Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain.

BACKGROUND: Antipsychotic-induced weight gain (AIWG) is a serious side-effect of antipsychotic medication leading to metabolic syndrome and increased cardiovascular morbidity. Unfortunately, there are still no valid predictors to assess an individual's risk to gain weight. Previous studies have indicated an impact of genetic variation in the genes encoding leptin, LEP, and leptin receptor, LEPR, on AIWG, but results have not been conclusive. Thus, we investigated polymorphisms in both genes for an association with AIWG. METHODS: A total of 181 schizophrenic and schizoaffective patients treated with various antipsychotics were included. In a small subset of patients, leptin plasma levels were additionally obtained. Five polymorphisms in LEP and LEPR (LEP: rs7799039 (-2548G/A polymorphism), rs10954173, rs3828942; LEPR: rs1327120, rs1137101 (Q223R polymorphism) were genotyped using TaqMan assays. Statistical association with % weight change from baseline weight was performed using ANCOVA with baseline weight as covariate. RESULTS: ANCOVA showed a non-significant trend for genotype association of the rs7799039 marker (p=.068). No significant association of the other LEP and LEPR SNPs with AIWG was detected. However, we found a significant association between a haplotype of LEP rs7799039G-rs10954173G-rs3828942G (p=.035) and AIWG. The rs7799039 G-allele (p=.042) and G-allele of rs3828942 (p=.032) were associated with higher weight gain. CONCLUSION: Our study supports the hypothesis of an impact of LEP gene variation on AIWG. Limitations of our study include heterogeneous samples, short treatment duration and multiple comparisons. Our findings were compared to previous studies in detail in order to provide the readers with a more conclusive picture. However, further studies are warranted including more gene variants and interaction analyses with other genes of the leptin-melanocortin pathway.

Neurotransmitter systems in alcohol dependence.

An interplay of different neurotransmitter systems has been implicated in the development and maintenance of alcohol dependence. Here we focus on neuroadaptations in reward-related neurotransmitter systems and their impact on central processing of alcohol-associated and reward-indicating stimuli. We discuss genotype effects on cue-induced neuronal activation and present new computational methods based on machine learning to deal with complex genotype-phenotype interactions, e.g. between brain atrophy and genes associated with glutamatergic and dopaminergic neurotransmission.

[Genetics of weight gain associated with antipsychotic medications]. / Genetik der Antipsychotika-assoziierten Gewichtszunahme.

Weight gain is a serious adverse event during neuroleptic or antipsychotic treatment of schizophrenic disorders. The risk of weight gain varies among the class of neuroleptics, however no reliable predictors exist that adequately estimate individual risk. It is hoped that molecular genetic tests will help determine individual risk in the future. This article summarizes studies performed till now and concludes that gene variants of the serotonin 2C receptor and leptin significantly correlated with weight gain in several studies. Further interesting findings were obtained with variants of CYP2D6, the synaptosome-associated protein of 25 kDa (SNAP-25) as well as with the adrenergic alpha-2A genes. The group sizes were however small, and more studies are required for genetic tests to become available. Nonetheless the first steps towards genetic risk assessment have been performed, and its application in the near future has become likely.

The concept of endophenotypes in psychiatric diseases meeting the expectations?

Although the prominent role of genetics in psychiatric diseases has been established in various family, twin and adoption studies over the last decades, the identification of concrete contributing genes has been demanding. The reasons for this are manifold, including inconsistencies in psychiatric classification systems, complexity and heterogeneity of psychiatric disorders, epistatic effects and intervening environmental factors. In recent years interest has focused increasingly on the concept of endophenotypes. Genetic analyses have concentrated on discrete phenotypes supposedly linked to a particular psychiatric disorder by common neurobiological pathways, instead of studying the complex disease itself. Several endophenotypes have been established for psychiatric diseases including electrophysiological abnormalities and alterations in structural and functional brain imaging. Although results seem to be getting more consistent and reliable, several concerns have also emerged with the experience gained on the topic. This review will give an overview of the prospects and limitations related to endophenotypes in psychiatric diseases. We will also summarize essential prerequisites for successful endophenotypes in the future as well as applications for psychiatric diseases which have been envisioned.

Synergistic effects of the dopaminergic and glutamatergic system on hippocampal volume in alcohol-dependent patients.

Several genes of the dopaminergic and glutamatergic neurotransmitter systems have been found to be associated with alcohol disease and related intermediate phenotypes. Here, we evaluated genetic variants of the catechol-O-methyltransferase (COMT) and the metabotropic glutamate receptor 3 (mGluR3) genes in alcohol-dependent patients and their association with volumetric measurements of brain structures. By combined analysis of imaging data and genotyping results, large numbers of variables are produced that overstrain conventional statistical methods based on tests for group differences. Limitations in assessment of epistatic effects and multiple testing problems are encountered. Therefore, we introduce a novel method for detecting associations between a set of genetic markers and phenotypical measurements based on machine learning techniques. Hippocampal volume was found to be associated with epistatic effects of the COMT-mGluR3 genes in alcohol-dependent patients but not in controls. These data are in line with prior studies supporting a role for dopamine-glutamate interaction in modulation of alcohol disease.

Progressive sudomotor dysfunction in amyotrophic lateral sclerosis.

Autonomic dysregulation is part of the complex degenerative process in amyotrophic lateral sclerosis (ALS). To investigate this, sweating was examined at rest in 39 patients with ALS in comparison with a control group. Sweat was collected over a 30 second period over the thenar and hypothenar eminences and on the sole of the foot, using a commercial device based on vapour pressure gradient. The measurements were repeated after three and six months in 10 patients for longitudinal analysis. In early ALS, patients had significantly higher skin water loss than control subjects over the thenar and the hypothenar eminences. In advanced disease stages, sweating was decreased at all sites compared with controls. A significant decline in sweat secretion of about 40% was found over a six month period. The findings suggest an abnormal sympathetic activity with hyperhidrosis in early ALS and a reduction in sweat production as the disease progresses.

Disease progression in amyotrophic lateral sclerosis: predictors of survival.

Predicting the rate of disease progression has become important as trials of new medical treatments for amyotrophic lateral sclerosis (ALS) are planned. Bulbar onset, early impairment of forced vital capacity, and older age have all been associated with shorter survival. We performed a retrospective study to compare survival factors with disease progression in a German ALS population. We analyzed disease progression in 155 patients at intervals of 4 months over a period of 3 years. To evaluate disease progression, the ALS functional rating scale (ALS-FRS), forced vital capacity (FVC%), and a Medical Research Council (MRC) compound score based on a nine-step modified MRC scale were used. We compared age (< 55 years vs. > or =55 years), different sites of disease onset (bulbar vs. limb), and gender to the rate of disease progression and performed survival analyses. No overall significant difference could be detected when analyzing these subgroups with regard to disease progression. By contrast, significantly longer survival was observed in the younger age group (56 months vs. 38 months, P < 0.0001) and in patients with limb-onset disease (51 months vs. 37 months, P = 0.0002). Using Cox analyses values we found that the declines of ALS-FRS, FVC%, and MRC compound score were predictive of survival (P < 0.0001, P = 0.002, and P = 0.003, respectively). Future studies are needed to clarify whether nonspecific factors including muscle atrophy, dysphagia, and coexisting diseases influence prediction of survival in ALS patients. A more precise set of predictors may help to better stratify patient subgroups for future treatment trials.

Early postoperative transcranial sonography (TCS), CT, and MRI after resection of high grade glioma: evaluation of residual tumour and its influence on prognosis.

PURPOSE: In this prospective study the results of multimodal postoperative neuro-imaging were related to the survival of patients with high grade gliomas. METHODS: All 73 patients included underwent microsurgical tumour resection and had postoperative CT and transcranial sonography (TCS) examinations. In addition, 35 of the 73 patients received an early postoperative MRI. Patients were followed up for at least one year. FINDINGS: At the end of the 7 year study period 56 patients had died. The median survival time was 371 days. Survival rate was significantly higher in patients with anaplastic astrocytomas and inpatients displaying complete tumour resection on MRI (log-rank-test, p < 0.05) or a small postoperative residual tumour bulk on TCS (log-rank-test, p < 0.05). Cox proportional hazards model identified histological tumour grade, postoperative Karnofsky index, complete resection based on MRI and small postoperative residual tumour mass on TCS as independent predictors of survival. INTERPRETATION: This study demonstrates that early postoperative neuro-imaging has prognostic implications for the survival of patients with high grade gliomas. According to our results postoperative imaging with MRI and TCS is a valuable prognostic with regard to patient survival and should therefore be implemented in postoperative follow-up. It also helps to evaluate the efficacy of adjuvant therapy.

Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis.

Sialorrhoea is a socially disabling problem in bulbar amyotrophic lateral sclerosis (ALS). Botulinum toxin A (BoNT/A) was injected into the salivary glands in five patients with bulbar ALS and sialorrhoea. The effect of BoNT/A was measured by the number of paper handkerchiefs used each day and by salivary gland scintigraphy. BoNT/A ameliorated sialorrhoea and quality of life without major adverse effects. BoNT/A may be a relatively safe and effective treatment for sialorrhoea in selected patients.

Measurement of cerebral blood flow volume by extracranial sonography.

Measurement of global cerebral blood flow (CBF) using extracranial duplex sonography has been described, but normal values are still lacking. In 85 healthy adults (median age 43.4 years, range 20 to 80 years), CBF was determined by duplex sonographic examination of both internal carotid arteries and vertebral arteries. The mean global CBF was 630+/-97 mL/min. Global CBF declined with age; sex did not influence the total CBF. When measurements were repeated, the intraindividual variability was low. This noninvasive sonographic measurement of CBF is reproducible, and values correspond closely to those obtained with positron emission tomography and magnetic resonance imaging.

Transcranial sonography of the brain parenchyma: comparison of B-mode imaging and tissue harmonic imaging.

Transcranial color-coded Duplex sonography (TCCS) has been used for the identification of cerebrovascular disorders. Recently, its value in the diagnosis of disorders of the brain parenchyma has been proposed. The object of this study was to determine systematically the echo pattern of the brain parenchyma and to compare conventional B-mode imaging with tissue harmonic imaging (THI). Transcranial sonography (TCS) was performed in 54 healthy individuals through the temporal bone window using conventional B-mode imaging and THI by two experienced investigators. Identification rates for several brain structures were assessed, and the quality of depiction of each method was graded semiquantitatively. In addition, several parts of the ventricular system and the basal cerebral cisterns were measured. Four subjects did not have an adequate bone window for transcranial examination. In the remaining people, the bone window was assessed to be adequate (59%) or excellent (33%). In the majority (> 80%), TCS allowed an unequivocal identification of various brain structures. Inter-rater variability of the assessments of tissue echogenicity and measurements of the ventricular width were found to be low for several structures (e.g., brainstem, thalamus, or 3rd ventricle). The echo pattern of brain tissue in THI is identical to that described for B-mode imaging. Using THI, contours of brain structures were typically visualized more clearly and the reproducibility of measurements was more consistent. In our experience, insonation of the contralateral lobes was limited when depths were higher than 12 cm using THI. In conclusion, TCS allowed the sonographic examination of the brain parenchyma in the majority of our subjects. THI substantially improves the identification of parenchymal structures when the depth is below 12 cm.

Volume reduction in cerebral blood flow in patients with vascular dementia.

Global volume of cerebral blood flow as measured by colour duplex sonography of the extracranial cerebral arteries is much lower in patients with vascular dementia than in healthy individuals matched for age and sex.

Diagnostic impact of cerebral transit time in the identification of microangiopathy in dementia: A transcranial ultrasound study.

BACKGROUND AND PURPOSE: The diagnosis and quantification of microangiopathy in dementia is difficult. The assessment of small-vessel disease requires expensive and sophisticated nuclear medicine techniques. This study was performed to identify microangiopathy related to the integrity of cerebral microcirculation by sonographic measurements (arteriovenous cerebral transit time [cTT]). METHODS: We performed transcranial color-coded duplex sonography in 40 patients with vascular dementia, 20 patients with Alzheimer's disease or Lewy body disease, and 25 age-matched controls. The clinical diagnosis was established by history of dementia and neuroimaging findings. Cognitive impairment was assessed by the Mini-Mental State Examination and Alzheimer's Disease Assessment Scale. cTT is defined as the time required by an ultrasound contrast agent to pass from a cerebral artery to a vein. This was measured by recording the power-Doppler intensity curves in the P2 segment of the posterior cerebral artery and the vein of Galen. Previous studies have shown a prolongation of cTT in patients with cerebral microangiopathy. RESULTS: cTT was substantially prolonged in patients with vascular dementia (5.8 seconds; 25th percentile 4.5; 75th percentile 7.5; U test, P<0.001) compared with controls (3.1 seconds; 2.3; 3.4) but not in patients with degenerative dementia (3.7 seconds; 3.7; 4.2). In patients with vascular dementia, cTT was significantly correlated with cognitive impairment. CONCLUSIONS: cTT may be useful tool to disclose small-vessel disease in demented patients. Examination is noninvasive and quickly performed. It may be also useful in follow-up examinations in patients undergoing therapy.

Cerebral arteriovenous transit time (CTT): a sonographic assessment of cerebral microcirculation using ultrasound contrast agents.

Transcranial color-coded sonography (TCCS) has been used to investigate major brain-supplying arteries, draining veins and brain parenchyma. Here, we describe a contrast-enhanced TCCS analysis of cerebral arteriovenous transit time (cTT) as a measure of cerebral microcirculation. We evaluate its reproducibility and its correlation with clinical impairment of brain function and neuropsychological tests. A total of 27 patients with cerebral microangiopathy and 30 healthy controls were examined. CTT is defined by the time an ultrasound contrast agent requires to pass from the P2-segment of the posterior cerebral artery to the vein of Galen. This was measured by comparison of power Doppler intensity in two off-line defined regions of interest. Serial intraindividual cTT measurements within several min showed a good reproducibility of this parameter. cTT was significantly longer in patients with cerebral microangiopathy than in controls (Mann-Whitney U test,p < 0.001) and related to cognitive impairment measured by the Mini-Mental-State examination. We conclude that it is a quick and reliable parameter related to increased vascular resistance of the microcirculation or a rarefaction of microvessels. Further studies are needed to show the sensitivity and specificity of cTT in the diagnosis of small vessel disease and the interference of important circulation factors, such as heart failure or blood viscosity.

[Clenbuterol in amyotrophic lateral sclerosis. No indication for a positive effect]. / Clenbuterol bei der Amyotrophen Lateralsklerose. Kein Hinweis für einen positiven Effekt.

The anabolic effects of clenbuterol have been recognized for a long time. Clenbuterol augments the expression of specific muscle proteins with a differential effect on type I and type II fibres. Furthermore, clenbuterol induces the synthesis of endogenous nerve growth factor (NGF) and may itself be a myotrophic factor released by neuron endings. Side effects include tremor and headache and dose dependent abnormalities of laboratory values (hypokalemia, hypoglycemia). After long-term medication increasing fatigue of muscles has been observed. Decreased expression of beta 2-adrenergic receptors may limit the expected functional improvement. The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved. Controlled treatment trials are warranted to assess this question.

[The treatment of arrhythmias in infants and children using propafenone]. / Die Behandlung von Herzrhythmusstörungen mit Propafenon bei Säuglingen und Kindern.

Antiarrhythmic treatment was required in 35 patients aged one day to 11 8/12 years (average 5 7/12 years) for one or several of the following arrhythmias: paroxysmal supraventricular tachycardia (17), ventricular extrasystole (16), ventricular tachycardia (17), ventricular extrasystole (16), ventricular tachycardia (4), junctional tachycardia (4), and atrial flutter (3). 300 mg/m2/day oral propafenone was administered in 3 to 4 divided doses. The arrhythmia in 21 of the 35 patients had been unsuccessfully treated by digoxin (6), verapamil (5), ajmalin (4), propranolol (3), spartein (1), phenytoin (1), and lidocain (1) prior to the propafenone therapy. However, the arrhythmias could be abolished or reduced in 30 patients (85.7%) by Propafenone. In 5 patients with supraventricular tachycardia (2), junctional tachycardia (2), or ventricular extrasystole (1), propafenone therapy had no effect. In two other patients propafenone led to atrioventricular conduction disturbances and had to be discontinued. Propafenone is an effective well tolerated antiarrhythmic drug without major side effects in pediatric patients.

[Plasma ammonia concentrations in mucoviscidosis]. / Plasma-Ammoniakkonzentration bei Mukoviszidose.

In 16 children and adolescents suffering from mucoviscidosis the ammonia concentration of the plasma determined by a modified ion exchange method was compared with the clinical degree of severity. The ammonia values of the plasma were compared with several parameters, such as Shwachman stage, the presence of cardio-respiratory insufficiency, blood gas values and liver function tests. In 5 children with cystic fibrosis and cardio-respiratory insufficiency high plasma ammonia values were found. In older children with the disease lasting for a longer time with medium Shwachman stage (stage III) but without cardiorespiratory insufficiency the ammonia values were also relatively high. Cardiorespiratory insufficiency and disturbance of the liver function may play a role in the development of hyperammonemia. A distinct hyperammonemia refers to a bad prognosis in children with cystic fibrosis.