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Biomedical subjects

S A Kaye

Publications and source records attributed to S A Kaye.

At least 19 recordsLinked to original sources
PubMed2003

Long-term remission from gout associated with fenofibrate therapy.

Short-term studies with fenofibrate, an established treatment for hyperlipidaemia, have shown that its unique side effect of urate lowering is mediated through enhanced renal urate clearance. The long-term effects of fenofibrate on hyperuricaemia and gout have not previously been reported. We report two patients with hyperlipidaemia in association with hyperuricaemia in whom long-term fenofibrate therapy was associated with a sustained reduction in serum urate and lipid levels, together with remission from recurrent attacks of acute gout. The mechanisms involved in these effects and the potential role for fenofibrate in the management of gout are discussed.

Fenofibrate↗
PubMed2003

Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout.

OBJECTIVE: To assess the short-term urate-lowering effect of fenofibrate in men on long-term allopurinol therapy for hyperuricaemia and gout. METHODS: Ten male patients (38-74 yr) with a history of chronic tophaceous or recurrent acute gout with hyperuricaemia and on established allopurinol at 300-900 mg/day for > or =3 months were studied in an open-crossover study of fenofibrate therapy. Allopurinol at the established dose was continued throughout the study. Clinical and biochemical assessments (serum urate and creatinine, 24-h urinary excretion of urate and creatinine, liver function tests, creatine kinase and fasting serum lipids) were undertaken at: (i) baseline, (ii) after 3 weeks of once-daily therapy with micronized fenofibrate (Lipantil Micro) at 200 mg and (iii) 3 weeks after fenofibrate was withdrawn. RESULTS: Fenofibrate was associated with a 19% reduction in serum urate after 3 weeks of treatment (mean+/-S.E. 0.37+/-0.04 vs 0.30+/-0.02 mM/l; P=0.004). The effect was reversed after a 3-week fenofibrate withdrawal period (0.30+/-0.02 vs 0.38+/-0.03 mM/l). There was a rise in uric acid clearance with fenofibrate treatment of 36% (7.2+/-0.9 vs 11.4+/-1.6 ml/min, normal range 6-11; P=0.006) without a significant change in creatinine clearance. Both total cholesterol and serum triglycerides were also reduced. No patient developed acute gout whilst taking fenofibrate. CONCLUSIONS: Fenofibrate has a rapid and reversible urate-lowering effect in patients with hyperuricaemia and gout on established allopurinol prophylaxis. Fenofibrate may be a potential new treatment for hyperuricaemia and the prevention of gout, particularly in patients with coexisting hyperlipidaemia or those resistant to conventional therapy for hyperuricaemia.

Acute Disease↗
PubMed1997

Determinants of nonthoracotomy biphasic defibrillation.

The clinical variables affecting DFT for ICD systems are not completely determined, especially with regard to biphasic shocking devices. To distinguish which factors correlate with DFT, we examined data from patients who were enrolled in the Ventak P2/Endotak protocol. A total of 284 patients were enrolled in the study. Two patients had a DFT > 25 J and did not receive the device; 154 did not undergo stepdown to failure DFT testing. The remaining 128 patients had formal DFT testing and were suitable for analysis. Variables available for analysis included age, body surface area (BSA), LVEF, gender, lead configuration, primary arrhythmia, primary cardiac disease, and use of cardioactive medication. Data were evaluated using regression analysis, fitting DFT (range, 1-25 J, mean 11 +/- 5 J) as a function of each variable. As a univariate predictor. BSA was found to be significant in predicting DFT, but accounted for only 9% of the total variation on the DFT (P < 0.01, r = 0.3). This study suggests that DFT using a biphasic shocking waveform is modestly in fluenced by the BSA of the patient. Other specific factors, including LVEF, do not predict DFT.

Age Factors↗
PubMed1996

Detection of early asymptomatic esophageal dysfunction in systemic sclerosis using a new scintigraphic grading method.

OBJECTIVE: To screen patients with systemic sclerosis (SSc) for esophageal disease and to demonstrate a new system of grading dysmotility; to determine the relationship between the symptom of dysphagia and the degree of hypomotility shown by scintigraphy. METHODS: 301 patients with SSc were studied by esophageal scintigraphy using a semisolid orally ingested bolus to detect esophageal dysfunction and gastroesophageal reflux. A new system of grading was used to quantitate the degree of dysfunction, ranging from grade 0 (normal) to grade 4 (severe abnormality). RESULTS: 246 (82%) patients in the study population had evidence of esophageal hypomotility. Gastroesophageal reflux was noted in 83 (28%) patient. The largest number of patients (33%) were found to have grade 2 abnormalities. The number of patients with reflux decreased with increasing severity of grade, from grade 2 to grade 4 (35 to 13%). A retrospective study of the symptoms of 50 of the total study population showed that increasing severity of grade correlated with increasing mean duration of SSc. There was no significant relationship between disease subset and the presence or severity of esophageal hypomotility. 60% of patients in grades 1 and 2 (i.e. with observed dysmotility shown on scintigraphy) had no symptoms of dysphagia. In the more severe grades (scan grades 3 and 4), symptoms of dysphagia correlated with increase in grade. CONCLUSION: Symptoms may be unreliable in judging the presence of extent of esophageal disease in SSc. Esophageal scintigraphy is a useful noninvasive screening test for the detection of asymptomatic disease. The new grading system provides information that rapidly identifies the stage of esophageal disease and gives comparative data for followup and interventional studies.

Adolescent↗
PubMed1995

Small bowel bacterial overgrowth in systemic sclerosis: detection using direct and indirect methods and treatment outcome.

Twenty-four patients with proven systemic sclerosis and with symptoms suggestive of malabsorption (i.e. chronic diarrhoea and weight loss) were investigated for small bowel bacterial overgrowth. Of the patients selected, six were suffering from the diffuse form of the disease. Jejunal aspiration was performed in all patients, and in nine normal volunteers. A specially designed double-lumen sterile catheter was used for this purpose and was introduced via a gastroscope. Twenty of these patients underwent a glucose hydrogen breath test. Eight patients (33%) had significant bacterial counts: > 10(5) colony forming units per ml (cfu/ml) of jejunal fluid. Less than 10(2) cfu/ml were found in the jejunal fluid from the nine control subjects. Glucose hydrogen breath testing was positive in seven patients, all of whom had significant jejunal bacterial growth. Diarrhoea rather than weight loss was shown to be the symptom which correlated best with the presence of bacterial overgrowth. Ciprofloxacin was used in six patients whose diarrhoeal symptoms ceased dramatically within 48 h of commencing the antibiotic. Trimethoprim produced a partial response despite bacterial sensitivity. A disadvantage of the hydrogen breath test is that subsequent antibacterial therapy cannot be specific, as bacterial species, antibiotic sensitivity and resistance are unknown. Systemic sclerosis involving the small intestine in the past has been said to more prevalent in patients with diffuse disease, whereas this study showed a preponderance of patients with long-standing limited cutaneous systemic sclerosis and small bowel involvement.

Adult↗
PubMed1995

Shiga toxin-associated hemolytic uremic syndrome: effect of sodium butyrate on sensitivity of human umbilical vein endothelial cells to Shiga toxin.

Escherichia coli O157:H7-related vascular damage such as hemolytic uremic syndrome is believed to require the Shiga-like toxins. This study demonstrated that sodium butyrate sensitized human umbilical vein endothelial cells to Shiga toxin and increased the expression of Shiga toxin receptor, globotriaosylceramide (Gb3), on human umbilical vein endothelial cells.

Bacterial Toxins↗
PubMed1994

Characterization of Pseudomonas aeruginosa mutants that are deficient in exotoxin A synthesis and are altered in expression of regA, a positive regulator of exotoxin A.

In Pseudomonas aeruginosa, production of exotoxin A, an ADP-ribosyltransferase, is a complex and highly regulated process. Two positively acting regulatory genes, regA and regB, have been cloned and characterized. To identify additional exotoxin A regulatory genes, we have characterized four N-methyl-N'-nitro-N-nitrosoguanidine-generated mutants of P. aeruginosa PA103 which are deficient in exotoxin A production. These mutants (PA103-8, PA103-15, PA103-16, and PA103-19) do not accumulate intracellular exotoxin A and are not complemented by the cloned toxA or regAB genes. This observation indicates that the lesion(s) in the mutants is probably in an exotoxin A regulatory gene(s) and is not in the genes for secretion of exotoxin A or in the toxA or regAB genes. To assess the effect of the putative regulatory mutations on the toxA and regAB genes, we compared the activity of the toxA and regAB promoters in the mutant and parental strains using plasmids containing the genes for beta-galactosidase or chloramphenicol acetyltransferase under the control of either the toxA or the regAB promoter. The toxA promoter-beta-galactosidase fusion plasmid could not be maintained in PA103-8. beta-Galactosidase expression driven by the toxA promoter was absent in the mutant PA103-19 and occurred at a low level, which was not repressed by iron in mutants PA103-15 and PA103-16. The regAB genes are temporally controlled by two promoters, P1 and P2. In all four mutants, regAB P1 promoter activity was reduced; however, expression under the control of the regAB P2 promoter was normal. These observations suggest the existence of one or more regulatory genes which directly affect expression of both the toxA and the regAB P1 promoters.

ADP Ribose Transferases↗
PubMed1994

Ischaemia of the small intestine in patients with systemic sclerosis: Raynaud's phenomenon or chronic vasculopathy?

We investigated duodenal and gastric mucosal blood flow by endoscopic laser Doppler flowmetry (LDF) in ten patients with systemic sclerosis (SSc) and in ten healthy volunteers. In addition, we tested for the presence of small bowel bacterial overgrowth by jejunal aspiration. Jejunal aspiration and LDF were done consecutively, via a gastroscope, using a flexible catheter and laser Doppler probe. Following these procedures, two duodenal biopsies were obtained for light and electron microscopy. Mean duodenal and gastric blood flow were significantly lower in patients with SSc than in normal subjects (516 flux units vs. 240, 521 vs. 202, both p < 0.001). There was no correlation between age and blood flow in patients or volunteers. Four of the ten patients had evidence of significant bacterial overgrowth on jejunal aspiration (> 10(5) colony-forming units/ml). These findings support the hypothesis that within the small intestine of patients with SSc, factors independent of bacterial overgrowth may be responsible for malabsorption. The observed reduction in small-intestine mucosal blood flow may play an important contributory role. Further studies are required to determine whether this represents reversible or chronic progressive ischaemia, and its effect on nutrient absorption.

Adult↗
PubMed1993

Body fat distribution and 5-year risk of death in older women.

OBJECTIVE: To test the hypothesis that both body mass index (expressed as the ratio of weight in kilograms per height in meters squared) and the ratio of waist circumference to hip circumference are positively associated with mortality risk in older women. DESIGN: Prospective cohort study with a 5-year follow-up period. SETTING: General community. PARTICIPANTS: Random sample of 41,837 Iowa women aged 55 to 69 years. MAIN OUTCOME MEASURE: Total mortality (1504 deaths). MAIN RESULTS: Body mass index, an index of relative weight, was associated with mortality in a J-shaped fashion: rates were elevated in the leanest as well as in the most obese women. In contrast, waist/hip circumference ratio was strongly and positively associated with mortality in a dose-response manner. Adjusted for age, body mass index, smoking, education level, marital status, estrogen use, and alcohol use, a 0.15-unit increase in waist/hip circumference ratio (eg, a 15-cm [6-in] increase in waist measurement in a woman with 100-cm [40-in] hips) was associated with a 60% greater relative risk of death. The observed associations were not explained to any great degree by bias from weight loss prior to baseline or higher early deaths among lean participants. CONCLUSIONS: Waist/hip circumference ratio is a better marker than body mass index of risk of death in older women. Waist/hip circumference ratio should be measured as part of routine surveillance and risk monitoring in medical practice.

Adipose Tissue↗
PubMed1993

Central adiposity and increased risk of coronary artery disease mortality in older women.

The relation between central adiposity, measured by the waist/hip circumference ratio (WHR), and 4-year risk of fatal coronary artery disease was examined in a large cohort (n = 32,898) of women aged 55 to 69 years. The age-adjusted relative risk of death from coronary artery disease (115 deaths) was 3.3 for women in the highest tertile of WHR compared to the lowest tertile (95% confidence interval: 2.0, 5.6). After adjustment for age, body mass, smoking, physical activity, estrogen use, marital status, and alcohol intake, the relative risk of coronary death for women in the middle and highest tertiles versus those in the lowest tertile of WHR were 1.3 and 2.8, respectively (P for linear trend < 0.001). Further adjustment for hypertension and diabetes mellitus reduced the estimates slightly to 1.2 and 2.0, but the trend in relative risk remained statistically significant (P = 0.03). In contrast, body mass index showed no independent association with coronary death. Hypertension, diabetes mellitus, cigarette smoking, estrogen nonuse, and being unmarried were significant predictors of greater risk of coronary death in the multivariate model. These results indicate that central adiposity, reflected by an increased WHR, is an important risk factor for death from coronary artery disease in women, most of whom were postmenopausal. The association of central adiposity with risk of coronary death is independent, for the most part, of its association with hypertension and diabetes.

Adipose Tissue↗
PubMed1993

Shiga toxin-associated hemolytic uremic syndrome: interleukin-1 beta enhancement of Shiga toxin cytotoxicity toward human vascular endothelial cells in vitro.

Development of hemolytic uremic syndrome (HUS) after infection by Shigella dysenteriae 1 or enterohemorrhagic Escherichia coli has been associated with the production of Shiga toxins (verotoxins). The putative target of Shiga toxins in HUS is the renal microvascular endothelium. This report shows that preincubation of human umbilical vein endothelial cells (HUVEC) with interleukin-1 beta (IL-1 beta) enhances the cytotoxic potency of Shiga toxin toward HUVEC. A preincubation of HUVEC with IL-1 beta is required for sensitization of HUVEC to Shiga toxin. Sensitization of HUVEC to Shiga toxin is IL-1 beta dose dependent. Development of the IL-1 beta response is time dependent, beginning within 2 h of IL-1 beta preincubation and increasing over the next 24 h. That these responses were due to IL-1 beta was demonstrated by heat inactivation of IL-1 beta, by neutralization of IL-1 beta by specific antibody, and by the ability of an IL-1 beta receptor antagonist to inhibit the effect of IL-1 beta. Shiga toxin-related inhibition of HUVEC protein synthesis preceded loss of cell viability. IL-1 beta incubation with HUVEC induced the receptor for Shiga toxin, globotriaosylceramide. Lipopolysaccharide included during IL-1 beta preincubation with HUVEC increased sensitivity to Shiga toxin in an additive manner. We conclude that IL-1 beta may induce Shiga toxin sensitivity in endothelial cells and contribute to the development of HUS.

Bacterial Toxins↗
PubMed1993

Psychosocial correlates of body fat distribution in black and white young adults.

We examined the association of fat distribution with a number of personality attributes and behaviours in a sample of 5115 young blacks and whites. Body fat distribution, measured by the ratio of waist-to-hip circumferences (WHR), was significantly and positively associated with cigarette smoking and negatively associated with education in all of the race and sex groups. WHR was positively associated with alcohol consumption in men and black women and with marijuana use in women. A number of psychosocial factors assessing personality attributes and behaviours were also examined, including the Cook-Medley hostility score, type A/B behaviour pattern, life events, social support, financial situation, and diagnosis of a nervous, emotional or mental disorder. In age- and BMI-adjusted analyses, only the Cook-Medley hostility score and a financial situation score were significantly and positively associated with WHR in all race and sex groups. In multivariate linear regression, these psychosocial factors were associated with WHR in some of the race and sex groups, accounting for less than 1% of the variation in WHR in any one group. These results suggest that fat distribution is weakly associated with these personality attributes and behaviours.

Adipose Tissue↗
PubMed1992

Dietary fat and postmenopausal breast cancer.

BACKGROUND: Although the results of animal studies and cross-cultural comparisons generally support a role for dietary fat in the etiology of breast cancer, results of analytic epidemiology studies are equivocal. PURPOSE: The association between dietary fat and subsequent breast cancer was examined in a cohort of 34,388 postmenopausal women from Iowa. METHODS: Dietary habits were assessed by a food-frequency questionnaire mailed in January 1986. Through December 31, 1989, 459 incident cases of breast cancer occurred in this cohort. Proportional hazards regression was used to examine the dietary fat-breast cancer association while adjusting for potential confounders. The effects on this association of four analytic approaches to adjustment for energy intake were also considered. RESULTS: After adjustment for known determinants of breast cancer, a modest positive association of total fat intake with risk of breast cancer was seen. Polyunsaturated fat intake was also positively associated with breast cancer (relative risk from lowest to highest intake, 1.0, 1.25, 1.31, and 1.49; P for trend = .052). Different approaches to adjustment for energy intake, however, provided different impressions of the dietary fat-breast cancer association. One method, involving categorization of crude fat intake and inclusion of total energy intake in regression analysis, gave relative risk estimates from low to high fat intake of 1.0, 1.17, 1.25, and 1.38 (P for trend = .18). Another method, based on categorization of fat intake residuals in which the variation in fat due to total energy intake was removed, gave corresponding estimates of 1.0, 1.24, 1.30, and 1.16 (P for trend = .29). The former suggests increasing breast cancer risk with increasing fat intake; the latter suggests no association. CONCLUSIONS: These results are consistent with other cohort studies that have shown a weak association or no association between dietary fat and breast cancer. They are also consistent with studies suggesting that fat intake is a determinant of breast cancer, particularly after accounting for inaccuracies in dietary assessment. The effects of different energy-adjustment methods may account in part for the varying interpretations of four previous cohort studies of dietary fat and breast cancer. IMPLICATIONS: Further work is needed to clarify not only the nature of the dietary fat-breast cancer association, but also the impact of different analytic methods used in the investigation of diet-disease associations.

Aged↗