Metabolic clearance of vasopressin and an analogue resistant to vasopressinase in human pregnancy.

The metabolic clearance rate (MCR) of arginine vasopressin (AVP) increases fourfold during human pregnancy. To explore whether circulating vasopressinase may play a role in this change, six women underwent a three-tier infusion clearance study, twice, in random order, to determine the MCRs of either AVP or 1-deamino-8-D-AVP (dDAVP, an analogue resistant to degradation by vasopressinase). Volunteers were tested in late pregnancy (LP), 24-48 h postdelivery (PD), and 5-6 (PP1) and 10-12 (PP2) wk postpartum, thus examining MCRs when vasopressinase levels were high, before and after removal of the placenta (LP and PD), and when plasma enzyme activity was becoming (PP1) and became (PP2) undetectable. Manipulation of infusate permitted comparison of MCRs at three plasma levels whose range was similar at each test period. PAVP and PdDAVP (2.2 and 10 pg/ml, respectively, during the initial infusion) increased to 8 and 31 pg/ml, stepwise increments that had no influence on respective MCRs (AVP: 3.4, 2.2, 0.77, and 0.67 l/min during LP, PD, PP1, and PP2 compared with 0.18, 0.21, 0.17, and 0.15 l/min for dDAVP). Comparison of similar and submaximal urinary osmolality revealed PdDAVP values three- to fourfold greater than PAVP. Von Willebrand factor (VWF) and factor VIIIc levels increased almost fourfold in response to dDAVP during pregnancy, but only doubled in the nonpregnant state; these differences did not reach significance. We conclude that although AVP disposal rates increase fourfold in pregnancy, those of dDAVP change little, suggesting a role of vasopressinase in the increased MCR of AVP in gestation (as well as in the genesis of certain polyuric disorders of pregnancy).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of humoral and volume factors on altered osmoregulation of normal human pregnancy.

These studies were designed to characterize mechanisms leading to decreased plasma osmolality (Posmol) and osmotic thresholds (T) for arginine vasopressin (AVP) release (TAVP) and thirst (Tthirst) in pregnancy. First, the influence of the pregnancy hormone, human chorionic gonadotrophin (hCG), was tested in six nonpregnant women who received hypertonic saline during the luteal phase of the menstrual cycle on two occasions (randomly allocated), once after 15,000 IU of hCG when Posmol, TAVP, and Tthirst decreased 6, 5, and 5 mosmol/kgH2O, respectively (P less than 0.01). In contrast, hCG pretreatment of males (n = 6) had no significant effect. Next, the role of decreased effective vascular volume (underfilling) was evaluated in seven women undergoing hypertonic saline infusion in the presence and absence of head-out water immersion (randomly allocated) during early and late pregnancy and postpartum. Posmol, TAVP, and Tthirst were not influenced by immersion and remained 10 mosmol/kgH2O lower in pregnancy (P less than 0.01). Central redistribution of intravascular volume consistently lowered hematocrit and rate of rise of PAVP per unit increment in Posmol (P less than 0.01). Although these data failed to support the hypothesis that the osmoregulatory change in human pregnancy is attributable to decrements in effective central volume (underfill), they do suggest that hCG may play a role.

A prospective study of haemostatic tests at 28 weeks gestation as predictors of pre-eclampsia and growth retardation.

A panel of haemostatic tests was performed on 400 primiparous women at 28 weeks to test whether one or more could predict the development of pregnancy complications. Fifteen women subsequently developed pre-eclampsia with significant proteinuria and 13 delivered growth retarded infants. There were no significant differences between mothers in the pre-eclampsia group and 22 randomly selected controls. A stepwise logistic discriminant analysis of the data did not produce a significant model. In the growth retarded group only beta thromboglobulin levels were significantly lower than in the controls (p less than 0.05), although in the logistic discriminant analysis the inclusion of both beta thromboglobulin and fibrin degradation products led to a borderline significant improvement in fit of the model. We conclude that the haemostatic variables studied are not significantly changed at 28 weeks nor clinically useful predictors of either pre-eclampsia or fetal growth retardation.

Suppression of AVP release by drinking despite hypertonicity during and after gestation.

Water drinking suppresses arginine vasopressin (AVP) release before changes in tonicity or volume. To further characterize this oropharyngeal neuroendocrine reflex, we took advantage of ongoing studies of osmoregulation in pregnancy as follows: five women studied serially in early (8 +/- 1 wk, mean +/- SD) and late (32 +/- 3 wk) pregnancy and 8-10 wk postpartum were slowly infused with hypertonic saline for 150 min while drinking water to satiety (drinking started at 120 min). Plasma osmolality (Posmol) at 120 min was increased (277 +/- 3 to 291 +/- 2, 280 +/- 6 to 295 +/- 5, and 287 +/- 1 to 307 +/- 1 mosmol/kg in 1st and 3rd trimesters and postpartum; P less than 0.01), accompanied by increments in plasma AVP (PAVP) up to 7 +/- 5, 5 +/- 3, and 8 +/- 3 pg/ml, respectively (P less than 0.01). PAVP declined as soon as drinking began (P less than 0.01 at 5 min), despite maintenance of peak osmolality for another 30 min. Similar events were recorded in three males. Calculation of normal disappearance rates (t1/2) demonstrated that AVP levels decreased more rapidly (P less than 0.01) in the 3rd trimester compared with early pregnancy and postpartum. Two other subjects became nauseated during their 1st trimester and postpartum tests which permitted comparison of nausea and drinking which evoke central reflexes with opposing action on AVP release. PAVP, which had increased markedly (range 17-42 pg/ml; P less than 0.01), was not abolished by drinking. These data demonstrate the potency of the drinking reflex on osmoregulation in pregnant and nonpregnant subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial evaluation of vasopressin release and thirst in human pregnancy. Role of human chorionic gonadotrophin in the osmoregulatory changes of gestation.

Serial studies were designed to characterized changes in osmoregulation throughout gestation. Eight women underwent a 2-h infusion of hypertonic saline before conception, during gestational weeks 5-8, 10-12, and 28-33, and then 10-12 wk postpartum. Basal plasma osmolality (Posmol) was already significantly decreased by 5-8 wk (P less than 0.001) and remained 10 mosmol.kg-1 below nonpregnant values throughout pregnancy. The apparent threshold for AVP release (defined as the abscissal intercept of the regression line relating plasma AVP [PAVP] to Posmol) was also decreased significantly throughout gestation, as was the osmotic threshold for thirst (derived from analogue scales relating desire to drink to Posmol). The decrement in osmotic thirst threshold appeared to precede that for AVP release, and consistent with this 24-h urine volumes were significantly greater at 5-8 wk gestation (P less than 0.05). The slopes of each regression equation defining PAVP vs. Posmol (whose r values ranged from 0.79 to 0.99), very reproducible before and after pregnancy, were similar at 5-8 and 10-12 wk, but were markedly reduced in the third trimester (P less than 0.001). These volunteers had randomly undergone an additional infusion before conception (both tests in the luteal phase of the menstrual cycle) when 10,000 IU of human chorionic gonadotrophin (hCG) had been given intramuscularly over a 5-d period. Serum hCG values between 0.2 and 3.3 U.ml-1 were lower than usually seen in pregnancy, but the osmotic thresholds for AVP release and thirst decreased by 3 and 4 mosmol.kg-1, respectively (P less than 0.05). Finally we studied a patient with a molar pregnancy in whom thresholds for hormone release and thirst were both decreased to values resembling normal gestation and remained so for approximately 6 wk postevacuation, only normalizing when hCG had virtually disappeared from her serum. In contrast, thresholds increased within the first two puerperal weeks in two women with normal pregnancies. These data demonstrate (a) osmotic thresholds for both AVP release and thirst decrease within the very first gestational weeks; (b) increment in PAVP per unit increase in Posmol is reduced late in gestation; and (c) hCG may be involved in the osmoregulatory changes of pregnancy.

Interprofessional collaboration in primary health care.

A study of interprofessional collaboration involving 148 general practitioner and district nurse pairs and 161 general practitioner and health visitor pairs was undertaken in 20 health districts throughout England in 1982-83. Data were collected using personal interviews and a prospective record of referrals and consultations. The ratings of collaboration recorded showed that only 27% of general practitioner-district nurse pairs and 11% of general practitioner-health visitor pairs were working in partial or full collaboration. Structural arrangements such as attachment, the number of general practitioners that community nurses work with, and working from the same building were found to be strongly associated with collaboration.

Indicators of depressed fibrinolytic activity in pre-operative prediction of deep venous thrombosis.

Euglobulin lysis time (ELT), tissue plasminogen activator (tPA), and the fast-acting inhibitor of tPA, were measured pre-operatively in 128 patients who underwent elective major abdominal surgery. Deep venous thrombosis (DVT) was detected by 125I-labelled fibrinogen scan in 37 patients (29 per cent) after operation. Pre-operatively, there was diminished euglobulin lysis activity (332 +/- 197 versus 255 +/- 156 min, mean +/- s.d.; P less than 0.025), and tissue plasminogen activator activity (4.2 +/- 9.9 versus 7.7 +/- 14.3 milliunits/ml, mean +/- s.d.; P = 0.094) in patients who subsequently developed postoperative DVT compared with those who did not. There was no significant difference between the two groups in the level of inhibition of tissue plasminogen activator (160.6 +/- 75.4 per cent versus 152.5 +/- 77.5 per cent, mean +/- s.d.; n = 47). Stepwise logistic discriminant analysis of the data obtained preoperatively showed that tissue plasminogen activator, a more specific measure of fibrinolytic activity, was a weaker predictor of DVT than euglobulin lysis time. The results confirm other observations which indicate that lowered fibrinolytic activity is a risk factor for postoperative DVT. In addition, they suggest that this is not due entirely to low levels of activity of tissue plasminogen activator in plasma.

Pre-operative identification of patients at high risk of deep venous thrombosis after elective major abdominal surgery.

Eighteen items of clinical and laboratory information were measured on the day before operation in 85 patients who underwent elective major abdominal surgery. Postoperatively, deep venous thrombosis (DVT) was detected by 125I-fibrinogen scan in 23 patients. Stepwise logistic discriminant analysis was used to identify factors which predicted DVT. Seven such factors were identified, which were then used to construct a predictive index. In descending order of predictive power, they were: age, euglobulin lysis time (ELT), previous abdominal surgery, varicose veins, antithrombin III concentration, cigarette smoking, and platelet count. Pre-operatively, the predictive index correctly identified 91% of the patients in whom DVT developed, and wrongly allocated to the high-risk group 19% of those in whom it did not. A shortened version of the predictive index based only on age and ELT (I = -11.5 + 0.133 age + 0.006 ELT) was 91% sensitive and 63% specific in the prediction of DVT. In a prospective study of 43 patients, this shortened predictive index correctly identified pre-operatively 93% of patients in whom DVT developed, and wrongly allocated to the high-risk group only 17% of those in whom it did not.

A study of 656 patients with "early" ovarian cancer.

Six hundred fifty-six patients with epithelial ovarian cancer that had been totally excised macroscopically were analyzed with the intention of providing information for a prospective randomized trial of adjuvant therapy. No deaths occurred in patients with tumors of borderline malignancy or those with stage Ia(i) well-differentiated tumors and hence adjuvant therapy was not justified in these patients. Survival of patients with clear cell carcinoma was poor, irrespective of stage. No statistically significant difference was found between the various modalities of adjuvant treatment, but those patients who had no further treatment after primary surgery had a significantly better survival. No obvious factors were found to account for this result. It is concluded that a "no adjuvant treatment" group must be included in any prospective study.

Changes in serum uric acid concentrations during normal pregnancy.

Serial changes in serum uric acid concentrations have been studied in a group of healthy women before conception, at regular intervals throughout pregnancy and finally 12 weeks after delivery. Compared with pre-pregnancy values uric acid concentrations decreased significantly by 8 weeks gestation and this reduced level was maintained until about 24 weeks. Thereafter the concentrations increased such that by term they were greater than the pre-pregnancy values in the majority of patients and remained elevated until at least 12 weeks after delivery. If clinical management during the second half of pregnancy is to be based on increases in serum uric acid concentrations then such increases will have to be carefully interpreted against the background of rising concentrations which occur as part of the physiological response to normal pregnancy.

Preoperative prognosis for cancer of the vulva.

Fourteen preoperative variables were individually assessed on 408 patients with primary vulvar cancer to determine their effect upon survival. Age, clinical node involvement, secondary tumor spread, tumor size, and menses were found to be the best individual indicators of survival time. Further analyses explored the dependence of survival time on these 5 variables jointly. Age was followed for by dividing the patients into 4 age groups; in each of these strata 4 prognostic categories, based on the variables clinical groin node involvement and secondary tumor spread, were defined: category 1, impalpable nodes and no secondary tumor spread; category 2, palpable nodes and no secondary tumor spread; category 3, impalpable nodes and secondary tumor spread; and category 4, palpable nodes and secondary tumor spread. Survival curves for each of these categories were plotted and showed progressively worsening prognoses from group 1 through group 4. It is believed that such methods should be used preoperatively to produce staging criteria and estimates of prognosis more objective and informative than those in common use.

Non-postural serial changes in renal function during the third trimester of normal human pregnancy.

Seventeen healthy women were investigated near the beginning and again near the end of the third trimester of their normal pregnancies. Infusion studies were performed in the left lateral position. There was a highly significant decrease in effective renal plasma flow but not in glomerular filtration rate, measured as inulin clearance. Plasma creatinine concentration increased significantly, but the renal handling of creatinine was unchanged; simultaneous 24-hour creatinine clearance showed a tendency to decrease. Serum urate concentration also increased significantly, apparently due to an increase in net tubular reabsorption of urate.

The effect of carcinoma of the cervix on the L-lactate-nicotinamide-adenine dinucleotide oxidoreductase activity in vaginal aspirates.

Lactate dehydrogenase (L-lactate-NAD+ oxidoreductase; EC 1.1.1.27) has been assayed in saline extracts of vaginal aspirates obtained from patients with carcinoma in situ and from patients with clinically detectable invasive carcinoma of the cervix. Taking premenopausal and postmenopausal patients separately, significant differences were found between the aspirate lactate dehydrogenase activities obtained from patients with carcinoma in situ and the activities obtained from patients with invasive carcinoma; generally higher activities were obtained from the latter. With the exception of postmenopausal patients with carcinoma in situ, aspirate enzyme activities obtained from both groups of patients were significantly different from those obtained from normal women. Significantly higher lactate dehydrogenase activity was found in aspirates from patients for whom histology showed the presence of an adenocarcinoma or certain highly malignant cell types. Treatment by radium insertion usually resulted in a fall total lactate dehydrogenase activity. Significant differences between groups were found for the proportions of single lactate dehydrogenase isoenzymes in a few instances but no significant difference in overall isoenzyme distribution was found.

The effect of the menopause on the L-lactate-nicotinamide-adenine dinucleotide oxidoreductase activity in vaginal aspirates.

Lactate dehydrogenase (L-lactate-NAD+ oxidoreductase; EC 1.1.1.27) activity has been assayed in saline extracts of vaginal aspirates obtained from patients attending a Well Woman Clinic and for whom exfoliative cytology was shown to be unequivocally normal. The majority (76 per cent) of premenopausal patients gave aspirate extracts containing less than 25 m units of enzyme while 71 per cent of postmenopausal patients gave aspirate extracts containing more than 50 m units of enzyme. This difference in distribution of activities was highly significant (P = less than 0.001). Analysis of the isoenzyme distribution showed that aspirates from postmenopausal patients contained a lower proportion of isoenzyme LDH-5 (P less than 0.01) and the M subunit (P less than 0.03) and a higher proportion of isoenzymes LDH-3 (P less than 0.001) and LDH-4 (P less than 0.01). There was no significant difference between the social class distributions of the pre- and postmenopausal patients. Lactate dehydrogenase activity was not related to social class or patients' multiparity. No difference in the distribution of enzyme activities was found between those premenopausal patients in the proliferative phase of the menstrual cycle, those in the secretory phase and those receiving hormone therapy.

Home and hospital confinement in Newcastle upon Tyne, 1960 to 1969.

During the decade 1960 to 1969, perinatal mortality rates in Newcastle upon Tyne fell in parallel with national trends, in association with a marked reduction of domiciliary midwifery. Analysis of the records of women booked for confinement at home or in specialist hospitals showed that the reduction of mortality occurred with unexpected uniformity in both categories, in low risk as well as high risk patients, and in all causes of mortality except congenital malformations. It could not be attributed to improvements in maternal characteristics nor to increased size of babies at birth. The most probably explanation seems to be a combination of many improvements in the quality of care, with increased awareness of risks, better selection of high-risk groups, and improved supervision and management throughout. There is no indication that single factor in obstetric management, such as more intervention during labour, had a dominant effect.

Obesity in childhood: A community study in Newcastle upon Tyne.

All children born of Newcastle upon Tyne mothers in 1960, 1961, and 1962 who were obese at the age of ten years have been investigated. Anthropometric, social, and psychological data were collected from the children and their families. The results confirm that obesity in childhood has many causes. The obesity was of early onset in 43% of the children, the remaining majority becoming obese after the age of five years. The commonest "at-risk" factors were obesity in a first degree relative, an elderly mother, being an only child, and absence of one parent. Two or more of these factors were present in at least 60% of the obese children.

Nurses and nursing in primary medical care in England.

In 1974 we sent questionnaires on attachment and employment of nurses to 9214 general practices in England. There were 7863 replies (85%), of which 551 were excluded from the study. A total of 2654 nurses were directly employed by 24% (1774) of the practices, and 68% (4972) had attached nurses. Practices in health centres were larger and had greater nursing resources than those in other premises. We suggest that practices may employ nurses to compensate for ineffective nursing attachments, and we conclude that general-practice-employed nurses are becoming "professionalised".