Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation.

OBJECTIVE: Machado-Joseph disease (MJD) is an autosomal dominant cerebellar ataxia with extensive phenotypic variability originally described in families of Portuguese ancestry. Recently, the mutation causing the disease has been identified as an expanded CAG trinucleotide repeat. In this study relations between genotype and phenotype were investigated. METHODS: A series of 180 German patients with degenerative forms of ataxia were clinically and genetically examined. Patients bearing the MJD mutation were assigned to three phenotypes: phenotype 1 characterised by early onset and dystonia or pronounced rigidity associated with ataxia and spasticity. Main symptoms in phenotype 2 were ataxia and spasticity. In phenotype 3 onset was relatively late and peripheral neuropathy accompanied ataxia. Clinical and molecular data were correlated. RESULTS: An expanded CAG array was found in 42 patients from 22 families. Repeat length of CAG varied between 67 and 80 CAG motifs and showed an inverse correlation with the age of onset. For the development of phenotype 1 early onset (< 20 years) seemed more decisive than extensive repeat length. Phenotype 2 was present in all patients with more than 73 CAG motifs and onset between 20 and 40. Phenotype 3 developed in most patients with less than 73 CAG motifs and onset was regularly beyond the age of 40. Intrafamilial variability of both repeat length and phenotype was large reflecting meiotic instability of the expanded CAG repeat. CONCLUSIONS: The MJD mutation is the most frequent cause of dominantly inherited ataxia in Germany. Variations in repeat lengths substantially influence age of onset as well as phenotype but cannot explain why MJD characteristics of Portuguese families such as "bulging eyes", dystonia, and rigidity are essentially missing in German families. Despite the genotypic and phenotypic relations found in this study a reliable individual prognosis of the course of the disease is not possible at a presymptomatic stage.     

Auditing paediatric diabetes care and the impact of a specialist nurse trained in paediatric diabetes

AIMS: To define outcome measures for auditing the clinical care of children and adolescents with insulin dependent diabetes mellitus (IDDM) and to assess the benefit of appointing a dedicated paediatric trained diabetes specialist nurse (PDSN). METHODS: Retrospective analysis of medical notes and hospital records. Glycaemic control, growth, weight gain, microvascular complications, school absence, and the proportion of children undergoing an annual clinical review and diabetes education session were assessed. The effect of the appointment of a PDSN on the frequency of hospital admission, length of inpatient stay, and outpatient attendance was evaluated. RESULTS: Children with IDDM were of normal height and grew well for three years after diagnosis, but grew suboptimally thereafter. Weight gain was above average every year after diagnosis. Glycaemic control was poor at all ages with only 16% of children having an acceptable glycated haemoglobin. Eighty five per cent of patients underwent a formal annual clinical review, of whom 16% had background retinopathy and 20% microalbuminuria in one or more samples. After appointing the PDSN the median length of hospital stay for newly diagnosed patients decreased from five days to one day, with 10 of 24 children not admitted. None of the latter was admitted during the next year. There was no evidence of the PDSN affecting the frequency of readmission or length of stay of children with established IDDM. Non-attendance at the outpatient clinic was reduced from a median of 19 to 10%. CONCLUSIONS: Outcome measures for evaluating the care of children with IDDM can be defined and evaluated. Specialist nursing support markedly reduces the length of hospital stay of newly diagnosed patients without sacrificing the quality of care.     

Inflammatory bowel disease and predisposition to osteopenia

The prevalence of osteopenia in children with inflammatory bowel disease (IBD) is unknown. The effect of nutritional state, disease activity, and steroid therapy on bone mineral content (BMC) of whole body, lumbar spine, and left femoral neck measured by dual energy x ray absorptiometry in 32 children with IBD was assessed by comparison with 58 healthy local school children. Using the control data, a predicted BMC was calculated taking into account bone area, age, height, weight, and pubertal stage. The measured BMC in children with IBD was expressed as a percentage of this predicted value (% BMC). Mean (SD) % BMC was significantly reduced for the whole body and left femoral neck in the children with IBD (97.0 (4.5)% and 93.1 (12.0)% respectively, p < 0.05). Of the children with IBD, 41% had a % BMC less than 1 SD below the mean for the whole body and 47% at the femoral neck. Reduction in % BMC was associated with steroid usage but not with the magnitude of steroid dose, disease activity, or biochemical markers of bone metabolism. In conclusion, osteopenia is relatively common in childhood IBD and may be partly related to the previous use of steroids.     

Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control

OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the control of early stage nasopharyngeal carcinoma (NPC) treated with a combination of external radiotherapy and brachytherapy, MATERIALS & METHODS: We reviewed the records of 133 patients with early stage nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who received definitive radiotherapy in Chang Gung Memorial Hospital from 1979 to 1991. The median follow-up time was 7.1 years with a minimum of 2 years. All patients were treated with megavoltage external radiotherapy to the nasopharynx area (63-72 Gy) followed by high dose rate intracavitary brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4 Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used to examine the effect of several variables on prognosis. RESULTS: The 5-year rates were 86.4% for local control, 84.7% for disease free survival, 88.5% for actuarial survival and 84.2% for overall survival. The treatment group (combination of time and dose of irradiation) was the most important prognostic factor according to Cox's proportional hazard model. Patients receiving radiation at a total dose of < or = 75 Gy completed in < 12 weeks showed the best prognosis. CONCLUSION: Treatment time and total treatment dose are both important factors in treating early stage NPC. Decreasing the total radiation time to < 12 weeks and not exceeding a radiation dose of 75 Gy gave the best results.      

Factors affecting mortality and morbidity in patients with abdominal gunshot wounds

Risk factors that may independently predict mortality and morbidity in patients with abdominal gunshot wounds have not been fully elucidated. We prospectively studied the effects of 12 potential risk factors on mortality and morbidity in 82 patients with abdominal gunshot wounds who required laparotomy. Univariate analysis of these factors revealed that shock on admission, presence of penetrating colon injury and number of intra-abdominal organs injured (NOI)>2 were associated with greater than threefold increased incidence of death (p<0.05). Penetrating abdominal trauma index (PATI) score>15 was associated with twentyfold increased incidence of death (P<0.0001). Multivariate analysis showed that only PATI (P=0.001), number of postoperative complications per patient (N(comp)) (P=0.023) and presence of shock on admission (P=0. 028) were independently significant in predicting mortality. PATI was the only risk factor that independently predicted the development of postoperative infectious complications and N(comp) (P<0.0001). The type of gun used was not a significant risk factor (P>0.05). The 15 (18.3%) non-survivors were significantly older than survivors (P=0.02), had longer operations (P=0.004) and their NOI, PATI and N(comp) were significantly higher (P<0.001). The uniformly prolonged injury to surgery time in all patients contributed to the high incidence of infectious complications (62.2%) and mortality. PATI score was the most important factor found to be independently associated with mortality and morbidity in our subset of patients with prolonged injury to surgery time and high rate of colon injury.     

Expression and Significance of Coxsackie and Adenovirus Receptor in Renal-Cell Carcinoma

OBJECTIVE To investigate the expression of Coxsackie and Adenovirus receptor (CAR) in renal-cell carcinoma and the relationship of the CAR to the biological behavior of the carcinomas.METHODS The immunohistochemical SP method was used to detect the expression of Coxsaekie and Adenovirus receptor in 48 cases of renalcell carcinoma and in 12 cases of normal renal tissue 2 cm away from the tumor tissue.RESULTS The positive rates of CAR were 100% in 12 cases of para-tumcr normal renal tissue and 35.4% in 48 cases of renal-cell carcinoma respectively. The difference of CAR expression between them was significant (P＜0.05). The grades of the tumor were as follows: 22 in Grade Ⅰ, 17in Grade Ⅱ and 9 in Grade Ⅲ with the CAR positive rate being 54.5%,23.5% and 11.1%, respectively. There was a negative correlation between CAR expression and tumor grading (P＜0.05). In addition, the number of the cases in stages Ⅰ to ⅣV were 19, 13, 11 and 5 respectively, with the respective positive rates being 57.9%, 30.8%, 18.2% and 0.0%, i.e. there also was a negative relationship between CAR expression and the stage (P＜0.05).CONCLUSION CAR expression is down-regulated in renal-cell carcinoma compared with normal tissue. The level of CAR may be a sensitive predictor of differentiation, invasion and metastasis. Loss of CAR expression correlates with the invasive phenotype in our analysis of renal-cell carcinoma.     

Deleterious effects of irradiation and bone marrow transplantation therapy in the genetically anemic an/an mouse

The efficacy and outcome of bone marrow transplantation therapy following lethal irradiation were examined in syngeneic mice that had a hereditary macrocytic anemia (an/an) or were genotypically normal (+/+). Successful RBC and WBC replacement, based on blood cell parameters and donor genetic markers, were observed in all combinations of transplant therapy. Nevertheless, the an/an mice died prematurely several months after treatment, whether they received +/+ or an/an marrow cells. In contrast, the +/+ recipients of either +/+ or an/an marrow cells survived for at least 1 year after transplantation. Premature death of the an/an mice was associated with lymphopenia, anemia, kidney lesions, and severe pathogen-free pneumonitis. On the basis of our results, we hypothesize that the premature deaths of an/an mice are caused by a kind of chronic irradiation damage to which an/an mice are especially susceptible.     

Surveillance of Creutzfeldt Jakob disease in the United Kingdom

By the end of May 2000, 54 definite cases and 13 probable cases of vCJD had been notified in the United Kingdom by the National CJD Surveillance Unit set up in 1990. All definite cases for whom data are available are methionine homozygous at codon 129 of