Prenatal diagnosis and fetal pathology of Tay-Sachs disease

1. The influence of the anorectic drugs fenfluramine, mazindol, mefenorex, phentermine and R 800, an experimental compound, on pulmonary vascular resistance has been studied in the isolated, perfused rat lung. 2. R 800 caused a strong vasoconstriction, which was not antagonized by methysergide of phentolamine; the other drugs listed did not alter vascular resistance. 3. Mazindol and phentermine significantly prolonged the vasoconstrictive effect of serotonin due to inhibition of its metabolic breakdown. 4. Although fenfluramine inhibited serotonin metabolism it also prevented the vasoconstrictive effect of serotonin, due to its ability to act as a serotonin antagonist. 5. Mefenorex did not affect pulmonary vascular resistance, either directly or indirectly via a serotoninergic mechanism.     

Novel mutations and DNA-based screening in non-Jewish carriers of Tay-Sachs disease

We have evaluated the feasibility of using PCR-based mutation screening for non-Jewish enzyme-defined carriers identified through Tay-Sachs disease-prevention programs. Although Tay-Sachs mutations are rare in the general population, non-Jewish individuals may be screened as spouses of Jewish carriers or as relatives of probands. In order to define a panel of alleles that might account for the majority of mutations in non-Jewish carriers, we investigated 26 independent alleles from 20 obligate carriers and 3 affected individuals. Eighteen alleles were represented by 12 previously identified mutations, 7 that were newly identified, and 1 that remains unidentified. We then investigated 46 enzyme-defined carrier alleles: 19 were pseudodeficiency alleles, and five mutations accounted for 15 other alleles. An eighth new mutation was detected among enzyme-defined carriers. Eleven alleles remain unidentified, despite the testing for 23 alleles. Some may represent false positives for the enzyme test. Our results indicate that predominant mutations, other than the two pseudodeficiency alleles (739C-->T and 745C-->T) and one disease allele (IVS9+1G-->A), do not occur in the general population. This suggests that it is not possible to define a collection of mutations that could identify an overwhelming majority of the alleles in non-Jews who may require Tay-Sachs carrier screening. We conclude that determination of carrier status by DNA analysis alone is inefficient because of the large proportion of rare alleles. Notwithstanding the possibility of false positives inherent to enzyme screening, this method remains an essential component of carrier screening in non-Jews. DNA screening can be best used as an adjunct to enzyme testing to exclude known HEXA pseudodeficiency alleles, the IVS9+1G-->A disease allele, and other mutations relevant to the subject's genetic heritage.     

Interacting factors affecting illegitimacy in preindustrial northern England

Illegitimacy in a historic, single community at Penrith, Cumbria (1557-1812), has been studied using aggregative analysis, family reconstitution and time series analysis. This population was living under extreme conditions of hardship. Long, medium and short wavelength cycles in the rate of illegitimacy have been identified by time series analysis; each represents a different response to social and economic pressures. In a complex interaction of events, the peaks of the cycles in wheat prices were associated with rises in adult mortality which promoted an influx of migrants and a concomitant rise in illegitimacy. The association between immigration and illegitimacy was particularly noticeable after the mortality crises of the late sixteenth and early seventeenth centuries. Children of immigrant families also tended to produce illegitimate offspring. Native and immigrant families responded differently to extrinsic fluctuations, and variations in their reproductive behaviour were probably related to access to resources.     

Correlates of anomie in French-Canadian adolescents

Patients (n = 1166) with various neurological disorders hospitalized in Dakar, Abidjan, Lomé and Ouagadougou were examined prospectively over a 42-month period. Seropositivity for HTLV-I alone was found to be 1.8%, which is comparable to that estimated for the general population in Africa. Eighteen of the patients with TSP and only 5 with PN were HTLV-I positive, but co-infections were found in 30-40% of cases. Discrete and unspecific lesions were observed on light and electron microscopic examination of peripheral nerve biopsies from 11 patients. Since spastic paraparesis emerges as the disorder containing the largest number of HTLV-I-positive individuals, it may be premature to conclude that HTLV-I is a causal agent in PN. Nevertheless, their rarity and the frequency of retroviral co-infections distinguish these cases of African HTLV-I-associated myelopathy from comparable cases observed in other parts of the world.     

Indications, practice, and procedural outcomes of percutaneous transluminal coronary angioplasty in northern New England in the early 1990s. The Northern New England Cardiovascular Disease Study Group

We conducted a prospective cohort study from October 1, 1989 to December 31, 1993 of the current indications, practices and procedural outcomes of percutaneous transluminal coronary angioplasty (PTCA) in Northern New England to determine how it compared with reports from other regions and registries. Thirty-five cardiologists contributed data on 12,232 admissions for PTCA performed at all hospitals in New Hampshire and Maine, plus 1 in Massachusetts, supporting PTCA. Mean patient age was 61.1 years, 67.5% were men, and 38.5% had multivessel disease. Unstable (45.6%), stable (22.9%), and postinfarction angina (21.0%) were common indications for the procedure. Of all patients, 86.9% had 1-vessel PTCA, including 65.7% of those with multivessel disease. Angiographic success was 90.4%, and 88.1% of patients had > or = 1 lesion successfully dilated and no adverse clinical event. The risk of death, nonfatal acute myocardial infarction, or coronary artery bypass grafting was 5.7%. The practice and outcomes of PTCA in Northern New England were somewhat similar to reports from other regional registries but different from a registry of select institutions. We conclude that PTCA as performed in Northern New England is safe and effective.     

The prevalence of Gasterophilus intestinalis in horses in northern England and Wales

The stomachs of 448 horses from northern England and Wales were examined for Gasterophilus larvae, and 237 (52.7%) were found to be infected with G. intestinalis. Larvae were present in stomachs examined during each month of the year except August. Second instar larvae occurred from September through February and third instars were present from November through July. Adult fly activity began in August as indicated by the presence of eggs on horses. The life-cycle of G. intestinalis in northern England and Wales is outlined from the data presented. The mean instar burdens were 15.7 second and 38.0 third instars, and more than 75% of the infections consisted of up to 50 larvae. Prevalence of infection and mean larval burdens declined with increasing age of host. Only one of 258 duodena examined was infected with G. nasalis and this horse originated from the south coast of England, outside of the catchment area of the other horses examined.     

Results of directional coronary atherectomy in Northern New England. Northern New England Cardiovascular Disease Study Group

The role of directional coronary atherectomy (DCA) in interventional cardiology remains uncertain. We report the Northern New England regional experience with DCA from 1991 to 1994. Data were collected on 11,178 patients having had an intervention on a single lesion in a single vessel (798 DCAs; 10,380 percutaneous transluminal angioplasties [PTCA]). The use of DCA increased from 1.8% of interventions in 1991 to 10% in 1994. Compared with PTCA, DCA patients were younger, more often men, had more 1-vessel disease and more coronary artery bypass surgery (CABG). DCA was more often used in the left anterior descending artery, in vein grafts, for restenoses, for subtotal occlusions, and with type A lesions. Angiographic success (96.7%) and clinical success (93%) were good. Adverse events were rare: mortality 0.9%, emergent CABG 2.2%, nonfatal myocardial infarction 2.8%. After adjusting for case-mix, there was no difference between DCA and PTCA for in-hospital mortality (odds ratio [OR] = 1.03, 95% confidence interval [CI] 0.44 to 2.43, p = 0.95) or need for emergent CABG (OR = 1.27, 95% CI 0.77 to 2.10, p = 0.34). Atherectomy patients were more likely to have a nonfatal myocardial infarction (OR = 2.0, 95% CI 1.26 to 3.20, p <0.01), to sustain an injury to the femoral or brachial artery (OR = 2.89, 95% CI 1.52 to 5.51, p <0.01), and to have a clinically successful procedure (OR = 1.37, 95% CI 1.01 to 1.88, p = 0.05). Our results support the relative safety and effectiveness of DCA as its use disseminated into the region.     

Sedation in primary dental care: an investigation in two districts of northern England

OBJECTIVE: To determine the current provision of sedation in primary dental care and investigate the knowledge and attitudes of dental practitioners and others on the use of sedation. DESIGN: Qualitative interviews and postal questionnaire survey. SETTING: Health districts of Bradford (West Yorkshire) and South Durham, UK in 1996. SUBJECTS AND MATERIALS: 15 key individuals associated with NHS primary dental services were interviewed. Questionnaires were sent to all 260 NHS general dental practitioners and community dental service clinicians. RESULTS: 208 questionnaires (80%) were returned. 42% of respondents reported current sedation use, with oral administration the favoured technique (26%). Significant differences were found between districts for intravenous sedation use (7% Bradford, 41% South Durham, P < 0.001). Almost all participants agreed the value of sedation in dental care for adults and children, for nervous, phobic patients or in association with unpleasant forms of treatment and 45% of dentists felt that provision should be expanded. Training, availability of referral services, finance and patient demand were seen as encouraging factors. CONCLUSIONS: Substantial variations in sedation provision between the two districts were associated with teaching at the nearest dental schools. Innovative use of resources could help the expansion of provision supported in this study.     

Carrier screening for cystic fibrosis, Gaucher disease, and Tay-Sachs disease in the Ashkenazi Jewish population: the first 1000 cases at New York University Medical Center, New York, NY

BACKGROUND: Ovarian cancer patients have a poor prognosis. In Norway, however, the prognosis has improved steadily since the 1950s, the age-adjusted 5-year relative survival reaching 37% in 1989 93. The aim of the present study was to explore the prognosis of patients with epithelial ovarian cancer diagnosed during 1975-94 (the prepaclitaxel period) and treated at The Norwegian Radium Hospital. METHOD: Relative risks (RR) of dying and 95% confidence intervals (95% CI) were derived from multivariate Cox proportional hazards regression models. RESULTS: A total of 2,769 patients with epithelial ovarian cancer were included in the present study. Altogether 54% of the patients were diagnosed with advanced stage disease (stages III and IV), whereas 32% were diagnosed with stage I disease. The prognosis of the patients improved from the 1970s to the 1990s, mainly due to increased short-term survival. In multivariate survival analysis, the RR of dying decreased with period of diagnosis. An RR of 0.77 (95% CI=0.66-0.89) was seen in 1990-94 compared with 1975-79. CONCLUSION: The short-term survival of patients with epithelial ovarian cancer improved from the late 1970s to the early 1990s. However, no major improvement in the long-term survival was seen.     

Bacterial chitobiase structure provides insight into catalytic mechanism and the basis of Tay-Sachs disease

Chitin, the second most abundant polysaccharide on earth, is degraded by chitinases and chitobiases. The structure of Serratia marcescens chitobiase has been refined at 1.9 A resolution. The mature protein is folded into four domains and its active site is situated at the C-terminal end of the central (beta alpha)8-barrel. Based on the structure of the complex with the substrate disaccharide chitobiose, we propose an acid-base reaction mechanism, in which only one protein carboxylate acts as catalytic acid, while the nucleophile is the polar acetamido group of the sugar in a substrate-assisted reaction. The structural data lead to the hypothesis that the reaction proceeds with retention of anomeric configuration. The structure allows us to model the catalytic domain of the homologous hexosaminidases to give a structural rationale to pathogenic mutations that underlie Tay-Sachs and Sandhoff disease.     

Meningococcal disease in England and Wales: 1995

The number of laboratory confirmed cases of meningococcal infection in England and Wales rose in 1995 for the first time since 1990. Culture confirmed cases rose to 1459, an increase of 29% over the 1994 total, due largely to increased disease activity in the last quarter of 1995. Cases diagnosed by non-culture methods totalled 431, giving a total of 1890 laboratory confirmed cases. Notifications reported to the Office of Population Censuses and Surveys also increased to a similar extent. Northern regions generally had higher rates of disease activity and greater increases in rates. Meningococcal disease caused by serogroup C strains accounted for the main increase in culture confirmed cases and made up 32% of the total in 1995. Disease caused by C2a strains showed a particularly large increase. A change in the age distribution was noted with a greater proportion of patients in older age groups. Among group B isolates, B4 P1.4 strains continued to be identified most commonly.     

Oral disease and physical disability in community-dwelling older persons

OBJECTIVE: The aim of this epidemiologic investigation was to determine whether poor oral health in older persons was associated with physical disability. DESIGN: The study was a cross-sectional survey involving in-home interviews and dental examinations of older persons. SETTING: A random sample of 68 cities and towns was selected from the six New England states, with stratification according to population size. PARTICIPANTS: The study sample consisted of 1,156 community-dwelling (non-institutionalized) individuals aged 70 and over, randomly selected from the Medicare beneficiary lists for each city and town. MEASUREMENTS: Oral health was assessed by three dichotomous indices: edentulism (no teeth); current caries, including either coronal or root decay; and periodontal disease, as measured by gingival pocket depth. Physical disability was indicated by the subject's self-report of difficulty in the areas of personal care (eating, bathing, dressing, and using the toilet) and mobility (walking, bed transfer, getting outside). Additional independent variables included age, sex, number of teeth, education, living alone, oral hygiene practices, and time since last dental visit. RESULTS: We found a direct association between specific areas of physical disability and current caries and edentulism. The risk of poor oral health did not increase with advancing age once the related risk factors were controlled for. Those subjects with mobility disabilities were at increased risk of tooth loss; those with personal care limitations were at increased risk of current caries. CONCLUSIONS: Physical disability should be added to the list of known risk factors for oral disease among the older population. Our findings call attention to the need for health care providers to screen for oral health problems among disabled older persons. Further gerontologic research is needed to identify the mechanisms linking physical disability with oral disease in older persons.     

Why is mortality higher in poorer areas and in more northern areas of England and Wales?

STUDY OBJECTIVE: To identify and quantify the factors responsible for the differences in mortality between affluent and deprived areas, the north and the south, and urban and rural areas in England and Wales. DESIGN: A multiple Poisson regression analysis of cause specific mortality in the 403 local authority districts, each classified by deprivation (using the Jarman Index), latitude (from 50 degrees to 55 degrees north) and urbanisation, adjusting for age, sex, and proportion of ethnic minorities. SETTING: England and Wales 1992. MAIN RESULTS: All cause mortality was 15% higher in the districts comprising the most compared with the least deprived tenth of the population, 23% higher in the most northern (55 degrees) than in the most southern (50 degrees) districts, and 4% higher in metropolitan (within large cities) than rural districts. Nationally these differences were associated with 40,000, 65,000, and 15,000 excess deaths respectively. More than two thirds of the overall excess mortality with deprivation, latitude, and urbanisation was from three diseases--ischaemic heart disease, lung cancer, and chronic bronchitis and emphysema. The excess mortality from these and other diseases closely matched that predicted from differences according to deprivation and latitude in smoking, heavy alcohol consumption, Helicobacter pylori infection, and temperature, and thus could be attributed to these causes. About 85% of the overall excess mortality with deprivation was attributable to heavier smoking and 6% to heavier alcohol consumption, but diet varied little. Deaths more directly related to deprivation (such as those caused by H pylori infection, drug misuse, psychoses) accounted for an estimated 12% of the excess deaths, but variation in provision and uptake of healthcare services only 1%. The direct effects of deprivation are more strongly related to morbidity than mortality. Of the difference in mortality with latitude, about 45% was attributable to differences in smoking, and 25% to climate (mainly the association of cardiovascular and respiratory disease with cold). The differences with urbanisation were mainly because of smoking. CONCLUSIONS: Differences in the prevalence of smoking account for much of the variation in mortality between areas. Alcohol accounts for some, diet little. The more direct material effect of deprivation contributes to the variation in mortality but is particularly important with respect to differences in morbidity.     

Detection of GM2-gangliosidosis (Tay-Sachs and Sandhoff disease) gene carriers by serum hexosaminidase assay

With a view to the biochemical detection of homo- and heterozygous carriers of GM2-gangliosidosis, serum hexosaminidase activities were investigated in patients from Tay-Sachs and from Sandhoff disease, respectively, in their relatives, and in normal controls. Two related methods for the differential determination of hexosaminidase A and B activities were tested. Homozygous carriers (patients) were detected by both methods in a similar manner. As regards the identification of heterozygous carriers more conclusive results were attained by the "heat inactivation method" (O'Brien, J.S., Okada, S., Chen, A. and Fillerup, D.L. (1970) New Engl. J. Med 283, 15).     

Comparative study of the prevalence of maxillary sinusitis in later Medieval urban and rural populations in northern England

Six hundred sixty-three Medieval individuals from Wharram Percy, a rural settlement in the Yorkshire Wolds, and 1,042 individuals from St. Helen-on-the-Walls, a poor parish in the Medieval city of York, were examined in order to test the hypothesis that maxillary sinusitis would be more prevalent in an urban population due to social and environmental conditions characteristic of an industrialized settlement. The results showed that the individuals from St. Helen-on-the-Walls, living in the urban environment, had a greater prevalence of maxillary sinusitis than the rural population; 39% (106) of the individuals from Wharram Percy had evidence of sinusitis compared to 55% (134) of the individuals from St. Helen-on-the-Walls. It is suggested that this pattern may be attributed to occupation and industrial air pollution in the Medieval city of York.     

Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin

The glycosphingolipid (GSL) lysosomal storage diseases result from the inheritance of defects in the genes encoding the enzymes required for catabolism of GSLs within lysosomes. A strategy for the treatment of these diseases, based on an inhibitor of GSL biosynthesis N-butyldeoxynojirimycin, was evaluated in a mouse model of Tay-Sachs disease. When Tay-Sachs mice were treated with N-butyldeoxynojirimycin, the accumulation of GM2 in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, limiting the biosynthesis of the substrate (GM2) for the defective enzyme (beta-hexosaminidase A) prevents GSL accumulation and the neuropathology associated with its lysosomal storage.     

The Northern New England Cardiovascular Disease Study Group: a regional collaborative effort for continuous quality improvement in cardiovascular disease

BACKGROUND: The Northern New England Cardiovascular Disease Study Group, a voluntary regional consortium, includes all cardiothoracic surgeons and interventional cardiologists, as well as nurses, anesthesiologists, perfusionists, administrators, and scientists associated with the six medical centers in Maine, New Hampshire, and Vermont and one Massachusetts-based medical center that support coronary artery bypass graft (CABG) surgery and percutaneous coronary interventions (PCI). Since 1987 the group has met at least three times a year to foster improvements in patient care. PROGRESS IN THE STUDY OF CABG SURGERY: The group's activities have included continued monitoring of outcomes, training in continuous quality improvement, and a benchmarking effort that allowed institutions to learn from one another. In the postintervention period (mid-1991 through early 1992) there were 293 fewer deaths (n = 575) than the 868 expected. In 1995 a new cycle of quality improvement work aimed at identifying the causes and correlates of postoperative mortality began. Study groups for each institution were organized to examine issues related to death from low-output states. PROGRESS IN THE STUDY OF PCIS: Major improvement in hospital outcomes have occurred in relation to the improving technology (primarily coronary stenting). Near-twofold variability in the use of stents has led to vigorous discussions about the role of new devices. LESSONS LEARNED: Randomized clinical trials are very important to assessing the effects of specific treatments, but most of what is known about actual clinical care will come from observational studies. Demonstrating the variability in practice patterns can be a potent stimulus to try to answer the important questions.