Intestinally derived lipoprotein particles in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia

We have previously demonstrated alterations in apolipoprotein B-48 metabolism in the post-prandial state in patients with non-insulin-dependent diabetes mellitus. This study investigates the relationship between hypertriglyceridaemia and post-prandial lipoprotein metabolism. Four groups of patients were examined: non-insulin-dependent diabetic patients, with normal serum triglyceride levels (serum triglyceride <2.1 mmol l⁻¹; haemoglobin HbA_1c 5.5%±0.4%); poorly controlled, non-insulin-dependent diabetic patients with hypertriglyceridaemia (serum triglyceride >2.1 mmol 1⁻¹; HbA_1c 8.8%±0.9%); nondiabetic subjects with serum triglycerides <2.1 mmoll⁻¹; and non-diabetic subjects with hypertriglyceridaemia (serum triglyceride>2.1 mmol l⁻¹). Subjects were studied fasting and following a high-fat meal (1300 kcal). The triglyceride-rich lipoprotein fraction was isolated by ultracentrifugation (d<1.006 g ml⁻¹). Apoprotein B-48, apoprotein B-100 and apoprotein E were separated on 4%–15% gradient gels and quantified as a percentage of the fasting concentration by densitometric scanning. Triglyceride-rich lipoprotein apolipoprotein B-48 and apolipoprotein B-100 post-prandial profiles demonstrated a maximum increase either at 2 h or rising still further to a peak at 6 h before falling in the diabetic groups and hypertriglyceridaemic non-diabetic subjects when compared with the normotriglyceridaemic control subjects whose levels decreased after 2 h (P<0.05). A significantly different triglyceride-rich lipoprotein apolipoprotein E profile was also exhibited by the diabetic patients (P<0.05). Levels of triglyceride-rich lipoprotein, cholesterol, triglyceride, total protein and apoprotein B were elevated in the hypertriglyceridaemic subjects, both diabetic and non-diabetic. These results indicate that hypertriglyceridaemia is associated with altered metabolism and composition of post-prandial triglyceride-rich lipoprotein particles in both poorly controlled diabetic and non-diabetic subjects.     

Evidence for endothelium-derived relaxing factor in cultured cells

Intracellular cyclic GMP concentration was used as a biochemical indicator of endothelium-dependent and organonitrate-induced responses to these vasodilators in cultured porcine aortic smooth muscle and endothelial cells. Sodium nitroprusside (10(-6) M) caused a rapid increase in cyclic GMP levels in confluent smooth muscle cell cultures but not in confluent endothelial monolayers. Adenosine triphosphate (10(-4) M) and methacholine (10(-5) M), two agents that elicit endothelium-dependent relaxation in intact vessels, failed to raise cyclic GMP concentrations in muscle or endothelial cultures alone. When the cell types were grown together in mixed culture, however, treatment with adenosine triphosphate or methacholine induced an elevation in intracellular cyclic GMP levels. These findings suggest that mixed cultures of arterial smooth muscle and endothelial cells can be used to study the phenomenon of endothelium-dependent responses in arterial smooth muscle.     

Abnormalities in apo B-containing lipoproteins in diabetes and atherosclerosis

Atherosclerosis is the major cause of death in patients with diabetes. Low-density lipoprotein (LDL) being the most important cholesterol-carrying lipoprotein has been studied extensively in both diabetes and non-diabetes. This paper reviews the literature but also focuses on the precursors of LDL and in particular the postprandial apo B-containing lipoproteins. Abnormalities in the postprandial lipoproteins and alteration in chylomicron assembly and clearance are discussed and the evidence presented suggesting the importance of dysregulation of these lipoproteins in atherosclerotic progression. The relationship between chylomicron production in the intestine and hepatic release of very low-density lipoproteins (VLDL) is explored, as is the interrelationship between clearance rates of these lipoproteins. The size of LDL influences its atherogenicity. VLDL composition and size in relation to its influence on LDL is discussed. The effect of diet on the composition of lipoproteins and the relationship between fatty acid composition and clearance is reviewed. Evidence that diabetic control beneficially alters lipoprotein composition is presented suggesting how improved diabetic control may reduce atherosclerosis. The review concludes with a discussion on the effect of the apo B-containing lipoproteins and their modification through glycation and oxidation on macrophage and endothelial function.     

The pharmacokinetics of s.c. Semitard MC,human NPH ge,Rapitard MC and human NPH 30:70 ge insulin in healthy,non-diabetic subjects

BACKGROUND: Plasma glucose and insulin responses to Semitard MC versus human NPH ge and Rapitard MC versus human NPH 30:70 ge were examined in fasted healthy, non-diabetic subjects. METHODS: Twelve male subjects with a mean (+/-S.D.) age of 33.9+/-11.1 years and a BMI of 24.9+/-2.9 kg/m(2) were each involved on four separate study days 1 week apart. After fasting samples were taken, 0.2 U/kg of the allocated insulin preparation was injected subcutaneously (s.c.) as a bolus into the anterior abdominal wall. Blood samples were taken over the next 24 h. RESULTS: Subcutaneous injection of Semitard MC caused a greater fall in plasma glucose concentration and lower mean plasma glucose levels throughout the study compared to NPH, reflecting the higher insulin concentrations observed during the 24-h study period. Following s.c. Rapitard MC the plasma glucose levels were consistently higher than those achieved with human NPH 30:70 ge as a result of the lower concentrations of insulin with Rapitard MC insulin. CONCLUSIONS: To obtain the same level of glycaemic control, transferring patients from Semitard MC to human NPH may require a dose increase of 30% in the first instance to be adjusted upwards as deemed necessary. Transferring patients from Rapitard MC to human NPH 30:70 ge, a dose reduction of 25% may be required. Frequent home blood glucose monitoring should be carried out.     

Plasma clearance and tissue distribution of labelled insulin-like growth factor-I (IGF-I), IGF-II and des(1-3)IGF-I in rats

Incubation of 125I-labelled insulin-like growth factor-I (IGF-I) with rat plasma at 4 degrees C led to the transfer of approximately half the radioactivity to 150 kDa and smaller complexes with IGF-binding proteins. The extent of association was greater with labelled IGF-II and essentially absent with the truncated IGF-I analogue, des(1-3)IGF-I. A greater degree of binding of IGF peptides with binding proteins occurred after i.v. injection of the tracers into rats, but most of the des(1-3)IGF-I radioactivity remained free. Measurement of the total plasma clearances showed the rapid removal of des(1-3)IGF-I compared with IGF-I and IGF-II; the mean clearances were 4.59, 1.20 and 1.34 ml/min per kg respectively. The mean steady-state volume of distribution was larger for des(1-3)IGF-I than for IGF-I and IGF-II (461, 167 and 181 ml/kg respectively), probably because of the differences in plasma protein binding. With all tracers, radioactivity appeared in the kidneys to a greater extent than in other organs. The amount of radioactivity found in the adrenals, brain, skin, stomach, duodenum, ileum plus jejunum and colon was in rank order, des(1-3)IGF-I greater than IGF-I greater than IGF-II. Since this ranking is the opposite of the abilities of the three IGF peptides to form complexes with plasma binding proteins, we propose that the plasma binding proteins inhibit the transfer of the growth factors to their tissue sites of action. Moreover, we suggest that IGF analogues that are cleared rapidly from blood may have greater biological potencies in vivo.     

Improving HIV Screening and Receipt of Results by Nurse-Initiated Streamlined Counseling and Rapid Testing

Background  HIV testing is cost-effective in unselected general medical populations, yet testing rates among those at risk remain low, even among those with regular primary care. HIV rapid testing is effective in many healthcare settings, but scant research has been done within primary care settings or within the US Department of Veteran’s Affairs Healthcare System. Objectives  We evaluated three methods proven effective in other diseases/settings: nurse standing orders for testing, streamlined counseling, and HIV rapid testing. Design  Randomized, controlled trial with three intervention models: model A (traditional counseling/testing); model B (nurse-initiated screening, traditional counseling/testing); model C (nurse-initiated screening, streamlined counseling/rapid testing). Participants  Two hundred fifty-one patients with primary/urgent care appointments in two VA clinics in the same city (one large urban hospital, one freestanding outpatient clinic in a high HIV prevalence area). Measurements  Rates of HIV testing and receipt of results; sexual risk reduction; HIV knowledge improvement. Results  Testing rates were 40.2% (model A), 84.5% (model B), and 89.3% (model C; p = <.01). Test result receipt rates were 14.6% (model A), 31.0% (model B), 79.8% (model C; all p = <.01). Sexual risk reduction and knowledge improvement did not differ significantly between counseling methods. Conclusions  Streamlined counseling with rapid testing significantly increased testing and receipt rates over current practice without changes in risk behavior or posttest knowledge. Increased testing and receipt of results could lead to earlier disease identification, increased treatment, and reduced morbidity/mortality. Policymakers should consider streamlined counseling/rapid testing when implementing routine HIV testing into primary/urgent care.     

Leptin expression in offspring is programmed by nutrition in pregnancy

Birth weight is a determinant of blood leptin concentrations in adults. Since nutrition during pregnancy can affect birth weight, the hypothesis that feed intake during pregnancy alters leptin expression in progeny was examined. Leptin mRNA was measured in subcutaneous adipose tissue and leptin protein was measuredin blood plasma from 59 day old female pigs whose mothers were fed at the same restricted rate except that half were permitted to consume 35% more feed during the second quarter of pregnancy. Leptin mRNA abundance in adipose tissue (P=0.015) and plasma leptin concentration (P=0.01) were higher in progeny from mothers provided with more feed. Body weight at birth was negatively correlated with the abundance of leptin mRNA in subcutaneous fat at 59 days of age (P=0.01). This study shows for the first time that maternal nutrition during pregnancy programs postnatal leptin expression in offspring.     

Alterations in the Density of Interstitial Cells of Cajal in Achalasia

The aim of this study was to assess the quantity of interstitial cells of Cajal (ICC) in the lower esophageal sphincter (LES) in achalasia. LES muscle was obtained from 11 achalasia and nine esophageal cancer (control) patients during surgery. Immunohistochemistry was performed and average cell counts per high-power field (HPF) were obtained. Overall, more ICC were observed in achalasia (median = 14.0 cells/HPF; range = 0–22.6 cells/HPF) as compared with controls (median = 6.2 cells/HPF; range = 1.6–10.8 cells/HPF) (P = 0.047). There were two subsets of findings within the achalasia group: 8/11(73%) had an increased quantity of ICC (median = 17.1 cells/HPF; range = 11.6–22.6; P = 0.015) as compared with controls, whereas the remaining 3/11(27%) had a paucity of ICC (median = 0 cells/HPF; range = 0–2; P = 0.02). ICC levels were positively correlated with age of the patient (P = 0.043). Our study demonstrates that subsets of abnormal ICC levels are observed in idiopathic achalasia of the esophagus.     

Significance of false-positive serologic tests for histoplasmosis and blastomycosis in an endemic area

False-positive serologic tests for histoplasmosis (H) and blastomycosis (B) are common in populations from endemic areas. In order to determine the significance of false-positive test results, we reviewed the final diagnoses of all patients whose sera were submitted to our laboratory for radioimmunoassay (RIA) and immunodiffusion (ID) during a 3-yr period. Of the 263 patients whose sera were examined, 29 (11%) had H or B; 41 (17.5%) of the remaining 234 patients had false-positive test results. Of these 41 patients, 31 were positive for H alone, and 10 had antibodies to both H and B. All three patients with false-positive ID tests for histoplasmosis also had positive titers (greater than or equal to 1:16) on RIA. No patient had a false-positive ID result for blastomycosis. The percentage of patients in each of five major diagnostic categories with and without false-positive serologic tests was similar (p greater than 0.05). The majority of patients had pulmonary infections, almost half of which were granulomatous infections other than H or B; this reflects the clinical indications for requesting fungal serologic tests. A positive fungal serology is not useful in suggesting the presence of a pulmonary disease other than H or B in patients from an endemic area suspected of having a pulmonary mycosis.