DMC1 functions in a Saccharomyces cerevisiae meiotic pathway that is largely independent of the RAD51 pathway.

Meiotic recombination in the yeast Saccharomyces cerevisiae requires two similar recA-like proteins, Dmc1p and Rad51p. A screen for dominant meiotic mutants provided DMC1-G126D, a dominant allele mutated in the conserved ATP-binding site (specifically, the A-loop motif) that confers a null phenotype. A recessive null allele, dmc1-K69E, was isolated as an intragenic suppressor of DMC1-G126D. Dmc1-K69Ep, unlike Dmc1p, does not interact homotypically in a two-hybrid assay, although it does interact with other fusion proteins identified by two-hybrid screen with Dmc1p. Dmc1p, unlike Rad51p, does not interact in the two-hybrid assay with Rad52p or Rad54p. However, Dmc1p does interact with Tid1p, a Rad54p homologue, with Tid4p, a Rad16p homologue, and with other fusion proteins that do not interact with Rad51p, suggesting that Dmc1p and Rad51p function in separate, though possibly overlapping, recombinational repair complexes. Epistasis analysis suggests that DMC1 and RAD51 function in separate pathways responsible for meiotic recombination. Taken together, our results are consistent with a requirement for DMC1 for meiosis-specific entry of DNA double-strand break ends into chromatin. Interestingly, the pattern on CHEF gels of chromosome fragments that result from meiotic DNA double-strand break formation is different in DMC1 mutant strains from that seen in rad50S strains.

Prognostic significance of heart rate variability in post-myocardial infarction patients in the fibrinolytic era. The GISSI-2 results. Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico.

BACKGROUND: Studies performed before the introduction of fibrinolysis showed that a low heart rate variability (HRV) is associated with higher mortality in post-myocardial infarction (MI) patients. We evaluated whether HRV adds information relevant to risk stratification in patients treated with fibrinolysis as well. METHODS AND RESULTS: From 24-hour ECG recordings obtained at discharge in patients treated with recombinant tissue-type plasminogen activator or streptokinase, we measured several time-domain indexes of HRV: standard deviation (SDNN), root-mean-square of successive differences (RMSSD), and number of RR interval increases > 50 ms ("NN50+"). The prognostic value of HRV for total and cardiovascular mortality was assessed. Of 567 patients with valid recordings, 52 (9.1%) died during the 1000 days of follow-up, 44 (7.8%) of cardiovascular causes. All indexes of low HRV were able to identify patients (16% to 18% of total population) with a higher total mortality (20.8% to 24.2% versus 6.0% to 6.8%, depending on index used). The independent predictive value of low HRV was confirmed by the adjusted analysis with the following relative risks: NN50+, 3.5 (95% CI, 1.9 to 6.7); SDNN, 3.0 (95% CI, 1.55 to 5.9); and RMSSD, 2.8 (95% CI, 1.5 to 5.3). Advanced age, previous MI, Killip class at entry, and use of digitalis were also independent predictors. Similar data were obtained for cardiovascular mortality. CONCLUSIONS: Time-domain indexes of HRV retain their independent prognostic significance even in post-MI patients of all ages treated with fibrinolysis.

Diabetic autonomic neuropathy and the heart.

This brief review summarises the relationship between autonomic nerve damage, diabetes, and the heart. Clinical aspects of cardiac autonomic involvement are first considered, then the evidence, both direct and indirect, for cardiac autonomic nerve involvement is reviewed. This evidence includes studies of heart rate, cardiovascular reflexes, heart rate variability, QT interval length, cardiac function, pathological studies, and cardiac scintiscanning. Brief consideration is given to the relation with other aspects of diabetes and treatment to prevent or reverse autonomic damage. Potential future research directions are then proposed.

Measurement of parasympathetic activity from 24-hour ambulatory electrocardiograms and its reproducibility and sensitivity in normal subjects, patients with symptomatic myocardial ischemia, and patients with diabetes mellitus.

The parasympathetic nervous system plays a major role in the pathophysiology of many cardiovascular disease, particularly in modulating myocardial electrical stability. Measurements of heart rate variability have been widely used to assess parasympathetic activity. The reproducibility of measurements obtained from 24-hour ambulatory electrocardiograms has not been well documented. We have developed a technique for measuring parasympathetic activity from clinical quality 24-hour ambulatory electrocardiograms by counting beat-to-beat increases in RR interval that are > 50 ms. To determine the reproducibility and sensitivity of our technique, we analyzed repeated 24-hour electrocardiograms of 173 subjects (19 normal subjects, 67 patients with ischemic heart disease, and 87 diabetics) followed up over periods of 2 to 16 weeks. In all subject groups, mean values for repeated measurements were virtually identical. Measurements were stable in all 3 groups throughout the course of the study, as assessed by intraclass correlation coefficients. This technique is sensitive enough to detect relatively small changes in parasympathetic activity in subjects, as demonstrated by the calculated Bland and Altman coefficients of repeatability. Reproducibility and sensitivity of our technique are particularly good in normal subjects and in patients with ischemic heart disease. The results obtained with this technique imply that other related measurements of parasympathetic activity will show similar excellent short- and long-term reproducibility and sensitivity.

Medical and dental staffing in the National Health Service in Scotland in 1994.

The Scottish Office Home and Health Department (SOHHD) has, since 1980, published a regular series of articles on medical staffing in Scotland. The articles have taken the form of a series of tables provided by the Information and Statistics Division (ISD) of the Common Services Agency from the annual 'Medman' Census of Medical and Dental Staff in Scotland. Although the information given this year is similar to previous years, the format of some of the tables has been changed, and in particular primary care medical and dental manpower information is now included. Comparable medical and dental manpower statistics are regularly published for England and Wales. The background to the present manpower planning strategies have been summarized. In the publications 'Achieving a Balance: Plan for Action', the 'Shaw' Report, 'Hospital Medical Staffing in Scotland' and the Report of the Working Party on the UK Specialist Medical Training (the 'Calman' Report). In essence the strategy has sought to improve and reshape the pyramidal staffing structure of NHS hospitals by matching the number of doctors in the training grades more closely with career opportunities, and by expanding the consultant grade. As the reforms in Specialist Medical Training are introduced, the length of training is likely to be shorter, but more structured. Additionally the 'New Deal' to reduce junior doctors' hours of work is also having a significant impact not only on the hours worked by training grade doctors, but also on local patterns of staffing. There are, too, increased opportunities for flexible and part-time working. SOHHD and the Department of Health have both published recent reports on flexible and part-time working for doctors.

A client/server approach to telemedicine.

This paper describes the Medical College of Ohio's efforts in developing a client/server telemedicine system. Telemedicine vastly improves the ability of a medical center physician or specialist to interactively consult with a physician at a remote health care facility. The patient receives attention more quickly, he and his family do not need to travel long distances to obtain specialists' services, and the primary care physician can be involved in diagnosis and developing a treatment program [1, 2]. Telemedicine consultations are designed to improve access to health services in underserved urban and rural communities and reduce isolation of rural practitioners [3].

Nonhomologous synapsis and reduced crossing over in a heterozygous paracentric inversion in Saccharomyces cerevisiae.

Homologous chromosome synapsis ("homosynapsis") and crossing over are well-conserved aspects of meiotic chromosome behavior. The long-standing assumption that these two processes are causally related has been challenged recently by observations in Saccharomyces cerevisiae of significant levels of crossing over (1) between small sequences at nonhomologous locations and (2) in mutants where synapsis is abnormal or absent. In order to avoid problems of local sequence effects and of mutation pleiotropy, we have perturbed synapsis by making a set of isogenic strains that are heterozygous and homozygous for a large chromosomal paracentric inversion covering a well marked genetic interval and then measured recombination. We find that reciprocal recombination in the marked interval in heterozygotes is reduced variably across the interval, on average to approximately 55% of that in the homozygotes, and that positive interference still modulates crossing over. Cytologically, stable synapsis across the interval is apparently heterologous rather than homologous, consistent with the interpretation that stable homosynapsis is required to initiate or consummate a large fraction of the crossing over observed in wild-type strains. When crossing over does occur in heterozygotes, dicentric and acentric chromosomes are formed and can be visualized and quantitated on blots though not demonstrated in viable spores. We find that there is no loss of dicentric chromosomes during the two meiotic divisions and that the acentric chromosome is recovered at only 1/3 to 1/2 of the expected level.

Autonomic function in cirrhosis assessed by cardiovascular reflex tests and 24-hour heart rate variability.

OBJECTIVES: To assess the prevalence of autonomic dysfunction in cirrhosis and to observe the effect of disease severity on autonomic dysfunction. METHODS: Seventy patients with cirrhosis (Child's class A, 42; Child's class B, 10; and Child's class C, 15) (45 alcoholic, 15 primary biliary cirrhosis, five chronic active hepatitis, and eight idiopathic) underwent standard cardiovascular reflex tests. In addition, in 40 patients, 24-h ECG RR variability tests were performed to detect autonomic dysfunction. RESULTS: Forty-two of 70 (60%) patients had abnormalities of cardiovascular reflex function of varying severity, whereas 24 of 34 (70%) had 24-h RR counts with the 95% age-related tolerance. The prevalence of abnormality increased with increasing severity of liver disease but not with different etiologies. CONCLUSION: Irrespective of etiology, there is a high prevalence of autonomic dysfunction in cirrhosis, and it is related to disease severity: the mechanism is unknown.

Cardiac parasympathetic activity in severe uncomplicated coronary artery disease.

BACKGROUND: Previous studies have suggested that coronary artery disease is independently associated with reduced cardiac parasympathetic activity, and that this is important in its pathophysiology. These studies included many patients with complications that might be responsible for the reported autonomic abnormalities. OBJECTIVE: To measure cardiac parasympathetic activity in patients with uncomplicated coronary artery disease. PATIENTS AND METHODS: 44 patients of mean (SD) age 56 (8) with severe uncomplicated coronary artery disease (symptoms uncontrolled on maximal medical treatment; > 70% coronary stenosis at angiography; normal ejection fraction; no evidence of previous infarction, diabetes, or hypertension). Heart rate variability was measured from 24 hour ambulatory electrocardiograms by counting the number of times successive RR intervals exceeded the preceding RR interval by > 50 ms, a previously validated sensitive and specific index of cardiac parasympathetic activity. RESULTS: Mean (range) of counts were: waking 112 (range 6-501)/h, sleeping 198 (0-812)/h, and total 3912 (151-14 454)/24 h. These mean results were unremarkable, and < 10% of patients fell below the lower 95% confidence interval for waking, sleeping, or total 24 hour counts in normal people. There was no relation between the severity of coronary artery disease or the use of concurrent antianginal drug treatment and cardiac parasympathetic activity. CONCLUSION: In contrast with previous reports no evidence of a specific independent association between coronary artery disease and reduced cardiac parasympathetic activity was found. The results of previous studies may reflect the inclusion of patients with complications and not the direct effect of coronary artery disease itself.

Subclinical autonomic dysfunction in patients with Hodgkin's disease and non-Hodgkin's lymphoma.

A prospective study was carried out to determine the prevalence of autonomic dysfunction in patients with lymphoma, and to assess the effect on this of chemotherapy. Twenty consecutive patients presenting with Hodgkin's disease, high-grade non-Hodgkin's lymphoma, or low-grade non-Hodgkin's lymphoma were studied. All had advanced disease, requiring combination chemotherapy which included the use of vinca alkaloids. Clinical assessment and standard cardiovascular autonomic function tests were carried out prior to and following completion of chemotherapy. Although no patients had clinical evidence of autonomic neuropathy at presentation, 16 (80%) had abnormal cardiovascular autonomic function tests. There was no correlation with the presence or absence of mediastinal disease. There was significant improvement in autonomic scores with treatment despite the use of drugs of known neurological toxicity. Some patients showed residual abnormalities of autonomic function despite disease resolution. We suggest that subclinical autonomic dysfunction is common in patients with lymphoma, and probably represents a paraneoplastic syndrome--the pathogenesis and prevalence of which deserve further study. This phenomenon may predispose patients with lymphoma to develop gastrointestinal and genitourinary dysfunction, or postural hypotension, and should be considered during the evaluation of the neurotoxicity of chemotherapy regimens.

Differing patterns of cardiac parasympathetic activity and their evolution in selected patients with a first myocardial infarction.

OBJECTIVES: The purpose of the study was to compare cardiac parasympathetic activity during the early and convalescent phases of acute anterior and inferior myocardial infarction. BACKGROUND: Previous studies have shown that cardiac parasympathetic activity may vary with the site of infarction and that recovery may occur after infarction. METHODS: Cardiac parasympathetic activity was measured from 24-h electrocardiograms by counting the number of times that successive RR intervals (counts) differed by > 50 ms. Recordings began within 12 h of admission and at 7, 42 and 140 days after acute myocardial infarction in 20 patients (mean age 57 +/- 7.9 years). All patients were treated with streptokinase, aspirin and oral beta-adrenergic blocking agents. RESULTS: For the entire group, mean total 24-h RR counts increased from 592 (range 78 to 3,812) at 48 h to 648 (range 109 to 5,473) at 7 days, 1,145 (range 162 to 6,268) at 42 days and 1,958 (range 344 to 9,632) at 140 days. Patients with anterior infarction had significantly lower counts (mean 277, range 78 to 2,708; n = 11) compared with those with inferior infarction (mean 2,172, range 897 to 3,812; n = 9) at 48 h (p < 0.05). There was no significant difference in counts between patients with anterior (mean 1,051, range 212 to 6,268) and inferior (mean 1,321, range 162 to 3,265) infarction after 42 or after 140 days (anterior: mean 1,655, range 344 to 9,632; inferior: mean 2,588, range 1,700 to 5,767). CONCLUSIONS: These data suggest that after anterior myocardial infarction there is impaired cardiac parasympathetic function that improves within 6 weeks, whereas in inferior infarction there is relative preservation of cardiac parasympathetic function.

Effects of ponalrestat, an aldose reductase inhibitor, on neutrophil killing of Escherichia coli and autonomic function in patients with diabetes mellitus.

In diabetic subjects, polyol pathway activity might inhibit neutrophil function and cause nerve damage. The effects of ponalrestat, an aldose reductase inhibitor, were assessed on neutrophil intracellular killing of Escherichia coli and on autonomic function in diabetic subjects in a randomized double-blind, placebo-controlled, crossover trial. We studied 31 diabetic subjects with autonomic dysfunction and 21 age- and sex-matched control subjects. During two 12-wk treatment periods, the diabetic subjects took either 600 mg of ponalrestat or matching placebo once daily. Neutrophil killing of E. coli was measured by a microbiological assay technique. Kmax by neutrophils from the diabetic subjects was lower than in the control group (Kmax of diabetic subjects 54.5 +/- 26.4 vs. control subjects 67.3 +/- 16.3, P = 0.045). Ponalrestat significantly increased bacterial killing in the diabetic subjects (Kmax of ponalrestat 75.1 +/- 16.5 vs. placebo 58.2 +/- 20.8, P = 0.003) so that there was no longer any significant difference in Kmax between the control subjects and the diabetic subjects on active treatment. Ponalrestat had no significant effect on a range of standard cardiovascular autonomic nerve function tests. We conclude that neutrophil killing of E. coli is impaired in diabetic subjects with autonomic dysfunction. This is restored to normal by ponalrestat.

Decreased cardiac parasympathetic activity in chronic heart failure and its relation to left ventricular function.

BACKGROUND: Activation of the sympathetic nervous system has been extensively studied in patients with chronic heart failure, but the parasympathetic nervous system has received relatively little attention. The objective in this study was to investigate cardiac parasympathetic activity in chronic heart failure and to explore its relation to left ventricular function. METHODS: Heart rate variability was measured from 24 hour ambulatory electrocardiograms by counting the number of times each RR interval exceeded the preceding RR interval by more than 50 ms (counts). This method provided a sensitive index of cardiac parasympathetic activity. RESULTS: Mean (range) of counts were: waking 48 (1-275)/h, sleeping 62 (0-360)/h, and total 1310 (31-7278)/24 h. These were lower than expected, and in 26 (60%) of the 43 patients counts fell below the lower 95% confidence intervals (95% CI) for RR counts in normal subjects. A significant correlation between total 24 hour RR counts and left ventricular ejection fraction was present (r = 0.49, p less than 0.05). CONCLUSIONS: These results indicate that most patients with chronic heart failure have reduced heart rate variability and therefore reduced cardiac parasympathetic activity. The degree of parasympathetic dysfunction is related to the severity of left ventricular dysfunction. This may be relevant to the high incidence of ventricular arrhythmias and poor prognosis of patients with chronic heart failure.

Effect of captopril on cardiac parasympathetic activity in chronic cardiac failure secondary to coronary artery disease.

Thirty-two patients with chronic cardiac failure underwent 24-hour ambulatory electrocardiographic monitoring on 2 separate occasions: 20 patients before and during treatment with captopril, and 12 acting as controls. Heart rate variability was calculated by counting the number of times successive RR interval differences were greater than 50 ms (this measurement being a reliable index of cardiac parasympathetic activity). During treatment with captopril, group mean total counts increased to 1,032 (range 48 to 7,437) from 482 (range 23 to 6,120) (p = 0.002). There was no change in mean hourly waking or sleeping heart rates. In the control group, no changes were seen: group mean total counts on the first occasion were 340 (range 120 to 3,255) and on the second occasion 400 (range 154 to 3,300) (p = not significant). These results show that treatment with angiotensin-converting enzyme inhibitors increases cardiac parasympathetic activity in patients with chronic cardiac failure. This may be relevant to the improved prognosis of this group of patients when treated with angiotensin-converting enzyme inhibitors.