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M Knapp

Publications and source records attributed to M Knapp.

At least 19 recordsLinked to original sources
PubMed1996

Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders.

The complete coding region of the norepinephrine transporter (NET) gene was systematically screened for genetic variants in 137 unrelated individuals (including 46 probands with bipolar affective disorder and 45 schizophrenic probands, as well as 46 blood donors) using single-strand conformation analysis. We identified 13 DNA sequence variants, among them five missense substitutions. The missense substitutions Val69Ile, Thr99Ile, Val245Ile, Val449Ile, and Gly478Ser are located at putative transmembrane domains (TMD) 1, 2, 4, 9, and 10, respectively. The Thr99Ile substitution is at the 5th position of the putative leucine-zipper in TMD2. In a case-control study distribution of missense substitutions was found to be similar in 103 patients with bipolar affective disorder, in 228 schizophrenia patients and in 187 controls, indicating that presence of these variants is not causally related to major psychiatric diseases. The detection of a highly polymorphic silent 1287G/A polymorphism was utilized to demonstrate biallelic expression of the NET in adult human brain.

Adult↗
PubMed1996

Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia.

Using single strand conformational analysis we screened the complete coding sequence of the serotonin 1F (5-HT1F) receptor gene for the presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic patients, 46 bipolar patients, as well as 46 healthy controls. We detected only three rare sequence variants which are characterized by single base pair substitutions, namely a silent T-->A transversion in the third position of codon 261 (encoding isoleucine), a silent C-->T transition in the third position of codon 176 (encoding histidine), and an C-->T transition in position -78 upstream from the start codon. The lack of significant mutations in patients suffering from schizophrenia and bipolar affective disorder indicates that the 5-HT1F receptor is not commonly involved in the etiology of these diseases.

Base Sequence↗
PubMed1996

Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia.

A statistically significant association between a silent mutation (102T/C) in the serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported in a sample of Japanese patients and healthy controls. This finding suggests that genetic predisposition to schizophrenia may be affected by a functional 5-HT2A receptor variant that is in linkage disequilibrium with 102T/C. In the present study, we have sought to identify genetic variation in the 5-HT2A receptor gene by screening genomic DNA samples from 91 unrelated subjects comprising 45 patients with schizophrenia and 46 healthy controls by using single-strand conformation analysis. We have identified four nucleotide sequence variants. Two sequence changes would result in protein alterations: a substitution of threonine by asparagine at position 25 (Thr25Asn), and a substitution of histidine by tyrosine at position 452 (His452Tyr). In order to test for a possible contribution to the development of schizophrenia, we have determined allele frequencies in extended samples of unrelated patients and healthy controls. The two amino acid substitutions are found with similar frequencies in patients and controls, indicating that the presence of these variants is not causally related to the development of schizophrenia. However, the reported association of the non-coding polymorphism 102T/C with the disease has also been detected in our sample (P=0.041, odds ratio=1.28, 95% confidence interval 1.012-1.623).

Alleles↗
PubMed1996

Working from upstream to improve health care: the IHI interdisciplinary professional education collaborative.

BACKGROUND: Recognizing the need to find new models for educating health professionals, the Institute for Healthcare Improvement (IHI) initiated the Interdisciplinary Professional Education Collaborative in April 1994. The goal of the Collaborative is to improve health care by working from upstream, to address the health professions workforce changes demanded by the need to deliver better care at a lower cost. With support and advice from IHI and others, faculty leaders in health professions education from the disciplines of medicine, nursing, and health administration framed a vision of the future in which "health professions education has evolved into an integrated teaching/learning environment in which health professionals are working together across discipline boundaries, using the best knowledge for improvement to continuously improve health care". This article describes the first year of the three-year project. SUMMARY: The 1994-1995 pilot year of the Collaborative involved more than 60 learners and 50 faculty members, across multiple disciplines. At each of the four sites, education was integrated with efforts to improve health care delivery. Education-oriented outcomes include assessment of student learning (applied knowledge and skills) and program evaluation (student and faculty feedback on the effect of the project on community-based experiential learning sites). Even at this early stage, there is evidence of change in participating institutions. The Collaborative in now planning how to increase the number of students and faculty involved in such a way that a deeper understanding of how to prepare new health professionals to improve health care may be determined.

Academies and Institutes↗
PubMed1996

One and two year outcomes for adults with learning disabilities discharged to the community.

BACKGROUND: Long-stay patients with learning disabilities (n = 214) were assessed in hospital and 12 and 24 months after discharge in order to examine the effects of relocation. METHOD: Each resident acted as his/her own control in a prospective repeated-measures design. Skills and behavioural problems were assessed by keyworkers. Self-perceived quality of life was obtained during interviews with researchers who also completed an environmental checklist of the residents' accommodation. RESULTS: There was little or no change in people's low pre-discharge skill levels. Certain aspects of problem behaviour improved after 12 months, although socially unacceptable behaviour increased slightly. People were less depressed (P < or = 0.01) 12 months after discharge (N = 119) and were more satisfied (P < or = 0.05) with their new 'homes' (n = 108). There were few changes in the pattern of activities or the social networks of people 12 months later. Little or no further change in outcomes was reported 24 months after discharge. CONCLUSIONS: The implementation of the deinstitutionalisation policy in Northern Ireland has been limited by the predominance of residential and nursing homes and the lack of 'ordinary' accommodation. There is a need for purchasers and providers to give more attention to ways in which the principles of normalisation could be incorporated in the process of contracting and delivering services.

Activities of Daily Living↗
PubMed1996

The mental health residential care study: classification of facilities and description of residents.

BACKGROUND: The NHS is no longer a virtual monopoly provider of mental health residential care. This makes it difficult to assess the volume, range and adequacy of local provision. METHOD: Local data collectors used standard instruments to collect detailed information about 368 facilities (with 1951 residents) providing mental health residential care in eight districts. Because local definitions were inconsistent, facilities were reclassified on the basis of facility size and extent of day and night cover. The eight categories of accommodation are compared on levels of staffing, staff qualifications and the characteristics of their residents. RESULTS: There was a nearly threefold variation between districts in the total number of residential places available per unit of population, and even greater variation in the number of places with 24-hour waking cover. Most residents have long-term, severe mental illness and severe impairment. Long-stay wards accommodate people who pose greater risk of violence than do the two types of non-hospital facility with 24-hour waking cover (P < 0.001). The former also employ a much greater proportion of staff with formal care qualifications and, in particular, nursing qualifications than the latter (49% v. 15%, P < 0.001). CONCLUSIONS: It is suggested that one consequence of the diversification in provision of mental health residential accommodation has been a relative reduction in the proportion of provision available to the most severely disabled. This might apply particularly to those who pose a risk of acting violently.

Aged↗
PubMed1995

Screening for linkage and association in nuclear families.

We applied linkage analysis with a sib-pair method, which also takes into account information on unaffected siblings, and family-based methods of association analysis to determine the disease affecting loci in Problem 1. Whereas the first two disease loci were correctly identified by association analysis, the sib-pair linkage method failed to detect the disease loci 3 and 4. We therefore determined the data structure and sample size necessary for demonstrating linkage to these loci.

Alleles↗
PubMed1995

Schizophrenia: shifting the balance of care.

Schizophrenia poses a major challenge to policy makers in health and social care in England. As deinstitutionalisation has progressed, public concern about people with the condition has increased owing to a small number of public incidents. This paper describes the overall balance of care or support for people with schizophrenia, particularly between different settings and the services received. Using these data we are able to provide a basic estimate of the current resource implications of schizophrenia care in England with respect to different public sector agencies, the voluntary sector and service users and their families. The targeting of public sector resources between different care settings is also considered. The discussion suggests that resources are still targeted at existing care facilities rather than on individuals, and examines the roles of individual care agencies and the relationships between them. Four broad resource guidelines are suggested that could improve the effective use of resources for schizophrenia care.

Health Care Costs↗
PubMed1995

Community mental health care for former hospital in-patients. Predicting costs from needs and diagnoses.

BACKGROUND: In the UK the replacement of long-term in-patient care with community-based support has been part of central government health policy for many years. One of the challenges of implementing such a policy is the prediction of support and service needs in the community and the associated costs. METHOD: Using research data from north London analyses were undertaken to examine the associations between service use and costs in the community and the characteristics of hospital in-patients. RESULTS: Although clinical diagnosis was not a useful predictor of either service utilisation or costs, more than a third of the variation in community care costs could be explained by symptoms, behaviour and personal characteristics at least one year earlier.

Adult↗
PubMed1995

The relative efficiency of the Hardy-Weinberg equilibrium-likelihood and the conditional on parental genotype-likelihood methods for candidate-gene association studies.

Selecting a control group that is perfectly matched for ethnic ancestry with a group of affected individuals is a major problem in studying the association of a candidate gene with a disease. This problem can be avoided by a design that uses parental data in place of nonrelated controls. Schaid and Sommer presented two new methods for the statistical analysis using this approach: (1) a likelihood method (Hardy-Weinberg equilibrium [HWE] method), which rests on the assumption that HWE holds, and (2) a conditional likelihood method (conditional on parental genotype [CPG] method) appropriate when HWE is absent. Schaid and Sommer claimed that the CPG method can be more efficient than the HWE method, even when equilibrium holds. It can be shown, however that in the equilibrium situation the HWE method is always more efficient than the CPG method. For a dominant disease, the differences are slim. But for a recessive disease, the CPG method requires a much larger sample size to achieve a prescribed power than the HWE method. Additionally, we show how the relative risks for the various candidate-gene genotypes can be estimated without relying on iterative methods. For the CPG method, we represent an asymptotic power approximation that is sufficiently precise for planning the sample size of an association study.

Genetic Diseases, Inborn↗
PubMed1994

Association analysis of the dopamine D2 receptor gene in Tourette's syndrome using the haplotype relative risk method.

Comings et al. [1991: JAMA 266: 1793-1800] have recently reported a highly significant association between Tourette's syndrome (TS) and a restriction fragment length polymorphism (RFLP) of the dopamine D2 receptor gene (DRD2) locus. The A1 allele of the DRD2 Taq I RFLP was present in 45% of the Tourette patients compared with 25% of controls. We tried to replicate this finding by using the haplotype relative risk (HRR) method for association analysis. This method overcomes a major problem of conventional case-control studies, where undetected ethnic differences between patients and controls may result in a false-positive finding, by using parental alleles not inherited to the proband as control alleles. Sixty-one nuclear families encompassing an affected child and parents were typed for the DRD2 Taq I polymorphism. No significant differences in DRD2 A1 allele frequency were observed between TS probands, subpopulations of probands classified according to tic severity, or parental control alleles. Our data do not support the hypothesis that the DRD2 locus may act as a modifying gene in the expression of the disorder in TS probands.

Adolescent↗
PubMed1994

Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer.

The clinical course of familial adenomatous polyposis (FAP) varies considerably between patients. Prediction of the severity of the disease is important in the interest of effective cancer prevention. We examined whether age at diagnosis of FAP due to gastrointestinal symptoms and age at death due to colorectal cancer are related to the site of mutation in the responsible gene. 225 families with FAP were screened for mutations. The deletion of 5 base pairs at codon 1309 within exon 15 (known to be the most common mutation) was identified in 20 families; other mutations within exons 7-15 were found in 49 families. In patients with the 5 base-pair deletion at codon 1309, gastrointestinal symptoms and death from colorectal cancer occurred about 10 years earlier than in patients with other mutations. The 1309 mutation leads to development of colonic polyps at a younger age, thus giving rise to an earlier malignant transformation. This relationship should be taken into account in strategies for preventing cancer in patients with FAP.

Adenomatous Polyposis Coli↗
PubMed1994

Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 CEPH families using 15 polymorphic loci in the region 5q11.2-q13.3.

The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q13.3 in 1990. Here, we present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at zmax = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557 (theta = 0.02 at zmax = 8.63). The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene (theta = 0.00 at zmax = 25.36). We localized a recently described polymorphic marker, D5S351 (Hudson et al., 1992), close to the SMA (theta = 0.00 at zmax = 19.01) and the 3'MAP1B gene (theta = 0.01 at zmax = 38.76). Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, we developed a new reverse primer for the nearest centromeric locus D5S435 (Soares et al., 1993), a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5S507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507- D5S6-D5S125-D5S680-D5S435-SMA-D5S557- D5S351-5'MAP1B-3'MAP1B-JK53CA1/2-(D5S127- D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable.

Base Sequence↗
PubMed1994

The costs of accommodation and care. Community provision for former long-stay psychiatric hospital patients.

The development of community services to replace two long-stay psychiatric hospitals in the North East Thames Health Authority region of the UK has been the subject of a research programme since 1985. The economic evaluation is conducted by the Personal Social Services Research Unit; research results relating to the first five cohorts of hospital leavers are reported in this paper. When followed up 1 year after discharge, almost half of the sample were living in highly supported residential care units, most of which were managed by district health authorities. More than 40 services provided outside the accommodation facility were used by clients and, although contact with certain professionals remained constant, some changes in service use over time were marked. The average total cost of community care for this group was 493 pounds per week (1992-93 prices), accommodation facility costs comprising approximately 85% of the total. In the new service configuration, district health authorities fund half of the costs of supporting the hospital leavers, 50% less than when they funded long-stay hospital placements. The rest of the funding burden is borne by a range of agencies, resulting in pressure on budgets and staff case loads.

Adult↗
PubMed1994

Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen.

Autosomal recessive polycystic kidney disease (ARPKD) is one of the major hereditary nephropathies in children predominantly presenting in early childhood. The clinical picture is variable but there is a fatal outcome in many cases. We have performed linkage analysis in 16 ARPKD families and localized the ARPKD gene to chromosomal region 6p21-cen with no evidence for genetic heterogeneity among different clinical phenotypes. Linkage was confirmed using six adjacent microsatellite markers and the highest lod score of 7.42 was obtained with D6S272 at theta = 0.00. Our findings should lead to more accurate forms of prenatal diagnosis than those currently available using ultrasound.

Base Sequence↗