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Biomedical subjects

S Wild

Publications and source records attributed to S Wild.

17 recordsLinked to original sources
PubMed2000

Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with higher prevalence of cardiovascular risk factors but the relative prevalence of cardiovascular disease in women with PCOS has not previously been reported. We have compared cardiovascular mortality and morbidity in middle-aged women previously diagnosed with PCOS and age-matched control women. DESIGN: A retrospective cohort study of women diagnosed with PCOS in the United Kingdom before 1979. PATIENTS: Seventy cohort members died before 31 March 1999. Morbidity data were collected from 319 women with PCOS and 1060 age-matched control women. Sixty-one women with PCOS and 63 control women attended a clinical examination. MEASUREMENTS: Data were collected from death certificates, general practitioners' records and questionnaires with measurement of cardiovascular risk factors in a subsample of questionnaire respondents. RESULTS: All-cause and cardiovascular mortality in the cohort were similar to women in the general population (standardized mortality ratios (95% CI): 93 (72-117) and 78 (45-124), respectively). Women with PCOS had higher levels of several cardiovascular risk factors: diabetes (P = 0.002) hypertension (P = 0.04), hypercholesterolaemia (P < 0.001), hypertriglyceridaemia (P = 0.02) and increased waist:hip ratio (P = 0.004). After adjustment for BMI, odds ratios (OR) were 2.2 (0.9-5. 2) for diabetes, 1.4 (0.9-2.0) for hypertension and 3.2 (1.7-6.0) for hypercholesterolaemia. A history of coronary heart disease (CHD) was not significantly more common in women with PCOS (crude OR (95%CI) 1.5 (0.7-2.9)) but the crude OR for cerebrovascular disease was 2.8 (1.1-7.1). CONCLUSION: At long-term follow-up, a history of nonfatal cerebrovascular disease and cardiovascular risk factors including diabetes are more prevalent among women with polycystic ovary syndrome. Morbidity and mortality from of coronary heart disease among women with polycystic ovary syndrome is not as high as previously predicted. This finding challenges our understanding of the aetiology of coronary heart disease in women.

Aged↗
PubMed1999

Synthesis of 1-(2-aminophenyl)isoquinolines and the biological activity of their cis-dichloro platinum(II) complexes.

The broad biological effects of isoquinolines prompted us to use them as chelating, nonleaving ligands in cis-platinum(II) antitumor complexes. The synthesis of several 1-(2-aminophenyl)isoquinoline derivatives with different levels of hydrogenation and varying substitution of the phenyl ring is reported. These compounds constitute a new class of ligands for the synthesis of oligocyclic platinum(II) complexes. In vitro cytotoxicity tests indicate that the most basic amine ligands afford the most effective complexes. Two of the new complexes were more potent against L1210 murine leukemia cells than the well-established antitumor compound cisplatinum.

Animals↗
PubMed1999

Serum vascular endothelial growth factor concentrations in in vitro fertilization cycles predict the risk of ovarian hyperstimulation syndrome.

OBJECTIVE: To explore the value of serum vascular endothelial growth factor (VEGF) concentrations during IVF cycles in predicting the risk of ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective study. SETTING: London Women's Clinic. PATIENT(S): One hundred seven women undergoing IVF. Mild OHSS developed in 10 women, moderate OHSS in 7, and severe OHSS in 3. INTERVENTION(S): Serum VEGF concentrations were measured before treatment, after pituitary desensitization, and on the days of hCG administration, oocyte collection, and ET. MAIN OUTCOME MEASURE(S): Serum VEGF concentrations. RESULT(S): Serum VEGF concentrations were higher in women in whom OHSS developed. The increase in the VEGF concentration that occurred between the day of hCG administration and the day of oocyte collection (the "VEGF rise") was an important marker of OHSS. The VEGF rise was higher in women in whom OHSS developed. A higher VEGF rise predicted all cases of OHSS and moderate/severe cases of OHSS with a sensitivity of 100% and a specificity of 60%. A likelihood ratio test showed that adding the VEGF rise or the VEGF concentration on the day of oocyte collection to a regression model as a continuous variable to the number of follicles, the E2 concentration, and the presence of polycystic ovaries significantly contributed to predicting the risk of OHSS. CONCLUSION(S): The results support the role of VEGF as an important nonsteroidal index of ovarian response. The VEGF rise may have an advantage over the E2 concentration, the number of follicles, and the number of oocytes, which individually predict only 15%-25% of cases of OHSS.

Adult↗
PubMed1998

Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide.

Glutathione peroxidases have been thought to function in cellular antioxidant defense. However, some recent studies on Gpx1 knockout (-/-) mice have failed to show a role for Gpx1 under conditions of oxidative stress such as hyperbaric oxygen and the exposure of eye lenses to high levels of H2O2. These findings have, unexpectedly, raised the issue of the role of Gpx1, especially under conditions of oxidative stress. Here we demonstrate a role for Gpx1 in protection against oxidative stress by showing that Gpx1 (-/-) mice are highly sensitive to the oxidant paraquat. Lethality was already detected within 24 h in mice exposed to paraquat at 10 mg.kg-1 (approximately (1)/(7) the LD50 of wild-type controls). The effects of paraquat were dose-related. In the 30 mg.kg-1-treated group, 100% of mice died within 5 h, whereas the controls showed no evidence of toxicity. We further demonstrate that paraquat transcriptionally up-regulates Gpx1 in normal cells, reinforcing a role for Gpx1 in protection against paraquat toxicity. Finally, we show that cortical neurons from Gpx1 (-/-) mice are more susceptible to H2O2; 30% of neurons from Gpx1 (-/-) mice were killed when exposed to 65 microM H2O2, whereas the wild-type controls were unaffected. These data establish a function for Gpx1 in protection against some oxidative stressors and in protection of neurons against H2O2. Further, they emphasize the need to elucidate the role of Gpx1 in protection against different oxidative stressors and in different disease states and suggest that Gpx1 (-/-) mice may be valuable for studying the role of H2O2 in neurodegenerative disorders.

Animals↗
PubMed1998

Hyperpolarization of the cell membrane of mouse hepatocytes by lactate, pyruvate, and fructose is due to Ca2+-dependent activation of K+ channels and of the Na+/K+-ATPase.

Using superfused mouse liver slices combined with a conventional microelectrode technique, we investigated: (1) the ionic mechanisms involved in the hyperpolarization of the hepatocyte membrane induced by lactate and other gluconeogenic substrates; (2) whether these mechanisms are similar to those underlying the hyperpolarization induced by cell swelling in hypo-osmotic medium; and (3) whether the hyperpolarizing effect of lactate on the hepatocyte membrane is related to gluconeogenesis. Lactate (5 mmol/l) hyperpolarized the hepatocyte membrane after an exposure of 10-20 min, and the hyperpolarization was still present after 70 min. The hyperpolarization induced by lactate, pyruvate (5 mmol/l) and fructose (10 mmol/l), and by exposure to hypo-osmotic medium (250 mosmol/l) was antagonized by ouabain, tetraethylammonium (TEA), and cetiedil (lactate; hypo-osmotic medium). Hyperpolarization induced by lactate was eliminated or attenuated by agents impairing activation of Ca2+-dependent K+ channels, by amiloride, and by a blockade of non-selective cation channels with flufenamic acid and gadolinium. Thapsigargin, increasing cytosolic Ca2+, mimicked lactate's hyperpolarizing effect. Lactate's effect was dependent on extracellular Ca2+. Finally, lactate's hyperpolarizing effect was reduced by inhibiting gluconeogenesis. These findings suggest that metabolism of lactate hyperpolarizes hepatocytes by mechanisms analogous to those underlying the hyperpolarization induced by cell swelling in hypo-osmotic medium. Gluconeogenesis from lactate may cause cell swelling, subsequent activation of Ca2+-dependent K+ channels and of the Na+/K+-ATPase, and thus hyperpolarize the hepatocyte membrane.

Amiloride↗
PubMed1997

Cross sectional analysis of mortality by country of birth in England and Wales, 1970-92.

OBJECTIVE: To compare mortalities for selected groups of immigrants with the national average. DESIGN: Analysis of mortality for adults aged 20-69 in 1970-2 and 1989-92 using population data from 1971 and 1991 censuses. Mortality of Scottish and Irish immigrants aged 25-74 was also compared with mortality in Scotland and Ireland for 1991. SETTING: England and Wales. MAIN OUTCOME MEASURES: Standardised mortality ratios for deaths from all causes, ischaemic heart disease, cerebrovascular disease, lung cancer, and breast cancer. RESULTS: In 1989-92 mortality from all causes was higher than the national average for Scottish immigrants, by 32% for men and 36% for women; for Irish immigrants it was higher by 39% for men and 20% for women; and for Caribbean born men it was lower by 23%. Ischaemic heart disease and lung cancer accounted for 30-40% of the excess mortality in Scottish and Irish immigrants. For south Asians, excess mortality from circulatory disease was balanced by lower mortality from cancer. Standardised mortality ratios for cerebrovascular disease in 1989-92 were highest for west African immigrants (271 for men and 181 for women). CONCLUSIONS: Widening differences in mortality ratios for migrants compared with the general population were not simply due to socioeconomic inequalities. The low mortality from all causes for Caribbean immigrants could largely be attributed to low mortality from ischaemic heart disease, which is unexplained. The excess mortality from cerebrovascular and hypertensive diseases in migrants from both west Africa and the Caribbean suggests that genetic factors underlie the susceptibility to hypertension in people of black African descent.

Adult↗
PubMed1997

The case-conferencing project: a first step towards shared care between general practitioners and a mental health service.

OBJECTIVES: The objectives of this study were: (i) to improve general practitioners' knowledge of the mental disorders they commonly treat, and to increase their confidence in managing people with these disorders; and (ii) to increase general practitioners' familiarity with the Logan-Beaudesert Mental Health Service. METHOD: Eleven general practitioners met with psychiatrists from the Logan-Beaudesert Mental Health Service in six 2-hour sessions held at monthly intervals. Each session comprised a teaching component, a consumer interview and a case-conference. Outcomes were measured using an objective test of general practitioners' knowledge, a subjective test of their confidence in dealing with mental health problems, and satisfaction surveys for participating consumers, general practitioners and psychiatrists. RESULTS: On the objective test, the scores of 10 out of the 11 general practitioners improved (p < 0.05). On the subjective test, the ranked scores improved in nine out of the 11 cases (p < 0.05). Consumers, general practitioners and psychiatrists expressed their satisfaction with the format and content of the course. CONCLUSIONS: Having improved the knowledge of a group of general practitioners who are familiar with the functioning of the Logan-Beaudesert Mental Health Service, the stage is now set to proceed to the next step: the shared-care project.

Adolescent↗
PubMed1996

Physicochemical and metabolic basis for the differing neurotoxicity of the pyrrolizidine alkaloids, trichodesmine and monocrotaline.

Monocrotaline and trichodesmine are structurally closely related pyrrolizidine alkaloids (PAs) exhibiting different extrahepatic toxicities, trichodesmine being neurotoxic (LD(50) 57 mu mol/kg) and monocrotaline pneumotoxic (LD(50) 335 mu mol/kg). We have compared certain physicochemical properties and metabolic activities of these two PAs in order to understand the quantitative and qualitative differences in toxicity. Both PAs were metabolized in the isolated, perfused rat liver to highly reactive pyrrolic dehydroalkaloids that appear to be responsible for the toxicity of PAs. More dehydrotrichodesmine (468 nmol/g liver) than dehydromonocrotaline (116 nmol/g liver) was released from liver into perfusate on perfusion for 1 hr with 0.5 mM of the parent PA. Dehydrotrichodesmine had a significantly longer aqueous half-life (5.4 sec) than that of dehydromonocrotaline (3.4 sec). In vivo, significantly higher levels of bound pyrroles were found in the brain 18 hr after injection of trichodesmine (25 mg/kg; i.p.) than were seen following either an equal dose (25 mg/kg; i.p.) or an equitoxic dose (90 mg/kg; i.p.) of monocrotaline. Trichodesmine had a higher partition coefficient than monocrotaline for both chloroform and heptane, indicating its greater lipophilicity. The pK(a) of trichodesmine (7.07) was only slightly higher than that of monocrotaline (pK(a¿ 6.83), suggesting that a difference in degree of ionization was not a major factor affecting the relative ability of the dehydroalkaloids to cross the blood-brain barrier. We conclude that the greater lethality and neurotoxicity of trichodesmine compared to monocrotaline is due to two structural characteristics: (i) steric hindrance at position 14 of dehydrotrichodesmine results in greater resistance to hydrolysis, allowing more to be released from the liver and to be delivered to the brain; (ii) the larger isopropyl substituent at position 14 of dehydrotrichodesmine renders the molecule more lipophilic, leading to greater penetration of the brain.

Alkaloids↗
PubMed1987

Atrial natriuretic factor in acute and chronic cardiac failure.

Water, sodium, and potassium balance and urinary excretion of norepinephrine and aldosterone were investigated in rats with left ventricular failure due to left ventricular infarction, and measurements were obtained of plasma levels of atrial natriuretic factor (ANF). Increased plasma levels of ANF in relation to the size of the infarction and to the right atrial and left ventricular end-diastolic pressure were found. The augmented levels of ANF were not able to prevent an accumulation of sodium in the rats with myocardial infarction in which urinary excretion of norepinephrine and aldosterone was unchanged in comparison to control values. Plasma levels of ANF in the pulmonary artery, aorta, and renal vein of six conscious dogs were studied during the development of heart failure due to rapid right ventricular pacing. A threefold increase in ANF was found: ANF levels did not differ between the pulmonary artery and the aorta, but a reduction in ANF of about 30% was reported in the renal vein in comparison to the arteries. A close positive correlation between right atrial pressure and plasma levels of ANF was noted. No correlation could be demonstrated between mean pulmonary arterial pressure and ANF or between the stimulated plasma renin concentration and plasma ANF values.

Acute Disease↗
PubMed1984

Evaluation of the effects of catheter sampling for the study of platelet behavior in the pulmonary and coronary circulation.

To study the effects of sampling through cardiac catheters on indices of platelet function, we measured the levels of platelet factor 4 (PF4), beta thromboglobulin (BTG), and platelet aggregate ratio (PAR) in 10 patients with atrioventricular accessory pathway (AVNAP), six patients with primary pulmonary hypertension (PPH), and six patients with critical narrowing of the left anterior descending artery (LAD). In AVNAP and LAD patients samples were drawn simultaneously from a peripheral vein, coronary sinus, and brachial artery; in AVNAP patients samples were also obtained from the axillary vein before the coronary sinus was entered. In PPH patients samples were drawn from pulmonary artery, aorta, and a peripheral vein; in these patients the effects of an intravenous infusion of prostacyclin (PGI2) (2 to 8 ng/kg/min) on PF4, BTG, and PAR were also studied at all sampling sites. In all patients arterial, coronary sinus, pulmonary arterial, and axillary venous levels of PF4, BTG, and PAR significantly exceeded those measured in the peripheral vein. PGI2 infusion resulted in a significant decrease of PF4 at all sampling sites, while no consistent BTG changes were observed and PAR levels did not decrease in the peripheral vein. Although a considerable interpatient variability in PF4 levels was observed, a significant (r = 0.91) correlation was found in patients with AVNAP between simultaneous coronary sinus and arterial PF4 levels. The value of PF4 coronary sinus-arterial difference in LAD patients was consistently higher than that calculated in AVNAP patients (54.5 +/- 28.9 vs 4.2 +/- 3.8 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗