Effects of obesity and body fat distribution on lipids and lipoproteins in nondiabetic American Indians: The Strong Heart Study.

OBJECTIVES: To examine the relationship between obesity and lipoprotein profiles and compare the effects of total obesity and central adiposity on lipids/lipoproteins in American Indians. RESEARCH METHODS AND PROCEDURES: Participants were 773 nondiabetic American Indian women and 739 men aged 45 to 74 years participating in the Strong Heart Study. Total obesity was estimated using body mass index (BMI). Central obesity was measured as waist circumference. Lipoprotein measures included triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein AI (apoAI), and apolipoprotein B (apoB). Partial and canonical correlation analyses were used to examine the associations between obesity and lipids/ lipoproteins. RESULTS: Women were more obese than men in Arizona (median BMI 32.1 vs. 29.2 kg/m2) and South Dakota and North Dakota (28.3 vs. 28.0 kg/m2), but there was no sex difference in waist circumference. Men had higher apoB and lower apoAI levels than did women. In women, when adjusted for center, gender, and age, BMI was significantly related to HDL cholesterol (r = -0.24, p < 0.001). There was a significant but weak relation with apoAI (r = -0.14, p < 0.001). Waist circumference was positively related to triglycerides (r = 0.14, p < 0.001) and negatively related to HDL cholesterol (r = -0.23, p < 0.001) and apoAI (r = -0.13, p < 0.001). In men, BMI was positively correlated with triglycerides (r = 0.30, p < 0.001) and negatively correlated with HDL cholesterol (r = -0.35, p < 0.001) and apoAI (r = -0.23, p < 0.001). Triglycerides increased with waist circumference (r = 0.30, p < 0.001) and HDL cholesterol decreased with waist circumference (r = -0.36, p < 0.001). In both women and men there was an inverted U-shaped relationship between obesity and waist with LDL cholesterol and apoB. In canonical correlation analysis, waist circumference received a greater weight (0.86) than did BMI (0.17) in women. However, the canonical weights were similar for waist (0.46) and BMI (0.56) in men. Only HDL cholesterol (-1.02) carried greater weight in women, whereas in men, triglycerides (0.50), and HDL cholesterol (-0.64) carried a large amount of weight. All the correlation coefficients between BMI, waist circumference, and the first canonical variable of lipids/lipoproteins or between the individual lipid/lipoprotein variables and the first canonical variable of obesity were smaller in women than in men. Triglycerides and HDL cholesterol showed clinically meaningful changes with BMI and waist circumference in men. All lipid/lipoprotein changes in women in relation to BMI and waist circumference were minimal. DISCUSSION: The main lipoprotein abnormality related to obesity in American Indians was decreased HDL cholesterol, especially in men. Central adiposity was more associated with abnormal lipid/lipoprotein profiles than general obesity in women; both were equally important in men.

Relation of generalized and central obesity to cardiovascular risk factors and prevalent coronary heart disease in a sample of American Indians: the Strong Heart Study.

OBJECTIVE: To examine the hypothesis linking measures of obesity including body mass index (BMI), waist circumference (waist) and percentage body fat to coronary heart disease (CHD) prevalence and its risk factors in American Indians. DESIGN: The Strong Heart Study assesses the prevalence of CHD and its risk factors in American Indians in Arizona, Oklahoma and South/North Dakota. Participants underwent a physical examination and an electrocardiogram; anthropometric and blood pressure measurements were taken, as were measurements of glucose, lipoproteins, fibrinogen, insulin, hemoglobin A1c and urinary albumin. PARTICIPANTS: Data were available for 4549 men and women between 45 and 74 y of age. MEASUREMENTS: Obesity, measured using body mass index, waist circumference and percentage body fat, was correlated with prevalent CHD and its risk factors. RESULTS: More than 75% of participants were overweight (BMI>25 kg/m2). Measures of obesity were greater in women than in men, in younger than in older participants, and in participants with diabetes than in nondiabetic participants. CHD risk factors were associated with measures of obesity but, except for insulin concentration, changes in metabolic variables with increasing obesity were small. Associations were not stronger with waist than with BMI. The prevalence of CHD in those whose BMI and/or waist measurements lay in the lowest and highest quintiles, by gender and diabetic status, was similar. CONCLUSIONS: Although CHD risk factors are associated with obesity in American Indians, distribution of obesity (ie waist) is no more closely related to risk factors than is generalized obesity (ie BMI), and changes in CHD risk factors with obesity were small. Thus, the relations among obesity, body fat distribution and CHD risk may differ in this population.

LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study.

Diabetes has been shown to increase the risk of coronary heart disease in all populations studied. However, there is a lack of information on the relative importance of diabetes-associated risk factors for cardiovascular disease (CVD), especially the role of lipid levels, because low density lipoprotein (LDL) cholesterol often is not elevated in diabetic individuals. The objective of this analysis was to evaluate CVD risk factors in a large cohort of diabetic individuals and to compare the importance of dyslipidemia (ie, elevated triglycerides and low levels of high density lipoprotein [HDL] cholesterol) and LDL cholesterol in determining CVD risk in diabetic individuals. The Strong Heart Study assesses coronary heart disease and its risk factors in American Indians in Arizona, Oklahoma, and South/North Dakota. The baseline clinical examinations (July 1989 to January 1992) consisted of a personal interview, physical examination, and drawing of blood samples for 4549 study participants (2034 with diabetes), 45 to 74 years of age. Follow-up averaged 4.8 years. Fatal and nonfatal CVD events were confirmed by standardized record review. Participants with diabetes, compared with those with normal glucose tolerance, had lower LDL cholesterol levels but significantly elevated triglyceride levels, lower HDL cholesterol levels, and smaller LDL particle size. Significant independent predictors of CVD in those with diabetes included age, albuminuria, LDL cholesterol, HDL cholesterol (inverse), fibrinogen, and percent body fat (inverse). A 10-mg/dL increase in LDL cholesterol was associated with a 12% increase in CVD risk. Thus, even at concentrations well below the National Cholesterol Education Program target of 130 mg/dL, LDL cholesterol is a strong independent predictor of coronary heart disease in individuals with diabetes, even when components of diabetic dyslipidemia are present. These results support recent recommendations for aggressive control of LDL cholesterol in diabetic individuals, with a target level of <100 mg/dL.

Circulating tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in proliferative diabetic retinopathy: a pilot study.

Several haemostatic abnormalities are associated with proliferative diabetic retinopathy. While abnormalities in plasma fibrinolytic activity have been described in diabetic retinopathy, platelets (a rich source of plasminogen activator inhibitor type 1, PAI-1) have received little attention. As a result, little is known about the fibrinolytic potential of circulating whole blood in diabetic retinopathy. The concentrations of tissue-type plasminogen activator (t-PA) and of its fast-acting inhibitor. PAI-1 were measured in plasma from eight patients with type 1 diabetes complicated by proliferative retinopathy, and from eight patients with type 1 diabetes and background or no retinopathy, matched for age, sex and duration of diabetes. The concentration of PAI-1 in platelets was also measured. The ratio of t-PTA to PAI-1 in plasma was significantly higher in patients with proliferative retinopathy than in those without (0.66 vs. 0.37, p < 0.02). The average quantity of PAI-1 per platelet was significantly lower in the group with proliferative retinopathy (0.33 vs. 0.50 ng/10(6) platelets, p < 0.02). These data suggest that among patients with type 1 diabetes, total circulating fibrinolytic potential is higher in those with proliferative retinopathy.

Social aspects of mortality in young and middle adulthood in Thailand.

PIP: This study examined the characteristics of adults who died during young-to-middle adulthood and identified the differences that may be associated with social roles during the 12-month follow-up period. Studies evidenced that mortality risks were closely associated with certain social characteristics. There are two explanations for these findings: the traditional explanation is that a bad state of health restricts entry into the states of marriage, employment and parenthood, while the less traditional explanation is that valued social roles are associated with lower morbidity and mortality because participation in the social process reduces the likelihood that adults will expose themselves to risk. The results presented in this paper resolve some of the issues surrounding the ¿social roles¿ and ¿selection¿ hypotheses on mortality differentials. The most important contribution were findings indicating that marital status differentials, except those associated with widowhood, represent higher mortality risks for both unmarried and married adults. Furthermore, people who were unemployed had a considerably higher mortality risk during young-to-middle adulthood for the ensuing 12 months than employed people. However, this difference did not apply to the external causes of death. The findings provide support to a more specific theory that control over aspects of everyday life has a protective effect against ill-health leading to mortality.^ieng

Risk factor clustering in the insulin resistance syndrome. The Strong Heart Study.

The objective of this study was to examine how the major components of the insulin resistance syndrome relate to each other and to macrovascular disease in American Indians in the Strong Heart Study. The study cohort (4,228 resident tribal members 45-74 years old) underwent a personal interview and a physical examination between July 1989 and January 1992 at three centers: Arizona, Oklahoma, and North and South Dakota; blood samples were drawn and a 75-g oral glucose tolerance test was performed. Factor analysis was used to assess the clustering and interdependence of groups of insulin resistance syndrome variables. Within both diabetic and nondiabetic groups, three factors emerged. In nondiabetic participants, a cluster of glucose, body mass index, and insulin accounted for 35% (male) and 32% (female) of the total variance in all variables considered, and a cluster of systolic blood pressure and diastolic blood pressure accounted for 25% and 22% in men and women, respectively. Both clusters were positively associated with coronary heart disease but not peripheral vascular disease. In diabetic participants, the combination of systolic and diastolic blood pressures was the most important factor, but the cluster was not associated with coronary heart disease or peripheral vascular disease. A component containing high density lipoprotein cholesterol, triglycerides, and glucose had a positive association with coronary heart disease in diabetic women and with peripheral vascular disease in both sexes. The association of clusters of risk factors and their relations with coronary heart disease provide important clues that may be used in understanding the metabolic disorders associated with insulin resistance and diabetes.

Does chronic smoking influence fibrinolytic potential in type 1 diabetes mellitus?

Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) were studied in 18 smokers and 18 closely matched non-smokers, all of whom had Type 1 diabetes mellitus (DM). None of the patients had advanced complications of diabetes. The t-PA and PAI-1 antigen levels were measured in plasma before and after venous occlusion, and were normal in Type 1 diabetes regardless of smoking status. Platelet PAI-1 levels were also measured and were found to be normal both in smokers and non-smokers. In smokers with Type 1 DM, plasma PAI-1 was significantly correlated with triglycerides. The normal fibrinolytic potential found in smokers with diabetes contrasts starkly with the significantly elevated plasma PAI-1 reported in smokers without diabetes. In smokers, triglycerides may effect low levels of PAI-1 release into plasma; this process may be significantly augmented in the presence of smoking-induced insulin resistance. The lack of endogenous insulin release in Type 1 diabetes may obviate the characteristic rise in plasma PAI-1 found in smokers who do not have diabetes.

Successful long-term kidney-pancreas transplants in diabetic patients with high C-peptide levels.

BACKGROUND: Pancreas transplants are rarely done in type 2 (noninsulin dependent) diabetic patients. Most researchers believe that in type 2 diabetic patients, peripheral insulin resistance plays a central role and also is associated with relative insulin deficiency or an insulin secretory defect. This suggests that in patients receiving transplants, the new beta cells will be overstimulated, leading to beta cell "exhaustion" and graft failure. METHODS: Early in our experience, simultaneous pancreas-kidney transplant candidates were selected using only clinical criteria for type 1 diabetes, i.e., early onset of diabetes and rapid onset of insulin use. Pretransplant sera were available for C-peptide analysis in 70 of 94 of those patients. Forty-four percent (31/70) were African American (AA). RESULTS: Thirteen patients (12 AA) with a nonfasting C-peptide level >1.37 ng/ml were identified. In these patients with high C-peptide levels, pancreas and kidney survival rates were 10O%. The results did not differ statistically from the low C-peptide group (< or =1.37 ng/ ml). There were no differences between patient and pancreas-kidney survival rates when the patients were separated into AA and non-AA groups. The follow-up was 1-89 months, with a mean of 45.5 months. CONCLUSIONS: Long-term pancreas graft function is attainable and beta cell "exhaustion" does not occur in patients with high preoperative C-peptide (>1.37 ng/ ml) levels. AA and non-AA patients have equivalent long-term patient, kidney, and pancreas-kidney graft survival rates.

Molecular cloning and characterization of an invertebrate cellular retinoic acid binding protein.

We have cloned a cDNA and gene from the tobacco hornworm, Manduca sexta, which is related to the vertebrate cellular retinoic acid binding proteins (CRABPs). CRABPs are members of the superfamily of lipid binding proteins (LBPs) and are thought to mediate the effects of retinoic acid (RA) on morphogenesis, differentiation, and homeostasis. This discovery of a Manduca sexta CRABP (msCRABP) demonstrates the presence of a CRABP in invertebrates. Compared with bovine/murine CRABP I, the deduced amino acid sequence of msCRABP is 71% homologous overall and 88% homologous for the ligand binding pocket. The genomic organization of msCRABP is conserved with other CRABP family members and the larger LBP superfamily. Importantly, the promoter region contains a motif that resembles an RA response element characteristic of the promoter region of most CRABPs analyzed. Three-dimensional molecular modeling based on postulated structural homology with bovine/murine CRABP I shows msCRABP has a ligand binding pocket that can accommodate RA. The existence of an invertebrate CRABP has significant evolutionary implications, suggesting CRABPs appeared during the evolution of the LBP superfamily well before vertebrate/invertebrate divergence, instead of much later in evolution in selected vertebrates.

Relation of LDL size to the insulin resistance syndrome and coronary heart disease in American Indians. The Strong Heart Study.

Small, dense LDL has been shown to be associated with the insulin resistance syndrome and coronary heart disease (CHD). We examined the distribution of LDL size and phenotype within a population-based sample of American Indians to determine the relationships with prevalent CHD and to examine associations with hyperinsulinemia and other components of the insulin resistance syndrome. Data were available for 4505 men and women between 45 and 74 years of age who are members of 13 American Indian communities in three geographic areas. Diabetes, CHD, and CHD risk factors were assessed by standardized techniques, and LDL size was measured by gradient gel electrophoresis. LDL size was smaller in men than in women and in individuals with diabetes than in those without diabetes. In multivariate analysis, LDL size was significantly related to several components of the insulin resistance syndrome, including triglycerides (inversely) and HDL cholesterol (positively). Although univariate relations were positive, LDL size was not significantly related to fasting insulin concentrations or body mass index in the multivariate model. LDL size also showed no relationship to apolipoprotein E phenotype. When LDL size was compared in individuals with and without CHD, no significant differences were observed, either in nondiabetic or diabetic individuals. We conclude that LDL size is most strongly related to lipoprotein components of the insulin resistance syndrome, especially plasma triglycerides. However, in this population with low LDL, it is not related to cardiovascular disease.

The effects of chronic smoking on the fibrinolytic potential of plasma and platelets.

We studied tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) in healthy individuals divided by smoking habit into current smokers, former smokers and non-smokers (who had never smoked). Plasma PAI-1 antigen was significantly higher in smokers than in non-smokers with intermediate levels in former smokers. A similar trend was observed for plasma PAI activity but this did not reach statistical significance. Platelet PAI-1 and plasma t-PA were not significantly different when comparing the three groups. After venous occlusion t-PA rose significantly in all groups; no significant change in plasma PAI-1 was observed. The ratio of t-PA to PAI-1 in plasma was similar in non-smokers and former smokers but lower in smokers, suggesting that there is at least partial restoration of plasma fibrinolytic potential after smoking cessation. Plasma PAI-1 antigen and PAI activity correlated with estimated pack-years of cigarettes smoked among smokers and former smokers. When all subjects were studied collectively, plasma PAI-1 correlated strongly with plasma t-PA and triglycerides: plasma t-PA also correlated strongly with triglycerdes. We conclude that chronic smoking is associated with impaired fibrinolysis in plasma and that this largely reflects elevated plasma PAI-1 in smokers. Smoking does not appear to affect the response to venous occlusion. The postulated effect of chronic smoking on plasma PAI-1 may be mediated by the influence of smoking on triglycerides and insulin resistance. Stopping smoking appears to return impaired fibrinolysis towards normal. Smoking does not quantitatively affect the platelet pool of PAI-1. Smoking habit should be controlled for in clinical analyses of PAI-1 and t-PA.

Life cycle expression of a bombyxin-like neuropeptide in the tobacco hornworm, Manduca sexta.

Immunocytochemistry was used to investigate the developmental expression of the insulin-like neuropeptide bombyxin in the tobacco hornworm, Manduca sexta. A mouse monoclonal antibody raised against a synthetic peptide corresponding to bombyxin's A-chain N-terminus was used to localize a bombyxin-like peptide to a group of cerebral medial neurosecretory cells, the M-NSC IIa(2). Immunostaining was first detected on day 0 of the second larval instar, localized in the M-NSC IIa(2) somata and in the neurohemal organ, the corpora allata (CA). By day 0 of the fourth larval instar, the peptide was present throughout the M-NSC IIa(2) somata, axons, dendritic fields and CA. Between days 7 and 9 of the fifth instar, a dramatic reduction in the dendritic fields and CA staining occurred, suggesting the peptide is released. After day 2 of the pupal period, only M-NSC IIa(2) somata immunostained, a pattern that persisted through day 2 of the adult stage. The specificity of immunostaining was demonstrated by using a synthetic bombyxin peptide to block staining. These developmental data reveal times of potential Manduca bombyxin-like peptide release which should provide insight into the peptide's function.

Acute myelocytic leukaemia presenting as anergic pulmonary tuberculosis.

This case report describes a patient with anergic pulmonary tuberculosis who presented with pyrexia of unknown origin and vasculitis. He did not exhibit any pulmonary symptoms at his initial presentation and developed acute myelocytic leukaemia, a recognised association, during the subsequent course of his illness.

Prednisolone metasulphobenzoate foam retention enemas suppress the hypothalamo-pituitary-adrenal axis.

BACKGROUND: Corticosteroid enemas represent effective treatment for ulcerative proctitis, but absorption into the systemic circulation may have undesirable metabolic consequences. Prednisolone metasulphobenzoate, a lipophobic corticosteroid derivative, is designed to be absorbed poorly through the recto-sigmoid mucosa, but the effects of foam enema preparations upon the hypothalamo-pituitary-adrenal axis have not been examined. METHODS: Nine patients suffering from active ulcerative proctitis underwent four weeks of therapy with prednisolone metasulphobenzoate foam enemas. The hypothalamo-pituitary-adrenal axis, defined using the modified single-dose metyrapone test, glucose homeostasis and lipid profiles were studied before and after treatment. RESULTS: The hypothalamo-pituitary-adrenal axis was significantly depressed after the treatment period; mean stimulated plasma cortisol concentration fell from 384 +/- 244 (s.d.) to 288 +/- 252 nmol/L, P < 0.02; stimulated mean plasma 11-deoxycortisol concentration fell from 677 +/- 333 to 407 +/- 326 nmol/L, P < 0.01. Mean fasting plasma glucose, insulin, C-peptide, fructosamine and triglyceride concentration were unchanged, whilst the mean serum cholesterol concentrations rose from 5.6 +/- 1.1 to 6.0 +/- 1.2 mmol/L (not significant). CONCLUSION: Prednisolone metasulphobenzoate foam enemas have significant systemic and endocrine metabolic effects, which could assume importance with long-term therapy.

Physical characteristics of the cerebral big prothoracicotropic hormone from Manduca sexta.

The prothoracicotropic hormones (PTTHs) are cerebral peptides that control insect postembryonic development by stimulating the prothoracic glands to synthesize ecdysteroids. In Manduca sexta, the tobacco hornworm, two classes of PTTH are distinguished by their M(r), small (ca. 7 kDa) and big PTTH (ca. 25-30 kDa). Little is known about the physical nature of the PTTHs and this study takes a first step towards defining characteristics of the Manduca big PTTH. The neurohormone has a Stokes radius of 2.59 nm and a sedimentation coefficient of 2.76 S. Based on these data, an M(r) of 29,443.7 and an f/fo of 1.27 were calculated. Combined, the physical data reveal Manduca big PTTH is an asymmetrical acidic homodimeric peptide with intra- and intermolecular disulfide bonds.

The prothoracicotropic hormone (PTTH) of the commercial silkmoth, Bombyx mori, in the CNS of the tobacco hornworm, Manduca sexta.

Immunocytochemistry revealed that a Bombyx mori prothoracicotropic hormone (PTTH)-like peptide is expressed by the Manduca sexta big PTTH-producing neurons, the lateral neurosecretory cell group III (L-NSC III). Independent PCR of genomic DNA and a L-NSC III cDNA library yielded products with 99% sequence similarity to the cDNA encoding Bombyx PTTH. This similarity necessitated evaluation of the relationship between Manduca big PTTH and Bombyx PTTH by 1) bioassay of IEF separated Manduca PTTH and 2) direct assessment of Bombyx PTTH biological activity with Manduca prothoracic glands. Together, these studies indicate that Bombyx PTTH and Manduca PTTH are different peptides expressed by the L-NSC III. The possible physiological significance of a Bombyx PTTH-like peptide in Manduca and its coexpression with Manduca big PTTH by the L-NSC III are discussed.

Immunoaffinity purification of the neuropeptide prothoracicotropic hormone from Manduca sexta.

The prothoracicotropic hormones (PTTH) are cerebral peptides that control insect postembryonic development by stimulating the prothoracic glands to synthesize ecdysteroids. Using immunoaffinity chromatography and SDS-PAGE, a 25.5 kDa big PTTH has been purified from Manduca sexta. Based upon SDS-PAGE and Western blot analysis, the native form of big PTTH appears to be a dimer with monomers of 16.5 kDa. Four HPLC-separated fragments of this acidic peptide were sequenced and exhibited no sequence similarity with Bombyx mori PTTH. In agreement with this finding, the basic Bombyx PTTH had no PTTH bioactivity in Manduca. One sequenced fragment of the Manduca PTTH is approximately 70% similar to the vertebrate cellular retinoid binding proteins, suggesting these binding proteins may be present in insects.

Collagen shields exacerbate ulceration of alkali-burned rabbit corneas.

OBJECTIVE: To determine the impact of collagen shields on ulceration of rabbit corneas after alkali burn. METHODS: After a 60-second 2N sodium hydroxide burn to rabbit corneas, 24-hour collagen shields were placed on the corneas daily for 21 days; control corneas did not receive collagen shields. The extent of corneal ulceration was documented daily for 21 days by slit-lamp examination of treated and control eyes. Three separate studies were performed using collagen shields from two commercial sources. RESULTS: In the three studies, corneas in the collagen shield-treated eyes began to ulcerate sooner than those in the control group; the corneas in collagen shield-treated eyes also began to perforate sooner. At 21 days after alkali injury, the mean (+/- SE) corneal ulceration score in the collagen shield-treated rabbits was 4.1 +/- 0.17 (descemetocele formation) compared with 2.7 +/- 0.28 (midstromal ulceration) in controls. This difference was significant at P < .005. CONCLUSION: Collagen shield treatment results in marked acceleration of corneal ulceration and perforation after alkali injury.

A 28-kDa cerebral neuropeptide from Manduca sexta: relationship to the insect prothoracicotropic hormone.

1. A 28-kDa peptide from the brain of the tobacco hornworm, Manduca sexta, was purified via HPLC. The peptide copurified with the insect neurohormone, prothoracicotropic hormone (PTTH), through two HPLC columns. 2. Immunocytochemistry using polyclonal antibodies against the 28-kDa peptide revealed that the peptide was produced in the same protocerebral neurons that produce PTTH. Western blot analysis demonstrated that the 28-kDa peptide and big PTTH are different molecules. 3. A PTTH in vitro bioassay indicated that despite having chromatographic properties similar to those of big PTTH and being produced by the same neurons, the 28-kDa peptide did not have PTTH activity. 4. Amino acid sequence analysis yielded a 27 N-terminal amino acid sequence that had no similarity with known peptides. 5. Immunocytochemical studies revealed that the 28-kDa peptide is present as early as 30% embryonic development and is absent by adult eclosion. This is in contrast to big PTTH, which is expressed throughout the Manduca life cycle. 6. These data suggest that the 28-kDa peptide is another secretory phenotype of the lateral neurosecretory cell group III (L-NSC III) which may have functions distinct from those for big PTTH or may act synergistically with big PTTH.