hand, calmodulin-binding IQ motifs, a myosin homology domain, and two paxillin-binding subdomains (PBS). Green fluorescent protein- (GFP-) tagged p95PKL localized to focal adhesions/complexes in CHO.K1 cells. Overexpression in neuroblastoma cells of a paxillin LD4 deletion mutant inhibited lamellipodia formation in response to insulin-like growth fac- tor-1. Microinjection of GST-LD4 into NIH3T3 cells significantly decreased cell migration into a wound. These data implicate paxillin as a mediator of p21 GTPase-regulated actin cytoskeletal reorganization through the recruitment to nascent focal adhesion structures of an active PAK/PIX complex potentially via interactions with p95PKL.

ADP-Ribosylation Factors↗
PubMed1999

Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure.

BACKGROUND: Incomplete suppression of the renin-angiotensin system during long-term ACE inhibition may contribute to symptomatic deterioration in patients with severe congestive heart failure (CHF). Combined angiotensin II type I (AT1) receptor blockade and ACE inhibition more completely suppresses the activated renin-angiotensin system than either intervention alone in sodium-depleted normal individuals. Whether AT1 receptor blockade with losartan improves exercise capacity in patients with severe CHF already treated with ACE inhibitors is unknown. METHODS AND RESULTS: Thirty-three patients with severe CHF despite treatment with maximally recommended or tolerated doses of ACE inhibitors were randomized 1:1 to receive 50 mg/d losartan or placebo for 6 months in addition to standard therapy in a multicenter, double-blind trial. Peak aerobic capacity (V(O2)) during symptom-limited treadmill exercise and NYHA functional class were determined at baseline and after 3 and 6 months of double-blind therapy. Peak V(O2) at baseline and after 3 and 6 months were 13.5+/-0.6, 15.1+/-1.0, and 15.7+/-1.1 mL. kg-1. min-1, respectively, in patients receiving losartan and 14.1+/-0.6, 14.3+/-0.9, and 13.6+/-1.1 mL. kg-1. min-1, respectively, in patients receiving placebo (P<0.02 for treatment group-by-time interaction). Functional class improved by at least one NYHA class in 9 of 16 patients receiving losartan and 1 of 17 patients receiving placebo. CONCLUSIONS: Losartan enhances peak exercise capacity and alleviates symptoms in patients with CHF who are severely symptomatic despite treatment with maximally recommended or tolerated doses of ACE inhibitors.

Adult↗
PubMed1999

Volume regulation following hypotonic shock in isolated crypts of mouse distal colon.

1. A video-imaging technique of morphometry was used to measure the diameter as an index of cell volume in intact mouse distal colon crypts submitted to hypotonic shock. 2. Transition from isotonic (310 mosmol l-1) to hypotonic (240 mosmol l-1) saline caused a pronounced increase in crypt diameter immediately followed by regulatory volume decrease (RVD). 3. Exposure of crypts to Cl--free hyposmotic medium increased the rapidity of both cell swelling and RVD. Exposure of crypts to Na+-free hyposmotic medium reduced the total duration of swelling. Return to initial diameter was followed by further shrinkage of the crypt cells. 4. The chloride channel inhibitor NPPB (50 microM) delayed the swelling phase and prevented the subsequent normal decrease in diameter. 5. The K+ channel blockers barium (10 mM), charybdotoxin (10 nM) and TEA (5 mM) inhibited RVD by 51, 44 and 32 %, respectively. 6. Intracellular [Ca2+] rose from a baseline of 174 +/- 17 nM (n = 8) to 448 +/- 45 nM (n = 8) during the initial swelling phase 7. The Ca2+ channel blockers verapamil (50 microM) and nifedipine (10 microM), the chelator of intracellular Ca2+ BAPTA AM (30 microM), or the inhibitor of Ca2+ release TMB-8 (10 microM), dramatically reduced volume recovery, leading to 51 % (n = 9), 25 % (n = 7), 37 % (n = 6), 32 % (n = 8) inhibition of RVD, respectively. TFP (50 microM), an antagonist of the Ca2+-calmodulin complex, significantly slowed RVD. The Ca2+ ionophore A23187 (2 microM) provoked a dramatic reduction of the duration and amplitude of cell swelling followed by extensive shrinkage. The release of Ca2+ from intracellular stores using bradykinin (1 microM) or blockade of reabsorption with thapsigargin (1 microM) decreased the duration of RVD. 8. Prostaglandin E2 (PGE2, 5 microM) slightly delayed RVD, whereas leukotriene D4 (LTD4, 100 nM) and arachidonic acid (10 microM) reduced the duration of RVD. Blockade of phospholipase A2 by quinacrine (10 microM) inhibited RVD by 53 %. Common inhibition of PGE2 and LTD4 synthesis by ETYA (50 microM) or separate blockade of PGE2 synthesis by 1 microM indomethacin reduced the duration of RVD. Blockade of LTD4 synthesis by nordihydroguaiaretic acid (NDGA) did not produce any significant effect on cell swelling or subsequent RVD. 9. Staurosporine (1 microM), an inhibitor of protein kinases, inhibited RVD by 58 %. Taken together the experiments demonstrate that the RVD process is under the control of conductive pathways, extra- and intracellular Ca2+ ions, protein kinases, prostaglandins and leukotrienes.

Animals↗
PubMed1999

Feedforward ankle strategy of balance during quiet stance in adults.

1. We studied quiet stance investigating strategies for maintaining balance. Normal subjects stood with natural stance and with feet together, with eyes open or closed. Kinematic, kinetic and EMG data were evaluated and cross-correlated. 2. Cross-correlation analysis revealed a high, positive, zero-phased correlation between anteroposterior motions of the centre of gravity (COG) and centre of pressure (COP), head and COG, and between linear motions of the shoulder and knee in both sagittal and frontal planes. There was a moderate, negative, zero-phased correlation between the anteroposterior motion of COP and ankle angular motion. 3. Narrow stance width increased ankle angular motion, hip angular motion, mediolateral sway of the COG, and the correlation between linear motions of the shoulder and knee in the frontal plane. Correlations between COG and COP and linear motions of the shoulder and knee in the sagittal plane were decreased. The correlation between the hip angular sway in the sagittal and frontal planes was dependent on interaction between support and vision. 4. Low, significant positive correlations with time lags of the maximum of cross-correlation of 250-300 ms were found between the EMG activity of the lateral gastrocnemius muscle and anteroposterior motions of the COG and COP during normal stance. Narrow stance width decreased both correlations whereas absence of vision increased the correlation with COP. 5. Ankle mechanisms dominate during normal stance especially in the sagittal plane. Narrow stance width decreased the role of the ankle and increased the role of hip mechanisms in the sagittal plane, while in the frontal plane both increased. 6. The modulation pattern of the lateral gastrocnemius muscle suggests a central program of control of the ankle joint stiffness working to predict the loading pattern.

Adult↗
PubMed1999

Case and control recruitment, and validation of cases for the MICA case-control study in England, Scotland and Wales.

OBJECTIVES: To describe the processes involved in the selection of cases and controls, and the validation of case diagnosis, in a large case-control study on the association between myocardial infarction (MI) and oral contraceptives. DESIGN: Community case-control study in England, Scotland and Wales. SUBJECTS: Cases were women aged 16-44 with a diagnosis of MI. Controls were age and general practice matched women without a diagnosis of MI. RESULTS: The proportion of interviewed cases per number eligible was 19% (95% CI 12-26%) lower in England and Wales than in Scotland. The kappa score for agreement between three cardiologists on diagnostic categories of the potential cases was 0.52 overall ('moderate' agreement). For the 35 cases resubmitted for categorization, the kappa scores for agreement between the first and second classification for the two national committee cardiologists were 0.32 and 0.23 ('fair' agreement). Age matching of controls was better in Scotland than England and Wales, the proportion of the first choice controls being 14% (95% CI 8-19%) higher in Scotland. The mean time to complete a cluster of interviews (one case and four controls) was 36 days in Scotland and 63 days in England and Wales. CONCLUSIONS: Very close age-matching was achieved overall, although the process was more efficient in Scotland than in England and Wales. Some suggestions for improvement in the case validation process are made.

Journal Article↗
PubMed1999

Tissue expression of the vesicle protein pantophysin.

The cell-type restricted expression of cytoplasmic microvesicle membrane protein isoforms may be a consequence of the functional adaptation of these vesicles to the execution of specialized processes in cells of different specialization. To characterize the expression of the vesicle protein pantophysin, an isoform of the synaptic vesicle proteins synaptophysin and synaptoporin, we have prepared and characterized antibodies useful for the immunological detection of pantophysin in vitro and in situ. Using these reagents, we show by immunoblot analyses that pantophysin expression is not homogeneous but differs significantly between various bovine tissues. Furthermore, these differences are not exactly paralleled by the expression of other vesicle proteins of the SCAMP (secretory carrier-associated membrane protein) and VAMP (vesicle-associated membrane protein) types that have previously been localized to pantophysin vesicles in cultured cells. By immunofluorescence microscopy, pantophysin expression is seen predominantly in non-neuroendocrine cells with pronounced membrane traffic. Pantophysin staining codistributes with SCAMP and VAMP immunoreactivities in most instances but differs in some. Remarkably, pantophysin staining in liver is restricted to cells surrounding sinusoids and is not detectable in hepatocytes, similar to that of the SCAMP and VAMP isoforms as detected by our reagents in tissue sections.

Animals↗
PubMed1999

Relationship between natriuretic peptides and hemodynamics in patients with heart failure at rest and after ergometric exercise.

Sixteen patients with heart failure who underwent right heart catherization were studied with regard to plasma natriuretic peptide levels and hemodynamic parameters at rest and immediately after symptom-limited ergometry. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured and correlated with left ventricular ejection fraction (LVEF), mean pulmonary arterial pressure (MPAP), pulmonary arterial wedge pressure (PAWP) and cardiac index (CI). Compared to normal controls, ANP and BNP were elevated at rest. During exercise ANP and BNP increased. BNP was highly significantly correlated with LVEF (P = 0.005) at rest, whereas ANP did not (P = 0.082). BNP significantly correlated with MPAP and PAWP after exercise and showed a significant inverse correlation with CI. Our data provide evidence that BNP might be a better indicator for LVEF at rest than ANP. In addition, BNP correlates very well with MPAP and PAWP, after exercise. This close correlation is likely to reflect a correlation of BNP with left ventricular enddistolic pressure in heart failure when patients are exposed to physical exercise.

Atrial Natriuretic Factor↗