Intergenerational instability of the CAG repeat of the gene for Machado- Joseph disease (MJD1) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by unstable expansion of a CAG repeat in the MJD1 gene at 14q32.1. To identify elements affecting the intergenerational instability of the CAG repeat, we investigated whether the CGG/GGG polymorphism at the 3' end of the CAG repeat affects intergenerational instability of the CAG repeat. The [expanded (CAG)n-CGG]/[normal (CAG)n- GGG] haplotypes were found to result in significantly greater instability of the CAG repeat compared to the [expanded (CAG)n- CGG]/[normal (CAG)n-CGG] or [expanded (CAG)nGGG]/[normal (CAG)n-GGG] haplotypes. Multiple stepwise logistic regression analysis revealed that the relative risk for a large intergenerational change in the number of CAG repeat units (< -2 or > 2) is 7.7-fold (95% CI: 2.5-23.9) higher in the case of paternal transmission than in that of maternal transmission and 7.4-fold (95% CI: 2.4-23.3) higher in the case of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes than in that of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n- GGG]/[normal (CAG)n-GGG] haplotypes. The combination of paternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes resulted in a 75.2-fold (95% CI: 9.0-625.0) increase in the relative risk compared with that of maternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n- GGG]/[normal (CAG)n-GGG] haplotypes. The results suggest that an inter- allelic interaction is involved in the intergenerational instability of the expanded CAG repeat.      

Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease

Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.      

Demonstration of cerebral perfusion abnormalities in moyamoya disease using susceptibility perfusion- and diffusion-weighted MRI

We describe the use of diffusion-weighted imaging and perfusion MRI using a contrast-medium bolus in the preoperative investigation for young man presenting with a cerebral ischaemic episode as a manifestation of moyamoya disease. Received: 9 October 1997 Accepted: 1 April 1998     

Mutation in the K-ras gene at codon 12 does not correlate with disease progression in colorectal carcinoma patients treated with 5-FU/folinic acid biomodulated chemotherapy

To date the response rates to biomodulated 5-fluorouracil in patients with metastatic or unresectable colorectal carcinoma have been varied. Potentially responsive patients are difficult to identify and treatment schedules are both expensive and toxic. Thus, any method that could be used to predict patient response would be both clinically and economically valuable. Increased p53 protein levels have previously been shown to correlate with disease progression in a series of colorectal carcinoma patients treated with 5-FU/folinic acid biomodulated chemotherapy. In addition to mutation of the p53 tumour suppressor gene, mutation of the K-ras gene at codon 12 has also been shown to be a frequent occurrence in the step-wise progression from normal colonic mucosa to adenocarcinoma. Oncogenic activity in the ras family has recently been shown to correlate with decreased levels of apoptosis and thus increased resistance to both radiation and certain chemotherapeutic agents. The aim of the present study was therefore to investigate if a correlation existed between mutation of the K-ras gene at codon 12 and disease progression in the series of colorectal carcinoma patients previously evaluated for levels of p53 protein expression. Response to 5-FU/folinic acid was assessed radiologically by CAT scan (WHO criteria) and clinically by Karnofsky performance scale (KPS) 3 months after the initial treatment. The presence of a K-ras gene mutation was assessed with radiolabelled oligonucleotide probes on amplified patient DNA, dot blotted on to a nylon membrane. Fifty-two patients were assessed and 25% were found to possess mutations at codon 12 of their K-ras gene. In contrast to increased levels of p53 protein, K-ras mutation at codon 12 did not correlate with disease progression when assessed either radiologically or clinically.     

First Nation Elders’ perspectives on healthy ageing in NSW,Australia

Objectives : Healthy ageing has been unattainable for many of Australia’s First Nation people, driven by an earlier onset of chronic disease when compared to the general Australian population. Our objective was to examine the perspectives of Australian First Nation people about healthy ageing. Methods : We used a conversational method to gather knowledge from older First Nation people from established communities in New South Wales, Australia. Discussions were audio recorded and transcribed and analysed using an Indigenous research standpoint methodology. Eight yarning circles were held in six locations with 76 participants aged 45 years and over. Results : Key issues around healthy ageing were identified; particularly, what the impact of chronic disease means to individuals. Study participants reported that healthy ageing is essential to continue to share knowledge of their history and culture. Conclusion : This article highlights the need for culturally appropriate healthy ageing programs addressing issues related to chronic disease among First Nation communities. Implications for public health : Research into what constitutes healthy ageing for older First Nation people is necessary for the development of culturally appropriate chronic disease interventions.     

A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder

OBJECTIVE: Some genome-wide scans and association studies for schizophrenia susceptibility genes have yielded significant positive findings, but there is disagreement between studies on their locations, and no mutation has yet been found in any gene. Since schizophrenia is a complex disorder, a study with sufficient power to detect a locus with a small or moderate gene effect is necessary. METHOD: In a genome-wide scan of 382 sibling pairs with a diagnosis of schizophrenia or schizoaffective disorder, 396 highly polymorphic markers spaced approximately 10 centimorgans apart throughout the genome were genotyped in all individuals. Multipoint nonparametric linkage analysis was performed to evaluate regions of the genome demonstrating increased allele sharing, as measured by a lod score. RESULTS: Two regions with multipoint maximum lod scores suggesting linkage were found. The highest lod scores occurred on chromosome 10p15-p13 (peak lod score of 3.60 at marker D10S189) and the centromeric region of chromosome 2 (peak lod score of 2.99 at marker D2S139). In addition, a maximum lod score of 2.00 was observed with marker D22S283 on chromosome 22q12, which showed evidence of an imprinting effect, whereby an excess sharing of maternal, but not paternal, alleles was present. No evidence of linkage was obtained at several locations identified in previous studies, including chromosomes 1q, 4p, 5p-q, 6p, 8p, 13q, 15p, and 18p. CONCLUSIONS: The findings of this large genome-wide scan emphasize the weakness and fragility of linkage reports on schizophrenia. No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies and the possibility raised that it may be epigenetic, i.e., related to gene expression rather than sequence variation. Nevertheless, the positive findings on chromosome 2, 10, and 22 should be pursued further.     

Physiological and psychological predictors of walking speed in older community-dwelling people

BACKGROUND: Six-metre walking speed (SMWS) is a commonly used test for measuring functional performance in older people. However, apart from lower limb strength, few studies have examined the range of physiological and psychological factors that influence performance in this test. OBJECTIVE: To investigate the relative contributions of a range of sensorimotor, balance and psychological factors to SMWS in a large sample of older people. METHODS: 668 community-dwelling people aged 75-98 years (mean age 80.1, SD = 4.4) underwent the SMWS test as well as quantitative tests of vision, peripheral sensation, strength, reaction time, balance, fear of falling, pain and vitality. RESULTS: Many physiological and psychological factors were significantly associated with SMWS in univariate analyses. Stepwise multiple regression analyses revealed that a composite lower limb strength measure (sum of knee extension, knee flexion and ankle dorsiflexion muscle strength scores), postural sway, leaning balance as assessed with the coordinated stability test, reaction time, edge contrast sensitivity, SF12 body pain and vitality scores and age were significant and independent predictors of SMWS. Of these measures, the combined lower limb strength measure had the highest beta weight indicating it was the most important variable in explaining the variance in SMWS. However, the other sensorimotor, balance and psychological measures each provided important independent information. The combined set of variables explained 40% of the variance in SMWS (multiple r = 0.63). CONCLUSIONS: The findings indicate that in community-dwelling older people, self-selected walking speed is influenced not only by lower limb strength but also by balance, reaction time, vision, pain and emotional well-being.     

Clinical predictors of abnormal computed tomography scans in paediatric head injury

OBJECTIVE: To evaluate whether clinical features associated with head injury in children can be correlated with an abnormal computed tomography (CT) scan. METHODOLOGY: Three hundred and eleven children aged 14 years or younger admitted with a diagnosis of acute head injury were studied retrospectively. RESULTS: A Glasgow Coma Scale (GCS) score of 12 or lower and the presence of focal neurological deficits were significant predictors of an abnormal CT scan. Ninety-five per cent of those with abnormal CT scans and 100% of those with intracranial injury could be identified by the presence of one or more of the nine clinical findings, particularly by a GCS score of 12 or lower, and the presence of focal neurological deficits. Identification was also possible to a lesser degree by loss of consciousness, ataxia, amnesia, drowsiness, headache, seizure or vomiting. CONCLUSION: Use of CT scans can be limited to children with ongoing specific symptoms and/or focal neurological signs. The implementation of guidelines in the management of head injuries in children could have a substantial effect on clinical practice and health-care costs.