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N Unwin

Publications and source records attributed to N Unwin.

At least 37 records · Page 2Linked to original sources
PubMed2000

The Croonian Lecture 2000. Nicotinic acetylcholine receptor and the structural basis of fast synaptic transmission.

Communication in the nervous system takes place at chemical and electrical synapses, where neurotransmitter-gated ion channels, such as the nicotinic acetylcholine (ACh) receptor, and gap junction channels control propagation of electrical signals from one cell to the next. Newly developed electron crystallographic methods have revealed the structures of these channels trapped in open as well as closed states, suggesting how they work. The ACh receptor has large vestibules extending from the membrane which shape the ACh-binding pockets and facilitate selective transport of cations across a narrow membrane-spanning pore. When ACh enters the pockets it triggers a concerted conformational change that opens the pore by destabilizing a gate in the middle of the membrane made by a ring of pore-lining alpha-helical segmets. The alternative 'open' configuration of pore-lining segments reshapes the lumen and creates new surfaces, allowing the ions to pass through. The gap junction channel uses a similar structural mechanism, involving coordinated rearrangements of alpha-helical segments in the plane of the membrane, to open its pore.

Acetylcholine↗
PubMed2000

Electron microscopic evidence for the assembly of soluble pentameric extracellular domains of the nicotinic acetylcholine receptor.

Exploitation of soluble extracellular domains (ECDs) of the nicotinic acetylcholine receptor may provide a route to crystallographic studies aimed at exploring the structure and function of the intact receptor. The first step towards this goal is to manufacture and isolate soluble fragments that fold and assemble to form a functionally relevant complex. The baculovirus insect cell expression system was used to co-express soluble ECDs of all four muscle-type nicotinic acetylcholine receptor subunits (alpha, beta, gamma & delta-ECD) from Torpedo. Protein complexes were purified using either the conformationally sensitive monoclonal antibody mAb35, specific for a folded alpha subunit, or a NiNTA affinity resin, specific for a polyhistidine tag engineered on the delta-ECD. Western blotting with subunit specific antibodies confirmed the co-expression of each ECD and furthermore, indicated that the alpha, beta and gamma-ECDs were being co-purified with the polyhistidine-tagged delta-ECD. Chemical cross-linking was used to show that these co-purified proteins had indeed interacted specifically to form soluble oligomeric complexes. A low-resolution, three-dimensional image of these purified complexes, composed only of ECDs, was obtained by electron microscopy. They were shown to resemble the extracellular vestibule of the native receptor, having the same pseudo-pentameric symmetry, size and shape. Expression of incomplete sets of the four nicotinic acetylcholine receptor ECDs did not yield detectable complexes.

Animals↗
PubMed2000

Stroke mortality in urban and rural Tanzania. Adult Morbidity and Mortality Project.

BACKGROUND: Most data for stroke mortality in sub-Saharan Africa are hospital based. We aimed to establish the contribution of cerebrovascular disease to all-cause mortality and cerebrovascular disease mortality rates in adults aged 15 years or more in one urban and two rural areas of Tanzania. METHODS: Regular censuses of the three surveillance populations consisting of 307,820 people (125,932 aged below 15 years and 181,888 aged 15 or more) were undertaken with prospective monitoring of all deaths arising in these populations between June 1, 1992 and May 31, 1995. Verbal autopsies were completed with relatives or carers of the deceased to assess, when possible, the cause of death. FINDINGS: During the 3-year observation period 11,975 deaths were recorded in the three surveillance areas, of which 7629 (64%) were in adults aged 15 years or more (4088 [54%] of these in men and 3541 [46%] in women). In the adults, 421 (5.5%) of the deaths were attributed to cerebrovascular disease, 225 (53%) of these in men and 196 (47%) in women. The yearly age-adjusted rates per 100,000 in the 15-64 year age group for the three project areas (urban, fairly prosperous rural, and poor rural, respectively) were 65 (95% CI 39-90), 44 (31-56), and 35 (22-48) for men, and 88 (48-128), 33 (22-43), and 27 (16-38) for women, as compared with the England and Wales (1993) rates of 10.8 (10.0-11.6) for men and 8.6 (7.9-9.3) for women. INTERPRETATION: We postulate that the high rates in Tanzania were due to untreated hypertension. Our study assessed mortality over a single time period and therefore it is not possible to comment on trends with time. However, ageing of the population is likely to lead to a very large increase in mortality from stroke in the future.

Adolescent↗
PubMed2000

Risk of cardiovascular disease measured by carotid intima-media thickness at age 49-51: lifecourse study.

OBJECTIVE: To quantify the direct and indirect effects of fetal life, childhood, and adult life on risk of cardiovascular disease at age 49-51 years. DESIGN: Follow up study of the "Newcastle thousand families" birth cohort established in 1947. PARTICIPANTS: 154 men and 193 women who completed a health and lifestyle questionnaire and attended for clinical examination between October 1996 and December 1998. MAIN OUTCOME MEASURES: Correlations between mean intima-media thickness of the carotid artery (carotid intima-media thickness) and family history, birth weight, and socioeconomic position around birth; socioeconomic position, growth, illness, and adverse life events in childhood; and adult socioeconomic position, lifestyle, and biological risk markers. Proportions of variance in carotid intima-media thickness that were accounted for by each stage of the lifecourse. RESULTS: Socioeconomic position at birth and birth weight were negatively associated with carotid intima-media thickness, although only social class at birth in women was a statistically significant covariate independent of adult lifestyle. These early life variables accounted directly for 2.2% of total variance in men and 2.0% in women. More variation in carotid intima-media thickness was explained by adult socioeconomic position and lifestyle, which accounted directly and indirectly for 3.4% of variance in men (95% confidence interval 0.5% to 6.2%) and 7.6% in women (2.1% to 13.0%). Biological risk markers measured in adulthood independently accounted for a further 9.5% of variance in men (2.4% to 14.2%) and 4.9% in women (1.6% to 7.4%). CONCLUSIONS: Adult lifestyle and biological risk markers were the most important determinants of the cardiovascular health of the study members of the Newcastle thousand families cohort at age 49-51 years. The limited overall effect of early life factors may reflect the postwar birth year of this cohort.

Cardiovascular Diseases↗
PubMed2000

Epidemiology of lower extremity amputation in centres in Europe, North America and East Asia

BACKGROUND: This study was established to enable a comparison of lower extremity amputation incidence rates between different centres around the world. METHODS: Ten centres, all with populations greater than 200 000, in Japan, Taiwan, Spain, Italy, North America and England collected data on all amputations done between July 1995 and June 1997. Patients were identified from at least two data sources (to allow checks on ascertainment); denominator populations were based on census figures. RESULTS: The highest amputation rates were in the Navajo population (43.9 per 100 000 population per year for first major amputation in men) and the lowest in Madrid, Spain (2.8 per 100 000 per year). The incidence of amputation rose steeply with age; most amputations occurred in patients over 60 years. In most centres the incidence was higher in men than women and the incidence of major amputations was greater than that of minor amputations. Diabetes was associated with between 25 and 90 per cent of amputations. CONCLUSION: Apart from the Navajo centre, differences in the known prevalence of diabetes could not account for the differences in overall incidence of amputation. Differences in the prevalence of peripheral vascular disease are likely to be important, but this and the role of other factors, including availability of health care, are worthy of further investigation.

Adolescent↗
PubMed2000

Hypertension prevalence and care in an urban and rural area of Tanzania.

OBJECTIVE: To describe the prevalence, detection, treatment and control of hypertension in an urban and rural area of Tanzania. DESIGN: Two linked cross-sectional population-based surveys. SETTING: A middle-income urban district of Dar es Salaam (Ilala) and a village in the relatively prosperous rural area of Kilimanjaro (Shari). PARTICIPANTS: Seven hundred and seventy adults (> 15 years) in Ilala and 928 adults in Shari were studied. RESULTS: Hypertension prevalence (blood pressure > or = 140 and/or 90 mmHg, or known hypertensives receiving anti-hypertensive treatment) was 30% (95% confidence interval, 25.1-34.9%) in men and 28.6% (24.3-32.9%) in women in Ilala, and 32.2% (27.7-36.7%) in men and 31.5% (27.8-35.2%) in women in Shari. Age-standardized hypertension (to the New World Population) prevalence was 37.3% (32.2-42.5%) among men and 39.1% (34.2-44.0%) in women in Ilala, and 26.3% (22.4-30.4%) in men and 27.4% (24A-30.4%) in women in Shari. In both areas, just under 20% of hypertensive subjects were aware of their diagnosis, approximately 10% reported receiving treatment and less than 1% were controlled (blood pressure < 140/90 mmHg). Hypertensive subjects were older, had greater body mass indices and waist: hip ratios, and had more risk factors for hypertension and its complications (smoking, heavy alcohol consumption, physical inactivity, obesity and diabetes) than non-hypertensives. CONCLUSIONS: There is a high prevalence of hypertension in rural and urban areas of Tanzania, with low levels of detection, treatment and control. This demonstrates the need for cost-effective strategies for primary prevention, detection and treatment of hypertension and the growing public health challenge of non-communicable diseases in Sub-Saharan Africa.

Adolescent↗
PubMed2000

Diabetes prevalence and socioeconomic status: a population based study showing increased prevalence of type 2 diabetes mellitus in deprived areas.

OBJECTIVE: To establish the relation between socioeconomic status and the age-sex specific prevalence of type 1 and type 2 diabetes mellitus. The hypothesis was that prevalence of type 2 diabetes would be inversely related to socioeconomic status but there would be no association with the prevalence of type 1 diabetes and socioeconomic status. SETTING: Middlesbrough and East Cleveland, United Kingdom, district population 287,157. PATIENTS: 4313 persons with diabetes identified from primary care and hospital records. RESULTS: The overall age adjusted prevalence was 15.60 per 1000 population. There was a significant trend between the prevalence of type 2 diabetes and quintile of deprivation score in men and women (chi 2 for linear trend, p < 0.001). In men the prevalence in the least deprived quintile was 13.4 per 1000 (95% confidence intervals (95% CI) 11.44, 15.36) compared with 17.22 per 1000 (95% CI 15.51, 18.92) in the most deprived. For women the prevalence was 10.84 per 1000 (95% CI 9.00, 12.69) compared with 15.48 per 1000 (95% CI 13.84, 17.11) in the most deprived. The increased prevalence of diabetes in the most deprived areas was accounted for by increased prevalence of type 2 diabetes in the age band 40-69 years. There was no association between the prevalence of type 1 diabetes and socioeconomic status. CONCLUSION: These data confirm an inverse association between socioeconomic status and the prevalence of type 2 diabetes in the middle years of life. This finding suggests that exposure to factors that are implicated in the causation of diabetes is more common in deprived areas.

Adult↗
PubMed1999

Heterogeneity of coronary heart disease risk factors in Indian, Pakistani, Bangladeshi, and European origin populations: cross sectional study.

OBJECTIVE: To compare coronary risk factors and disease prevalence among Indians, Pakistanis, and Bangladeshis, and in all South Asians (these three groups together) with Europeans. DESIGN: Cross sectional survey. SETTING: Newcastle upon Tyne. PARTICIPANTS: 259 Indian, 305 Pakistani, 120 Bangladeshi, and 825 European men and women aged 25-74 years. MAIN OUTCOME MEASURES: Social and economic circumstances, lifestyle, self reported symptoms and diseases, blood pressure, electrocardiogram, and anthropometric, haematological, and biochemical measurements. RESULTS: There were differences in social and economic circumstances, lifestyles, anthropometric measures and disease both between Indians, Pakistanis, and Bangladeshis and between all South Asians and Europeans. Bangladeshis and Pakistanis were the poorest groups. For most risk factors, the Bangladeshis (particularly men) fared the worst: smoking was most common (57%) in that group, and Bangladeshis had the highest concentrations of triglycerides (2.04 mmol/l) and fasting blood glucose (6.6 mmol/l) and the lowest concentration of high density lipoprotein cholesterol (0.97 mmol/l). Blood pressure, however, was lowest in Bangladeshis. Bangladeshis were the shortest (men 164 cm tall v 170 cm for Indians and 174 cm for Europeans). A higher proportion of Pakistani and Bangladeshi men had diabetes (22.4% and 26.6% respectively) than Indians (15.2%). Comparisons of all South Asians with Europeans hid some important differences, but South Asians were still disadvantaged in a wide range of risk factors. Findings in women were similar. CONCLUSION: Risk of coronary heart disease is not uniform among South Asians, and there are important differences between Indians, Pakistanis, and Bangladeshis for many coronary risk factors. The belief that, except for insulin resistance, South Asians have lower levels of coronary risk factors than Europeans is incorrect, and may have arisen from combining ethnic subgroups and examining a narrow range of factors.

Adult↗
PubMed1999

Nicotinic acetylcholine receptor at 4.6 A resolution: transverse tunnels in the channel wall.

The nicotinic acetylcholine (ACh) receptor is the neurotransmitter-gated ion channel responsible for the rapid propagation of electrical signals between cells at the nerve/muscle synapse. We report here the 4.6 A structure of this channel in the closed conformation, determined by electron microscopy of tubular crystals of Torpedo postsynaptic membranes embedded in amorphous ice. The analysis was conducted on images recorded at 4 K with a 300 kV field emission source, by combining data from four helical families of tubes (-16,6; -18,6; -15,7; -17,5), and applying three-dimensional corrections for lattice distortions. The study extends earlier work on the same specimen at 9 A resolution. Several features having functional implications now appear with better definition. The gate of the channel forms a narrow bridge, consisting of no more than one or two rings of side-chains, across the middle portion of the membrane-spanning pore. Tunnels, framed by twisted beta-sheet strands, are resolved in the extracellular wall of the channel connecting the water-filled vestibule to the putative ACh-binding pockets. A set of narrow openings through which ions can flow are resolved between alpha-helical segments forming part of the cytoplasmic wall of the channel. It is suggested that the extracellular tunnels are access routes to the binding pockets for ACh, and that the cytoplasmic openings serve as filters to exclude anions and other impermeant species from the vicinity of the pore. Both transverse pathways are likely to be important in achieving a rapid postsynaptic response.

Animals↗
PubMed1999

A comparison of proxy measures of abdominal obesity in Chinese, European and South Asian adults.

AIMS: To assess whether four proxy measures of abdominal obesity (waist circumference; waist-to-hip ratio (WHR); waist-to-height ratio and C index, a measure of body shape) were uniformly associated with features of the metabolic syndrome (triglycerides, high density lipoprotein (HDL) cholesterol, 2-h glucose) in three ethnic groups. METHODS: Anthropometric and biochemical data were collected in 629 Europeans (320 men, 309 women), 380 Chinese (183 men, 197 women) and 597 South Asians (275 men, 322 women) aged 25-64 years in Newcastle upon Tyne, UK. Linear regression models were used to determine whether relationships differed between ethnic groups. RESULTS: Linear regression analysis showed that most proxy measures of abdominal obesity were associated with features of the metabolic syndrome. There were significant interactions between WHR and ethnicity and C index and ethnicity in the relationship with log triglycerides when comparing European and Chinese women. Interactions existed between all proxy measures and ethnicity in the relationship with log triglycerides and HDL cholesterol when comparing European and South Asian women. In men, interactions between ethnicity and waist circumference, WHR and C index when comparing Europeans and South Asians, and between ethnicity and WHR and C index when comparing South Asian and Chinese for log 2-h glucose were significant (P < 0.001). All interactions remained significant when differences in smoking, alcohol and physical activity were taken into account. CONCLUSIONS: Not all the proxy measures of abdominal obesity were consistently related to features of the metabolic syndrome across the ethnic groups studied. However, waist circumference and waist to height ratio were the most consistent and WHR the least when comparing across the ethnic groups.

Abdomen↗
PubMed1999

Tackling the emerging pandemic of non-communicable diseases in sub-Saharan Africa: the essential NCD health intervention project.

There is evidence that the prevalence of certain non-communicable diseases, such as diabetes and hypertension, is increasing rapidly in parts of sub-Saharan Africa. Others, such as asthma and epilepsy, are known to be common but to be poorly managed. This paper describes a project, funded by the Department for International Development of the British Government, which aims to provide costed and evaluated treatment packages for use at primary health care level, methods and materials for evaluating the quality of non-communicable disease care, and a protocol for the assessment for national opportunities for the prevention of hypertension, heart disease and diabetes. Methods are being developed and piloted in urban and rural Tanzania and Cameroon.

Asthma↗
PubMed1998

Implications of applying widely accepted cholesterol screening and management guidelines to a British adult population: cross sectional study of cardiovascular disease and risk factors.

OBJECTIVE: To compare the implications of four widely used cholesterol screening and treatment guidelines by applying them to a population in the United Kingdom. DESIGN: Guidelines were applied to population based data from a cross sectional study of cardiovascular disease and risk factors. SETTING: Newcastle upon Tyne, United Kingdom. SUBJECTS: General population sample (predominantly of European origin) of 322 men and 319 women aged 25-64 years. MAIN OUTCOME MEASURES: Proportions recommended for screening and treatment. METHODS: Criteria from the British Hyperlipidaemia Association, the British Drugs and Therapeutics Bulletin (which used the Sheffield table), the European Atherosclerosis Society, and the American national cholesterol education programme were applied to the population. RESULTS: Proportions recommended for treatment varied appreciably. Based on the British Drugs and Therapeutics Bulletin guidelines, treatment was recommended for 5.3% (95% confidence interval 2.9% to 7.7%) of men and 3.3% (1.5% to 5.3%) of women, while equivalent respective values were 4.6 (2.3 to 6.9) and 2.8 (1.0 to 4.6) for the British Hyperlipidaemia Association, 23% (18.4% to 27.6%) and 10.6% (7.3% to 14.0%) for the European Atherosclerosis Society, and 37.2% (31.9% to 42.5%) and 22.2% (17.6% to 26.8%) for the national cholesterol education programme. Only the British Hyperlipidaemia Association and Drugs and Therapeutics Bulletin guidelines recommend selective screening. Applying British Hyperlipidaemia Association guidelines, from 7.1% (4.3% to 9.9%) of men in level one to 56.7% (51.3% to 62.1%) of men in level three, and from 4.4% (2.1% to 6.7%) of women in level one to 54.4% (48.9% to 59.9%) of women in level three would have been recommended for cholesterol screening. Had the Drugs and Therapeutics Bulletin guidelines been applied, 22.2% (16.5% to 27.9%) of men and 12.2% (8. 6% to 15.8%) of women would have been screened. CONCLUSIONS: Without evidence based guidelines, there are problems of variation. A consistent approach needs to be developed and agreed across the United Kingdom.

Adult↗
PubMed1998

Comparison of the current WHO and new ADA criteria for the diagnosis of diabetes mellitus in three ethnic groups in the UK. American Diabetes Association.

The American Diabetes Association have recommended that the fasting plasma glucose level for the diagnosis of diabetes is lowered and that this becomes the main diagnostic test. We have used population-based data from three ethnic groups in Newcastle upon Tyne to examine the implications of this change. Data were available on 824 European (25-74 years), 375 Chinese (25-64 years), and 680 South Asian (25-74 years) subjects. All subjects apart from those reporting a prior diagnosis of diabetes underwent a standard 75 g oral glucose tolerance test (WHO criteria) which included the measurement of fasting glucose. The prevalence of diabetes was higher in all three ethnic groups using the new ADA criteria compared to the WHO criteria: 7.1% vs 4.8% in Europeans; 6.2% vs 4.7% in Chinese; and 21.4% vs 20.1% in South Asians. There was much variation in individuals categorized by the ADA and WHO criteria. Agreement between the two for the diagnosis of previously unknown diabetes was only moderate (kappa statistics 0.42 to 0.59). Thus in the populations studied the new criteria would increase the prevalence of diabetes in addition to classifying some individuals diabetic by current criteria as non-diabetic. It should be stressed however that diagnosis of the individual should not be based on a single test.

Adult↗
PubMed1998

The nicotinic acetylcholine receptor of the Torpedo electric ray.

The nicotinic acetylcholine receptor is a neurotransmitter-gated ion channel that mediates the rapid propagation of electrical signals at the nerve-muscle synapse. Its structure at 9 A resolution, in both the closed- and the open-channel forms, has been examined by electron microscopy of tubular crystals grown from Torpedo postsynaptic membranes. Binding of acetylcholine to open the channel causes a localized disturbance in the extracellular domain and initiates small rotations of the protein subunits, which trigger a change in configuration of alpha-helices lining the membrane-spanning pore. A method recently developed to correct in three dimensions for distortions present in the crystals, combined with improvements in the electron imaging, should eventually allow these conformational changes to be seen at atomic resolution.

Acetylcholine↗