Ovarian follicular cysts in dairy cows: an abnormality in folliculogenesis.

Ovarian follicular cysts are a major reproductive problem in lactating dairy cows. The primary physiological defect leading to the formation of ovarian follicular cysts is a failure of the hypothalamus to trigger the preovulatory surge of luteinizing hormone (LH) in response to estradiol. The factor responsible for this hypothalamic defect may be progesterone. Intermediate levels of progesterone have been shown to prevent ovulation and promote persistence of dominant follicles in normal cycling cows. Recently, we found that 66% of cows with ovarian follicular cysts had progesterone concentrations in an unusual, intermediate range (0.1-1.0 ng/mL) at the time of their detection. A majority of new follicles (76%) that develop in the presence of these intermediate progesterone concentrations became cysts. Only 10% ovulated. Based on these observations, a novel model for the formation and turnover of ovarian follicular cysts is proposed.

Sleep complaints and risk factors for excessive daytime sleepiness in adult males in Northern Ireland.

The prevalence of sleep complaints in Northern Ireland is unknown. Sleep disruption can result in excessive daytime sleepiness (EDS), with significant socioeconomic consequences. The aim of this study was to assess the prevalence of sleep complaints and to determine risk factors for EDS in a Northern Irish community. From an urban and rural community of 499,111 people, a random sample of 3391 adult men were sent a questionnaire by mail. Questions were asked regarding sleep, EDS and medical history. There were 2364 completed questionnaires returned (response rate 70%). The mean age of respondents was 46.0 years (range 18--91 years). 26.7% of men were not satisfied with their usual night's sleep and 68% of men woke up at least once during the night. Based on pre-defined criteria, 24.6% of the population had insomnia and 19.8% had EDS. The strongest risk factor identified for EDS was a history of snoring loudly (odds ratio 2.62; 95% CI 1.82--3.77). Other risk factors included ankle swelling, feeling sad or depressed stopping sleep, experiencing vivid dreams while falling asleep, waking up feeling unrefreshed and age > 35 years. The prevalence rates of sleep complaints and EDS in this community-based study is high, although this does depend directly on the criteria used to define insomnia and EDS. Recognition of risk factors for EDS may help to identify and treat those affected.

Neuropeptide variability in man.

BACKGROUND: Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides. METHODS: We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant. RESULTS: Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L-1] of VIP [patients 27 (2.1-85.5); controls 9.8 (0-34)] and NPY [patients 20 (0-110); controls 12 (5-19)] were higher in patients (P < 0.05). Circulating plasma levels of ET-1 and CGRP were about the same in both groups [ET-1: patients 18 (2-84); controls 18 (0-48); CGRP: patients 4 (1-18.5), controls 5.5 (1-15); P = NS]. Levels of CGRP, VIP and ET-1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery. CONCLUSIONS: The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10-15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.

Effect of thoracotomy and lung resection on exercise capacity in patients with lung cancer.

BACKGROUND: Resection is the treatment of choice for lung cancer, but may cause impaired cardiopulmonary function with an adverse effect on quality of life. Few studies have considered the effects of thoracotomy alone on lung function, and whether the operation itself can impair subsequent exercise capacity. METHODS: Patients being considered for lung resection (n = 106) underwent full static and dynamic pulmonary function testing which was repeated 3-6 months after surgery (n = 53). RESULTS: Thoracotomy alone (n = 13) produced a reduction in forced expiratory volume in one second (FEV1; mean (SE) 2.10 (0.16) versus 1.87 (0.15) l; p<0.05). Wedge resection (n = 13) produced a non-significant reduction in total lung capacity (TLC) only. Lobectomy (n = 14) reduced forced vital capacity (FVC), TLC, and carbon monoxide transfer factor but exercise capacity was unchanged. Only pneumonectomy (n = 13) reduced exercise capacity by 28% (PVO2 23.9 (1.5) versus 17.2 (1.7) ml/min/kg; difference (95% CI) 6.72 (3.15 to 10.28); p<0.01) and three patients changed from a cardiac limitation to exercise before pneumonectomy to pulmonary limitation afterwards. CONCLUSIONS: Neither thoracotomy alone nor limited lung resection has a significant effect on exercise capacity. Only pneumonectomy is associated with impaired exercise performance, and then perhaps not as much as might be expected.

Cardiopulmonary exercise testing in the pre-operative assessment of patients for repair of abdominal aortic aneurysm.

We have investigated the value of cardiopulmonary exercise testing in the pre-operative assessment to patients for abdominal aortic aneurysm repair. Thirty-six patients were entered into the study. All had a pre-operative clinical assessment and investigations including chest radiograph, electrocardiograph, spirometry and echocardiogram with measurement of left ventricular ejection fraction. Each patient performed a symptom limited treadmill exercise test using a STEEP protocol with on-line measurement of respiratory gas exchange. Patients were followed up for 12 months post-operatively by review of casenotes. Thirty out of 36 patients had surgical repair of abdominal aortic aneurysm. There was 1 death in the perioperative period and 2 deaths in the following 12 months. Seven other patients suffered post-operative complications. There were no significant differences in left ventricular ejection fraction, spirometry and peak achieved oxygen consumption (PVO2) between those patients who died or who had post-operative complications and those who had not. However, PVO2 < 20 ml/min/kg was found in 70 per cent of patients who had complications compared with 50 per cent of those who had not. Also 4 patients considered medically unfit for surgery all had PVO2 < 20 ml/min/kg. Cardiopulmonary exercise testing with measurement of PVO2 may be helpful in identifying patients more at risk of post-operative complications but should not be used in isolation without through clinical assessment.

Exercise responses in patients with IDDM.

OBJECTIVE: The hemodynamic, respiratory, and metabolic responses to exercise were studied in IDDM patients and control subjects to detect diabetic cardiomyopathy. RESEARCH DESIGN AND METHODS: Eight subjects aged 25-40 years with diabetes of at least 10 years' duration were compared with eight control subjects aged 21-46 years. All subjects underwent a progressive incremental bicycle exercise test with measurement of gas exchange, blood glucose, lactate, fat metabolite, and catecholamine levels and two steady-state exercise tests with measurement of cardiac output by a CO2 rebreathing method. A new first-pass radionuclide method was used to measure cardiac ejection fractions (EFs) at rest, peak exercise, and steady-state exercise. RESULTS: The peak achieved oxygen consumption was similar in the diabetic and control subjects (29.9 [25.1-34.6] and 31.4 [26.9-35.9] ml.min-1.kg-1, respectively; mean [95% CI]). There were no significant differences in heart rate, double product, ventilation, respiratory exchange ratio, or ventilatory equivalents for oxygen and CO2 during the incremental test. Glucose levels were higher in the diabetic subjects, but there were no significant differences in levels of lactate, catecholamines, free fatty acids, glycerol, or beta-hydroxybutyrate. Left ventricular EF fell from rest to peak exercise within the diabetic group (66.0% [59.6-72.4] at rest; 53.6% [45.6-61.6] at peak; P < 0.05) but this did not differ significantly from the control group (58.7% [52.3-65.1] at rest; 60.3% [48.9-71.7] at peak). Right ventricular EFs were similar in each group, and there was no reduction in peak filling rate to suggest diastolic dysfunction. The cardiac output responses to exercise were also similar in the two groups. CONCLUSIONS: There is no evidence of impairment of the exercise response in subjects with long-standing diabetes, and the apparent fall in left ventricular EF at peak exercise could be related to hemodynamic adaptation.

Non-invasive measurement of cardiac output and ventricular ejection fractions in chronic cardiac failure: relationship to impaired exercise tolerance.

1. The role of cardiac output limitation in the pathophysiology of exercise in patients with chronic failure remains undefined. During steady-state submaximal exercise, oxygen uptake is similar in patients and control subjects, but it is not known if cardiac output is also similar. We wished to determine if the reduced exercise tolerance of patients with chronic cardiac failure during such exercise is related to reduced cardiac output, or to peripheral factors. 2. Ten male patients with stable chronic failure and ten age-matched male normal controls were studied at rest and during exercise. Each subject performed a familiarization exercise test, a symptom-limited maximal exercise test and two submaximal exercise tests. Cardiac output was measured by a carbon dioxide rebreathing method. We also measured oxygen consumption, ventilation, Borg score of perceived exertion and venous lactate concentration, and ejection fractions. 3. As expected, patients had lower peak oxygen consumption [median (range) 1.18 (0.98-1.76) versus 1.935 (1.53-2.31) l/min; P < 0.001], lower peak venous lactate concentration but a similar overall level of perceived exertion. At the same submaximal workload, patients and control subjects had similar oxygen consumption [0.67 (0.59-0.80) versus 0.62 (0.52-0.82) l/min] and cardiac output [6.92 (5.79-9.76) versus 7.3 (5.99-10.38) l/min] but the patients had a greater perceived level of exertion [Borg score: 4 (1-6) versus 3 (1-5); P < 0.005], higher venous lactate concentration [1.6 (1-3.3) versus 1.14 (0.7-1.7) mmol/l; P < 0.05] and higher heart rate [106 (89-135) versus 87 (69-112) beats/ min; P < 0.005]. 4. During submaximal exercise at a similar absolute workload, patients with cardiac failure have a similar oxygen uptake and cardiac output but greater anaerobiosis and increased fatigue when compared with normal subjects. These findings appear to relate predominantly to changes that occur in the periphery rather than abnormalities of central cardiac function.

Cytokine profile in chronic cardiac failure.

Elevated tumour necrosis factor alpha (TNF-alpha) has been demonstrated in chronic cardiac failure (CCF) and may relate to severity of CCF and development of cachexia. We measured TNF receptor p55 in addition to TNF-alpha in an attempt to improve the detection rate of TNF-alpha activation, and simultaneously measured interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein. Thirty-four patients with CCF and 24 control subjects were studied. Only TNF receptor p55 [6.95 (0.77-42.3) vs. 5.52 (1.50-13.36) ng mL-1 (median (range)] and IL-6 [0.335 (0-9.79) vs. 0(0-14.71) pg mL-1) were significantly elevated in patients compared with control subjects (both P < 0.05). All inflammatory markers were more frequently elevated in patients, but none correlated with any of the clinical parameters studied. Reasons for inflammatory marker elevation in CCF are uncertain, but future studies should measure the p55 TNF receptor and IL-6 in addition to TNF-alpha, to improve detection of cytokine activity.

Home ventilation in Northern Ireland.

Thirteen patients were identified as receiving assisted ventilation at home in Northern Ireland in 1994. Two patients have since died. An increasing number of patients are starting home ventilation, especially by nasal mask. Recognition of the needs of these patients and provision of care require further consideration.

Neuroendocrine changes in chronic cardiac failure.

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.

The effect of minimal exercise on fitness in elderly women after hip surgery.

To determine the effect of minimal exercise on functional fitness following total hip replacement in elderly women, 20 women (13 exercisers, 7 controls) who had undergone unilateral or bilateral hip replacement surgery for primary osteoarthritis were studied. An exercise treadmill test with respiratory gas and blood lactate analyses, and a field test of walking speed on a measured course, were administered before and after a twice weekly exercise programme of three months' duration. Markers of cardiorespiratory fitness, including peak achieved oxygen uptake (VO2) and ventilatory and lactate thresholds were measured. Maximum self-selected walking speed was also measured over a flat course. Peak VO2 increased in the exercise group when compared to baseline (P < 0.05) but did not differ from the control group. The exercise group significantly improved their walking speed by 10.1% compared with non-exercising controls (1.41 vs 1.20 m/sec, P < 0.05), and increased VO2 at lactate threshold. The improvements occurred despite the twice weekly exercise sessions being below the recommended frequency of exercise for improving cardiorespiratory fitness. Minimal exercise in elderly women after hip surgery can substantially improve submaximal exercise capacity, as well as walking speed.

Variable patterns of atrial natriuretic peptide secretion in man.

Peripheral circulating levels of atrial natriuretic peptide may exhibit short-term variation compatible with a pulsatile pattern of secretion. We obtained samples every 2 min for 90 min from the antecubital vein of 16 patients with chronic cardiac failure and 13 controls. Overall levels were higher in the patients (median and quartiles 230 (125,325) vs. 26 (16,48) ng l-1; P < 0.001). In both groups there was considerable variability, with 10 (2-12) peaks, 9 (7-15) troughs (both defined as > 2 SD from the mean) and 16 (13-18) pulses (defined by computer) during the sampling period in controls, and a similar number in patients. We then carried out simultaneous sampling in the pulmonary artery, femoral artery and peripheral vein in eight subjects with normal cardiac function and six patients with impaired function due to valvular heart disease. The pattern of variability was preserved in all three sites in both groups, suggesting intermittent secretion rather than variable breakdown of the peptide in the lung. No changes in right atrial pressure or heart rate were observed to coincide with the variations, but levels of the peptide in the pulmonary artery correlated with right atrial pressure in patients (r = 0.87; P < 0.05). The mechanism of such periodicity and its pathophysiological importance remain unknown.

Non-invasive measurement of cardiac output by a carbon dioxide rebreathing method at rest and during exercise.

Cardiac output was measured in 11 patients undergoing routine cardiac catheterization using a carbon dioxide rebreathing technique and compared with cardiac output measured by direct Fick and thermodilution. The carbon dioxide rebreathing technique gave consistently lower values for cardiac output than the other two methods (mean difference -0.73, 95% CI -0.95 to -0.51 l.min-1 with the direct Fick and -0.72, 95% CI -1.19 to -0.26 l.min-1 with thermodilution). The direct Fick and thermodilution methods gave similar results (mean difference -0.08, 95% CI -0.32 to 0.16 l.min-1). Cardiac output was also measured in 10 healthy subjects at rest and during two steady-state levels of exercise using the carbon dioxide rebreathing technique. Measurements were made in triplicate on 3 separate days. The technique gave reproducible results between replicates at rest (coefficient of variation 9.1%) and became more reproducible on exercise (coefficients of variation 5.6% and 5.4% respectively at each exercise level). There was a good correlation between cardiac output and oxygen consumption (r = 0.98). The carbon dioxide rebreathing technique is a feasible non-invasive way of measuring cardiac output. It tends to underestimate cardiac output at rest but is reproducible and becomes more so on exercise which is where it should be of most value.

Stress responses after treatment of hypercholesterolaemia with simvastatin.

In order to determine whether treatment of hyperlipidaemia with simvastatin impairs exercise stress responses and so may contribute to an excess of suicides and violent deaths, the effects of simvastatin 20 mg daily and placebo on exercise physiology were compared in 19 patients. After 6 weeks of treatment there was no evidence of reduced exercise capacity, or of reduced cortisol or catecholamine responses. It is concluded that treatment of hyperlipidaemia with an inhibitor of HMG-CoA reductase does not significantly modify stress responses, and so the explanation for a possible increase in non-cardiac mortality must be sought elsewhere.

Respiratory gas exchange and metabolic responses during exercise in McArdle's disease.

During normal progressive exercise, the gas exchange anaerobic threshold occurs when CO2 production (VCO2) and ventilation (VE) increase so as to depart from a linear relationship to O2 consumption (VO2). This is thought to represent a gas exchange response to metabolic acidosis due to lactate accumulation. Patients with McArdle's disease have previously been reported to exhibit a steepened ventilatory response relative to VCO2, despite an inability to produce lactate. However, the VCO2 response has not been studied. We therefore investigated the VCO2-VO2 and VE-VO2 relationships in seven McArdle's disease patients and seven control subjects during symptom-limited maximal treadmill exercise. Analysis of gas exchange showed that whereas all control subjects had an easily identifiable anaerobic threshold, four of the patients had none and the other three displayed an attenuated threshold. The occurrence of the threshold in one patient was associated with a small rise in lactate and in another patient with an abrupt rise in leg discomfort, suggesting a pain response. Ammonia and the purine metabolite hypoxanthine were elevated during exercise in all patients, suggesting that ammonia may be a product of adenosine monophosphate degradation. Free fatty acid levels were also elevated, and a shift toward utilization of lipid may contribute to abnormal gas exchange responses. It is concluded that lactic acidosis contributes to the gas exchange anaerobic threshold but that other factors, such as discomfort, may be involved in the excess Ve seen during heavy exercise.

Time course of serum amyloid A response in myocardial infarction.

Plasma concentrations of serum amyloid A (SAA), high density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and apolipoproteins (Apo) A-I and B were measured daily for 6 days in 10 patients following myocardial infarction (MI) and in 10 secular controls admitted to a coronary care unit. SAA concentrations peaked 3 days following MI (mean 47 mg/dl) and correlated with creatine kinase (CK) (r = 0.67, P less than 0.001). Non-HDL cholesterol and Apo B fell 15 and 18%, respectively, reached nadirs 3-4 days after MI and were inversely related to CK concentrations (P less than 0.01 for both). HDL cholesterol levels, in contrast, increased 15% and were significantly higher than baseline by day 3 when SAA concentrations were maximum. HDL cholesterol subsequently fell in parallel with SAA and had returned to baseline by day 6. Apo A-I declined throughout the 6 days of observation and was 13% lower than initial values on day 6 (P less than 0.05). The Apo A-I reduction was inversely related to both CK and SAA concentrations. There were no significant changes in any of the analytes in control subjects. We conclude that Apo A-I and possibly Apo B containing lipoproteins are negative acute phase reactants. HDL cholesterol is transiently elevated after MI despite decreasing Apo A-I levels and this may relate to incorporation of SAA into HDL particles.

Effect of atenolol or prazosin on maximal exercise performance in hypertensive joggers.

We evaluated maximal performance during cycle ergometry and treadmill exercise in 14 hypertensive male joggers treated with prazosin or atenolol in an unblinded, placebo-controlled, crossover design. Maximal oxygen uptake was measured during both exercise modalities; cardiac output was measured only during cycle ergometry using the acetylene rebreathing technique. Both drugs reduced resting systolic and diastolic blood pressures. Prazosin reduced total peripheral resistance during submaximal exercise but had little effect on maximal cycle and treadmill performance. Atenolol, in contrast, reduced treadmill duration, maximal oxygen uptake, and heart rate compared with placebo. Atenolol also increased stroke volume and the arterial venous oxygen difference and reduced cardiac output during cycle exercise. Both drugs produced similar reductions in exercise diastolic pressure, but exercise systolic pressure was lower only during atenolol treatment. Prazosin was better tolerated by the subjects and was preferred by 10 of the men. We conclude that both drugs effectively reduced resting blood pressure, but that atenolol decreased exercise cardiac output and may impede exercise performance in physically active hypertensive subjects.