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1. Insomnia is an even more frequent complaint in elderly patients with Parkinson's disease than might be expected from the effect of age alone on sleep. 2. A double-blind, placebo-controlled trial in eleven patients with Parkinson's disease of mean (s.d.) age 80(5) years, showed that nocturnal dosing with levodopa produced a clinically significant improvement in sleep both as assessed subjectively and by measurement of number of spontaneous moves in bed. 3. Despite the long interval between tablet administration and morning assessment, walking time was faster on mornings following active treatment. [ABSTRACT FROM AUTHOR]

A double-blind, placebo-controlled, cross-over trial of quinine in leg cramps occurring at rest was conducted in 22 elderly cramp sufferers. Despite demonstration of impaired quinine elimination in the elderly, prescription of the traditional dose of 300 mg quinine bisulphate at night failed to produce a significant (P = 0.1) reduction in the number or severity of cramps. There was a significant relationship between serum quinine concentration and attenuation of cramps. However, the simple expedient of increasing the nightly dose of quinine may carry the concomitant risk of cinchonism. [ABSTRACT FROM AUTHOR]

The accuracy of routine information on the response of a patient to rehabilitation was questioned. At the multidisciplinary ward round there may be on the one hand an inhibitory effect on the patient's performance due to the presence of a large team, but on the other reluctance of nurses and therapists to concede that all their efforts may only have maintained status quo. We present a randomised, controlled, crossover study of the effect of the ward round on a test of the ability to stand, walk a fixed distance, turn and sit down. Surprisingly, performance was not inhibited by the round: the 20 patients studied performed the test with equal skill, but greater speed, on the round than in a more private context. Cognitive function had a greater influence on the amount of help needed in standing and sitting safely, than on ability to walk and turn independently. [ABSTRACT FROM PUBLISHER]

Background: A high level of comorbidity at dialysis initiation is associated with an increased risk of death. However, contemporary assessments of the validity and prognostic value of comorbidity indices are lacking., Objectives: To assess the validity of two comorbidity indices and to determine if a high degree of comorbidity is associated with mortality among dialysis patients., Design: Cohort study., Setting: QEII Health Sciences Centre (Halifax, Nova Scotia, Canada)., Patients: Incident, chronic dialysis patients between 01 Jan 2006 and 01 Jul 2013., Exposure: The Charlson Comorbidity Index (CCI) and End-Stage Renal Disease Comorbidity Index (ESRD-CI) were used to classify individual comorbid conditions into an overall score. Comorbidities were classified using patient charts and electronic records., Outcome: All-cause mortality. Confounders: Patient demographics, dialysis access, cause of ESRD and baseline laboratory data., Methods: Regression coefficients were estimated on the CCI and ESRD-CI. Discrimination for death was assessed using Harrell's c-index. Adjusted Cox proportional hazard models were used to calculate relative hazards and 95 % confidence intervals for each category of the CCI and ESRD-CI., Results: The cohort consisted of 771 ESRD patients from 01 Jan 2006 to 01 Jul 2013. Most were male (62 %) and Caucasian (91 %). The cohort had a high proportion of diabetes (48 %), history of previous myocardial infarction (31 %) and heart failure (22 %). Regression coefficients on the CCI and ESRD-CI were 0.55 and 0.52, respectively. The c-index, for the prediction of death, was 0.61 for the CCI and 0.63 for the ESRD-CI. ESRD-CI scores of 4, 5 and ≥6 were associated with a similar mortality risk (adjusted relative hazard of 1.95, 1.89 and 1.99, respectively). There was a small increased mortality risk for CCI scores of 4, 5 and ≥6 (adjusted relative hazard of 1.86, 2.38 and 2.71, respectively)., Limitations: Classification of comorbidities for each patient was determined by clinical impression., Conclusions: The CCI and ESRD-CI have a limited ability to discriminate mortality risk for incident dialysis patients. Acknowledging the frequency with which they are used, this study emphasizes the need to re-examine the usefulness of previously derived comorbidity indices in contemporary dialysis cohorts.

Erythrokinetic studies were performed in subjects on continuous ambulatory peritoneal dialysis, during a trial examining the effectiveness of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) in correcting the anaemia associated with end stage renal disease. 15 subjects (mean haemoglobin concentration 6.9 g/dl, SD 1.1) entered the study, and during treatment 9 were restudied at a haemoglobin concentration of 11-11.5 g/dl and six underwent a third study at haemoglobin 13-13.5 g/dl. By adjusting the dose of r-HuEPO, a stepwise increase in haemoglobin concentration was achieved, and this was accompanied by increases in total red cell volume and erythron transferrin uptake. Plasma volume decreased as red cell volume increased, leaving total blood volume essentially unchanged. Red cell survival, modestly reduced before treatment (mean 64, range 44-96 d, n = 6) tended to increase during treatment and when subjects were retested at a haemoglobin concentration of 13-13.5 g/dl (after 38-62 weeks treatment), the mean increase in red cell survival was 20 d (95% confidence interval 1-39 d). Thus subcutaneous r-HuEPO is effective in correcting the anaemia of end stage renal disease when administered thrice weekly to subjects on continuous ambulatory peritoneal dialysis. It produces an increase in haemoglobin concentration primarily by expanding the erythron, and may have a secondary effect, seen after several months of treatment, of increasing red cell survival.

We have previously shown the depletion of cutaneous calcitonin gene-related peptide (CGRP)- and substance P-containing nerves in human leprosy. The aims of this study were to investigate the temporal effects of leprosy on nerves in skin and spinal cord. Tissues were taken from nude mice, 6 and 12 months after inoculation of Mycobacterium leprae into the hind footpads, and from age-matched controls. Sections were immunostained with antisera to substance P or CGRP. After 6 months of infection, substance P- and CGRP-immunoreactive nerves were reduced in skin from all body areas; by 12 months, the reduction was substantially greater. In the spinal cord, sensory fibres immunoreactive for substance P had decreased compared with controls at 6 and 12 months [by 60 per cent (0.022 mm2) and 80 per cent (0.048 mm2), respectively, P less than 0.001], as with CGRP [30 per cent (0.018 mm2) (P less than 0.02) and 40 per cent (0.028 mm2) (P less than 0.01), respectively]. CGRP immunoreactivity was completely absent in motor neurones after 12 months of infection. Loss of CGRP- and substance P-immunoreactive fibres in skin and spinal cord, and CGRP in motor neurones is in accord with impaired pain sensation and muscle weakness in leprosy.

Recent trends in family planning demonstrate an increasing interest in natural methods of birth regulation. In their present form, however, these methods are highly subjective and individualistic. A further trend in fertility programmes has been a very rapid development of technological methods to detect fertility in the female cycle, some of which could possibly benefit natural family planning users. One such technique--that of changing volumes of cervico-vaginal fluid (CVF), which is a mixture of cervical mucus and vaginal transudate--has been tested in a pilot study to ascertain its reliability to demarcate the fertile phase of the cycle. Results show that in all cycles tested, it is possible using the Rovumeter aspirator to detect the beginning of the fertile phase by rapidly increasing volumes of CVF; this volume reaches a peak approximately 1 day before ovulation detected by ultrasound and demonstrates an abrupt fall after ovulation and the onset of the infertile phase. From the results of this pilot study, we believe that, by the use of suitable algorithms and larger studies, it should be possible to develop a CVF volume method which could be offered as an objective alternative method for users of natural family planning and programmes.

1. Covert changes in energy intake were made by giving preloads of disguised energy density three times daily to 14 obese and 6 lean subjects. 2. The preloads contained 2.51 MJ (600 kcal)/d on days 2 and 3 and either 3.77 MJ (900 kcal)/d or 1.26 MJ (300 kcal/d) on days 4 and 5 and 1.26 MJ (300 kcal)/d or 3.77 MJ (900 kcal)/d on days 6 and 7. The order of testing was alternated for each subject. 3. Subsequent energy intake at each meal (lunch, dinner and breakfast) was measured with an automated food-dispensing machine. 4. Overall the obese subjects ate significantly less from the machine, 3.28 +/- 1.89 MJ (785 +/- 452 kcal)/d, than the lean subjects, 6.03 +/- 1.26 MJ (1442 +/- 300 kcal)/d. 5. Both groups of subjects adjusted their energy intake in the right direction to counterbalance the effect of the preloads but the lean subjects changed their intake by an average of 0.74 MJ (176 kcal)/d compared with the obese subjects who changed their intake by an average of 0.29 MJ (70 kcal)/d. 6. Although the lean subjects were better at adjusting their energy intake than the obese subjects, regulation was still imprecise relative to the 2.51 MJ (600 kcal)/d difference in energy intake that was imposed. 7. There were no significant differences in hunger or appetite between subjects or test situations.

The effects were studied of bromocriptine, 10 mg daily for 1 year, on luteinizing hormone (LH) pulse characteristics in patients with classical polycystic ovarian syndrome (PCOS). All patients were hirsute, had been oligomenorrhoeic since menarche, had LH: FSH ratios of greater than 3:1, and either elevated serum testosterone (T) or dehydroepiandrosterone sulphate (DHAS) concentrations. In 10 subjects who completed the study menstrual frequency increased from an average of 3.6 to 8 per year but few of the cycles were ovulatory. Mean (SE) serum testosterone fell from 4.4 (0.5) nmol/l pretreatment to 2.8 (0.3) nmol/l (P less than 0.01) and DHAS from 7.9 (1.1) mumol/l to 5.4 (1.1) mumol/l (P less than 0.05). Serum delta 4 androstenedione and oestradiol did not change with bromocriptine treatment. Mean serum LH fell from 17.4 (2.4) IU/l to 11.2 (1.8) IU/l (P less than 0.03) after 12 months of bromocriptine. No pattern of LH pulsatility specific to PCOS was detected during 10 min sampling for an 8 h period prior to dopamine agonist treatment. LH interpeak interval (58 (5.2) min) and peak amplitude (156 (7.2%) of mean nadir) in untreated PCOS were similar to that of the mid-follicular stage of ovulatory cycles, and bromocriptine for 1 year did not alter these variables. We conclude that while bromocriptine reduces serum androgen levels and increases menstrual frequency it has no effect centrally to modify hypothalamic GnRH secretion. The reduction in LH levels by bromocriptine may be the result of diminished gonadotroph sensitivity to GnRH or reduced pituitary stores of LH available for release. Despite the return towards normal of various hormonal characteristics of PCOS, bromocriptine has little place in the management of this condition.

Characteristic changes in cervico-vaginal fluid (CVF) volume which occur during the menstrual cycle might be used to detect the fertile phase. Twenty-five normal women were asked to withdraw CVF and measure its volume at home using a small, disposable, graduated vaginal aspirator. In 16 cycles day 0 (ovulation) was defined as the day of maximum follicular diameter according to serial ultrasound examination. A rise in CVF volume occurred between day -9 and -2 and a peak between day -4 and 0. In these sixteen, and in a further 72 cycles, day 0 (time of maximum fertility) was taken as the day of peak cervical mucus secretion. CVF volume rose, on the average, on day -6.2 (range -17 to -2) and peaked on day -0.8 (range -5 to +2). In two cycles, no rise and peak were identified. Changes in CVF volume were easy to recognise and could be useful to couples wishing to achieve pregnancy.

The risks of conception, due to sexual intercourse at various times before and after the periovulatory rise in the woman's basal body temperature, are evaluated. In general, the risk is small nine or more days before, and two or more days after, the first day of elevated temperature. The model for the conception probabilities assumes exponential survival distributions for sperm and egg and a specific probability that an egg is viable. Median survival times for sperm and egg are estimated at 1.0 days and 0.5 days, respectively. The Pearl indices for intercourse on the third and fourth day of elevated temperatures are 4.7 and 1.2 pregnancies per 100 woman-years, respectively.

An increased prevalence of classical migraine was found in 30 female patients with systemic lupus erythematosus (SLE) compared with an age and sex-matched control group by means of a detailed questionnaire. No significant difference were found between the patients and controls, who had classical and common migraine or visual auras without headache, with regard to a family history of migraine, the age of onset of the migraine, Raynaud's phenomenon, or use of oral contraceptives. Increased activity of the lupus was not generally associated with an increase in migraine attacks. It is suggested that migrainous phenomena may be a feature of SLE.

We report our efforts to make a rehabilitation hospital work. The simple intervention of introducing a patient record system, in which problems, management, achievements and discharge plans were clearly documented, doubled the number of patients who returned home over an eight-month period. This resulted in greater availability of acute geriatric beds at the District General Hospital (DGH), where two thirds of the elderly medical inpatients occupy beds on other units, and in an improvement in morale of patients and staff. Greater co-operation between geriatric and medical teams in selecting those patients who would benefit from continuing rehabilitation is required. The advantages of accommodating such patients separately from patients with a poor prognosis and those requiring long-term care are discussed.

A method is described to measure specific airway conductance in mechanically ventilated patients. Airflow resistance (R) was measured continuously using the forced airflow oscillation method and plotted against volume during slow deflation of the lungs. The previously reported hyperbolic configuration of the resistance-volume curve was confirmed, but a nonlinear conductance-volume relationship was found that could be explained by a constant resistance (A) in series with the volume-dependent resistance of the lower airways. A computer-aided analysis of the resistance-volume curve determined the parameters of the hyperbola that best fitted the data and from this the volume-dependent conductance, Glaw = 1/(R - A), was calculated. This method consistently provided a very good fit to the data and resulted in a linear lower airway conductance-volume relationship in anesthetized and in awake subjects. The slope of this linear relationship (Glaw) was therefore independent of volume, and specific lower airway conductance was used as an index of bronchomotor tone. In awake subjects given bronchoconstrictor and bronchodilator aerosols, good correlation was shown between changes in specific conductance measured by this technique and by the standard plethysmographic method.

The body and organ weights of twenty-four intra-uterine growth retarded neonatal piglets were compared with those of seventeen normal littermate controls. There was a highly significant relation between organ weight and body weight for the following organs which all showed a reduction as body weight decreased: liver, kidneys, heart, lungs, spleen and pancreas. In contrast, brain, pituitary, adrenal and thyroid weights did not change significantly with body weight implying preferential protection from the pathological effects of intra-uterine growth retardation. Our results also show that the pattern of natural growth retardation in the piglet is similar to that reported in man, and to that of the experimental growth retardation produced in a number of animal species.

The choice of site for body temperature measurement and consistency in positioning the thermometer are important in achieving reliable and interpretable basal body temperature graphs in women. The distribution of temperatures in vagina (TV) and rectum (TR) were measured in women upon awakening. There were no significant differences between TR and TV at insertion depths of 5, 9, or 13 cm. Estimation of deep body temperature was not improved by inserting a thermojunction beyond 5 cm in vagina or rectum. Rates of change in TV following ingestion of a 300-ml iced drink were significantly greater than rates of change in TR.

The statistical distribution of birthweights in 64 litters of pigs, 48 litters of dogs, 59 litters of rabbits, 130 litters of rats and 46 litters of mice was examined. Birthweight followed a Gaussian or normal distribution in about two-thirds of the litters inspected, as judged visually using a normal probability plot, and by the W-test statistic. In the remainder, a single outlying observation in an otherwise normal sample was detected by Dixon's test, and/or a separate sub-population of low birthweight animals could be identified by fitting two normal populations to the observed samples. In the non-Gaussian litters, the average proportion of affected members was 40% of the litter. These results suggest that growth-retarded neonates should not be regarded simply as the tail-end of a normal distribution.

We have introduced enalapril, in doses equal to or less than the 2.5 mg currently recommended, as an adjuvant to digoxin and diuretics in 17 patients of mean (SD) age 83 (5) years with severe heart failure. Only eleven patients tolerated its introduction. Unlike those reported in younger patients, all but one of the adverse drug reactions occurred 8 h or more after the first dose. Aged patients started on ACE inhibitors should be observed in hospital until stabilized on a maintenance dose. Three patients had an adverse reaction which differed in nature from those previously reported: acute confusional state, ataxia and mesenteric ischaemia. Ten patients were discharged on 5 mg or 10 mg maintenance doses of enalapril. In nine of them improvement on triple therapy was sustained for a minimum of three months. ACE inhibition was lost in the other patient when her compliance with enalapril therapy fell to around 75%: monitoring compliance is essential when ACE inhibitors are used in low dosages. Enalapril was withdrawn during follow up in three patients because of symptoms of mesenteric ischaemia and in four because of dramatic deterioration of renal function. One of the latter was found subsequently to have severe bilateral atheromatous renal artery stenosis. When isosorbide dinitrate was substituted for enalapril, symptoms of mesenteric ischaemia resolved and renal function returned to baseline. Continuing surveillance for adverse effects is essential in patients of this age group with severe heart failure, and the risk of occult renal artery stenosis requires regular biochemical screening during follow up.(ABSTRACT TRUNCATED AT 250 WORDS)

Ovarian volumes have been determined by pelvic ultrasonography in 2246 apparently healthy postmenopausal women of whom 2221 were included in the statistical analysis. Factors associated with gonadal size have been identified, and reference ranges for derived indices have been determined for use (in association with criteria for abnormal morphology) in a screening programme for ovarian carcinoma. The right ovary was present in 98.9% of subjects and the left in 99.1%. The mean (SD; range) of right and left ovarian volumes were 3.58 (1.40; 1.00-14.01) and 3.57 (1.37; 0.88-10.9) ml respectively. Significant predictors of ovarian volume were years since the menopause, weight, parity, age at menopause, a history of hormone replacement therapy, and previously diagnosed breast cancer. Abnormal ovarian volumes were assessed from a score equal to the (observed mean log volume (MLV) minus the predicted MLV)/0.327. A simplified nomogram has been prepared for routine clinical use. The relative abnormality of one ovary was assessed from a ratio score equal to loge (larger ovarian volume/smaller ovarian volume)/0.211 compared with the 99th centile for the Gaussian distribution.

The effect of cigarette smoke exposure on pulmonary epithelial permeability was studied in 45 smokers and 22 non-smokers. An index of cigarette smoke exposure was obtained from the carboxyhaemoglobin concentration (HbCO%). Pulmonary epithelial permeability was proportional to the half-time clearance rate of technetium-99m-labelled diethylene triamine pentacetate (99mTc DTPA) from lung to blood (T1/2LB). The relationship between T1/2LB and HbCO% was hyperbolic in form and the data could be fitted to the quadratic formula (formula; see text) where the parameters a0, a1, and a2 represent respectively the asymptotic T1/2LB value at large carboxyhaemoglobin values and the slope and shape of the curve. The values of these parameters were a0 4.4 (2.6), a1 = 77.8 (15.5), and a2 -25.5 (9.7) (SE). This is the first demonstration of a dose-response relationship between carboxyhaemoglobin and an increased permeability of the lungs in man and provides a technique for identifying the roles of carbon monoxide and other cigarette smoke constituents in causing increased pulmonary epithelial permeability.

Two trials of an electronic thermometer (Rite Time), designed to record and interpret basal body temperature (BBT) patterns in normal ovulating women, are described. A total of 140 menstrual cycles from 34 women, who used the thermal or symptothermal methods of natural family planning, were studied. Rite Time gave a signal for the start of the infertile period in 117 cycles, of which 114 (97%) appeared to have occurred at appropriate times. Further studies using hormonal and ultrasound reference points for ovulation were carried out in 21 cycles. Rite Time generally produced BBT patterns of quality acceptable for interpretation of the periovulatory BBT shift. About one-half of the volunteers said that they would be willing to replace their conventional charting methods with Rite Time.

It is customary to regard datasets as homogeneous with respect to the order of collection of the measurements. Examples are given in which this assumption is breached. Hidden time trends have implications for the design of studies, their analysis and interpretation. It is suggested that, if the order of observations is known, a plot by time should be performed, perhaps using a cusum.

In subjects capable of normal everyday activity, exercise has been shown to lower the serum digoxin concentration by increasing uptake into skeletal muscle. A randomized cross-over study of the effect on the serum digoxin concentration of treatments consisting of rest for, or exercise during, 30 min was carried out in 20 elderly patients undergoing rehabilitation. In one patient exercise was associated with a marked (40%) reduction in the serum digoxin concentration. In the remainder there was a very small, but statistically significant, fall in concentration in the exercise as compared with the rest period. Unexpectedly low serum digoxin concentrations in in-patients of geriatric units, may occasionally be an artefact due to temporary redistribution of digoxin.

The upward shift in basal body temperature (BBT) observed in women of child-bearing age is often used as an indicator that ovulation has occurred and that a period of infertility has begun. In natural family planning programmes it is important to detect the BBT shift reliably and with a minimum of user uncertainty, against a background of physiologically induced temperature variations. The cumulative sum (CUSUM) test is adapted to the problem of detecting BBT shift and applied to 137 BBT charts obtained from 21 women using natural family planning. Results show successful detection of the shift in all cases. Shifts occurred at gynaecologically appropriate times in the menstrual cycle.

Disturbances of glucose homeostasis are a common clinical problem in low birth weight human infants. Previous studies have demonstrated that the intra-uterine growth-retarded piglet is a suitable animal model for the study of such problems. The effects of an intravenous glucose infusion on glucose homeostasis have been studied in normal and intrauterine growth-retarded neonatal piglets using a non-steady state tracer technique. Despite suppression of hepatic glucose output, hyperglycaemia (plasma glucose greater than 10.0 mmol/l) developed in the majority of animals. The hyperglycaemia resulted from a failure to increase glucose utilisation adequately in response to the glucose infusion. Growth-retarded animals had an impaired ability to increase their rate of glucose utilisation, although, in common with the normally grown animals, they demonstrated a graded response to different infusion rates of glucose.

Axillary (Tax), vaginal (Tv), and sublingual (Tsl) temperatures were measured in 12 women between 0600 and 0730 h prior to their arising from bed. Isothermal maps made of closed axilla 30 min after thermojunctions had been inserted showed a distribution of several temperatures, the lowest Tv-Tax isotherm occupying approximately 40% of the anteroposterior distance. Tax at this point was 0.1 to 0.5 degrees C less than Tv and -0.03 to 0.26 degrees C less than Tsl. The time course of Tax rise varied considerably among subjects, with the slowest still rising 30 min after insertion, whereas the fastest was almost steady after 3 min. The width of the 0.5 degrees C isotherm along the fold averaged 5.8 cm and occupied about 60% of the axillary width. A significant negative correlation was noted between width of the 0.5 degrees C isotherm and Tv-Tax. Effects on the time course of 1) preexposure to air of the axilla for 5 min and 2) different initial thermometer temperatures (10 and 30 degrees C) were studied in 6 women. Analysis of variance showed a significantly higher value of Tax (10 min)-Tax (3 min), i.e., a slower time course with the cooler thermometer. The effects of exposure of the axilla were much more pronounced.

Twelve obese and four lean subjects increased their energy expenditure by 100 kcal/day by cycling on a bicycle ergometer. The order of testing was alternated so that half of the subjects did exercise on the first three days and the remainder on the last three days. Ad lib energy intake was measured over six days using an automated food dispensing machine. The obese subjects ate 1196 +/- 517 kcal/day and the lean subjects ate 1162 +/- 301 kcal/day and showed no overall significant difference in energy intake or eating patterns. However, these obese subjects ate 18 kcal/day less and the lean subjects ate 155 kcal/day more during the exercise period. The difference in response confirms the hypothesis that lean subjects tend to regulate energy intake more accurately than obese subjects. Exercise increased the frequency of eating and drinking and decreased hunger and appetite for all subjects. There was a significantly greater decrease in hunger and appetite with exercise for the obese subjects. However, as there was no accompanying decrease in energy intake and some subjects had difficulty in completing the exercise, the value of small increases in voluntary exercise in the treatment of obesity is questioned.

A combined series of 101 twin pregnancies for whom routine hospital rest during the last trimester was replaced by intensified antenatal care in a special twins clinic was studied. Perinatal mortality and morbidity was similar to that found in a comparison group of 137 twin pregnancies under the care of consultants and not referred to the twins clinic. Routine cervical assessments and uterine activity measurements were unhelpful in predicting premature delivery. Urinary oestrogens and ultrasonic measurements of fetal biparietal diameter were of little or no value in predicting weight for gestational age but the ultrasonic measurement of abdominal circumference provided limited information on fetal growth. The contribution of a placebo effect to the results of patients receiving more personalised care cannot be discounted.

Studies were directed to characterization of the anaemia of renal failure of 11 patients on haemodialysis and determination of the way in which it is corrected by human erythropoietin derived from recombinant DNA expressed in Chinese hamster ovary cells (r-HuEPO) administered intravenously. Erythrokinetics before treatment showed that total red cell mass was below normal and that both erythron transferrin uptake and red cell survival were modestly reduced; treatment increased both total red cell mass and erythron transferrin uptake but did not change red cell survival in previously untransfused patients. When BFU-e and CFU-e from patient bone marrow were cultured in autologous serum we found no evidence for inhibitors of erythroid progenitor maturation in patient serum compared with normal. Erythroid expansion in response to r-HuEPO was not limited by the availability of iron, iron requirements for new red cell formation being met from stores (if adequate) or from oral iron supplements. In pharmacokinetic studies the plasma clearance of r-HuEPO could be expressed by a three-parameter exponential curve with T1/2 range of 2.3 to 7.3 h. T1/2 after the first dose of r-HuEPO was not significantly different from that after 14 to 54 weeks treatment when the erythron had expanded to a new steady state. Erythron transferrin uptake before treatment was related to endogenous production of erythropoietin estimated from the plasma clearance of the first dose of r-HuEPO administered intravenously. This finding suggested that the availability of erythropoietin was the main factor limiting expansion of the erythron. This conclusion was supported by the continuity of the relationship during the response to treatment.

It has previously been shown that the incidence of pressure sores is related inversely to the amount of movement made during the night. The present study of 30 in-patients of geriatric units suggests that the measurement of mean lateral displacement of the centre of gravity may better characterize those at risk than the total amount of movement. The mean displacement was reduced in Parkinson's disease and in dementia. The prevalence of pressure sores was markedly increased where Parkinson's disease and dementia coexisted.

Variation in indices used to characterize the maximum frequency outline of waveforms obtained from the uteroplacental and fetal circulations by duplex Doppler ultrasound was studied between observers, over a 24-h period and before and after a meal. No significant differences were found. Reference ranges were derived for three indices, the A/B ratio, the resistance index and the pulsatility index, for waveforms from the fetal descending aorta, umbilical artery, and the placental and maternal sides of the uteroplacental circulation. Indices from waveforms from the uteroplacental circulation demonstrated a fall from 16 to 24 weeks gestation with no change thereafter. The umbilical artery indices demonstrated a continuing fall with increasing gestation but the A/B ratio and resistance index from the fetal descending aorta did not change with gestation. The pulsatility index from the aorta demonstrated a gentle rise.

The association between growth failure and serum IGF-I levels has been assessed in 32 children with Juvenile Chronic Arthritis (JCA) aged 5-16 years. A spectrum from normal growth to severe growth failure was included in the study population. Height Standard Deviation Score (SDS) ranged from -5.79 to +1.41 (median -1.22) and Height Velocity from 0.72-8.85 cm/yr (median 3.81 cm/yr). Known risk factors for growth failure (disease activity, steroid treatment, vertebral collapse) were confirmed. Additionally, height SDS was significantly correlated with serum IGF-I levels (rs = 0.49; p = 0.008); height velocity was significantly, although less strongly correlated with IGF-I levels (rs = 0.41; p = 0.027). There was no correlation between IGF-I levels and either of two indices of nutritional status, or between IGF-I levels and current steroid dose. The correlation of serum IGF-I with parameters of growth failure may be due to either insufficient secretion of growth hormone (GH) or defective GH action. In view of the recently increased availability of GH for treatment of short stature, it is important to distinguish between these two mechanisms.

Percutaneous needle biopsy of the vastus lateralis muscle was performed in a patient with a generalised accumulation of neutral triglyceride. Light microscopy revealed a type I fibre predominance, with neutral lipid droplets in both fibre types but larger and with a greater quantity of lipid per unit area in the type I fibre population. Within type I fibres there were at least two populations based on the lipid droplet size and total accumulated lipid per cell. These observations are discussed, and it is concluded that they support the hypothesis of metabolic differences within the type I fibre population with respect to the use of free fatty acids as a fuel source.

Some physicians regard patients of Geriatric Units as a homogeneous population with respect to digoxin dosage requirements. Others advocate the use of pharmacokinetic models in prescribing digoxin for the elderly. Sixty in-patients of Geriatric Units were studied and the results compared with those previously obtained from 129 patients of other adult Units; all were receiving maintenance digoxin. For each patient the dose required to achieve a mean steady-state serum digoxin concentration of 1.6 nmol X l-1, the standardized dose, was calculated, assuming proportionality between the dose given and the concentration achieved. A mean of four estimates of standardized dose for each individual was used in the analysis. Threefold ranges of standardized dose covered the requirements of approximately 85% of patients both of Geriatric Units (62.5 to 187.5 micrograms per day) and of other adult Units (125 to 375 micrograms per day). The variables, serum creatinine concentration, sex, age, and body weight were of relatively little value in predicting the standardized dose for the patients in Geriatric Units. There was a sub-group of these in-patients for whom the standardized dose was extremely large.

During one menstrual cycle, each of eleven volunteer student nurses at Northwick Park Hospital recorded their vaginal temperature on waking and noted the clock time. Waking times varied between 0530 hours and 1100 hours. Regression analysis revealed significant linear relation between temperature and time of waking, with a slope of 0.086 degrees C/hour (SE, 0.009 degrees C/hr) in the postmenstrual (hypothermal) phase. A rounded adjustment factor of 0.1 degrees C/hour is shown to improve the interpretability of basal body temperature (BBT) charts in a group of seven women regularly using natural family planning methods. The adjustment factor is simple to apply and only involves counting one square on a BBT chart for each hour that the waking time differs from normal.

Detailed profiles of bile acids in faeces were evaluated as a diagnostic test for colorectal cancer in rats. Twenty-seven bile acid peaks were measured using improved methods of extraction and separation followed by the sensitive and specific techniques of capillary column gas liquid chromatography and mass spectrometry. Colorectal cancer was induced in experimental animals (female Sprague-Dawley rats, n = 20) by subcutaneous injection of dimethylhydrazine (DMH) and faecal unconjugated bile acids compared with those in the control group (n = 20). The amount of total faecal unconjugated bile acids was lower in the animals administered DMH (255 mg/day vs 334 mg/day: (P = 0.04), and the excretion of seven individual bile acids was reduced when compared with those in the control group (P less than 0.01). In order to use the faecal bile acid profiles as a diagnostic test, linear discriminant analysis was performed. A discriminant score was derived which was applied to each profile, to determine to which group (control or DMH) each animal belonged retrospectively. All analyses were performed blind, and 90% of the animals were correctly assigned. In man, as in rats, the bile acid profile of faces is equally complex and the bile acid profile may be useful as a diagnostic test.

The ability of frequent feeding of bovine milk diets to prevent the colonization of the small intestines of newborn guinea-pigs with orally inoculated Escherichia coli was tested. At 3--4 days small intestinal samples from suckled controls were frequently sterile or were colonized with only very low numbers of Esch. coli. No bovine milk diet exhibited a significant "protective" effect but the diets could, however, be ranged in order of effectiveness in decreasing colonization by Esch. coli. Raw, fresh bovine milk was best, followed by milk pasteurized at 56 degrees or 63 degrees, then boiled milk; frozen milk was the worst. Because of this last finding, neither the bacteriostatic lactoferrin-dependent activity nor the lactoperoxidase could be correlated with the ability to decrease the colonization of the small intestines by Esch. coli.

Hepatic methionine synthase activity has been determined in rats continuously exposed (24 h day-1 and 7 day week-1) to concentrations of nitrous oxide ranging from 500 to 50 000 p.p.m. for periods ranging from 24 h to 28 days. The inactivation of this enzyme was dependent upon both time and concentration of nitrous oxide exposure, but there was no statistical evidence that exposure continuing beyond 48 h increased the effect. However, the dose-response curve for 24 h was significantly different from the curve for pooled data from exposures lasting 2-28 days. These latter data indicated no significant effect with 450 p.p.m. and an ED50 of 5400 p.p.m. Significant inhibition was detected at 1000 p.p.m. These results suggest that the limit of exposure of 25 p.p.m. recommended by the American National Institute of Occupational Safety & Health may be unduly restrictive.

Steady state glucose kinetics were measured in 19 premature and 16 full-term piglets. Bodyweight, plasma glucose concentration, total body glucose turnover rate, and glucose pool size were not significantly different between the two groups. This suggests that the premature piglet is capable of maintaining glucose homeostasis during the first 24 h of life. Although there appeared to be a correlation between glucose turnover and plasma glucose concentration, analysis of covariance showed that it was spurious, suggesting that glucose utilization proceeds independently of the glucose concentration in plasma. Glucose turnover rate in the premature piglet is closely comparable with that reported in the premature human infant. These findings encourage the use of the neonatal piglet as an animal model for the study of the problems of the neonatal human.

1. Radiocalcium absorption was measured in duplicate in 10 subjects by the double-isotope method, with calcium as the oral carrier (2.5 mmol). Analysis of variance gave 95% confidence limits for a single measurement of fractional absorption and maximum absorption rate in a given individual of +/- 16.5% of administered dose and +/- 18.2% of dose/h respectively. 2. The size of these within individual variations suggests that alterations in the rate of calcium absorption may contribute to the week-to-week stabilization of some other controlled variable, such as plasma concentration of calcium. 3. In six of the subjects, calcium absorption was also measured with calcium loads at concentrations of 0.5, 5.0 and 20 mmol. Significant falls in fractional absorption, maximum absorption rate and mean transfer rate occurred as the load increased, together with a rise in mean transit time. Although between-individual differences at a given load were considerable, given a single-test result with a known carrier load, it is possible to predict quite accurately the results which would be obtained if a different carrier load were to be given.

We studied 20 patients with chronic airflow obstruction, 10 patients without polycythaemia and 10 patients with compensatory polycythaemia having respectively mean red cell mass 24.7 (SD 4.2) and 47.8 (SD 7.5) ml/kg, mean daytime PaO2 7.6 and 6.9 kPa, mean FEV1 0.85 and 0.821. Groups were matched for severity of daytime arterial hypoxaemia but nocturnal arterial oxygen desaturation was more severe in the patients with polycythaemia than in those without. We also studied six additional patients with chronic airflow obstruction and polycythaemia and 19 normal controls. Estimates of serum immunoreactive erythropoietin (siEp) in those without polycythaemia were 19 m-i.u./ml (geometric mean) with 95% confidence range 11-35 m-i.u./ml and stable during 3 months. In those with polycythaemia they were similar and consistent in five and, in the other five, higher on at least one occasion. There was no significant difference between siEp in daytime (12.00 hours to 16.00 hours) and morning (07.00 hours) samples but geometric mean estimates of erythropoietin in paired daytime and morning samples were higher and more variable in patients with polycythaemia than in those without. The geometric mean estimate of siEp in all patients with chronic airflow obstruction and polycythaemia was greater than in normal subjects but, despite secondary polycythaemia, siEp could be in the range for normal subjects. In the patients with polycythaemia we were unable to predict the finding of normal or elevated siEp. Changes in siEp after erythrapheresis (10-26% reduction in packed cell volume) were observed in the 10 patients with polycythaemia and in one without. One month after erythrapheresis, packed cell volume remained below and siEp was above initial pretreatment levels, implying an erythropoietin secretory response and that the development of secondary polycythaemia had induced a fall in siEp.

Defined changes in the concentration of estrone glucuronide in daily samples of early morning urine have been used to locate the limits of the fertile period and the time of maximum conception probability during 118 cycles (106 menstrual, 12 conceptional) in 73 women. The peak day of urinary luteinizing hormone was used as an index of ovulation. Follicular growth was monitored daily by ultrasonography throughout 38 cycles, and the time of maximum follicular diameter was used as an alternative reference point to define the times of potential fertility according to the life spans of the gametes. With optimized algorithms and the best index of ovulation, the estrogen test delineated the limits of the fertile period in 89% of the tests (mean length, 10.8 days; range, 5 to 17 days) and the time of maximum conception probability in 82% of the cycles, with a mean time to the maximum follicular diameter of 0.42 days (range, -4 to +4 days).

In 429 placentae, measurements were made of weight, diameter, shape, eccentricity of the cord and weight and length of the cord, and the results were compared with Apgar score of the infant at birth and its standardized birth weight. There was no evidence that cord eccentricity, placental shape or "thickness", or the dimensions of the cord had any significant relation to the growth of the fetus or its condition at birth. The value of routine recording of crude measurements and qualitative assessments of the placenta in case notes is questioned.