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Biomedical subjects

M Knapp

Publications and source records attributed to M Knapp.

At least 55 records · Page 3Linked to original sources
PubMed2000

Investigation of the human serotonin 6 [5-HT6] receptor gene in bipolar affective disorder and schizophrenia.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5-HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study, we performed a systematic mutation scan of the complete coding region and splice junctions of the 5-HT(6) receptor gene to explore the contribution of this gene to the development of bipolar affective disorder and schizophrenia. Investigating 137 unrelated individuals (including 45 bipolar affective patients, 46 schizophrenic patients, and 46 unrelated controls), we identified six single base substitutions (126G/T, 267C/T, 873+30C/T, 873+128A/C, 1128G/C, 1376T/G). Comparing frequencies between patients and controls, we observed a significant overrepresentation of the 267C allele among bipolar patients (P=0. 023 not corrected for multiple testing). This finding was followed up in an independent sample of 105 bipolar family trios using a family-based association design. Fifty-one transmissions could be examined. In 30 cases allele 267C and in 21 cases allele 267T were transmitted to the affected offspring. Although this result was far from statistical significance (transmission disequilibrium test=1.59, P=0.208), the limited number of possible transmissions may have prevented detection of smaller effects. Our preliminary data suggest that bipolar affective disorder may be associated with variation in the 5-HT(6) gene. It will be important to extend the present analysis to larger samples. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:217-221, 2000.

Bipolar Disorder↗
PubMed2000

Complex segregation analysis of families ascertained through Gilles de la Tourette syndrome.

Although family and twin studies suggest that genetic factors are involved in the etiology of Tourette syndrome and other related tic disorders, further evidence is needed to demonstrate that the familial transmission is consistent with known genetic factors. We performed a complex segregation analysis that allowed for a variable age of onset of Gilles de la Tourette, other tic disorders and obsessive compulsive phenotype information on 108 extended families, each ascertained through one Tourette proband by using regressive models that are able to incorporate additional explanatory variables and major gene effects. A special version of the S.A.G.E. program, REGTLhunt, was used to explore the likelihood surface of all examined models. Results indicated that the pattern of Tourette and other related tic disorders in our data sample is not consistent with Mendelian inheritance even after modelling explanatory variables such as obsessive compulsive symptomatology.

Adolescent↗
PubMed2000

Dopamine D3 receptor variant and tardive dyskinesia.

In the search for genetic factors contributing to tardive dyskinesia, dopamine receptor genes are considered major candidates. The dopamine D3 receptor is of primary interest as dopamine D3 receptor knock-out mice show locomotor hyperactivation resembling extrapyramidal side-effects of neuroleptic treatment. Furthermore, Steen and colleagues (1997) recently reported an association between tardive dyskinesia and a dopamine D3 receptor gene variant. In the present study we tried to replicate this finding. We investigated 157 patients with schizophrenia or schizoaffective disorder receiving long-term neuroleptic medication who never or persistently displayed tardive dyskinesia. As advanced age is a main risk factor for tardive dyskinesia, we also compared older patients with a long duration of schizophrenia not displaying tardive dyskinesia to younger patients with a shorter duration of the illness displaying tardive dyskinesia. However, we found no evidence that the dopamine D3 receptor gene is likely to confer susceptibility to the development of tardive dyskinesia.

Adult↗
PubMed2000

A European perspective on social anxiety disorder.

Epidemiologic surveys conducted across Europe indicate that the lifetime prevalence of social anxiety disorder in the general population is close to 7%. The disorder in adulthood rarely presents in its 'pure' form and 70-80% of patients have at least one other psychiatric disorder, most commonly depression. Social anxiety disorder is a risk factor for the development of depression and alcohol/substance use or dependence, especially in cases with an early onset (< 15 years). Individuals with social anxiety disorder have significant functional impairment, notably in the areas of initiation and maintenance of social/romantic relationships and educational and work achievement. The economic consequences of social anxiety disorder are considerable, with a high level of diminished work productivity, unemployment and an increased utilisation of medical services amongst sufferers. Effective treatment of social anxiety disorder would improve its course and its health and economic consequences.

Comorbidity↗
PubMed2000

DRD4 exon III VNTR polymorphism-susceptibility factor for heroin dependence? Results of a case-control and a family-based association approach.

Dopaminergic abnormalities are implicated in the pathogenesis of substance abuse.1 Recently, two reports have been published suggesting an association between opioid dependence and presence of long alleles of the dopamine D4 receptor (DRD4) gene exon III VNTR.2, 3 We have attempted to replicate this finding using a two-tiered strategy employing independent case-control and family-based association samples. Our study was possibly the largest candidate gene association study to date on opioid dependence in a sample of 815 subjects, 396 of whom were patients. We found long alleles of the DRD4 exon III VNTR in similar frequency among 285 heroin addicts and 197 controls. Furthermore, no preferential transmission of long alleles to affected offspring was observed in a sample of 111 patients and their parents. Our results, therefore, do not support the hypothesis that alleles of the DRD4 exon III VNTR are susceptibility factors for opioid dependence in man. Molecular Psychiatry(2000) 5, 101-104.

Adult↗
PubMed2000

Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings.

The serotonergic (5-HT) system has been implicated in the etiopathogenesis of psychoses. Since the 5-HT transporter plays an important role in regulation of 5-HT transmission, its gene can be considered as a candidate for vulnerability to psychiatric disorders. Two polymorphic sites of the 5-HT transporter gene-5-HTTLPR, a VNTR in the 5' regulatory region, and a VNTR in the second intron-were studied in a sample of 61 families with schizophrenia for transmission disequilibrium. Each family contained at least two siblings affected with schizophrenia or schizoaffective disorder (mainly schizophrenic). One hundred and thirty-nine affected offspring with parental information for genotyping, were available for analysis. No preferential transmission of either short or long alleles of the promoter polymorphism was observed. However, a transmission distortion was detected for alleles of the intronic VNTR polymorphism (chi2TDT max =14.33; P = 0.0002; corrected P value = 0.0003) resulting in more frequent than expected transmission of the 12 repeat allele. This finding adds additional evidence to the idea that the serotonergic system may be involved in development of psychoses. Molecular Psychiatry (2000) 5, 91-95.

Brain Chemistry↗
PubMed2000

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1).

The dopamine transporter (DAT) plays a central role in dopaminergic neurotransmission in the human brain. Genetic association studies have used a variable number of tandem repeat (VNTR) polymorphism in the 3'-flanking region of the dopamine transporter gene (DAT1) to implicate the DAT in the development of various neuropsychiatric disorders. In this study, we have examined the possibility that a mutation exists in the coding region of the DAT1 gene which through linkage disequilibrium accounts for the observed associations. The complete coding region, as well as exon-intron boundaries, was screened in 91 unrelated individuals including 45 patients with bipolar affective disorder and 46 healthy control individuals by the means of single strand conformation analysis. Our findings suggest that the DAT1 gene is highly conserved since we detected only two rare missense substitutions (Ala559Val, Glu602Gly) and three silent mutations (242C/T, 1342A/G, and 1859C/T) in the whole coding region. Five sequence variants were observed in intronic sequences but none affects known splice sites. The lack of frequent variants of possible functional relevance indicates that genetic variation in the coding region of the DAT1 gene is not responsible for the previously observed associations with neuropsychiatric disorders. The two rare missense substitutions were found in single bipolar patients but not in controls. Investigation of the patients' families revealed independent segregation between the Ala559Val variant and affective disorder. The Glu602Gly variant was inherited by the proband from an affected father. It therefore remains possible that Glu602Gly may be a rare cause of bipolar affective disorder.

Amino Acid Substitution↗
PubMed2000

A distinct gene close to the hairless locus on chromosome 8p underlies hereditary Marie Unna type hypotrichosis in a German family.

BACKGROUND: Hypotrichosis of the Marie Unna type (HMU) is a rare autosomal dominant disorder characterized by male-pattern hair loss with childhood onset and anomalies of the hair shaft. OBJECTIVES: We aimed to evaluate a number of chromosomal loci as possible candidate regions for HMU. METHODS: A linkage analysis was performed in a large German family using microsatellite markers spanning candidate regions on chromosomes 8, 12 and 17. RESULTS: We found that the HMU locus maps to chromosomal region 8p21 in a 13.01-cM interval between markers D8S1145 and D8S1771. This interval harbours the hairless gene (HR). Mutational analysis of HR on the genomic and transcript levels revealed no pathogenic mutation. CONCLUSIONS: Our findings, together with a recent report of two unrelated families of Dutch and British origin, provide evidence for a hair growth regulatory gene distinct from HR in chromosomal region 8p21.

Adult↗
PubMed2000

Schizophrenia costs and treatment cost-effectiveness.

OBJECTIVE: The paper sets out to summarize evidence on the costs of schizophrenia and on the cost-effectiveness of three broad treatment areas. METHOD: Evidence from a number of countries was examined, both published and unpublished, and systematic reviews and meta-analyses were consulted. RESULTS: The costs of schizophrenia are high and wide-ranging. They fall not only to health-care agencies but also to other parts of the public sector, to families, to sufferers themselves and to the wider society. However, there are interventions--a counselling intervention to address non-compliance with medication, family interventions to reduce levels of expressed emotion, and atypical antipsychotic drugs--that have been found to be not only effective (improving patient outcomes) but also appear to be cost-effective. CONCLUSION: Resource constraints and policy pressures make it increasingly common for economic as well as clinical questions to be asked about new modes of treatment. This is the new reality of mental health practice. Reliable evidence is now available to address these economic questions and can be factored into decision-making processes.

Cost of Illness↗
PubMed2000

[Clinical characteristics of patients with tardive dyskinesias].

UNLABELLED: Although there is a great number of studies on the relationship between tardive dyskinesia and patient characteristics, too often their validity is impaired by the lack of operationalized criteria for the description of patients and signs. Reliable phenotyping is of utmost importance for linking clinical data with data from methods in neurobiology or molecular genetics. 241 patients with the DSM IV diagnosis "schizophrenia" or "schizoaffective disorder" were examined with the instruments SADS-L, OPCRIT, BPRS and PANSS. Motor phenomena were analyzed on 2 separate days within 3 months with the scales TDRS, AIMS, SAS, BAS. Tardive dyskinesia was diagnosed following the research criteria of Schooler and Kane. Lifetime medication with neuroleptics and anticholinergic drugs was assessed quantitatively. RESULTS: 97 out of 233 patients (= 41.6%) displayed persistent tardive dyskinesia. In univariate analysis, significant associations were found between tardive dyskinesia and the following independent variables (higher values means greater risk): Age (p = 0.0001), years from onset of the disorder (p = 0.001), total length of stay in hospital (p = 0.001), PANSS (single scales and sum score) (p = 0.0001), total amount of neuroleptics expressed as CPZ equivalents (p = 0.004). Logistic regression analysis showed that only the variables "age" and "negative symptoms" expressed as score on the PANSS negative subscale showed an association with tardive dyskinesia that could not be explained by covariation with other variables. The same results were found when, instead of the dichotomous variable "tardive dyskinesia yes/no" the associations with the TDRS score were analyzed. Future research should aim to approach the neurobiological correlates of "age" and "negative symptoms" in relationship to tardive dyskinesia.

Adult↗
PubMed2000

The transmission/disequilibrium test and parental-genotype reconstruction for X-chromosomal markers.

Family-based association methods have recently been introduced that allow testing for linkage in the presence of linkage disequilibrium between a marker and a disease even if there is only incomplete parental-marker information. No such tests are currently available for X-linked markers. This report fills this methodological gap by presenting the X-linked sibling transmission/disequilibrium test (XS-TDT) and the X-linked reconstruction-combination transmission/disequilibrium test (XRC-TDT). As do their autosomal counterparts (S-TDT and RC-TDT), these tests make no assumption about the mode of inheritance of the disease and the ascertainment of the sample. They protect against spurious association due to population stratification. The two tests were compared by simulations, which show that (1) the X-linked RC-TDT is, in general, considerably more powerful than the X-linked S-TDT and (2) the lack of parental-genotype information can be offset by the typing of a sufficient number of sibling controls. A freely available SAS implementation of these tests allows the calculation of exact P values.

Alleles↗
PubMed2000

Altered splicing of the ATDC message in ataxia telangiectasia group D cells results in the absence of a functional protein.

The ATDC gene was cloned using functional complementation and complements the radiosensitivity of ataxia telangiectasia (AT) group D cells. Although a number of transcripts have been detected, only a 3.0 kb cDNA found in a HeLa cell cDNA library has been cloned. Since AT group D cells express only a 2.4 kb transcript, efforts were made to clone and sequence this transcript. Using a biotinylated oligonucleotide probe, mRNA preparations were enriched in ATDC-related sequences. After this enrichment, 2.4 kb clones were obtained from the resulting library. The 2.4 kb transcript appears to be untranslated, since no protein from this transcript has been detected in AT group D cells, and this transcript is probably non-functional, since a splicing variation has positioned part of intron 1 near the first methionine codon in exon 1, eliminating most of exon 1 and important functional regions from this transcript. This transcript now has a stop codon located 33 bp in front of the first methionine, which would stop translation after the eleventh amino acid. As a result of these changes, the AT group D cell line (AT5BI) expresses no functional ATDC protein.

Alleles↗
PubMed2000

Conformational flexibility in the apolipoprotein E amino-terminal domain structure determined from three new crystal forms: implications for lipid binding.

An amino-terminal fragment of human apolipoprotein E3 (residues 1-165) has been expressed and crystallized in three different crystal forms under similar crystallization conditions. One crystal form has nearly identical cell dimensions to the previously reported orthorhombic (P2(1)2(1)2(1)) crystal form of the amino-terminal 22 kDa fragment of apolipoprotein E (residues 1-191). A second orthorhombic crystal form (P2(1)2(1)2(1) with cell dimensions differing from the first form) and a trigonal (P3(1)21) crystal form were also characterized. The structures of the first orthorhombic and the trigonal form were determined by seleno-methionine multiwavelength anomalous dispersion, and the structure of the second orthorhombic form was determined by molecular replacement using the structure from the trigonal form as a search model. A combination of modern experimental and computational techniques provided high-quality electron-density maps, which revealed new features of the apolipoprotein E structure, including an unambiguously traced loop connecting helices 2 and 3 in the four-helix bundle and a number of multiconformation side chains. The three crystal forms contain a common intermolecular, antiparallel packing arrangement. The electrostatic complimentarity observed in this antiparallel packing resembles the interaction of apolipoprotein E with the monoclonal antibody 2E8 and the low density lipoprotein receptor. Superposition of the model structures from all three crystal forms reveals flexibility and pronounced kinks in helices near one end of the four-helix bundle. This mobility at one end of the molecule provides new insights into the structural changes in apolipoprotein E that occur with lipid association.

Animals↗
PubMed2000

Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence.

OBJECTIVE: An association between the 5-HTTLPR short variant polymorphism in the promoter region of the serotonin transporter gene and risk for alcohol dependence has been reported from case-control studies that are, however, prone to chance findings related to artifacts of population structure. The authors sought additional evidence for this association from a family-based study. METHOD: Ninety-two alcohol-dependent probands and their parents were tested for nonrandom transmission of alleles from heterozygous parents to affected probands. RESULTS: Preferential transmission of the short allele was found (65 of 102 transmissions from heterozygous parents). CONCLUSIONS: The results suggest allelic association between a variant in the promoter region of the serotonin transporter gene and the risk for alcohol dependence. However, it remains to be seen whether the functional properties of this variant are directly responsible for the increased risk to alcohol dependence.

Adult↗
PubMed2000

Psychiatric patients at greatest risk and in greatest need. Impact of the Supervision Register Policy.

BACKGROUND: Mental health provider trusts in England were required in 1994 to establish local Supervision Registers of patients at risk. AIMS: To identify the factors associated with registration, and obtain clinicians' views on its effectiveness. METHOD: At a random sample of 14 trusts data were collected from case notes, key workers and responsible medical officers. RESULTS: A sample of 133 registered patients were more disabled and had more extensive histories of violence and self-harm than 126 comparison patients on the upper tier of the Care Programme Approach (CPA). Those registered were a heterogeneous group. For some there was little evidence of risk. In most cases clinicians did not believe registration had improved care. CONCLUSIONS: The Supervision Register policy has not resulted in the identification of a well-defined group. Its effectiveness is limited by the lack of operationalized measures of risk.

Adult↗
PubMed2000

Aims, outcome measures, study sites and patient sample. EPSILON Study 1. European Psychiatric Services: Inputs Linked to Outcome Domains and Needs.

BACKGROUND: Cross-national research into the care of people with severe mental illnesses is hampered by a lack of standardised measures. The European Psychiatric Services: Inputs Linked to Outcome Domains and Needs (EPSILON) Study is a European Union funded project within the BIOMED-2 programme. The project aims to develop standardised instruments to facilitate future cross-national research. AIMS: To describe the aims, outcome measures, study sites and patient samples of the EPSILON Study. METHOD, RESULTS, CONCLUSIONS: See companion papers in this supplement.

Adolescent↗
PubMed2000

Quality and costs of community-based residential supports, village communities, and residential campuses in the United Kingdom.

The costs, nature, and benefits of residential supports were examined for 86 adults with mental retardation living in village communities, 133 adults living in newly built residential campuses, and 281 adults living in dispersed housing schemes (small community-based group homes and supported living). Results indicated that (a) the adjusted comprehensive costs of provision in dispersed housing schemes were 15% higher than in residential campuses and 20% higher than in village communities; (b) dispersed housing schemes and village communities offered a significantly greater quality of care than did residential campuses; and (c) there appeared to be distinct patterns of quality of life benefits associated with dispersed housing schemes and village communities, with both approaches offering a greater quality of life than did residential campuses.

Adult↗