Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure

BACKGROUND: Chronic renal failure (CRF) is associated with an atherogenic lipid profile and an increased risk of ischaemic cardiovascular disease. The associated hyperlipidaemia is reportedly ameliorated by erythropoietin (Epo) therapy. According to a recent report, rats studied 3 weeks after 5/6 nephrectomy and fed a high- protein diet exhibited increased activities of hepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase (Ch-7 alpha- H), despite normal corresponding mRNA values. DESIGN AND METHODS: This study was designed to examine the effects of naturally progressing CRF of longer duration as well as those of Epo therapy on gene expressions of the key factors involved in hepatic cholesterol metabolism, i.e., LDL receptor (LDLR), HMG-CoAR, and Ch-7 alpha-H. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy), Epo-treated CRF group (given Epo 150 U/kg/twice weekly) and sham-operated, placebo- treated normal controls. They were allowed free access to regular rat chow and studied 6 weeks after surgery. Liver mRNAs and protein mass or activities of the above factors were studied. RESULTS: Plasma cholesterol concentration was significantly increased in the CRF group (P < 0.001) and was modestly lowered (P < 0.05) by Epo therapy. However, microsomal cholesterol concentration and LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA as well as HMG-CoAR activity, and Ch-7 alpha-H and LDLR protein mass measurements were virtually identical in the three groups. Thus, hepatic LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA and protein measurements in rats with CRF were similar to those of the normal control group representing an inappropriate response to the associated hypercholesterolemia. Epo therapy led to partial amelioration of CRF- associated hypercholesterolaemia with no discernible effect on hepatic tissue expression of the above factors.      

Comparative PET studies of the kinetics and distribution of cocaine and cocaethylene in baboon brain.

Recent studies have suggested that cocaethylene, an active metabolite of cocaine found in blood and postmortem brain of individuals self-administering cocaine and alcohol, may play a role in the increased toxicity seen when coadministering these 2 drugs. We have used positron emission tomography (PET) and carbon-11 (t1/2:20.4 min) labeled cocaine and cocaethylene to compare the short-term kinetics of cocaine and cocaethylene in baboon brain. The regional uptake of [11C]cocaine cocaethylene in baboon brain. The regional uptake of [11C]cocaine ([11C]COC) and [11C]cocaethylene ([11C]CE), 5-8 mCi and 4-6 micrograms, in baboon brain (n = 7) were similar but clearance from whole brain (global, GL) and from striatum (SR), thalamus (TH), and cerebellum (CB) was slower for cocaethylene. Steady-state distribution volumes (DV) were not significantly different in the striatum but were greater for cocaethylene in the thalamus, cerebellum, and whole brain. Debenzoylation of cocaethylene proceeded at about one-third the rate of cocaine, as determined by in vitro incubation of labeled cocaethylene and labeled cocaine with baboon plasma and with purified horse butyryl-cholinesterase (EC 3.1.1.8). Even though the slower clearance of cocaethylene could lead to longer tissue exposures and potentially accentuated or different physiological effects relative to cocaine, the difference between the 2 drugs is not large. Thus it is more likely that the direct actions of cocaine and alcohol on some organs, rather than cocaethylene, account for this enhanced toxicity.     

Impact of HIV antibody testing on changes in sexual behavior among homosexual men in The Netherlands.

Between October 1984 and May 1986, 746 homosexual men, living in and around Amsterdam, The Netherlands, were surveyed at three consecutive six months periods regarding their sexual behavior. At the start of the study all subjects, of whom 234 (31 per cent) were HIV-Ab seropositive, were informed about their HIV antibody status. Seropositives initially reported more sexual partners than seronegatives; they also showed a greater reduction in the number of sexual partners and the number of partners with whom all forms of sexual practices were performed than did seronegatives. In both groups subjects were more likely to terminate orogenital intercourse than anogenital intercourse and masturbation.     

Longitudinal in vivo effects of growth hormone overexpression on bone in transgenic mice.

In this study we examined the effect of systemic overexpression of GH on bone in transgenic mice longitudinally in vivo over a period of 9 months. We observed substantially increased BMC in GH transgenic mice and a significant reduction in serum osteocalcin. GH effects on bone were strongly dependent on gender and developmental stage. INTRODUCTION: State-of-the-art bone marker and microimaging technology was applied in this longitudinal study to examine bone metabolism, BMC, bone density, and cortical bone structure over the life span of growth hormone (GH) transgenic (tg) mice. MATERIALS AND METHODS: Thirty-eight mice from four genetic groups (male, female, tg, and controls) were examined with DXA, and their femur and tibia were examined with peripheral QCT (pQCT). Osteocalcin (formation) and collagen cross-links (resorption) from serum and urine were also measured at postnatal weeks 3, 6, 9, 12, 18, 26, and 38. RESULTS: GH tg mice displayed a significant increase in body weight (up to 50%) and BMC (up to 90%), but serum osteocalcin was significantly reduced compared with controls. GH tg females (but not males) displayed increased trabecular density over controls up to week 12. In contrast, male (but not female) GH tg mice displayed a higher cortical cross-sectional area than controls. Cortical density was significantly lower in both male and female GH tg mice compared with control mice. CONCLUSIONS: The increase in BMC in GH tg mice is associated with reduced serum osteocalcin levels, indicating that bone turnover may be lower than in the control mice. On a structural level, bone responds to GH excess in a gender-specific manner, with alterations varying substantially between different developmental stages.     

Prevalence of impaired glucose tolerance 6 years after gestational diabetes.

AIM: Prevalence of glucose metabolism disorders in women six years after gestational diabetes in the index pregnancy (GDM). METHOD: 227 Caucasian women who developed GDM between 1995 and 1996 were investigated; 173 women (BMI 27.5+/-6.0 kg/m2) received 75 g oGGT on average 5.8+/-2.0 years after delivery. RESULTS: Impaired glucose metabolism was found in 31.2%, IGT or IFG 19.1%, diabetes mellitus type 2 (DM2) 9.2%, diabetes mellitus type 1 (DM1) 2.3%, second GDM 0.6%. 27.2% (BMI 25-29.9 kg/m2) were overweight, 23.1% suffered from obesity (BMI 30-39.9 kg/m2) and 5.2% morbid obesity (BMI>or=40 kg/m2). In comparison to a healthy control group, women with DM2 at re-examination were: older in age (32.1+/-5.9 vs. 29.1+/-4.8 years, p<0.05), had higher BMI (29.4+/-6.9 vs. 24.6+/-4.8 kg/m2, p<0.05), higher fasting blood glucose (6.5+/-1.9 vs. 5.2+/-0.9 mmol/l, p<0.05), earlier diagnosis of GDM (25+/-8 vs. 29+/-5 SSW, p<0.05), more frequent insulin therapy during pregnancy (75 vs. 24%) and had significantly higher insulin- and C-peptide for all measures of the oGTT, whereas HbA1c was not different (4.9+/-0.5 vs. 4.8+/-0.3%, n. s.). CONCLUSION: In an average of 5.8 years after the diagnosis of GDM, the majority of women still have chronic insulin resistance. One third has either IGT, IFG or diabetes mellitus. Therefore, a long term follow-up is strongly recommended for women diagnosed with GDM.     

Use of the competing-hypotheses heuristic to reduce 'pseudodiagnosticity'

A quasiexperimental research design involving a nonequivalent control group was used to examine the efficacy of a brief educational intervention in teaching medical students to select optimal diagnostic data consistent with the competing-hypotheses heuristic and Bayes' theorem when solving clinical problems. There was no significant difference between intervention (n = 119) and control (n = 89) groups in performance at baseline, but the intervention group performed significantly better (p less than .001) than the control group after training. The results suggest that some problem-solving skills, such as learning to use the competing-hypotheses heuristic, can be enhanced or learned independent of the acquisition of content knowledge.     

Low molecular weight heparin and prevention of postoperative thrombosis in abdominal surgery.

In a prospective, double-blind, randomized multicenter trial the efficacy and safety of low molecular weight heparin and unfractionated heparin were compared for the prevention of postoperative deep vein thrombosis in patients undergoing abdominal surgery. Six hundred and seventy-three patients were randomly allocated to the two prophylaxis groups; 20 of these, however, did not undergo surgery and did not receive any prophylaxis. Of the remaining 653 patients 323 received one subcutaneous injection of 3,000 anti-Xa units of low molecular weight heparin and 330 received subcutaneously 5,000 U heparin three times a day. Treatment was initiated 2 h preoperatively and continued for 7 to 10 days. The occurrence of DVT was determined by the 125I-labelled fibrinogen uptake test and phlebography. Venous thrombosis was diagnosed in 24 of 323 patients (7.4%) treated with low molecular weight heparin and in 26 of 330 patients (7.9%) treated with low-dose heparin. DVT of proximal veins was detected in four patients of the low molecular weight heparin group and in three patients of the low-dose heparin group. During the observation period three pulmonary emboli - one fatal and two non-fatal - occurred in patients receiving prophylaxis with low-dose heparin. No pulmonary embolism was found in patients treated with low molecular weight heparin. Both prophylactic schemes were well tolerated. Intra- and postoperative blood loss, incidence of wound hematoma, frequency and volume of intra- and postoperative blood transfusion were similar in both groups with a slight advantage for the low molecular weight heparin group.(ABSTRACT TRUNCATED AT 250 WORDS)