Leptin and high-sensitivity C-reactive protein and their interaction in the metabolic syndrome in middle-aged subjects

High-sensitivity C-reactive protein (hsCRP) and leptin, known to interact at the molecular level, have been associated with the metabolic syndrome (MS). We examined the independent and joint effects of high leptin and hsCRP levels on the development of MS in a population-based cohort of middle-aged subjects (N = 1035). Leptin and hsCRP levels increased with an increase in the number of metabolic abnormalities (P < .001). However, additional adjustment for body mass index diluted the association of leptin with MS in women. In men, the association of high leptin with insulin resistance and waist circumference (P < .001), and in women, the association of high hsCRP with insulin resistance (P = .029) and waist circumference (P = .009) persisted in the multivariate logistic regression models. High leptin in men and high hsCRP in women were significant predictors of MS in logistic regression analysis (P < .001). The highest prevalence of MS (86% in men and 71% in women) was observed in the subjects who belonged to the highest quartile in both leptin and hsCRP. MS is associated independently with high leptin in men and with hsCRP in women, whereas individuals with both of these markers belong to the highest risk of metabolic cluster. The study suggests sex-specific interplay between metabolic and inflammatory markers in the pathogenesis of MS.     

Loss of neurturin in frog--comparative genomics study of GDNF family ligand-receptor pairs

Four different GDNF family ligand (GFL)-receptor (GFRalpha) binding pairs exist in mammals, and they all signal via the RET receptor tyrosine kinase. However, the evolution of these molecules is poorly understood. We identified orthologs of all four GFRalpha receptors and GRAL (GDNF Receptor Alpha-Like) in all vertebrate classes, and a predicted GFR-like protein in several invertebrates. In addition, Gas1 (growth arrest-specific 1), a distant member of the GFR-superfamily, is present in both vertebrates and invertebrates. Analysis of exon structures suggests a common origin of GFR-superfamily proteins and early divergence of Gas1 from the common ancestor. Bony fishes have orthologs of all four mammalian GFLs, consistent with genome duplications in early vertebrates. Surprisingly, the clawed frog and chicken have only three GFLs: synteny analysis indicates loss of neurturin in frog and of persephin in chicken. Evolutionary trace analysis and protein structure homology modeling points at GDNF as the endogenous ligand of frog GFRalpha2.     

Functional expression,inhibition and induction of CYP enzymes in HepaRG cells

Practically all human hepatocyte cell lines are deficient in major cytochrome P450 (CYP)-related enzyme activities, making them unrepresentative of in vivo hepatocytes. We have used the recently developed HepaRG cell line to determine the spectrum of most important CYP enzyme activities involved in xenobiotic metabolism (CYP1A1/2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) and the effect of the prototypical CYP-inducer phenobarbital and a panel of known CYP-selective inhibitors on these activities. Comparison of these activities was carried out with two human primary hepatocyte populations. We show that excluding CYP2A6 and CYP2E1, HepaRG cells express high functional levels of most of the major xenobiotic metabolising CYPs. These activities were found to be selectively inhibited and induced by prototypical CYP-selective inhibitors and inducer at comparable levels to primary hepatocytes. In conclusion, HepaRG cells may be a promising cell line for various applications, which currently employ hepatic subcellular preparations or cultured primary hepatocytes.     

Metabolism and pharmacokinetics in children and the elderly

In drug development, clinical trials are commonly carried out in either healthy volunteers or carefully selected patients. However, it has been recognised for a long time that both extremes of age, children and elderly, display a number of important metabolic and pharmacokinetic differences as compared with adults. This also has important consequences as to the toxic reactions and risk assessment of chemicals. What is known, what is not known and what should we do to improve the situation?     

Gender-related differences in the management of non-ST-elevation acute coronary syndrome patients

OBJECTIVES: To compare management and outcome of female and male non-ST-elevation acute coronary syndrome (ACS) patients. DESIGN: FINACS Studies are prospective registries of non-ST-elevation ACS patients conducted in 2001, 2003, and 2005 in nine hospitals. RESULTS: The studies enrolled 1,399 patients from which 39% were women. During hospitalisation women were treated less often than men with aspirin (odds ratio [OR]) for women 0.60, 95% confidence interval [CI] 0.41 to 0.88, p=0.03). Women underwent less often in-hospital coronary angiography than men (adjusted OR 0.71, 95% CI 0.55 to 0.93, p=0.01). Also in the subgroup of younger (<75 years) high-risk patients, female sex was independent predictor for not performing in-hospital angiography (OR 0.64, 95% CI 0.42 to 0.97, p=0.04). Age-adjusted mortality at 6 months was similar between men and women. CONCLUSIONS: Compared to men women received less often aspirin. Women were referred less often to in-hospital coronary angiography. Under-use of in-hospital angiography was evident also in patients with high-risk features when guidelines recommend early invasive treatment.     

The role of CYP enzymes in cocaine-induced liver damage

 Cocaine is hepatotoxic in several species, including man. A high dose of cocaine produces metabolism-dependent, mainly pericentral, liver damage. At 24 h after a single dose of cocaine, mouse hepatic P450 content decreases but CYP2A activities; coumarin 7-hydroxylase and testosterone 15α-hydroxylase increase concomitant with prominent diffuse cell necrosis. Repeated administration of cocaine for up to 5 days decreases CYP1A1/2, 2A4/5, 2Cx, and 2E1 related enzymatic activities. However, after five doses of cocaine, CYP2B10 increases in conjunction with the healing process. In the acute phase, the increased CYP2A activities do not participate in cocaine bioactivation. CYP3A enzymes are principally responsible for the cocaine N-demethylation in human and mouse liver microsomes. The hepatic metabolic CYP enzyme profile will change during prolonged cocaine intake, this being accompanied by altered cell morphology. Possible connections to cocaine toxicity in man are discussed. Received: 5 September 1994 / Accepted: 21 November 1994     

Increase in cerebral blood flow of right prefrontal cortex in man during orgasm

The functional anatomy of human emotional responses has remained poorly understood, mainly because invasive experiments in humans are unacceptable due to ethical reasons. The new functional imaging techniques such as positron emission tomography and single photon emission computed tomography have made it possible to study the neurophysiology of living humans non-invasively. We studied the regional cerebral blood flow with semi-quantitative ^99mTC-HMPAO single photon emission computed tomography in eight healthy right-handed heterosexual males during orgasm. The results showed decrease of cerebral blood flow during orgasm in all other cortical areas except in right prefrontal cortex, where the cerebral blood flow increased significantly (P < 0.005).     

Lumbar spinal stenosis patients are satisfied with short-term results of surgery - younger age, symptom severity, disability and depression decrease satisfaction

Purpose. To study the lumbar spinal stenosis (LSS) patients' (n = 98) satisfaction with surgery outcome and associated factors at three months post-operative stage.

Method. LSS-related physical functioning and pain were assessed with Oswestry disability index, Stucki questionnaire, Visual Analogue Scale and pain drawings. Depression was assessed with 21-item Beck Depression Inventory. Psychological well-being was assessed with the Life satisfaction scale, Toronto Alexithymia Scale and Sense of Coherence Scale. All questionnaires were administered before and 3 months after surgical treatment of LSS. Satisfaction with surgery outcome was assessed with a separate scale.

Results. Considerable improvement was evident in all the functional and pain-related variables. Two-thirds (66%) of the patients were at least clearly satisfied with the surgery outcome. Younger age, symptom severity, disability and depression were independently associated with dissatisfaction with surgery outcome.

Conclusion. The lack of physical, functional and emotional well-being is associated with the patients' dissatisfaction with the surgery outcome. Patient satisfaction is a valid outcome to be measured in LSS patients undergoing surgery. It is recommended that patients should be provided with realistic pre-operative patient information and that depression be assessed pre-operatively.