Monovalent cation transport in irreversibly sickled cells.

Using discontinuous density gradients of Stractan II, we have separated sickle cell blood into discrete subpopulations of reticulocytes, mature discoid cells, and irreversibly sickled cells (ISCs). We have measured active and passive fluxes of monovalent cations in mature discoid cells, ISCs, and normal control cells, also separated upon density gradients. These measurements revealed a decreased active cation transport in ISC-rich populations. However, parallel measurements of Na, K-ATPase activity showed normal ouabain-sensitive ATPase activity in ISCs. Passive permeability to external Rb was also normal in ISCs. The observation of depressed pump activity in intact ISCs, contrasted with normal ATPase activity in ISC membranes, suggests the presence of factors in the intact cell which inhibit the active transport of Na and K in ISCs.

Phenotypic features of myoclonus-dystonia in three kindreds.

BACKGROUND: Myoclonus-dystonia (M-D) is a movement disorder with involuntary jerks and dystonic contractions. Autosomal dominant alcohol-responsive M-D is associated with mutations in the epsilon-sarcoglycan gene (SGCE) (six families) and with a missense change in the D2 dopamine receptor (DRD2)gene (one family). OBJECTIVE: To investigate the clinical phenotype associated with M-D including motor symptoms, psychiatric disorders, and neuropsychological deficits. METHODS: Fifty individuals in three M-D families were evaluated and a standardized neurologic examination and DNA analysis were performed. Psychiatric profiles were established with the Diagnostic Interviews for Genetic Studies (DIGS) and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Cognition was evaluated with standardized neuropsychological tests. RESULTS: Distinct truncating mutations in the SGCE gene were identified in each family. Additionally, a missense alteration in the DRD2 gene was previously found in one family. Motor expression was variable, with onset of myoclonus or dystonia or both affecting the upper body and progression to myoclonus and dystonia in most cases. Psychiatric profiles revealed depression, obsessive-compulsive disorder, substance abuse, anxiety/panic/phobic disorders, and psychosis in two families, and depression only in the third family. Averaged scores from cognitive testing showed impaired verbal learning and memory in one family, impaired memory in the second family, and no cognitive deficits in the third family. CONCLUSIONS: Cognitive deficits may be associated with M-D. Psychiatric abnormalities correlate with the motor symptoms in affected individuals. Assessment of additional M-D families with known mutations is needed to determine whether these are characteristic phenotypic manifestations of M-D.

Associations of plasma fibrinogen assays, C-reactive protein and interleukin-6 with previous myocardial infarction.

BACKGROUND: The association of plasma fibrinogen with myocardial infarction (MI) may (like that of C-reactive protein, CRP) be a marker of subclinical inflammation, mediated by cytokines such as interleukin-6 (IL-6). There are well-recognized discrepancies between commonly performed fibrinogen assays. Increased ratio of clottable fibrinogen to intact fibrinogen (measured by a recently developed immunoassay) has been proposed as a measure of hyperfunctional fibrinogen, and is elevated in acute MI. OBJECTIVE: To compare the associations of intact fibrinogen and four routine fibrinogen assays (two von Clauss assays; one prothrombin-time derived; and one immunonephelometric) in a case-control study of previous MI. PATIENTS/METHODS: Cases (n=399) were recruited 3-9 months after their event; 413 controls were age- and sex- matched from the case-control study local population. Intact fibrinogen was measured in 50% of subjects. RESULTS: All routine fibrinogen assays showed high intercorrelations (r=0.82-0.93) and significant (P<0.0001) increased mean levels in cases vs. controls. These four routine assays correlated only moderately with intact fibrinogen (r=0.45-0.62), while intact fibrinogen showed only a small, nonsignificant increase in cases vs. controls. Consequently, the ratio of each of the four routine assays to the intact fibrinogen assay was significantly higher (P<0.0003) in cases vs. controls. Each fibrinogen assay correlated with plasma levels of CRP and IL-6 (which were also elevated in cases vs. controls). Each routine fibrinogen assay remained significantly elevated in cases vs. controls after further adjustment for C-reactive protein and interleukin-6. CONCLUSIONS: These data provide evidence for acquired, increased hyperfunctional plasma fibrinogen in MI survivors, which is not associated with markers of inflammatory reactions. The causes and significance of these results remain to be established in prospective studies.

The prevalence of dyspepsia and use of antisecretory medication in North Glasgow: role of Helicobacter pylori vs. lifestyle factors.

AIMS: To determine the prevalence of dyspepsia and associated antisecretory medication usage, and their associations with H. pylori infection in the general population. In addition, to compare the importance of H. pylori infection relative to other potential causes of dyspepsia: alcohol, smoking and obesity. METHODS: The study examined a random population sample of 784 men and 827 women from Glasgow. They completed a validated dyspepsia questionnaire and had their H. pylori status determined by serology. RESULTS: The overall prevalence of dyspepsia was 12%; prescribed antisecretory medication had been used over the last 6 months by 7%. The odds ratio (95% CI) for dyspepsia, comparing H. pylori-positives to negatives was 1.79 (1.03, 3.09) for men and 1.11 (0.70, 1.78) for women. Ever-smoking (both sexes) and obesity (women) had higher odds ratios for dyspepsia than did H. pylori. Adjustment for age, social class, ever-smoking, ever-drinking and obesity reduced the H. pylori odds ratios for dyspepsia to 1.38 (0.73, 2.60) for men and 0.99 (0. 57, 1.73) for women. The association between H. pylori and antisecretory medication usage was similar to that for dyspepsia. CONCLUSION: Obesity and smoking are more important risk factors, for dyspepsia and antisecretory medication usage, than is H. pylori. Reducing the burden and cost of dyspepsia will require lifestyle modification and not merely H. pylori eradication.

Contribution of modern cardiovascular treatment and risk factor changes to the decline in coronary heart disease mortality in Scotland between 1975 and 1994.

OBJECTIVE: To estimate the fall in coronary heart disease (CHD) mortality in Scotland attributable to medical and surgical treatments, and risk factor changes, between 1975 and 1994. DESIGN: A cohort model combining effectiveness data from meta-analyses with information on treatment uptake in all patient categories in Scotland. SETTING AND PATIENTS: The whole Scottish population of 5.1 million, including all patients with recognised CHD. INTERVENTIONS: All cardiological, medical, and surgical treatments, and all risk factor changes between 1975 and 1994. Data were obtained from epidemiological surveys, routine National Health Service sources, and local audits. MAIN OUTCOME MEASURES: Deaths from CHD in 1975 and 1994. RESULTS: There were 15 234 deaths from CHD in 1994, 6205 fewer deaths than expected if there had been no decline from 1975 mortality rates. In 1994, the total number of deaths prevented or postponed by all treatments and risk factor reductions was estimated at 6747 (minimum 4790, maximum 10 695). Forty per cent of this benefit was attributed to treatments (initial treatments for acute myocardial infarction 10%, treatments for hypertension 9%, for secondary prevention 8%, for heart failure 8%, aspirin for angina 2%, coronary artery bypass grafting surgery 2%, and angioplasty 0.1%). Fifty one per cent of the reduction in deaths was attributed to measurable risk factor reductions (smoking 36%, cholesterol 6%, secular fall in blood pressure 6%, and changes in deprivation 3%). Other, unquantified factors apparently accounted for the remaining 9%. These proportions remained relatively consistent across a wide range of assumptions and estimates in a sensitivity analysis. CONCLUSIONS: Medical treatments and risk factor changes apparently prevented or postponed about 6750 coronary deaths in Scotland in 1994. Modest gains from individual treatments produced a large cumulative survival benefit. Reductions in major risk factors explained about half the fall in coronary mortality, emphasising the importance and future potential of prevention strategies.

Out-of-hospital cardiac arrest due to coronary heart disease: a comparison of survival before and after the introduction of defribrillators in ambulances.

OBJECTIVE: To assess the actual impact on coronary mortality of equipping ambulances with defibrillators. DESIGN: Retrospective analysis of routine medical and legal records of all those who had a cardiac arrest attributed to coronary heart disease occurring outside hospital in a defined population before and after the introduction of Heartstart. SETTING: City of Glasgow, North of the River Clyde, 1984 and 1990. PATIENTS: 296 and 267 men and women aged 25-64 inclusive in 1984 and 1990 respectively who had a cardiac arrest outside hospital which was attributed to coronary heart disease (International Classification of Diseases codes 410-414, ninth revision). RESULTS: The impact on coronary mortality in 1990 of equipping ambulances with defibrillators concurred with the earlier prediction of less than 1% of all coronary deaths. The circumstances of cardiac arrest were largely unchanged; most occurred outside hospital in the victim's home and the principal witnesses were members of the victim's family. A call for help before cardiac arrest was made in very few cases and cardiopulmonary resuscitation was attempted by laypersons in less than a third of the deaths they witnessed. There was a significant increase in the number of cardiopulmonary resuscitation attempts made by ambulance crews (16% v 32%, P < 0.01). Ambulance crews, however, still attended less than half of all cases (44% and 47%). CONCLUSION: The impact of equipping ambulances with defibrillators will remain small unless strategies are introduced that focus on improving the public's response to coronary emergencies by calling for help promptly and initiating cardiopulmonary resuscitation before the arrival of the emergency services.

Age and health indications assessed by silhouette photographs.

OBJECTIVE: To test the hypothesis that overweight and central fat distribution make people look older and have poorer health. DESIGN: We asked 201 male and 161 female observers aged 28-67 y with body mass index (BMI) 17-45 kg/m2, to estimate the age of eight silhouette photographs of female volunteers with known BMI and waist and hips. Silhouette photographs were presented individually and grouped in three trios for analysis: trio A, each subject had waist to hip ratio = 0.7, BMI for each subject was 22, 24, 29 kg/m2; trio B, each subject had BMI = 22 kg/m2, waist to hip ratio for each subject was 0.66, 0.73, 0.99; and trio C, each subject had BMI = 29 kg/m2, waist to hip ratio for each subject was 0.76, 0.88, 0.99. The observers were then asked to judge the likelihood of developing heart disease, health and longevity of the silhouettes which were presented in four pairs controlling either for BMI or waist to hip ratio. RESULTS: The age of a silhouette with BMI 22 kg/m2 was estimated to be 35 y, 24 kg/m2 to be 45 y, and 30 kg/m2 to be 55 y, when waist to hip ratio was matched at 0.7. When BMI was controlled at either 22 or 29 kg/m2, higher waist to hip ratio led to a greater age estimation. An increase from a 65 cm to 88 cm waist circumference led to an estimate of 25 y older. Narrow hips was also judged as older. The silhouettes judged the more likely to be healthy and live longer were those with the lower waist to hip ratio (by 70% observers), and the lower BMI (by 90% observers). Waist to hip ratio appeared less influential when BMI of the silhouettes was high. The observers' own BMI, age or sex had little influences on their assessments of the age and health status of the silhouette photographs. CONCLUSIONS: Using novel sets of silhouette photographs, it was shown that overweight or central fat distribution and narrow hips suggest a person is older and has poorer health: People with BMI 29.7 kg/m2 appear to be 15-18 y older than those with BMI 22.2 kg/m2, each extra cm on the waist makes women appear to look a year older, and progressively less healthy. BMI and age of the observers had little influences on the findings.

Skeletal proportions and metabolic disorders in adults.

OBJECTIVE: The present study investigated the associations of stature, lower leg length (LLL) and demi-arm span (demi-AS) with major predisposing cardiovascular risk factors and coronary heart disease. STUDY DESIGN AND SUBJECTS: Cross-sectional study set at Glasgow Royal Infirmary of a subsample of 543 men and 646 women aged 25-66 y from the random MONICA sample. ASSOCIATED MEASURES: LLL, demi-AS, blood pressure, plasma total cholesterol, diabetes mellitus and coronary heart disease (angina, angioplasty, heart attack, and coronary artery bypass graft). RESULTS: The numbers (and proportions) of men and women, respectively, with hypertension were 126 (23.6%) and 80 (14.0%), hypercholesterolaemia 155 (29.0%) and 171 (30.1%), coronary heart disease 53 (10.1%) and 47 (8.4%), and diabetes 15 (2.9%) and 9 (1.6%). Results were adjusted for age, social class and smoking. Analysis of variance showed that in men, shortness of height, LLL or demi-AS were all associated significantly (P < 0.05) with hypercholesterolaemia. Long LLL, high ratios of LLL:height or LLL:demi-As were associated significantly (P < 0.05) with diabetes mellitus. In women, shortness of height or LLL were associated with significantly (P < 0.05) with coronary heart disease. High ratio of demi-AS:height or low ratio of LLL:demi-AS was associated significantly (P < 0.05) with coronary heart disease. CONCLUSIONS: Short stature and limb lengths, and also altered skeletal proportions, which may reflect interrupted early growth, are associated with several metabolic disorders. Skeletal disproportion associates with diabetes in men and coronary heart disease in women.

Neuropsychological functioning following bilateral subthalamic nucleus stimulation in Parkinson's disease.

The cognitive effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) have been examined. However, there are no reported studies that evaluate, by incorporating a disease control group, whether neuropsychological performance in surgical patients changes beyond the variability of the assessment measures. To examine this issue, 17 PD patients were tested before and after bilateral STN stimulator implantation, both on and off stimulation. Eleven matched PD controls were administered the same repeatable neuropsychological test battery twice. Relative to changes seen in the controls, the surgery for electrode placement mildly adversely affected attention and language functions. STN stimulation, per se, had little effect on cognition. The STN DBS procedure as a whole resulted in a mild decline in delayed verbal recall and language functions. There were no surgery, stimulation, or procedure effects on depression scale scores. In contrast to these group findings, one DBS patient demonstrated significant cognitive decline following surgery.

Waist circumference as a measure for indicating need for weight management.

OBJECTIVE: To test the hypothesis that a single measurement, waist circumference, might be used to identify people at health risk both from being overweight and from having a central fat distribution. DESIGN: A community derived random sample of men and women and a second, validation sample. SETTING: North Glasgow. SUBJECT: 904 men and 1014 women (first sample); 86 men and 202 women (validation sample). MAIN OUTCOME MEASURES: Waist circumference, body mass index, waist:hip ratio. RESULTS: Waist circumference > or = 94 cm for men and > or = 80 cm for women identified subjects with high body mass index (> or = 25 kg/m2) and those with lower body mass index but high waist:hip ratio (> or = 0.95 for men, > or = 0.80 women) with a sensitivity of > 96% and specificity > 97.5%. Waist circumference > or = 102 cm for men or > or = 88 cm for women identified subjects with body mass index > or = 30 and those with lower body mass index but high waist:hip ratio with a sensitivity of > 96% and specificity > 98%, with only about 2% of the sample being misclassified. CONCLUSIONS: Waist circumference could be used in health promotion programmes to identify individuals who should seek and be offered weight management. Men with waist circumference > or = 94 cm and women with waist circumference > or = 80 cm should gain no further weight; men with waist circumference > or = 102 cm and women with waist circumference > or = 88 cm should reduce their weight.

Randomised controlled trial of specialist nurse intervention in heart failure.

OBJECTIVES: To determine whether specialist nurse intervention improves outcome in patients with chronic heart failure. DESIGN: Randomised controlled trial. SETTING: Acute medical admissions unit in a teaching hospital. PARTICIPANTS: 165 patients admitted with heart failure due to left ventricular systolic dysfunction. The intervention started before discharge and continued thereafter with home visits for up to 1 year. MAIN OUTCOME MEASURES: Time to first event analysis of death from all causes or readmission to hospital with worsening heart failure. RESULTS: 31 patients (37%) in the intervention group died or were readmitted with heart failure compared with 45 (53%) in the usual care group (hazard ratio=0.61, 95% confidence interval 0.33 to 0.96). Compared with usual care, patients in the intervention group had fewer readmissions for any reason (86 v 114, P=0.018), fewer admissions for heart failure (19 v 45, P<0.001) and spent fewer days in hospital for heart failure (mean 3.43 v 7.46 days, P=0.0051). CONCLUSIONS: Specially trained nurses can improve the outcome of patients admitted to hospital with heart failure.

Myxococcus xanthus mutants with temperature-sensitive, stage-specific defects: evidence for independent pathways in development.

Fruiting-body formation in the bacterium Myxococcus xanthus consists of a temporal sequence of cellular aggregation and sporulation. To examine the developmental stages more closely, we established synchronous and reproducible conditions for fruiting-body formation. Mutants that are temperature sensitive for fruiting-body formation were isolated and analyzed under these conditions. The terminal morphologies of the mutant strains at the nonpermissive temperature were found to resemble intermediate stages of fruiting-body formation and therefore were grouped in the following phenotypic classes: (i) rough mutants, which show no aggregation; (ii) swirl mutants, which show defective aggregation; (iii) flat-mound mutants and translucent-mound mutants, mutants which aggregate but show very low levels of sporulation. The mutants were characterized by temperature-shift experiments and found to exhibit discrete and reproducible temperature-sensitive periods. The ends of the temperature-sensitive periods in the various mutants covered a broad range of the developmental cycle. No correlation was found between the terminal morphologies at the restrictive temperature and the timing of the temperature-sensitive periods. However, the terminal morphologies correlated well with sporulation. The rough and swirl mutants produced normal numbers of myxospores at 34 degrees C even though they failed to aggregate. In contrast, the flat-mound and translucent-mound mutants, which aggregate normally, produced very few spores. The translucent-mound mutants were also temperature sensitive for induction of glycerol spores. The results indicate that both aggregation and sporulation are initiated early in the developmental cycle and that these processes are largely independent of each other.

Regulation of lysine transport by feedback inhibition in Saccharomyces cerevisiae.

A steady-state level of about 240 nmol/mg (dry wt) occurs during lysine transport in Saccharomyces cerevisiae. No subsequent efflux of the accumulated amino acid was detected. Two transport systems mediate lysine transport, a high-affinity, lysine-specific system and an arginine-lysine system for which lysine exhibits a lower affinity. Preloading with lysine, arginine, glutamic acid, or aspartic acid inhibited lysine transport activity; preloading with glutamine, glycine, methionine, phenylalanine, or valine had little effect; however, preloading with histidine stimulated lysine transport activity. These preloading effects correlated with fluctuations in the intracellular lysine and/or arginine pool: lysine transport activity was inhibited when increases in the lysine and/or arginine pool occurred and was stimulated when decreases in the lysine and/or arginine pool occurred. After addition of lysine to a growing culture, lysine transport activity was inhibited more than threefold in one-third of the doubling time of the culture. These results indicate that the lysine-specific and arginine-lysine transport systems are regulated by feedback inhibition that may be mediated by intracellular lysine and arginine.

Pethidine compared with meptazinol during labour. A prospective randomised double-blind study in 1100 patients.

A randomised double-blind comparison of pethidine and meptazinol used as analgesics in labour was carried out in 1,100 consecutive women who would normally have received intramuscular pethidine. Pain assessments at 30-minute intervals were made independently by patients and midwives. Maternal and neonatal side effects were noted. The babies' requirements for resuscitation and weight changes in the first 5 days were studied. There was no difference in the analgesia provided by the two drugs; the pattern of side effects was similar, but the incidence of vomiting was greater following meptazinol administration. The babies in the two groups were similar with respect to resuscitation received, weight gains or losses and the incidence of clinical neonatal jaundice. The most striking findings were the poor quality of pain relief experienced by both groups following parenteral analgesics and the high incidence of side effects.

Delay in calling for help during myocardial infarction: reasons for the delay and subsequent pattern of accessing care.

OBJECTIVE: To determine the reasons for delay in calling for help during acute myocardial infarction and the reasons for choice of first medical contact. DESIGN: Review of routine medical records and one to one semi-structured interviews. SETTING: Community survey in city of Glasgow, north of the river Clyde. PATIENTS: 228 men and 85 women aged between 25 and 65 years, respectively, who survived acute myocardial infarction between October 1994 and December 1996. RESULTS: Only 25% of the subjects made a call for help within one hour of the onset of coronary symptoms; in 40% the delay was greater than four hours. Symptoms were not recognised as coronary in origin in the majority of cases. In all cases where delay was more than one hour the main reasons for the delay were thinking that symptoms would go away or that they were not serious. Requesting the attendance of a general practitioner was the first course of action in the majority of cases (55%); the main reason given was that the patient believed this should always be the first course of action. Reluctance to call the emergency services reflected the belief that the symptoms were not serious enough to warrant an ambulance. CONCLUSIONS: Strategies to reduce patient delay times in this deprived urban population must focus on educating the public on the recognition and diversity of coronary symptoms and the benefits of presenting promptly to hospital by way of the emergency ambulance service.

Trends in hospitalization for heart failure in Scotland 1980-1990.

Heart failure is a growing public health problem in industrialized countries with ageing populations. Scotland has a relatively stable population of approximately 5 million and a well described system for recording details of hospitalizations (Scottish Hospital In-Patients Statistics-SHIPS). We have examined SHIPS data for hospitalizations for heart failure in Scotland 1980-1990. Discharges for heart failure as the primary diagnosis increased by almost 60%, from 1.30 to 2.12/1000 population in this period (as either primary or secondary diagnosis the rate increased from 2.51 to 4.24/1000). Seventy-eight percent of discharges were in persons aged > or = 65 years and 48% of discharges were male. Heart failure (primary diagnosis) accounted for almost 4% of all general (internal) medicine discharges. In-patient case fatality was 18% in 1990. Mean duration of in-patient stay on Internal Medicine wards was approximately 11 days. The number of hospitalizations for heart failure is now almost identical to those for myocardial infarction. These trends mirror those recently reported from the United States. Heart failure is an increasingly common and costly cause of hospitalization in Scotland. Approaches which can reduce this burden on the hospital service require urgent attention.

Prescribing and emergency admissions for heart failure in greater Glasgow.

BACKGROUND: We sought to determine whether there is an association between the rate of prescription of angiotensin-converting enzyme (ACE) inhibitors and the rate of hospitalization for heart failure. METHODS AND RESULTS: We conducted a cross-sectional study linking prescribing data with hospital admission data from 215 primary health care practices in Greater Glasgow, United Kingdom. We obtained numbers of prescriptions of diuretics. ACE inhibitors, and digoxin and numbers of admissions for heart failure. The mean practice rate of diuretic prescription was 0.7 per patient per year, the mean practice rate of ACE inhibitor prescription was 0.06 per patient per year, the mean practice rate of digoxin prescription was 0.09 per patient per year, and the mean practice rate of admission for heart failure was 3.29 per 1,000 patients per year. There was a strong and significant association between the rate of diuretic prescription and the rate of digoxin prescription. There was only a moderate inverse association between the ratio of ACE inhibitor to diuretic prescriptions and the rate of admissions for heart failure. CONCLUSIONS: ACE inhibitors are underused. Rates of diuretic and digoxin prescriptions correlate strongly and are presumably both markers for similar cardiovascular morbidity. There was no evidence that ACE inhibitors modulated the rate of heart failure admissions.

Effects of levodopa on cognitive functioning in moderate-to-severe Parkinson's disease (MSPD).

Although improved cognition has been reported in patients with mild Parkinson's disease (PD) following the administration of levodopa, mixed results have been found in moderately-to-severely affected PD patients (MSPD), particularly in studies conducted since 1980. In the present study, 16 MSPD patients were tested on separate days, once following overnight levodopa withdrawal and once while optimally treated. A battery of neuropsychological tests that assess a range of cognitive functions (i.e., attention, language, visuospatial, memory, and executive), as well as a measure of depression, were used. Although patients performed better on a measure of confrontation naming in the untreated than in the treated condition, there were no significant differences for any of the other cognitive variables or for the depression scale variable. Thus, these data suggest that there are generally no adverse or beneficial effects of levodopa therapy on cognition in MSPD patients.