PubMed Health⌕ Search

Biomedical subjects

J Thome

Publications and source records attributed to J Thome.

At least 55 records · Page 3Linked to original sources

Ciliary neurotrophic factor null mutation and schizophrenia in a Swedish population.

According to the maldevelopmental hypothesis, the neurotrophic factor system represents an important area which might be genetically and neurochemically involved in the etiopathogenesis of schizophrenic psychoses. Patients suffering from schizophrenic psychoses and control persons were genotyped for a null mutation of the ciliary neurotropic factor gene. There were no significant differences in the allelic and genotypic distributions in the total schizophrenic and control samples. However, there was a negative association with a family history of psychosis. Thus, it cannot be excluded that this genetic variant represents a vulnerability marker for specific schizophrenic subtypes. The development of valid diagnostic instruments based on biological criteria is crucial for schizophrenia research; more homogeneous subgroups are more likely to represent distinct nosological entities than the heterogenous group of diseases presently categorized as schizophrenia.

Alleles↗

Evidence for increased oxidative stress in alcohol-dependent patients provided by quantification of in vivo salicylate hydroxylation products.

The hypothesis of increased oxidative stress in alcohol-dependent patients postulates that altered free radical metabolism is involved in the various symptoms associated with this disease, including brain atrophy, peripheral polyneuropathy, alcoholic liver fibrinogenesis, and cancer. Using an in vivo assay for quantitation of hydroxyl radical (.OH) levels in peripheral blood, we detected increased values in patients suffering from alcohol dependence when compared with non-dependent control persons. The assay used in this study involves the injection of acetylsalicylic acid, which is metabolized in vivo by direct reaction with .OH to 2,3-dihydroxybenzoic acid (DHBA). The time curve for the concentration of the reaction product (2,3-DHBA), determined by high-performance liquid chromatography, thus estimates the .OH radical level in the peripheral blood of individuals undergoing this test. For the first time, we used the intravenous application of acetylsalicylic acid to avoid artifacts arising from differences in gastrointestinal resorption, known to be disturbed in alcoholism. The areas under the 2,3-DHBA time curves differed significantly (p < 0.05) between patients and controls (0.54 +/- 0.27 vs. 0.36 +/- 0.19 microM.h). This study presents further evidence for alterations in radical metabolism in vivo in patients suffering from alcohol dependence. The assay can also be used in further studies dealing with antioxidative treatment (radical scavengers) to evaluate the effectiveness of such therapy.

Adult↗

Ciliary neurotrophic factor (CNTF) genotypes: influence on choline acetyltransferase (ChAT) and acetylcholine esterase (AChE) activities and neurotrophin 3 (NT3) concentration in human post mortem brain tissue.

Cell culture and animal models suggest a significant influence of ciliary neurotrophic factor (CNTF) on cholinergic neurotransmitter systems. We therefore conducted an explorative pilot study to investigate the influence of a null mutation allele of the CNTF gene on ChAT (choline acetyltransferase) and AChE (acetylcholine esterase) activities in various regions of human post mortem brain tissue. Additionally, we determined NT3 (neurotrophin 3) levels, a factor which exhibits neurotrophic properties at cholinergic neurons, and the concentration of which in these brain regions varies with CNTF genotype. Homozygous carriers of the mutation lack CNTF completely, whereas heterozygotes have a CNTF level which is about half that of non-carriers. There was a trend toward lower ChAT and AChE activity levels in the cingulate cortex in individuals homozygous or heterozygous for the mutation when compared with non-mutant individuals. Additionally, higher NT3 concentrations were found in this region, as well as in the frontal cortex and caudate nucleus. ChAT and AChE activities in the frontal cortex and caudate nucleus were not significantly linked to CNTF genotype. These results are, however, preliminary and need to be further explored. The individuals investigated were heterogenous with respect to a range of parameters; nevertheless, the hypothesis that genetic variants for neurotrophic factors play a role in diseases of neural development and plasticity deserves further examination.

Acetylcholinesterase↗

Homozygosity at the dopamine D3 receptor gene in schizophrenic patients.

Dopamine receptors have long been implicated in the etiology of schizophrenia. It has been reported an association of schizophrenia with homozygosity at the dopamine D3 receptor gene locus. We have investigated the distribution of a D3 receptor gene polymorphism (BalI) in 107 schizophrenic Spanish patients and 100 healthy matched controls. No statistically significant differences between the patients and control group were detected with respect to either allele frequencies or genotype distribution. However, if not corrected for multiple testing, a correlation was found between homozygosity and early age of onset of schizophrenia (chi 2 = 3.1, df = 1, P = 0.03) and between A1 allele frequency and disorganized and undifferentiated schizophrenia (chi 2 = 3.4, df = 1, P = 0.03; chi 2 = 2.7, df = 1, P = 0.05, respectively). These results suggest the possibility that D3 polymorphisms may be among the physiological factors underlying schizophrenia; though not the determining factor.

Aged↗

The Gly/Glu polymorphism of the neurotrophin 3 gene: allele frequencies in a Caucasian population and relevance for psychiatric disorders.

Using a modified method for the determination of the genotype of the neurotrophin 3 Gly/Glu polymorphism by PCR, we investigated allele frequencies in patients suffering from different psychiatric diseases as well as in healthy controls. There was a much lower frequency of the allele Glu among Caucasians (0.006) than previously reported for a Japanese population (0.203). No homozygotes and only three heterozygotes for the rare allele could be detected: the latter belonged to the patient group and suffered from endogenous depression (two patients) and hebephrenia (one patient). Due to its very low frequency it seems unlikely that the allele Glu plays a decisive role in the aetiopathogenesis of schizophrenic psychoses or other psychiatric diseases. However, it cannot be excluded that it represents a risk or vulnerability factor.

Adult↗

A null mutation allele in the CNTF gene and schizophrenic psychoses.

The maldevelopmental theory postulates disturbances in neural development as crucial factors in the aetiopathogenesis of schizophrenia. Neurotrophic factors, including ciliary neurotrophic factor (CNTF), play a central role in the regulation of such development. A mutation has been described for the CNTF gene, whereby subjects homozygous for the mutation lack CNTF. The polymerase chain reaction was used to amplify the CNTF gene region containing this mutation in whole blood genomic DNA. The mutation was detected by analysis of restriction fragment length polymorphisms. Patients suffering from schizophrenic psychosis (ICD-10 criteria) (51 from Würzburg, 83 from Barcelona), and healthy controls (62 from Würzburg, 50 from Barcelona) were investigated. In the Würzburg group, the frequency of subjects homozygous or heterozygous for the mutation was significantly higher among schizophrenic patients than in controls. However, no difference could be detected in the Spanish sample; the possible reasons for the different allele distribution in the two patient groups is discussed. It is concluded that the CNTF null mutation may be relevant to the aetiopathogenesis of schizophrenia in some patients, but further work is required to identify specifically the patient group for which it is important.

Adult↗

Association between a null mutation in the human ciliary neurotrophic factor (CNTF) gene and increased incidence of psychiatric diseases?

We report a possible association between a null mutation in the human ciliary neurotrophic factor (CNTF) gene and psychiatric diseases. Prior findings that the mutant allele frequency is not significantly elevated in patients suffering from neurological diseases are confirmed. The frequency of the mutant allele was higher among psychiatric patients (0.192, n = 297) than among healthy controls and neurological patients (0.142, n = 267). This difference (one-tailed 2 x 2 chi-square test, P < 0.05) might be evidence that disturbances in the neurotrophic factor system could play a crucial role in the etiopathogenesis of psychiatric disorders, mainly psychoses.

Adult↗

[New hypothesis on etiopathogenesis of Alzheimer syndrome. Advanced glycation end products (AGEs)].

Despite intense efforts, it has not yet been possible to clarify the etiopathogenesis of Alzheimer's dementia. There are, however, hypotheses which focus on certain aspects of this type of dementia, characterized by particular neuropathological alterations and clinical correlates. Recently, evidence has accumulated that advanced glycation endproducts (AGEs) could play an important role in the etiology of the Alzheimer's syndrome. AGEs are generated by an irreversible reaction through the non-enzymatic, long-term glycosylation of proteins. They are strongly resistant to proteolytic processes and induce protein crosslinking. They could thus inhibit the physiological functions of many proteins. Moreover, it is suggested that they contribute to the transformation of the soluble form of beta-amyloid into its unsoluble version. AGEs are also demonstrable in neurofibrillary tangles (NFTs). A further mechanism by which AGEs might be pathogenic is via their induction of oxidative stress. AGEs probably exert their pathological effects not only directly because of their chemical properties, but also by indirect receptor-mediated mechanisms. Further investigation of AGE-mediated mechanisms should reveal their role in the etiopathogenesis of the Alzheimer's syndrome and, finally, lead to the development of new pharmacological strategies aimed at inhibiting protein cross-linking.

Aged↗

Advanced glycation endproducts-associated parameters in the peripheral blood of patients with Alzheimer's disease.

Advanced glycation endproducts (AGEs), structural components of beta-amyloid plaques and neurofibrillary tangels, have been implicated in the pathogenesis of Alzheimer's disease. AGE levels, measured by fluorescence, and their precursor molecules such as glucose and its Amadori product, fructosylamine, were measured to examine the question whether the reported increased level of AGEs in the brain is reflected in an increase in AGE-associated parameters in peripheral blood. Lactoferrin, proposed to play an important role in the interaction of AGEs with their receptors, was determined by ELISA. All AGE-associated parameters showed trends to lower values in patients with Alzheimer's disease compared with non-demented controls. Albumin and total iron were not significantly different between the groups. In contrast to diabetes and renal failure, where high levels of AGEs and their precursors are present in tissue as well as in peripheral blood, elevated CNS AGE levels in patients with Alzheimer's disease are manifested without detectable peripheral changes.

Aged↗

Alcohol withdrawal and dopamine receptor sensitivity after prolonged abstinence.

1. Forty-four male inpatients suffering from moderate to severe alcohol dependence (DSM-III-R and ICD-10) as well as 14 healthy controls entered this study. Individuals were classified according to the severity of their withdrawal symptoms during detoxification i.e. group 1) no withdrawal, group 2) autonomic hyperactivity, group 3) withdrawal delirium and group 4) controls. 2. During the 6th week of treatment, that is, when all patients were recovered, controlled abstinent, and several weeks away from the end of their withdrawal syndrome, dopamine receptor sensitivity was neuroendocrinologically assessed by stimulating human growth hormone (HGH) with apomorphine (APO). 3. In a repeated measures model ANOVA, the four groups differed significantly in their HGH release. However, when excluding the controls from the analysis and focusing on alcoholics only (group 1 - 3), the significant difference disappeared. Covariates such as age, weight, quantity of drinking and duration of dependence were not related to the dependent variable. 4. In conclusion, the first significant result (with controls) reflects a blunted HGH response in alcoholics. It confirms earlier reports. The second, non significant result with the alcohol dependents only, suggests that the severity of withdrawal is not reflected by the amount of HGH released. Therefore, in alcoholics, a reduced dopamine receptor function after six weeks of abstinence, as neuro-endocrinologically assessed with apomorphine, seems to be related to alcohol dependence rather than to the severity of alcohol withdrawal.

Adult↗

Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies.

Orphenadrine has been used as an antiparkinsonian, antispastic and analgesic drug for many years. Here we show that orphenadrine inhibits [3H]MK-801 binding to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA)-receptor in homogenates of postmortem human frontal cortex with a Ki-value of 6.0 +/- 0.7 microM. The NMDA receptor antagonistic effects of orphenadrine were assessed using concentration- and patch-clamp techniques on cultured superior colliculus neurones. Orphenadrine blocked open NMDA receptor channels with fast kinetics and in a strongly voltage-dependent manner. The IC50-value against steady state currents at -70 mV was 16.2 +/- 1.6 microM (n = 6). Orphenadrine exhibited relatively fast, concentration-dependent open channel blocking kinetics (Kon 0.013 +/- 0.002 10(6) M-1S-1) whereas the offset rate was concentration-independent (Koff 0.230 +/- 0.004 S-1). Calculation of the ratio Koff/Kon revealed an apparent Kd-value of 17.2 microM which is nearly identical to the IC50 calculated at equilibrium.

Aged↗

Alpha-1-antichymotrypsin bi-allele polymorphism, apolipoprotein-E tri-allele polymorphism and genetic risk of Alzheimer's syndrome.

The alpha1-antichymotrypsin and apolipoprotein-E polymorphisms were investigated in patients suffering from Alzheimer's syndrome and non-demented psychiatric inpatients as controls. The apolipoprotein E allele 4, well known as risk factor, tended to be elevated in the index group. The frequency of the alpha1-antichymotrypsin allele A was significantly increased in patients with Alzheimer's syndrome: 0.647 vs. 0.483 (chi-square test, p < 0.05). We conclude that, apart from the apolipoprotein E allele 4, the alpha1-antichymotrypsin allele A possibly represents a second genetic factor increasing individual's risk for Alzheimer's syndrome.

Aged↗

Neuroendocrine support for a relationship between "novelty seeking" and dopaminergic function in alcohol-dependent men.

The personality traits "novelty seeking", "harm avoidance", and "reward dependence" were rated using Cloninger's Tridimensional Personality Questionnaire in 20 male inpatients, suffering from moderate to severe alcohol dependence (ICD-10, DSM-III-R). The same individuals' dopamine receptor sensitivity was determined by stimulating a neuroendocrine response with a dopamine receptor agonist (apomorphine). The amount of growth hormone released was measured and taken as a biological parameter for the sensitivity of D2 dopamine receptors located in the hypothalamus. Our data indicate that in abstinent alcohol-dependent men no statistically significant correlation exists between a person's apomorphine-induced growth hormone release and his "harm avoidance" or "reward dependence" score. On the other hand, a significant correlation (r = .47; p = .035) was found between growth hormone release and the person's "novelty seeking" score. This result supports Cloninger's hypothesis by giving neuroendocrine evidence that the personality dimension "novelty seeking" is related to dopaminergic activity in alcohol-dependent men.

Adult↗

Alcohol dependence, family history, and D2 dopamine receptor function as neuroendocrinologically assessed with apomorphine.

Fifteen alcohol dependent men with an alcohol dependent first degree relative (i.e. family history positive or FHP), 15 well matched alcohol dependent men without a family history for alcohol dependence (i.e. family history negative or FHN), and 15 healthy controls (CONTR) participated in this study. The three groups were compared according to their postsynaptic D2 dopamine receptor function as assessed by growth hormone release after stimulation with the dopamine receptor agonist apomorphine. Statistical evaluation was done by planned comparisons within a one-way ANOVA. Alcohol dependent subjects significantly differed from CONTRs as long as family history was not taken into account (t(42) = 2.38; P = 0.022*). When differentiating according to family history, both FHPs and FHNs maintained a blunted growth hormone response. However, the difference between FHNs and CONTRs, though present, dropped out of statistical significance (t(42) = 1.65; P = 0.105); at the same time, the difference between FHPs and CONTRs became slightly stronger (t(42) = 2.47; p = 0.017*). In conclusion, our data give neuroendocrinological support to the assumption that a reduced D2 dopamine receptor function in alcohol dependent men is not only a state marker of residual heavy drinking but also a genetically determined trait marker.

Adult↗

[Zolpidem dependence and depression in the elderly].

In a 75 years-old patient with chronic senile depression criteria of zolpidem dependency were fulfilled. There was no history of benzodiazepine or alcohol abuse. Positive psychotropic effects were emphasized by the patient who spread intake over the day.

Aged↗

The antiparkinsonian drug budipine binds to NMDA and sigma receptors in postmortem human brain tissue.

We have estimated the affinity of the antiparkinsonian drug budipine to the PCP binding site of the NMDA receptor and to sigma 1 binding sites in membranes from postmortem human brain frontal cortex. The affinity of budipine to both binding sites is in a concentration range that may be reached under therapeutic conditions (Ki-values of about 12 and 2 microM at the PCP and sigma 1 binding site, respectively). Interactions with NMDA receptors as well as sigma 1 binding sites may contribute to the antiparkinsonian effects of budipine.

Adult↗

[Carbamazepine in treatment of alcohol withdrawal syndrome--an overview of current research].

Originally only intended as an anti-epileptic carbamazepine has nowadays a multitude of applications in the treatment of neurological and psychiatric diseases. It is also being used for the treatment of alcohol withdrawal symptoms. Its pharmacological properties and side-effects are well known and very effective dosage schedules already exist. The exact physiological action of carbamazepine, however, as well as the pathophysiological basis of withdrawal itself have not been entirely discovered. Evidence exists that "anti-kindling-effects" are of particular importance. A number of controlled clinical studies were able to demonstrate the effectiveness of carbamazepine in the treatment of alcohol withdrawal symptoms and have also compared its properties to other substances such as clomethiazole and benzodiazepine. Due to its effectiveness and the lack of additive potential carbamazepine offers a useful alternative to conventional therapeutic approaches, especially in the treatment of mild and moderately severe alcohol withdrawal symptoms.

Alcohol Withdrawal Delirium↗