Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient

BACKGROUND: Patient views are important in the evaluation of the quality of health care. The use of surveys needs to be evaluated to determine their cost-effectiveness and benefits. OBJECTIVES: To determine the costs of conducting patient opinion surveys in general practice and to find out how effective patient surveys are in stimulating changes which are beneficial for patient care. METHOD: Postal questionnaire to all 102 medical audit advisory groups (MAAGs) and 98 family health services authorities (FHSAs) in England and Wales, followed by postal questionnaire to 302 general practices reported to have conducted surveys, sampled by the type or questionnaire used. Numbers of MAAGs and FHSAs reporting surveys in general practice; types of questionnaire used; estimated costs; changes made; and benefits identified were measured. RESULTS: Eighty-five (83%) MAAGs and 75 (77%) FHSAs responded. One hundred and fifty-four (96%) of MAAGs or FHSAs reported survey activity. Types of questionnaire used were 1) designed by the practice, 2) designed by the MAAG or FHSA, possibly in collaboration with a practice, or 3) standard 'off-the-shelf'. One hundred and thirty-three (44%) practices responded. Total costs to a practice of conducting a survey ranged from nothing to over 2200 Pounds. Questionnaires designed by the practice are likely to be more costly than other designs. Some practices had surveys provided free of charge by MAAG or FHSA. Sixty-one per cent of practices said changes had been implemented and a further 22% of practices said changes were planned. The most common change was to appointment systems. Benefits were identified for patients, staff, the practice, the MAAG or FHSA and the NHS. Surveys also brought benefits in relationships and understanding. Only 8.2% of practices felt the costs of surveys outweighed the benefits. CONCLUSIONS: Many practices are surveying patients' opinions. Surveys can be costly but MAAGs and FHSAs can provide expertise and resources. Surveys using any of the types of questionnaire are likely to lead to changes and identifiable benefits. Benefits of surveys are perceived by the majority of practices to outweigh the costs.     

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文章论述了我国有色金属工业已达到有色金属产量突破 10 0 0万t的新里程碑 ,已成为拥有一定规模和竞争实力及具有发展优势的产业。我国有色金属工业要走新型工业化道路 ,实施可持续发展战略 ,当前 ,必须重视和解决好资源保障、实施集团化战略和贯彻科技兴国方针三个方面的问题。     

A point mutation associated with a severe phenotype of neurofibromatosis 2

Neurofibromatosis 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other nonmalignant tumors of the brain, spinal cord, and peripheral nerves. Although the average age of onset of NF2 is 20 years, some individuals may become symptomatic in childhood. We studied 5 unrelated NF2 patients who became symptomatic before age 13. All 5 had multiple tumors in addition to vestibular schwannoma, and none had a positive family history. Sequence analysis of the NF2 gene revealed identical nonsense mutation of exon 6 in 3 patients. Because this mutation destroys a restriction enzyme recognition site, genomic DNA from the 2 other children was directly tested for this change and identical alterations were detected. Although the work of our laboratory and others has not, in general, detected identical mutations in unrelated patients, this mutation seems to occur particularly frequently in the pediatric population and thus may be associated with an especially severe phenotype. Restriction analysis in children with NF2 may be a cost effective way of identifying their mutation. Further work is needed to characterize the effects of this change on the NF2 protein product and its relationship to this severe phenotype.     

A dysfunctional desmin mutation in a patient with severe generalized myopathy

Mice lacking desmin produce muscle fibers with Z disks and normal sarcomeric organization. However, the muscles are mechanically fragile and degenerate upon repeated contractions. We report here a human patient with severe generalized myopathy and aberrant intrasarcoplasmic accumulation of desmin intermediate filaments. Muscle tissue from this patient lacks the wild-type desmin allele and has a desmin gene mutation encoding a 7-aa deletion within the coiled-coil segment of the protein. We show that recombinant desmin harboring this deletion cannot form proper desmin intermediate filament networks in cultured cells, nor is it able to assemble into 10-nm filaments in vitro. These findings provide direct evidence that a mutation in desmin can cause human myopathies.     

Enhancer point mutation results in a homeotic transformation in Drosophila

In Drosophila, the misexpression or altered activity of genes from the bithorax complex results in homeotic transformations. One of these genes, abd-A, normally specifies the identity of the second through fourth abdominal segments (A2 to A4). In the dominant Hyperabdominal mutations (Hab), portions of the third thoracic segment (T3) are transformed toward A2 as the result of ectopic abd-A expression. Sequence analysis and deoxyribonuclease I footprinting demonstrate that the misexpression of abd-A in two independent Hab mutations results from the same single base change in a binding site for the gap gene Krüppel protein. These results establish that the spatial limits of the homeotic genes are directly regulated by gap gene products.     

Point mutation in a Becker muscular dystrophy patient

Occupational therapy intervention in the area of seating and positioning may play a vital role in improving the quality of life for nursing home residents. This case report indicates that appropriately positioning a client may increase comfort, decrease agitation, and decrease the administration of mood-altering drugs. Research would help to delineate the effects of appropriate seating systems, both to ensure reimbursement and to ensure that all who might benefit from positioning intervention receive the appropriate services. OBRA 1987 regulations are forcing nursing homes to assess residents for the least restrictive restraints. These assessments offer a golden opportunity for occupational therapists to become involved in determining the most appropriate seating systems and to conduct research on their benefits.     

A novel thrombomodulin gene mutation in a patient suffering from sagittal sinus thrombosis

Thrombomodulin is an endothelial cell membrane glycoprotein that promotes protein C activation. It has been clearly demonstrated that the anticoagulant functions of the protein C system are important in the prevention of thromboembolic disease. Patients with protein C or protein S deficiency and/or resistance to activated protein C (APC resistance) are at higher risk for developing thromboembolic disease. The first mutation in the thrombomodulin gene was discovered in an American patient suffering from pulmonary embolism at the age of 45 (Ohlin and Marlar 1995). Here we report a case of sagittal sinus thrombosis in a 42-year-old Swedish woman. She was found to carry a heterozygous point mutation changing G127 to A, predicting an Ala25 to a Thr change in the mature thrombomodulin protein. This mutation was also found in her 16-year-old daughter, who so far has not suffered from any thrombotic events. The patient had no other detectable prothrombotic genetic defects associated with the coagulation system. This case supports the hypothesis of an association between mutations in the thrombomodulin gene and venous thrombosis.     

A new point mutation affecting the fourth transmembrane domain of PMP22 results in severe de novo Charcot-Marie-Tooth disease

OBJECTIVE: Fiji is a Pacific nation with roughly equal numbers of indigenous Fijians and Indians. Previous studies, using police and medical records, have suggested significant racial, regional, age and gender differences in suicidal behaviour. The objective of the present study is to use a unique data set (autopsy reports) in the evaluation of earlier reports and to identify groups at greater risk. METHOD: Hanging and poisoning autopsy reports from two distinct regions were examined. RESULTS: The rate of autopsy (per 100000 population per year) among Indians (19.5) is significantly greater (p < 0.0001) than among Fijians (1.53). In the north, among the Indians, there are more autopsies in females (21.2) than males (16.8), and hanging constitutes 85% of total suicides, while in the Central and Eastern Divisions hanging constitutes only 58% of the total. These are regional influences. Among Fijians, the rates of hanging autopsy are significantly greater (p < 0.001) in males (1.98) than females (0.40); however, among Indians there is no significant difference. This is a racial difference. Hanging remains the preferred option for all groups. The mean age at autopsy is 31.7. There is no significant difference between the mean ages of the races, the sexes or the regions. There is no significant difference between the mean age of poisoning (31.5) and hanging (31.8). CONCLUSION: There is a significant racial difference in rates of suicide but the influences of region, age and method are relatively slight.     

A novel TP53 splicing mutation in a Li-Fraumeni syndrome family: a patient with Wilms'' tumour is not a mutation carrier

The authors describe the case of a patient with treatment-resistant schizophrenia who became pregnant after switching from conventional neuroleptic medications to clozapine, an atypical antipsychotic medication that does not cause hyperprolactinemia. Gestational diabetes, possibly exacerbated by clozapine, complicated management of her pregnancy. Comprehensive community support and psychiatric rehabilitation, combined with a positive response to clozapine, contributed to satisfying the patient's goal of having a healthy baby and being able to take the baby home to live with her and her husband.     

A novel mitochondrial DNA point mutation associated with mitochondrial encephalocardiomyopathy

A novel mitochondrial DNA (mtDNA) mutation at position nt 4320 in the tRNA(Ile) gene was associated with severe encephalopathy in a 7-month-old infant, who died of intractable hypertrophic cardiomyopathy. The mutation was present in heteroplasmic fashion (88%) in muscle and fulfills accepted criteria for pathogenicity. This is the fourth pathogenic mutation identified in this gene, which appears to be a "hotspot" for deleterious mutations affecting the heart. This report adds to the evidence of genetic heterogeneity in hypertrophic cardiomyopathies.     

A new point mutation (3426, A to G) in mitochondrial NADH dehydrogenase gene in Korean diabetic patients which mimics 3243 mutation by restriction fragment length polymorphism pattern

Periodontitis is a chronic destructive inflammatory disease associated with periodontopathic bacteria. In addition, autoantigens such as collagen and heat shock proteins (hsp) have been suggested to play a role. Established periodontal lesions are characterized by dense infiltrations of immune cells such as cytokine-producing CD4+ and CD8+ T cells. CD4+ T cells specific for Prevotella intermedia can be isolated from lesional gingiva, suggesting an active role for CD4+ T cells in the response to this bacterium. We therefore investigated the characteristics of a panel of 13 P. intermedia-specific CD4+ T cells generated from the peripheral blood of a patient with chronic adult periodontitis. All 13 P. intermedia-specific CD4+ T cells recognized the antigens in the context of HLA-DR. The T cell clones were mainly classified as Th0, producing comparable amounts of interferon-gamma (IFN-gamma) and IL-4, and Th2, producing high amounts of IL-4 and almost no IFN-gamma. None of the P. intermedia-specific T cell clones recognized antigens of the periodontopathic bacteria Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis and of the autoantigens collagen and hsp. The reactivity profile of the T cell clones to size-fractionated cell envelope antigens of P. intermedia indicated that P. intermedia-specific CD4+ T cell clones recognize probably five different antigen specificities in the context of the MHC class II molecules, DR7 or DR15. These results suggest that a broad panel of cell-associated protein antigens play a role in the induction of P. intermedia-specific CD4+ T cell response.     

Loricrin gene mutation in a Japanese patient of Vohwinkel's syndrome

It has been suggested that nitric oxide (NO) could be implicated in the pathogenesis of multiple sclerosis (MS). Recently, two groups reported increased cerebrospinal fluid (CSF) nitrate levels (oxidation product that provides an indirect estimation of NO) in MS patients. However, another group did not confirm these findings. We studied the CSF and plasma levels of nitrate with a kinetic cadmium reduction method in 11 MS patients and 25 matched controls. The CSF nitrate levels and the CSF/plasma nitrate ratio did not differ significantly between the two study groups. Plasma nitrate levels were nearly significantly lower in MS patients. CSF and plasma nitrate levels did not correlate with age at onset and duration of the disease in the patient group. These data suggest that measurement of CSF levels of nitrate is not a marker of the activity of MS.     

A new cardiology patient simulator

The apolipoprotein E (APOE) epsilon4 allele is a risk factor in Alzheimer disease (AD), but not in vascular dementia (VaD). We have investigated whether the epsilon4 allele is more common in twin pairs concordant for AD, compared with those discordant for AD, and whether the epsilon4 allele is more common in AD twins than in VaD twins. In addition, we have investigated the relationship of the epsilon4 allele and the age at onset in AD and VaD. APOE genotype was analysed in 29 senile demented twin pairs. The epsilon4 allele was associated with AD and not with VaD. However, there was no difference in the frequency of the APOE epsilon4 allele in concordant (33.3%) and discordant (31.3%) AD dizygotic twin pairs. Age at onset in AD was significantly lower in epsilon4 homozygotes than in individuals with one or no copies of epsilon4 (62.4 vs. 73.5, p<0.01). In concordant AD twin pairs, the epsilon4 allele frequency was somewhat higher in the twins with earlier onset (41.7% vs. 25%), but the difference was not statistically significant. In the VaD group the age at onset was not significantly different between individuals with or without epsilon4 in their genotypes.     

Inhibition of PCR amplification by a point mutation downstream of a primer

A T-->C point mutation is shown to specifically inhibit PCR amplification when compared to wild-type controls in exon H of the factor IX gene. Multiple primers of different lengths and locations were designed to examine this phenomenon. The experiments suggest that poor annealing and/or extension from the downstream primer are responsible for the observed inhibition and that the mutation can exert an inhibitory effect upon PCR amplification at a distance of at least 84 bp. The inhibition was not alleviated when amplification conditions such as annealing temperature, time of extension, type of DNA polymerase or concentration of DNA template, primer or DNA polymerase were varied. The inhibitory factor(s) are likely to be contained within the amplified segment itself because neither the use of a previously amplified PCR product as template for nested PCRs nor the restriction enzyme digestion of that previously amplified product relieved the inhibition of PCR amplification in the mutant sample. Computer analyses with the FOLDRNA and FOLDDNA programs did not reveal the mechanism of inhibition. Although dramatic inhibition, as shown here, may be uncommon, more subtle inhibition may be frequent. Documentation of differential amplification caused by a single-base substitution in template sequence has implications for certain commonly used PCR-based methods such as quantitative PCR, differential display and DNA fingerprinting. In addition, heterozygous single-base pair mutations down-stream of a primer may be missed if the PCR is inhibited; alternatively; the mutation may appear to be homozygous if amplification of the mutated allele is selectively enhanced.