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Biomedical subjects

J Norton

Publications and source records attributed to J Norton.

At least 19 recordsLinked to original sources
PubMed1998

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Alternative Splicing↗
PubMed1998

Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype.

OBJECTIVE: To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype. SETTING: Washington University Alzheimer's Disease Research Center, St Louis, Mo. DESIGN AND SUBJECTS: Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD. MAIN OUTCOME MEASURES: Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype. RESULTS: Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E epsilon4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to epsilon4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to epsilon4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD causing their dementia. CONCLUSIONS: (1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E epsilon4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque-based neuropathologic criteria for AD are highly accurate.

Aged↗
PubMed1998

Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.

OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Adult↗
PubMed1997

Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation.

OBJECTIVES: To characterize clinical features of a very large pedigree with early-onset Alzheimer disease (AD) in which all affected individuals carry the identical glutamic acid-to-alanine mutation at codon 280 in the presenilin-1 gene. DESIGN: Clinical histories were obtained by patient and family interviews and through medical or civil records. Using standard diagnostic criteria, a case series of 128 individuals was identified, of which 6 have definitive (autopsy-proven) early-onset AD, 93 have probable early-onset AD, and 29 have possible early-onset AD. SETTING: Community based in Antioquia, Colombia. PATIENTS: A population-based sample in which all members of 5 extended families (nearly 3000 individuals) were surveyed. Criteria for inclusion required obtaining sufficient information to categorize the individual as affected. MAIN OUTCOME MEASURES: Age at onset, neuropsychological profile, neurologic history, and examination. RESULTS: The patients had a mean age at onset of 46.8 years (range, 34-62 years). The average interval until death was 8 years. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentation was memory loss followed by behavior and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent. CONCLUSIONS: Other than the early onset, this clinical phenotype is indistinguishable from sporadic AD except that affected individuals frequently complained of headache preceding and during the disease. Despite the uniform genetic basis for the disease, there was significant variability in the age at onset, suggesting an important role for environmental factors or genetic modifiers in determining the age at onset.

Adult↗
PubMed1997

E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles.

A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS-1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two-point lod score between the mutation and AD was Z = 8.14 at theta = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS-1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the epsilon4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations.

Adult↗
PubMed1997

Promoting HIV prevention: a problem identification approach to interventions in post-HIV test counselling.

HIV antibody testing now occurs in a wide variety of clinical settings. Counselling at the time of HIV testing involves more than obtaining informed consent and there can be an active role for HIV prevention strategies. Whilst research has not clearly identified the effectiveness of either HIV testing or counselling for HIV prevention, HIV testing does allow for focused discussions with individuals about risk behaviour. Therefore all efforts to refine interventions to enhance HIV prevention must be encouraged. Interventions which encourage clients to examine beliefs about behaviours and relationships can bring about an increase in perceived choices, and thereby lead to changes in behaviour. A model is presented for conducting post-HIV test counselling for use by health professionals involved in HIV testing. Examples of questions and question styles are provided to illustrate this framework which addresses prevailing beliefs and encourages contributions from clients.

AIDS Serodiagnosis↗
PubMed1997

Childhood sexual and physical abuse. Incidence in patients with vulvodynia.

OBJECTIVE: To compare the incidence of sexual and/or physical abuse in women with vulvodynia (chronic, burning vulvar pain in the absence of clear medical findings) as compared to women with chronic vulvar symptoms due to specific, objective vulvar disease and with women from a general dermatology practice. STUDY DESIGN: An invitation to participate in this questionnaire study was sent to 300 women over 18 years of age from a vulvo-vaginal clinic and 280 women from a general dermatology practice. These questionnaires asked for basic demographic information as well as information on childhood sexual experiences and physical abuse. RESULTS: Questionnaires from 89 patients with vulvodynia, 65 patients with chronic vulvar symptoms due to specific, objective vulvar disease and 166 patients from a general dermatology practice were examined. There were no differences as to the incidence of childhood sexual or physical abuse between patients with vulvodynia and either those with general dermatology complaints or those with chronic vulvar symptoms due to objective disease. CONCLUSION: There is no evidence from these data that women with vulvodynia experience a higher incidence of sexual or physical abuse during childhood as compared to women in a general dermatology office or women with chronic vulvar symptoms from specific, observable pathology.

Adult↗
PubMed1997

Neuropsychological function in patients with Gerstmann-Sträussler-Scheinker disease from the Indiana kindred (F198S).

Three patients with Gerstmann-Sträussler-Scheinker disease (GSS) caused by a serine-for-phenylalanine substitution at codon 198 of the prion protein gene (PRNP) were compared to 9 age- and education-matched non-mutation-carriers from the same large Indiana kindred (GSS-IK) on a comprehensive neuropsychological test battery. Clinically significant impairments in intelligence, secondary memory, attention and cognitive processing speed, executive ability, and manual motor skills were noted in 2 patients. The wide range and the severity of the cognitive deficits indicated generalized cerebral dysfunction consistent with global dementia. One patient, symptomatic for less than 1 year, had more selective deficits involving memory, motor skills, and verbal fluency, suggesting early subcortical involvement.

Adult↗
PubMed1997

Repeat HIV testers at a London same-day testing clinic.

OBJECTIVE: To compare the characteristics of repeat HIV testers with first-time testers in a National Health Service HIV testing clinic in London. SUBJECTS AND METHODS: A self-administered questionnaire was distributed to clinic attenders between September 1995 and January 1996. The sample was stratified by gender and sexual orientation. Repeat and first-time testers were compared with respect to recent sexual risk behaviour, reasons for taking the HIV test, condom use, knowledge of sex partner's HIV status, and sociodemographic and psychosocial variables. RESULTS: Of 965 clinic attenders surveyed, 404 (41.9%) reported at least one previous HIV test outside the window period and were classified as repeat testers: homosexual men, 62.5% (178 out of 285); heterosexual men, 35.1% (126 out of 359); heterosexual women, 31.2% (100 out of 321). Among homosexual men, repeat testers were more likely to report the following: two or more partners in the previous 6 months for both unprotected anal sex (25.8 versus 9.3%; P < 0.01) and unprotected oral sex (53.9 versus 37.4%; P < 0.01); ever having had a sexually transmitted disease (STD) other than HIV (49.4 versus 29.0%; P < 0.01); taking the present test "as part of a regular health check' (48.9 versus 28.0%; P < 0.01); and knowing others who had tested for or been infected with HIV. Repeat testing heterosexual men were more likely to report the following: two or more partners in the previous 6 months for unprotected vaginal sex (42.9 versus 30.9%; P < 0.05) and unprotected oral sex (41.3 versus 25.3%; P < 0.01); ever having had an STD other than HIV (31.7 versus 20.6%; P < 0.05); taking the present test "as part of a regular health check' (36.5 versus 26.2%; P < 0.05); and knowing others who had tested for or been infected with HIV. For heterosexual women, repeat testers were more likely to report ever having had an STD other than HIV (25.0 versus 14.5%; P < 0.05), and knowing others who had tested for or been infected with HIV. CONCLUSIONS: Repeat testing was associated with high-risk sexual behaviour, a previous STD, knowledge of others who have tested for or been infected with HIV, and seeking the test as part of a regular health check. Factors contributing to repeat testing are multi-faceted and vary between groups of different sexual orientation. Use of the impact of knowledge of others infected by HIV and the experience of contracting an STD other than HIV may guide the development of HIV counselling interventions aimed at reducing sexual risk behaviour.

Adult↗
PubMed1996

A homology model of the Id-3 helix-loop-helix domain as a basis for structure-function predictions.

The function of the dominant negative Id (inhibitor of differentiation) helix-loop-helix (HLH) proteins is to dimerize with, and prevent the DNA binding of basic HLH (bHLH) transcription factors. A three-dimensional homology model was constructed for the HLH domain of human Id3 based on the X-ray crystal structures of the E47, MyoD, and Max bHLH proteins. The model showed that, in contrast to bHLH proteins, Id proteins appear able to dimerize without DNA stabilization because of better packing of the hydrophobic core, and the absence of destabilizing polar loop residues and of repulsive positive charges in the monomer interface at the base of the four alpha-helix bundle. This prediction was tested by in vitro protein-binding experiments, which showed that Id3 did indeed self-associate. It also showed that the inability of Id proteins to bind DNA arises from the non-basic, poorly defined, random coil structure of the region corresponding to that responsible for bHLH DNA-binding. A model of the Id1 protein was constructed and revealed a potential site of charge-charge repulsion in the hypothetical homodimer interface that may explain its observed inability to form homodimers.

Amino Acid Sequence↗
PubMed1996

Concept formation vs. logistic regression: predicting death in trauma patients.

This study compares two classification models used to predict survival of injured patients entering the emergency department. Concept formation is a machine learning technique that summarizes known examples cases in the form of a tree. After the tree is constructed, it can then be used to predict the classification of new cases. Logistic regression, on the other hand, is a statistical model that allows for a quantitative relationship for a dichotomous event with several independent variables. The outcome (dependent) variable must have only two choices, e.g. does or does not occur, alive or dead, etc. The result of this model is an equation which is then used to predict the probability of class membership of a new case. The two models were evaluated on a trauma registry database composed of information on all trauma patients admitted in 1992 to a Level I trauma center. A total of 2155 records. representing all trauma patients admitted for more than 24 h or who died in the Emergency Department, were grouped into two databases as follows: (1) discharge status of 'died' (containing 151 records), and (2) any discharge status other than 'died' (containing 2004 records). Both databases contained the same variables.

Artificial Intelligence↗
PubMed1996

Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies.

The dominant, contemporary paradigm for developing and refining diagnoses relies heavily on assessing reliability with kappa coefficients and virtually ignores a core component of psychometric practice: the theory of latent structures. This article describes a psychometric approach to psychiatric nosology that emphasizes the diagnostic accuracy and confusability of diagnostic categories. We apply these methods to the Diagnostic Interview for Genetic Studies (DIGS), a structured psychiatric interview designed by the NIMH Genetics Initiative for genetic studies of schizophrenia and bipolar disorder. Our results show that sensitivity and specificity were excellent for both DSM-III-R and RDC diagnoses of major depression, bipolar disorder, and schizophrenia. In contrast, diagnostic accuracy was substantially lower for subtypes of schizoaffective disorder-especially for the DSM-III-R definitions. Both the bipolar and depressed subtypes of DSM-III-R schizoaffective disorder had excellent specificity but poor sensitivity. The RDC definitions also had excellent specificity but were more sensitive than the DSM-III-R schizoaffective diagnoses. The source of low sensitivity for schizoaffective subtypes differed for the two diagnostic systems. For RDC criteria, the schizoaffective subtypes were frequently confused with one another; they were less frequently confused with other diagnoses. In contrast, the DSM-III-R subtypes were often confused with schizophrenia, but not with each other.

Bipolar Disorder↗
PubMed1995

Amelioration of the behavioral phenotype in weaver mutant mice through bilateral intrastriatal grafting of fetal dopamine cells.

Weaver mutant mice lose more than two-thirds of their nigral dopamine neurons. Behaviorally, weaver homozygotes display tremor, gait instability, and toppling over to the sides after a few steps. The recovery of functional responses was determined in a battery of behavioral tests in weaver mutants after bilateral transplantation of mesencephalic cell suspensions (prepared from wild-type mice) to the striatum. Equilibrium was tested by the time mice were able to stay on a suspended balance rod before falling off. Locomotor coordination was measured by the number of times mice toppled over to the sides as they moved about in an open-field matrix. Locomotor activity was quantified by the number of square crossings in an open-field matrix. Grafted weaver mutants performed significantly better than non-grafted mutant mice in all of these three tasks. The findings clearly demonstrate that bilateral transplants of foetal DA cells enhance motor performance in the weaver model of chronic nigrostriatal DA deficiency.

Animals↗