Bariatric surgery is increasingly employed to improve fertility and reduce obesity-related co-morbidities in obese women. Surgical weight loss not only improves the chance of conception but reduces the risk of pregnancy complications including pre-eclampsia, gestational diabetes, and macrosomia. However, bariatric procedures increase the incidence of intrauterine growth restriction (IUGR), fetal demise, thromboembolism, and other gestational disorders. Using our rodent model of vertical sleeve gastrectomy (VSG), we tested the hypothesis that VSG in diet-induced, obese dams would cause immune and placental structural abnormalities that may be responsible for fetal demise during pregnancy. VSG dams studied on gestational day (G) 19 had reduced circulating T-cell (CD3 + and CD8 + ) populations compared with lean or obese controls. Further, local interleukin (IL) 1β and IL 1 receptor antagonist ( il1rn ) cmRNA were increased in placenta of VSG dams. Placental barrier function was also affected, with increased transplacental permeability to small molecules, increased matrix metalloproteinase 9 expression, and increased apoptosis in VSG. Furthermore, we identified increased placental mTOR signaling that may contribute to preserving the body weight of the fetuses during gestation. These changes occurred in the absence of a macronutrient deficit or gestational hypertension in the VSG dams. In summary, previous VSG in dams may contribute to fetal demise by affecting maternal immune system activity and compromise placental integrity.

In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n = 354; Type II, n = 392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P <0.01), remaining significant when additionally adjusted for serum folate ( P = 0.043 and P = 0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes ( P <0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.

Since the initial report of the association of the deletion/insertion (D/I) polymorphism in the gene for angiotensin-converting enzyme (ACE) with myocardial infarction (MI), there has been considerable controversy. Some have found the D allele to be associated with MI, coronary heart disease (CHD) or other cardiac pathology, while others have not. In the present study 713 consecutive patients, < 50 years of age, documented prospectively with angiographic CHD (> 50% diameter stenosis of at least one coronary artery), with or without MI, were studied, along with 688 community control subjects, also < 50 years of age, selected randomly from the electoral rolls and without a history of CHD or MI. Genotyping was done by standard methods. Most of the subjects in both groups were Anglo–Celtic Caucasians (547 in the CHD group and 642 in the community group), and the report concerns primarily these subjects. ACE genotype distributions were not different between the Caucasian community control group and the CHD or the MI subgroups; the odds ratios and 95% confidence limits for the CHD group were 0.96 (0.73–1.27) for the D allele and 1.02 (0.80–1.31) for D homozygotes; for the MI group these values were 1.00 (0.83–1.20) and 0.99 (0.74–1.32) respectively. This negative result was supported in multivariate analysis accounting for conventional risk factors. There was a significant racial difference in ACE genotypes between Caucasians, Asians and Australian Aborigines in the CHD group ( P < 0.001); for example, in this group, 158 of 540 (29%) Caucasians had the DD genotype compared with eight of 84 (10%) Aboriginals ( P < 0.001) and six of 59 (10%) Asians ( P = 0.002). Failure to account for such racial differences would have led to erroneous conclusions. In conclusion, we found no evidence that the D/I ACE gene polymorphism plays a role in the development of CHD or MI at an early age in a Western Australian Caucasian population. While this result refers uniquely to premature CHD and MI, and could be population specific, it is in general agreement with recent meta-analysis of the larger previous studies.

1. Vitamin E administration improves endothelial function in hypercholesterolaemic animals but, generally, has not been found to do so in man. The aim of this study was to determine whether vitamin E administration improves basal or stimulated function of the nitric oxide (·NO) dilator system in patients with hypercholesterolaemia. 2. Seven subjects aged 47±3 (±S.E.M.) years with moderately elevated serum cholesterol concentrations (6.0±0.1 ;mmol/l) were given 4 weeks of placebo therapy followed by 500 i.u. of vitamin E twice daily for 4 weeks. Endothelium-dependent and -independent vasodilatation were assessed by intrabrachial infusion of acetylcholine and sodium nitroprusside, and forearm blood flow was measured by strain-gauge plethysmography. Basal ·NO function was assessed by infusion of N G -monomethyl- l -arginine. 3. Plasma α-tocopherol concentration was enhanced after administration of vitamin E (34.6±1.8 to 86.9±9.6 ; μ mol/l; P < 0.001). In addition, vitamin E administration significantly increased acetylcholine-mediated vasodilatation whether the results were expressed in terms of changes in absolute forearm blood flow ( P < 0.01), forearm vascular resistance ( P < 0.05) or forearm blood flow ratios ( P < 0.001). Similarly, absolute forearm blood flow ( P < 0.05), forearm vascular resistance ( P < 0.01) and forearm blood flow ratio ( P < 0.01) responses to N G -monomethyl- l -arginine were augmented by vitamin E therapy. Sodium nitroprusside responses were unaltered. 4. These results indicate that 4 weeks therapy with 1000 i.u. of vitamin E daily improves basal and stimulated ·NO-related endothelial function in subjects with hypercholesterolaemia.

1. Platelet-activating factor is inactivated in plasma by the action of a specific acetylhydrolase that cleaves the acetate moiety from the sn -2 position. Degradation was determined under optimized conditions and under conditions closer to those which may occur in vivo. The latter, or platelet-activating factor half-life, was measured by a modified method that is simple, inexpensive and reliable. 2. A hyperbolic relationship was found to exist between the two measures of degradation, the values in both normal subjects and patients with coronary artery disease falling on the tail of the hyperbola. Thus, there is an increase in platelet-activating factor half-life associated with a lowering of acetylhydrolase activity, but this increase is relatively small. 3. There were significant direct linear relationships between acetylhydrolase activity and serum total cholesterol and low-density-lipoprotein-cholesterol concentrations in both subject groups. Although acetylhydrolase activity was most closely associated with the low-density-lipoprotein-cholesterol fraction, the activity for a given serum level of low-density-lipoprotein-cholesterol was higher in patients with coronary artery disease.

1. Experimental elevation of plasma non-esterified fatty acid concentrations has been postulated to decrease insulin-stimulated glucose oxidation and storage rates. Possible mechanisms were examined by measuring skeletal muscle glycogen synthase activity and muscle glycogen content before and during hyperinsulinaemia while fasting plasma non-esterified fatty acid levels were maintained. 2. Fasting plasma non-esterified fatty acid levels were maintained in seven healthy male subjects by infusion of 20% (w/v) Intralipid (1 ml/min) for 120 min before and during a 240 min hyperinsulinaemic euglycaemic clamp (100 m-units h −1 kg −1 ) combined with indirect calorimetry. On the control day, 0.154 mol/l NaCl was infused. Vastus lateralis muscle biopsy was performed before and at the end of the insulin infusion. 3. On the Intralipid study day serum triacylglycerol (2.24 ± 0.20 versus 0.67 ± 0.10 mmol/l), plasma non-esterified fatty acid (395 ± 13 versus 51 ± 1 μmol/l), blood glycerol (152 ± 2 versus 11 ± 1 μmol/l) and blood 3-hydroxybutyrate clamp levels [mean (95% confidence interval)] [81 (64–104) versus 4 (3–5) μmol/l] were all significantly higher (all P < 0.001) than on the control study day. Lipid oxidation rates were also elevated (1.07 ± 0.07 versus 0.27 ± 0.08 mg min −1 kg −1 , P < 0.001). During the clamp with Intralipid infusion, insulin-stimulated whole-body glucose disposal decreased by 28% (from 8.53 ± 0.77 to 6.17 ± 0.71 mg min −1 kg −1 , P < 0.005). This was the result of a 48% decrease in glucose oxidation (3.77 ± 0.32 to 1.95 ± 0.21 mg min −1 kg −1 , P <0.001), with no significant change in nonoxidative glucose disposal (4.76 ± 0.49 to 4.22 ± 0.57 mg min −1 kg −1 , not significant). 4. Basal and insulin-stimulated glycogen synthase activities (13.1 ± 1.9 versus 11.4 ± 2.3% and 30.8 ± 2.3 versus 27.6 ± 4.5%, respectively) were unaffected by the increased plasma non-esterified fatty acid levels. Similarly, basal (36.1 ± 2.7 versus 37.2 ± 1.4 μmol/g) and stimulated (40.0 ± 0.6 versus 37.6 ± 4.4 μmol/g) muscle glycogen levels were unaltered. Insulin-stimulated hexokinase activity was also not affected (0.52 ± 0.08 versus 0.60 ± 0.08 units/g wet weight). 5. Maintenance of plasma non-esterified fatty acid levels at fasting values resulted in an increase in lipid oxidation and was associated with a decrease in insulin-stimulated whole-body glucose uptake and glucose oxidation rates, but no change in non-oxidative glucose disposal. Increased plasma non-esterified fatty acid levels did not appear to have a direct inhibitory effect on glycogen synthase activity or storage of glucose as glycogen at these insulin levels.

1. Evidence suggests that activation of phospholipase A 2 and production of eicosanoids and platelet-activating factor (PAF) are involved in various responses associated with severe tissue damage and shock. It was postulated that the plasma level of the precursor and degradation product of PAF, lyso-platelet-activating factor (lyso-PAF), might be increased in acute severe illness. 2. After plasma extraction, lyso-PAF was acetylated in vitro to PAF, which was measured by bioassay using 5-[ 14 C]hydroxytryptamine-labelled rabbit platelets. Measurements were made in 18 severely ill patients (five with cardiogenic shock; five with severe infection, five after repair of abdominal aortic aneurysm, two with acute pancreatitis; 13 males, five females). Plasma lyso-PAF in these patients was 33 ± 15 (sd) ng/ml (range 5–111 ng/ml), whereas values in normal males (40–65 years) ranged from 102 to 253 ng/ml ( n = 15) and in females from 74 to 174 ng/ml ( n = 10). Depression of plasma lyso-PAF did not relate closely to the patient group nor to specific therapy, but repeated measurements in each of 10 patients showed an increase in plasma lyso-PAF ( P < 0.002), associated with clinical improvement. 3. Evidence was obtained indicating that neither the presence of an inhibitor in the assay system nor reconversion of PAF to lyso-PAF in vitro produced the unexpected depression of plasma lyso-PAF. 4. The mechanisms responsible, which may have therapeutic implications, remain to be elucidated.

1. A three-step hyperinsulinaemic euglycaemic clamp was performed in six uraemic patients before dialysis and after 3 months of treatment with continuous ambulatory peritoneal dialysis, and in seven matched normal control subjects. Glucose turnover was assessed basally and during the clamp using [3- 3 H]glucose as a tracer. 2. The glucose infusion rate required to maintain euglycaemia was insignificantly higher in normal subjects compared with undialysed uraemic subjects at each insulin infusion rate. 3. The isotopically assessed total glucose turnover was also similar in normal and uraemic subjects. Basal hepatic glucose output was again similar in uraemic and control subjects and output was suppressed to a similar degree at each insulin infusion rate. 4. After treatment with continuous ambulatory peritoneal dialysis, the glucose infusion rate and the total glucose turnover during the clamp rose significantly at all three insulin concentrations ( P < 0.05), but remained insignificantly different from normal control values. Hepatic glucose output was unchanged. 5. Peripheral insulin action was improved during continuous ambulatory peritoneal dialysis, but hepatic insulin action was unchanged.

1. Studies were conducted to test the hypothesis that glycerol-induced acute renal failure in rats may be mediated by 5-hydroxytryptamine. 2. The tryptophan hydroxylase inhibitor, β-chlorophenylalanine, or saline was administered for 4 days before performance of 24 h clearance studies after glycerol administration. 3. p -Chlorophenylalanine significantly reduced the nephrotoxic effect of glycerol, as evidenced by improved glomerular filtration rate, urine volume excretion and absolute sodium excretion, and reduced plasma creatinine concentration. 4. These results suggest that glycerol-induced acute renal failure may be mediated by the renovascular and/or tubular actions of 5-hydroxytryptamine.

1. The effect of age on the plasma level of the lyso-derivative of platelet-activating factor (lyso-PAF) was studied in 72 normal subjects, (32 females, 40 males) aged 12–64 years. Lyso-PAF was acetylated in vitro to PAF which was measured by bioassay using 5-[ 14 C]hydroxytryptamine-labelled rabbit platelets. 2. Under 40 years there were similar direct relations between plasma lyso-PAF and age in both sexes (linear regression; males, P < 0.001; females, P < 0.002), the level approximately doubling from the adolescent level around 100 ng/ml. However, in the later years the levels fell, the fall seeming to commence earlier in females, so that between 40 and 65 years the level was greater in males [169 ± 47( sd ) vs 120 ± 30 ng/ml; P < 0.01]. 3. The increase in plasma lyso-PAF up to middle-age may be related to the reported increase in prostanoid production with age, since these platelet and vasoactive compounds can have a common origin in membrane phospholipid. This would be consistent with increasing phospholipase A 2 activity and decreasing stability of cell membranes with age, but the later fall in lyso-PAF is then unexplained; the lesser values in females than males in the more advanced years could be related to females' generally lesser vascular disease. However, knowledge of the biological roles and metabolism of PAF is still very limited and the real significance of the findings remains to be determined.