Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior

The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.     

The effects of five-year growth hormone replacement therapy on muscle strength in elderly hypopituitary patients

OBJECTIVE: Little is known of the long-term effects of GH replacement therapy on muscle strength in elderly adults with adult onset GH deficiency (GHD). In this study, the effects of 5 years of GH replacement therapy on muscle function were determined in adults over 60 years of age with adult onset GHD. DESIGN: A prospective, open-label, single-centre study. Patients Twenty-six (12 male and 14 female) consecutive hypopituitary adults with adult onset GHD, mean age 65.0 (range 61-74) years. MEASUREMENTS: Upper leg muscle strength was measured using a Kin-Com dynamometer. Right and left handgrip strength were measured using an electronic grip force instrument. RESULTS: The mean insulin-like growth factor-I (IGF-I) SD score increased from -1.10 at baseline to 1.21 at end of the study. Body weight was unchanged during the 5-year study. A sustained increase in lean body mass and a sustained reduction of body fat was observed as measured using dual-energy X-ray absorptiometry (DEXA). The GH replacement therapy induced a sustained increase in isometric (60 degrees ) knee flexor strength. After statistical correction for age and sex variables using observed/predicted value ratios, a sustained increase was also observed in concentric knee flexor strength at an angular velocity of 60 degrees /s, concentric knee extensor strength at 60 degrees /s and 180 degrees /s, and peak right handgrip strength. At baseline, knee flexor strength was 90-96% of predicted, knee extensor strength was 85-87% of predicted, and hand-grip strength was 74-80% of predicted values. At study end, knee flexor strength was 98-106% of predicted, knee extensor strength was 90-100% of predicted, and hand-grip strength was 80-87% of predicted values. CONCLUSION: Elderly patients with adult onset GH deficiency had decreased baseline muscle strength also after correction for age and sex. The 5-year GH replacement therapy normalized knee flexor strength and improved, but did not fully normalize, knee extensor strength and handgrip strength.     

Do lipids,blood pressure,diabetes, and smoking confer equal risk of myocardial infarction in women as in men? The Reykjavik Study

BACKGROUND: Studies on coronary risk factors in men and women are mainly based on mortality data and few compare results of both sexes with consistent study design and diagnostic criteria. This study assesses the major risk factors for coronary events in men and women from the Reykjavik Study. DESIGN: Within a prospective, population-based cohort study individuals without history of myocardial infarction were identified and the relative risk of baseline variables was assessed in relation to verified myocardial infarction or coronary death during follow-up. METHODS: Of the 9681 women and 8888 men who attended risk assessment from 1967-1991, with follow-up period of up to 28 years, 706 women and 1700 men suffered a non-fatal myocardial infarction or coronary death. RESULTS: Serum cholesterol was a significant risk factor for both sexes, with hazard ratios (HR) decreasing with age. Systolic blood pressure was a stronger risk factor for women as was ECG-confirmed left ventricular hypertrophy (women HR 2.89, 95% confidence interval [CI] 1.67-5.01; men HR 1.11 [CI 0.86-1.43]). Fasting blood glucose > or =6.7 mmol/L identified significantly higher risk for women (HR 2.65) than men (HR 2.08) as did self-reported diabetes. Triglyceride risk was significantly higher for women and decreased significantly with age. Smoking increased risk two- to five-fold, increasing with dose, for women, which was significantly higher than the doubling in risk for men. CONCLUSIONS: This large study of the major risk factors compared between the sexes demonstrates similar relative risk of myocardial infarction associated with cholesterol for both sexes, however, the relative risk is higher in women for many other risk factors such as smoking, diabetes, elevated triglycerides and left ventricular hypertrophy.     

Discontinuing Long-Term GH Replacement Therapy--A Randomized, Placebo-Controlled Crossover Trial in Adult GH Deficiency

Context: Adult GH deficiency (GHD) is associated with impaired quality of life (QoL) and increased cardiovascular risk. Continued long-term efficacy in terms of QoL and cardiovascular risk factors has been indicated in open surveillance studies. Objectives: The aim was to study the impact of discontinuation of long-term GH replacement on QoL, body composition, and metabolism. Design and Setting: We conducted a randomized, double-blind, placebo-controlled 4-month crossover trial in a referral center. Patients: Sixty adult hypopituitary patients with GHD and more than 3 yr of continuous GH replacement therapy (mean treatment duration, 10 yr) participated in the study. Intervention: Patients received GH or placebo. Main Outcome Measurements: We measured QoL using validated questionnaires; body composition using computer tomography, dual-energy x-ray absorptiometry, and bioelectrical impedance spectroscopy; and insulin sensitivity using the short insulin tolerance test. Results: Mean serum IGF-I decreased from 168 ± 52 to 98 ± 47 μg/liter during the placebo period (P < 0.001). Two QoL domains (emotional reactions and positive well-being) in the Nottingham Health Profile and Psychological General Well-Being questionnaires deteriorated during placebo, compared with GH treatment (P < 0.05). Waist circumference and sc and visceral fat mass increased, and extracellular water and muscle area decreased during the placebo period (all P < 0.05). C-reactive protein and total-, low-density lipoprotein-, and high-density lipoprotein-cholesterol increased, and insulin sensitivity improved during placebo, compared to GH treatment (P < 0.05). Conclusion: After more than 3 yr of GH replacement therapy, a 4-month period of placebo treatment caused self-perceived deterioration in QoL and increased abdominal fat accumulation. Moreover, markers of systemic inflammation and lipid status deteriorated, whereas insulin sensitivity improved. Long-term continuous GH replacement is needed to maintain therapeutic effects of GH on QoL and cardiovascular risk factors.     

Long-Term Cognitive Impairments and Attentional Deficits in Patients with Cushing's Disease and Cortisol-Producing Adrenal Adenoma in Remission

Context: Cognitive function is impaired in patients with active Cushing's syndrome (CS). Objective: The aim was to study cognitive function in patients with CS in long-term remission. Design: We conducted a cross-sectional, case-controlled, single center study. Patients: Fifty-five patients previously treated for Cushing's disease (n = 43) and cortisol-producing adrenal adenoma (n = 12) and 55 controls matched for age, gender, and educational level participated in the study. Methods: Working memory, attention, information-processing speed, verbal fluency, and reading speed were studied using standardized neuropsychological testing and alerting, orienting, and executive control using the Attentional Network Test. Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue and affective disorder. Results: Median (interquartile range) duration of remission was 13 (5-19) yr and the mean ± sd age at follow-up was 54 ± 14 yr. Compared to controls, patients had a higher score on the fatigue impact scale, indicating greater burdens of fatigue, and a higher score on the comprehensive psychopathological rating scale subscales for depression and anxiety. In a multivariate analysis, attention, spatial orienting, alerting, working memory, verbal fluency, and reading speed were all diminished in comparison to controls, independent of scores for affective disorder and fatigue. No overall difference in outcome was seen between patients in long-term remission for Cushing's disease and cortisol-producing adrenal adenoma. Conclusion: Patients with CS in remission have impaired cognitive function that cannot be explained by the coexistence of affective disorder or chronic fatigue. The pattern of cognitive and attentional deficits suggests a more global involvement of the brain function than has previously been suggested.     

The metabolic consequences of thyroxine replacement in adult hypopituitary patients

The metabolic consequences of thyroxine replacement in patients with central hypothyroidism (CH) need to be evaluated. The aim was to examine the outcome of thyroxine replacement in CH. Adult hypopituitary patients (n?=?1595) with and without CH from KIMS (Pfizer International Metabolic Database) were studied before and after 2?years of GH replacement. CH patients (CH, n?=?1080) were compared with TSH sufficient patients (TSHsuff n?=?515) as one group and divided by thyroxine dose/kg/day into tertiles (CHlow-mid-high). Anthropometry, fasting glucose, glycosylated haemoglobin (HbA1c), blood pressure, lipids, IGF-I SDS, quality of life and morbidity were studied. Analyses were standardized for gender, age, number and types of pituitary insufficiencies, stimulated GH peak, age at GH deficiency onset, aetiologies and, when appropriate, for weight and GH dose. At baseline, TSHsuff patients did not differ from CH or CHmid in any outcome. CHlow (≤1.18?μg thyroxine/kg/day) had increased weight, BMI and larger waist circumference (WC), CHhigh (≥1.58?μg thyroxine/kg/day) had lower weight, BMI, WC and IGF-I than TSHsuff and compared to their predicted weights, BMIs and WCs. For every 0.1?μg/kg/day increase of thyroxine dose, body weight decreased 1.0?kg, BMI 0.3?kg/m(2), and WC 0.65?cm. The GH sensitivity of the CH group was higher (0.76?±?0.56 SDS/mg GH) than that of TSHsuff patients (0.58?±?0.64 SDS/mg GH), P?相似文献