Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clozapine (CLZ) and metabolites norclozapine and clozapine-N-oxide were assayed with a new, sensitive (2 pmol), and selective method in 68 serum samples from 44 psychotic subjects, 20 to 54 years old, ill 16 years, and treated with CLZ for 2.2 years (currently at 294 mg, 3.4 mg/kg daily). CLZ levels averaged 239 ng/ml (0.73 microM; 92 ng/ml per mg/kg dose) or 48% of total analytes (norclozapine = 41% [91% of CLZ] and clozapine-N-oxide = 11%); metabolite and CLZ levels were highly correlated (rs = 0.9), and CLZ levels varied with daily dose (rs = 0.7). Sampling twice yielded similar within-subject analyte levels (r = 0.8 to 0.9; difference = 24% to 33%). Range and variance narrowed when levels were expressed per weight-corrected dose (ng/ml per mg/kg). Levels per dose were 40% higher in nonsmoking women than men, despite a 60% lower milligram per kilogram dose in women, and did not vary by diagnosis or age in this limited sample. Fluoxetine increased serum CLZ analytes by 60%; valproate had less effect. Patients rated treatment very positively; observer-assessed benefits typically were more moderate. Common late side effects were sialorrhea (80%), excess sedation (58%), obesity (55% > 200 lb), mild tachycardia (51%), constipation (32%), and enuresis (27%); there were no seizures or leukopenia. There was little evident relationship of drug dose or serum level to current clinical measures or side effect risks.
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PMID:Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients. 819 52

The central autonomic network (CAN) is an integral component of an internal regulation system through which the brain controls visceromotor, neuroendocrine, pain, and behavioral responses essential for survival. It includes the insular cortex, amygdala, hypothalamus, periaqueductal gray matter, parabrachial complex, nucleus of the tractus solitarius, and ventrolateral medulla. Inputs to the CAN are multiple, including viscerosensory inputs relayed on the nucleus of the tractus solitarius and humoral inputs relayed through the circumventricular organs. The CAN controls preganglionic sympathetic and parasympathetic, neuroendocrine, respiratory, and sphincter motoneurons. The CAN is characterized by reciprocal interconnections, parallel organization, state-dependent activity, and neurochemical complexity. The insular cortex and amygdala mediate high-order autonomic control, and their involvement in seizures or stroke may produce severe cardiac arrhythmias and other autonomic manifestations. The paraventricular and other hypothalamic nuclei contain mixed neuronal populations that control specific subsets of preganglionic sympathetic and parasympathetic neurons. Hypothalamic autonomic disorders commonly produce hypothermia or hyperthermia. Hyperthermia and autonomic hyperactivity occur in patients with head trauma, hydrocephalus, neuroleptic malignant syndrome, and fatal familial insomnia. In the medulla, the nucleus of the tractus solitarius and ventrolateral medulla contain a network of respiratory, cardiovagal, and vasomotor neurons. Medullary autonomic disorders may cause orthostatic hypotension, paroxysmal hypertension, and sleep apnea. Neurologic catastrophes, such as subarachnoid hemorrhage, may produce cardiac arrhythmias, myocardial injury, hypertension, and pulmonary edema. Multiple system atrophy affects preganglionic autonomic, respiratory, and neuroendocrine outputs. The CAN may be critically involved in panic disorders, essential hypertension, obesity, and other medical conditions.
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PMID:The central autonomic network: functional organization, dysfunction, and perspective. 841 66

High physical fitness and physical activity are associated with favourable lipid levels, especially a high level of high density lipoprotein cholesterol (HDL-C). A person's skeletal muscle properties, metabolism and percentage of different muscle fibres (ST-%), which may modify coronary heart disease (CHD) risk factors, such as serum insulin, obesity and serum sex hormones may also influence his fitness level and leisure-time physical activity. We studied the associations of physical fitness, physical activity and ST-% with serum lipids and lipoproteins in 72 healthy men. Their parameters were compared with those of 20 men with defined CHD. Significant interrelationships between ST-%, fitness and leisure-time physical activity index (LTPAI) were observed. Multiple regression analysis showed that ST-%, fitness and leisure-time physical activity explained about 32% of the variation in HDL-C in the healthy men. In healthy men ST-% correlated positively with fitness (r(s) = 0.62, P < 0.001) and with LTPAI (r(s) = 0.62, P < 0.001). Fitness level also correlated significantly with LTPAI (r(s) = 0.81, P < 0.001). Serum insulin showed negative associations with ST-% (r(s) = -0.63, P < 0.001) and fitness (r(s) = -0.54, P < 0.001) and LTPAI (r(s) = -0.62, P < 0.001). Free fraction of testosterone correlated negatively with serum HDL-C level (r(s) = -0.34, P < 0.01), with fitness (r(s) = -0.41, P < 0.001) and with LTPAI (r(s) = -0.54, P < 0.001). In sedentary men with the lowest fitness and physical activity the mean of ST-% (45%) was similar to that in CHD patients (44%). However, ST-% in men in the highest tertile of physical activity and fitness (68%) was significantly higher than in CHD patients and in men in the lowest tertile of physical activity and fitness. Skeletal muscle enzyme activity in lipid metabolism was significantly lower in both CHD patients and in sedentary and low-fit men than that in fitter and physically active men. The present data imply that skeletal muscle properties are important determinants of risk profiles, such as physical activity, fitness and serum lipid and lipoprotein patterns. Although fitness is a graded, independent predictor of mortality from CHD, a relatively high fitness level is not enough. This was clearly observed in the clustering analysis, in which the healthy men, according to their ST-%, fitness, leisure-time physical activity and serum sex hormone binding globulin (SHBG), fell into three natural groups: (i) Inactive men with lowest ST-% (mean 42%), lowest fitness (10.7 METs) and lowest HDL-C (1.36 mm/l); (ii) Fit men with high ST-% (66%), high fitness (14.5 METs) and moderately high HDL-C (1.54 mol/l); (iii) Active men with high ST-% (66%), highest fitness (14.9 METs) and highest serum HDL (1.83 mmol/l). The results support the idea that both fitness and physical activity give further protection against CHD by modifying risk factors. Our findings also suggest that skeletal muscle properties should be considered in the studies which assess CHD risk factors and their modifications especially in the field of health-related fitness.
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PMID:Associations between skeletal muscle properties, physical fitness, physical activity and coronary heart disease risk factors in men. 962 81

Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.
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PMID:Life without neuropeptide Y. 976 8

A previously unrecognised X-chromosomal mental retardation syndrome is described. Clinical hallmarks are mental retardation, epileptic seizures, hypogonadism, and -genitalism, microcephaly and obesity. Life expectancy of patients is less than two years. Based on the major clinical symptoms this condition is referred to by the acronym MEHMO. Haplotype and two-point linkage analyses in a large three-generation family assign the disease locus to Xp21.1-p22.13, to a region that is flanked by CYBB and DXS365.
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PMID:MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to xp21.1-p22.13. 1048 47

Although the GnRH agonist analogs have become an established treatment for precocious puberty, there have been few long term studies of reproductive function and general health after discontinuation of therapy. To this end, we compared peak LH and FSH after 100 microg sc GnRH, estradiol, mean ovarian volume (MOV), age of onset and frequency of menses, body mass (BMI), and incidence of neurological and psychiatric problems in 2 groups of girls: those with precocious puberty due to hypothalamic hamartoma (HH; n 18) and those with idiopathic precocious puberty (IPP; n = 32) who had been treated with deslorelin (4-8 microg/kg x day, s.c.) or histrelin (10 microg/kg x day, s.c.) for 3.1-10.3 yr and were observed at 1, 2, 3, and 4-5 yr after discontinuation of treatment. The endocrine findings were also compared to those in 14 normal perimenarcheal girls. There were no differences between the HH and IPP groups in age or bone age at the start of treatment, at the end of treatment, or during GnRH analog therapy. We found that whereas the peak LH level was higher in HH than in IPP girls before (165.5 +/- 129 vs. 97.5 +/- 55.7; P < 0.02) and at the end (6.8 +/- 6.0 vs. 3.9 +/- 1.8 mIU/mL; P < 0.05) of therapy, this difference did not persist at any of the posttherapy time points. LH, FSH, and estradiol rose into the pubertal range by 1 yr posttherapy in both HH and IPP. However, the mean posttherapy peak LH levels in both HH and IPP groups tended to be lower than normal, whereas the peak FSH levels were not different from normal, so that the overall posttherapy LH/FSH ratio was decreased compared to that in the normal girls (HH, 2.7 +/- 0.3; IPP, 2.6 +/- 0.1; normal, 5.2 +/- 4.8; P < 0.05). The MOV was larger in HH than IPP at the end of treatment (3.7 +/- 3.5 vs. 2.0 +/- 1.2 mL; P < 0.05) and tended to increase in both groups over time to become larger than that in normal girls by 4-5 yr posttherapy (HH, 14.9 +/- 12.9; IPP, 7.6 +/- 2.2; normal, 5.4 +/- 2.5 mL; P < 0.05). Whereas the onset of spontaneous menses varied widely in both groups, once menses had started, the HH group had a higher incidence of oligomenorrhea. Pelvic ultrasonography revealed more than 10-mm hypoechoic regions in 4 HH patients, 15 IPP patients, and 3 normal girls, all of whom were reporting regular menses. Live births of normal infants were reported by 2 HH and 2 IPP patients, and elective terminations of pregnancy were reported by 1 HH and 2 IPP patients. BMI was greater than normal in HH and IPP both before treatment and at all posttherapy time points and tended to be higher in the HH patients. Marked obesity (BMI, +2 to +5.2 SD score) was observed in 5 HH and 6 IPP patients, 1 of whom had a BMI of +2.5 SD score and developed acanthosis nigricans, insulin resistance, and hyperglycemia. Seizure disorders developed during GnRH analog therapy in 5 HH and 1 IPP patient, and 2 additional HH girls developed severe depression and emotional lability posttherapy. Although the mean anterior-posterior dimension of the hamartoma was larger in the HH patients with seizure than in those who were seizure free (1.7 +/- 1.2 vs. 0.9 +/- 0.4 cm; P < 0.05), no change in hamartoma size was observed either during or after therapy, and no patient has reported the onset of a seizure disorder posttherapy. Other than a tendency toward a larger MOV, a higher incidence of oligomenorrhea, obesity, and frequency of neurological disorders, recovery of the reproductive axis after GnRH analog therapy was not markedly different in HH compared to IPP. Continued follow-up of these patients may determine whether the decreased LH responses and increased BMI in both groups compared to those in normal girls remain clinically significant problems.
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PMID:Reproductive axis after discontinuation of gonadotropin-releasing hormone analog treatment of girls with precocious puberty: long term follow-up comparing girls with hypothalamic hamartoma to those with idiopathic precocious puberty. 992 60

Serotonin 5-HT2C receptor null mutant mice were generated to assess the contribution of this receptor to the actions of serotonin. Mutant mice displayed both an epilepsy and obesity phenotype. The epilepsy syndrome was characterized by spontaneous seizures, lowered seizure threshold, enhanced seizure propagation and sound-induced seizure susceptibility. These findings implicate 5-HT2C receptors in the regulation of neuronal network excitability. It was also observed that body weight and adipose tissue deposition were elevated in adult mutant mice relative to their wild type littermates. Paired-feeding studies suggest that the obesity syndrome is a result of increased food intake. In addition, mutants displayed reduced sensitivity to the appetite suppressant actions of non-specific serotonergic agonists. These studies establish a role for 5-HT2C receptors in the serotonergic regulation of body weight and food intake.
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PMID:Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. 992 41

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.
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PMID:Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy. 1076 74

We have reviewed published reports on patients with segmental aneusomy for chromosome 1p36 to help geneticists and other health professionals in the recognition of this emerging chromosomal syndrome. Terminal deletions of the short arm of chromosome 1 are associated with hypotonia and developmental delay (usually severe), growth abnormalities (growth retardation, microcephaly, obesity), and craniofacial dysmorphism with a large anterior fontanelle, prominent forehead, deep set eyes, flat nasal bridge and midface hypoplasia, ear asymmetry, a pointed chin, and orofacial clefting. Minor cardiac malformations, cardiomyopathy, seizures, and ventricular dilatation are the more common additional findings. Sensorineural hearing loss and variable ophthalmological anomalies have also been frequently observed. Although the deletions can be detected by high resolution cytogenetic studies, confirmation by fluorescence in situ hybridisation is required in most cases. The majority of deletions are maternally derived. Molecular characterisation of 1p36 deletions has been undertaken in several cases, and it is likely that this condition is a contiguous gene deletion syndrome.
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PMID:Monosomy 1p36. 1050 20

The drug combination of phentermine plus fenfluramine has been used clinically in both the treatment of obesity and alcoholism. The aim of the current study was to assess the interaction of the two drugs on consumption of both an alcohol-containing and a nonalcoholic diet. Furthermore, the efficacy of the drug combination on suppression of withdrawal seizures was determined. Animals were either maintained on a 6% alcohol-containing diet, free-fed an isocaloric control, or pair-fed the control diet. It was observed that, with regard to body weight growth curves, alcohol provides about 2.5 kcal/g. Both phentermine and fenfluramine caused a decrease in consumption 1 h after administration; however, during the next 23 h, 4 mg/kg phentermine significantly increased consumption of all diets. At doses of 1 and 2 mg/kg, fenfluramine selectively reduced consumption of the alcohol-containing diet as compared to the isocaloric diets. Lower doses of fenfluramine blocked the increases in consumption induced by phentermine. Furthermore, in animals fed the nonalcoholic diet, the drug combination of 2 mg/kg fenfluramine plus 8 mg/kg phentermine produced a 63-82% reduction in consumption, an effect not seen when either drug was administered alone. This greater than additive effect was also seen in the earlier time periods in animals pair-fed the control diet. Neurochemical analysis from these animals revealed that the alcohol-dependent animals displayed a significant reduction of DOPAC and 5-HIAA levels in the striatum, frontal cortex, and hypothalamus after a 9-h withdrawal period, further implicating the serotonergic and dopaminergic systems in mediation of withdrawal symptoms and alcohol craving. Finally, 8 mg/kg phentermine plus 8 mg/kg fenfluramine completely abolished alcohol withdrawal seizures, compared to a 78% rate in saline treated rats. In conclusion, the coadministration of phentermine plus fenfluramine produced a moderate reduction of alcohol consumption and was completely effective at reducing alcohol withdrawal seizures.
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PMID:Effects of phentermine and fenfluramine on alcohol consumption and alcohol withdrawal seizures in rats. 1068 Jul 13


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