Mutant allele-specific imbalance modulates prognostic impact of KRAS mutations in colorectal adenocarcinoma and is associated with worse overall survival.

The prognostic impact of distinct KRAS mutations in colorectal carcinomas is not fully characterized. We hypothesized that the prognostic impact of KRAS mutations is modulated by KRAS mutant allele-specific imbalance (MASI). KRAS MASI was assessed by sequencing electropherograms in KRAS-mutated colorectal carcinomas (N = 394, prospectively tested). The mechanism of KRAS MASI was studied by fluorescence in situ hybridization (FISH; N = 50). FISH showed that KRAS MASI developed by chromosome 12 hyperploidy (9/18, 50%) or KRAS amplification (1/18, 5.5%). KRAS MASI was more common in tumors with KRAS codon 13 than with codon 12 mutations [24/81, 30% vs. 54/313, 17%; odds ratio (OR), 2.0, 95% confidence interval (CI), 1.2-3.5; p = 0.01]. KRAS MASI was correlated with overall survival (N = 358, median follow-up = 21 months). In a multivariate analysis, KRAS codon 13 MASI was an independent adverse prognostic factor (compared to codon 13 mutants without MASI combined with all codon 12 mutants; adjusted hazard ratio, 2.2, 95% CI: 1.2-3.9; p = 0.01). KRAS MASI arises through chromosome 12 hyperploidy or KRAS amplification and, when affects KRAS codon 13, is associated with worse overall survival.

Assessment of glomerular filtration rate during pregnancy using the MDRD formula.

It is now recommended practice to use estimated glomerular filtration rate (eGFR) values to screen for and monitor chronic renal disease. The most frequently used formula in the general population is that described following the Modification of Diet in Renal Disease (MDRD) study whereby serum creatinine is adjusted for age, gender and race. This study evaluates the performance of the MDRD formula in pregnancy by comparing eGFR with measured values obtained by inulin clearance studies in early and late normal pregnancy and in pregnancies complicated by renal disease or pre-eclampsia. Our results indicate that in all situations, MDRD substantially underestimates glomerular filtration rate during pregnancy and cannot be recommended for use in clinical practice.

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.

Changes in the metabolic clearance of vasopressin and in plasma vasopressinase throughout human pregnancy.

Metabolic clearance rates (MCR) of arginine vasopressin (AVP) were measured serially in five women starting before conception, during gestational weeks 7-8 (early), 22-24 (middle), and 36-38 (late pregnancy), and again 10-12 wk postpartum. Hormonal disposal rates were determined after water loading to suppress endogenous AVP release using a constant infusion method designed to achieve three different steady-state concentrations of plasma AVP (PAVP) on each test occasion. Dose schedules were altered in mid- and late pregnancy to obtain comparable AVP levels at each stage of the protocol. Prehydration decreased plasma osmolality sufficiently to suppress AVP release, as circulating AVP-neurophysin measured serially in three of the women was undetectable. The MCR of AVP was similar before conception (0.75 +/- 0.31, 0.79 +/- 0.34, and 0.76 +/- 0.28 liters/min at PAVP of 2.6 +/- 1.9, 4.7 +/- 2.4, and 8.3 +/- 3.9 pg/ml), in early pregnancy (0.89 +/- 0.34, 0.97 +/- 0.04, and 0.95 +/- 0.40 liters/min at PAVP of 2.2 +/- 2.1, 3.9 +/- 3.2, and 7.9 +/- 3.4 pg/ml), and postpartum (0.70 +/- 0.21, 0.69 +/- 0.24, and 0.75 +/- 0.20 liters/min at PAVP 3.5 +/- 1.8, 5.1 +/- 3.7, and 9.1 +/- 4.2 pg/ml). Values at mid-pregnancy (2.8 +/- 1.3, 3.0 +/- 1.2, and 2.7 +/- 1.2 liters/min at PAVP 2.3 +/- 2.2, 4.0 +/- 3.6, and 7.7 +/- 3.9 pg/ml) and late pregnancy (3.2 +/- 1.4, 3.3 +/- 1.4, and 2.9 +/- 1.2 liters/min at PAVP 1.9 +/- 2.0, 3.8 +/- 2.6, and 7.4 +/- 4.1 pg/ml) increased 3-4-fold (all P less than 0.01). Plasma vasopressinase, undetectable at 7-8 gestational wk, increased markedly by mid- and slightly more by late gestation. Finally, relationships between PAVP and urine osmolality were similar before, during, and after pregnancy. We conclude that marked increments in the MCR of AVP occur between gestational weeks 7 and 8 and mid-pregnancy, which parallel the period of greatest rise in both trophoblastic mass and plasma vasopressinase. There was no evidence of a renal resistance to AVP during gestation.

Primary cutaneous Ewing's sarcoma: immunophenotypic and molecular cytogenetic evaluation of five cases.

Cutaneous small blue cell tumors are relatively uncommon and include primary lesions of either adnexal or neuroendocrine differentiation, as well as metastatic disease. Extraosseous Ewing's sarcoma/malignant primitive neuroectodermal tumor (MPNET) rarely may occur as a primary, superficially based neoplasm in children and young adults. We describe a series of five cases of Ewing's sarcoma/malignant primitive neuroectodermal tumor occurring as a primary cutaneous malignancy supported diagnostically both by immunohistochemical stains and fluorescence in situ hybridization (FISH). All five cases occurred as a solitary dermal nodule and were located in the lower extremities (3 cases), the axilla (1 case), and the flank (1 case). Three of the cases were clinically polypoid. Four of the five patients were female, and age at presentation ranged form 8 to 50 years of age (median, 18 years). All five tumors consisted of nodular proliferations of monomorphous, small blue cells with round, vesicular nuclei, and scant to moderate cytoplasm that were uniformly immunoreactive for the CD99 cell surface glycoprotein in a characteristic membranous pattern. Fluorescence in situ hybridization analysis of paraffin-embedded tissue revealed that three of four tumors were positive for a chromosomal translocation involving the EWS locus at 22q12, seen in more than 90% of cases of Ewing's sarcoma/malignant primitive neuroectodermal tumor. One case was not analyzable. All five patients were treated using local excision, and two patients additionally received postoperative chemotherapy and radiotherapy. Clinical follow-up is available in three cases (median duration, 33 months) and to date none has shown evidence of either local recurrence or metastasis. Because similar cases reported in the literature have likewise had favorable clinical courses after excision, primary cutaneous Ewing's sarcoma/malignant primitive neuroectodermal tumor may represent a clinically favorable subset of this otherwise highly aggressive neoplasm.

Relation of immediate post-transplant renal function to long-term function in cadaver kidney recipients.

Renal function studies 12 to 41 months after transplantation have been performed on seven cadaver renal allograft recipients who demonstrated immediate primary function after transplant (group A) and seven similar recipients who had delayed primary function (group B). The groups were matched as closely as possible for major physical characteristics and their postoperative management; in particular, only one patient had a post-transplant renal biopsy. Glomerular filtration rate was determined by 24-hr creatinine clearance, endogenous creatinine clearance, and inulin clearance was usually lower in those patients having delayed primary function and they excreted more glucose per 24 hr and reabsorbed a smaller proportion of the filtered glucose load under infusion conditions. These results are discussed in relation to the effect of immediate and delayed primary function on the long-term prognosis of such patients.

The kidney and hypertension in pregnancy: twenty exciting years.

Before 1980 research on the kidney and hypertension during pregnancy was neglected, although these diseases, especially hypertension, are major causes of morbidity to mother and child. The past 20 years, however, has witnessed a striking reversal of this neglect. This review focuses on recent progress in renal physiology, kidney disease, and hypertension as relates to pregnancy. Why do renal hemodynamics increase markedly in pregnancy? Studies have suggested roles for nitric oxide synthase, prostaglandins, endothelin and relaxin. This area of research is exciting, as unraveling why glomerular filtration rate and renal plasma flow increase in pregnancy may eventually help all patients with acute and chronic renal function loss. Concerning other advances: Micropuncture studies in rats, and the interpretation of fractional dextran clearances in humans show that the hyperfiltration that occurs during normal gestation is not associated with increased glomerular capillary pressure. Finally, description of changes in osmoregulation and in the metabolic disposal of arginine vasopressin in human pregnancy led to identification and appropriate treatment of a new group of disorders termed "transient diabetes insipidus of pregnancy." Chronic renal disease of any severity once led to proscription or interrupting of pregnancy. Clinical-pathological correlation studies and long-term follow-up of the mothers have revealed that most of these gestations succeed with little risk of worsening the natural history of the kidney disorder. This is also true in allograft recipients, and we now have guidelines to counsel both groups of patients. Progress relating to hypertension in pregnancy has been in 2 broad areas; systematic attempts to accurately define and differentiate the various disorders and population studies to predict, prevent, and improve the management of preeclampsia. There has also been considerable progress in unraveling the pathophysiology and identifying the cause of preeclampsia.

Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy.

This review stresses changes in osmoregulation as well as the secretion and metabolism of arginine vasopressin during pregnancy, focusing on human gestation. Pregnant women experience a decrease in body tonicity, plasma osmolality decreasing immediately after conception to a nadir approximately 10 mosmol/kg below non-pregnant levels early in pregnancy, after which a new steady state is maintained until term. Data from both human and rodent gestation have led to a formation of how these changes occur. The osmotic thresholds for thirst and antidiuretic hormone release decrease in parallel. Lowering the threshold to drink stimulates increased water intake and dilution of body fluids. Because arginine vasopressin (AVP) release is not suppressed at the usual level of body tonicity, the hormone continues to circulate and the ingested water is retained. Plasma osmolality declines until it is below the osmotic thirst threshold, and a new steady state with little change in water turnover is established. Pregnancy is characterized by increments in intravascular volume, but volume-sensing AVP release mechanisms appear to adjust as gestation progresses so that each new volume status is "sensed" as normal. The metabolic clearance of AVP increases fourfold, the rise paralleling that of circulating cystine aminopeptidase (vasopressinase), and enzyme produced by the placenta. Furthermore, the disposal rate of 1-deamino-8-D-AVP, and AVP analogue resistant to inactivation by vasopressinase, is unaltered in pregnancy. Thus, the increase in AVP's metabolism and the high circulating aminopeptidase levels have been implicated in certain forms of transient diabetes insipidus that occur in late pregnancy. Finally, mechanisms responsible for the altered osmoregulation in pregnancy are obscure, but chorionic gonadotropin and relaxin may be implicated in the changes.

Perinatal outcome in renal allograft recipients: prognostic significance of hypertension and renal function before and during pregnancy.

With more renal allograft recipients becoming pregnant, it is important to refine existing pre-pregnancy assessment criteria and to identify other factors influencing perinatal outcome. We analyzed gestational renal response and acute or chronic hypertension in relation to perinatal outcome for 22 pregnancies that continued beyond 28 weeks' gestation in 17 allograft recipients (mean age 27 years, range 20-40) transplanted between 1967-1987. Before pregnancy, all had plasma creatinine of 1.62 mg/dL or less and 24-hour creatinine clearance of 39 mL/minute or greater. Six pregnancies were to four women on antihypertensive therapy. Mean arterial pressure (MAP), antihypertensive therapy, plasma creatinine, and 24-hour creatinine clearance were recorded before and during pregnancy. Perinatal outcome was adverse in ten pregnancies: five stillbirths, four growth-retarded infants, and one neonatal death, whereas 12 pregnancies had satisfactory perinatal outcome. Early-pregnancy increments and late-pregnancy decrements in renal function were identical in both groups. Mean arterial pressure was significantly higher at 16-28 weeks in women having adverse outcomes. Hypertension (MAP above 107 mmHg) occurred in 16 pregnancies (73%); it appeared before 28 weeks in seven and was invariably associated with adverse outcome. Hypertension appeared after 28 weeks in nine women and was associated with adverse outcome in only two cases. Five of six pregnancies in women who were on pre-pregnancy antihypertensive therapy ended in adverse outcome. It can be concluded that renal function was identical in pregnancies having adverse or satisfactory perinatal outcome, whereas hypertension before or during early pregnancy, albeit apparently satisfactorily controlled, appeared to be associated with adverse perinatal outcome.

Clinical outcomes of pregnancy in women with type 1 diabetes(1).

OBJECTIVE: To evaluate predictors of neonatal hypoglycemia and macrosomia in 107 consecutive pregnancies in type 1 diabetic women. METHODS: We conducted a case record analysis of singleton type 1 diabetic pregnancies between January 1994 and January 1999 following institution of standardized management. RESULTS: The duration of diabetes in the women was 12.9 +/- 6.8 years, and 44 were primigravidas. The mean HbA1c throughout pregnancy was 7.2 +/- 0.8%. There was no relationship between neonatal blood glucose (checked before the second feed) and HbA1c at any point in pregnancy or mean pregnancy HbA1c (R = 0.20, P >.1). However, there was a negative correlation between neonatal blood glucose and maternal blood glucose during labor (R = -0.33, P <.001). When maternal blood glucose during labor was greater than 8 mM (144 mg/dL), neonatal blood glucose was usually less than 2.5 mM (mean 1.7 +/- 0.4 mM or 31 mg/dL). There was no relationship between mean HbA1c and birth weight (R = 0.02, P >.1) or between maximum insulin dose and birth weight (R = 0.09, P >.1). Fetal abdominal circumference measured by ultrasound at 34 weeks correlated strongly with birth weight (R = 0.72, P <.001). CONCLUSION: Neonatal hypoglycemia correlates with maternal hyperglycemia in labor, not with HbA1c during pregnancy. Macrosomia does not correlate with HbA1c during pregnancy.

Edema in pregnancy.

During normal pregnancy total body water increases by 6 to 8 liters, 4 to 6 liters of which are extracellular, of which at least 2 to 3 liters are interstitial. At some stage in pregnancy 8 out of 10 women have demonstrable clinical edema. There is also cumulative retention of about 950 mmol of sodium distributed between the maternal extracellular compartments and the product of conception. Thus, changes in factors governing renal sodium and water handling accompany alterations in local Starling forces whereby there is a moderate fall in interstitial fluid colloid osmotic pressure (COPi) and a rise in capillary hydrostatic pressure (Pc), as well as changes in hydration of connective tissue ground substance. Edema is a traditional criterion for diagnosing pre-eclampsia, but should no longer be used as its detection is not clinically useful. The role of diuretics in obstetric practice should be restricted to the management of pulmonary edema in pre-eclampsia. Volume expansion therapy in pregnancy runs the risk of pulmonary or cerebral edema, particularly in the immediate puerperium. Vulval edema and erythematous edema associated with deep venous thrombosis are rare but dangerous complications of pregnancy.

Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes.

Successful pregnancy outcomes are possible after solid organ transplantation. While there are risks to mother and fetus, there has not been an increased incidence of malformations noted in the newborn of the transplant recipient. It is essential that there is closely coordinated care that involves the transplant team and an obstetrician in order to obtain a favourable outcome. Current data from the literature, as well as from reports from the National Transplantation Pregnancy Registry (NTPR), support the concept that immunosuppression be maintained at appropriate levels during pregnancy. At present, most immunosuppressive maintenance regimens include combination therapy, usually cyclosporin or tacrolimus based. Most female transplant recipients will be receiving maintenance therapy prior to and during pregnancy. For some agents, including monoclonal antibodies and mycophenolate mofetil, there is either no animal reproductive information or there are concerns about reproductive safety. The optimal (lowest risk) transplant recipient can be defined by pre-conception criteria which include good transplant graft function, no evidence of rejection, minimum 1 to 2 years post-transplant and no or well controlled hypertension. For these women pregnancy generally proceeds without significant adverse effects on mother and child. It is of note that the epidemiological data available to date on azathioprine-based regimens are favourable in the setting of a category D agent (i.e. one that can cause fetal harm). Thus, there is still much to learn regarding potential toxicities of immunosuppressive agents. The effect of improved immunosuppressive regimens which use newer or more potent (and potentially more toxic) agents will require further study.

Coexistent hemoconcentration and hypoosmolality during superovulation and in severe ovarian hyperstimulation syndrome: a volume homeostasis paradox.

OBJECTIVE: To investigate the concomitant time courses of the changes in osmolality and calculated blood volume during the genesis of ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective longitudinal study. SETTING: IVF-ET program in a university-based assisted reproductive technology center. PATIENT(S): Thirty women undergoing superovulation for IVF-ET. INTERVENTION(S): Blood and urine samples were obtained on seven occasions from the start of FSH stimulation until a pregnancy test. Five women with severe OHSS had daily blood and urine tests during hospitalization. MAIN OUTCOME MEASURE(S): Changes in serum and urine osmolality, serum electrolytes, albumin, hemoglobin, and hematocrit. RESULT(S): Blood volume in women with OHSS decreased significantly by 20% from days hCG +2 to +4, followed by a sustained increase of 30% above baseline from days hCG +8 to +12. There was no statistically significant change in blood volume in women without OHSS. There was a sharp decrease in serum osmolality in women without OHSS between days 0 and hCG +2, which recovered toward baseline from day 4 after hCG. In women with OHSS, there was an unexpected increase in osmolality of 6 mOsm/kg between days hCG -2 and 0, followed by a decrease of 8 mOsm/kg by day hCG +2; this was sustained until day hCG +12. Patients with OHSS demonstrated a concentration and dilution of their urine during the acute and recovery phases of the syndrome, respectively, despite persistence of the hypoosmolar state. CONCLUSION(S): Decreased osmolality in severe OHSS is maintained despite significant decreases and increases in blood volume, suggestive of fundamental alterations in osmoregulation.

Altered osmotic thresholds for arginine vasopressin secretion and thirst during superovulation and in the ovarian hyperstimulation syndrome (OHSS): relevance to the pathophysiology of OHSS.

OBJECTIVE: To test the hypothesis that decreases in and maintenance of a new steady state in plasma osmolality and sodium level in ovarian hyperstimulation syndrome (OHSS) are due to altered osmoregulation of arginine vasopressin secretion and thirst. DESIGN: Prospective study. SETTING: IVF-ET program in a university-based assisted reproductive treatment center. PATIENT(S): Eight women undergoing superovulation for IVF-ET and five women with normal menstrual cycles. INTERVENTION(S): Two-hour infusion of 5% saline on day 3 or 4 after hCG administration in patients undergoing IVF or in the early luteal phase in controls. A 5% saline infusion test was done on day 10 after hCG administration in one patient with OHSS and one patient without OHSS, both of whom were undergoing IVF. MAIN OUTCOME MEASURE(S): Comparison of changes in thresholds for thirst and plasma vasopressin to plasma osmolality. Changes in urine osmolality, plasma electrolytes, hemoglobin level, and hematocrit were assessed at baseline and during infusion of 5% saline. RESULT(S): The sensitivity of the changes in arginine vasopressin secretion and thirst after 5% saline infusion was similar in IVF patients on day 3 or 4 after hCG and controls. However, the osmotic threshold was significantly lower by 6 mOsm/kg in IVF patients. By day 10 after hCG, the lower osmotic thresholds for arginine vasopressin secretion and thirst persisted in OHSS, although the sensitivity to arginine vasopressin secretion was markedly reduced. CONCLUSION(S): The osmotic thresholds for arginine vasopressin secretion and thirst are reset to lower plasma osmolality during superovulation for IVF-ET. This new lower body tonicity is maintained until at least day 10 after hCG in OHSS. Decreases in plasma osmolality and plasma sodium levels in OHSS are due to altered osmoregulation rather than electrolyte losses; correction of apparent "electrolyte imbalance" in OHSS is therefore inappropriate.

Kidney disease and pregnancy: obstetric outcome and long-term renal prognosis.

In patients with chronic renal disease, all advice and decisions must take into account the balance between pregnancy outcome and the long-term impact that pregnancy might have on the disease. To help the clinician address these concerns, the authors focus on the renal changes in normal pregnancy, the problems of chronic renal disease in pregnancy, and the effect pregnancy has on long-term renal prognosis.

Sex and the pregnant kidney: does renal allograft gender influence gestational renal adaptation in renal transplant recipients?

BACKGROUND: Animal work indicates that ovarian hormones are important in initiating and maintaining enhanced renal function in pregnant rats and that a renal response resembling pregnancy can be provoked in male rats exposed to pregnancy hormones. Women becoming pregnant following renal transplantation provide an opportunity to compare the functional response of male and female allografts to the gestational endocrine environment. METHODS: This retrospective observational study included 20 renal allograft recipients (age 29.7 +/- 2.4 yrs) (mean +/- SE) who had 22 pregnancies beyond 24 weeks (gestation at delivery 35.5 +/- 0.6 weeks). Donor characteristics, transplant details, renal follow-up data, and information about pregnancy and allograft function were obtained from hospital notes. RESULTS: Thirteen women received male allografts (donor age 30.0 +/- 3.9 years) (mean +/- SEM) and 7 women, female allografts (donor age 45.1 +/- 6.0 years) (P = .04). There were no significant differences between the two groups in maternal recipient age, transplant to pregnancy interval, antenatal complications, pregnancy outcome, or postnatal graft function. Compared to prepregnancy values serum creatinine (SCr) decrements and augmented 24-hour creatinine clearance (CrCl) were observed over the first trimester in both male and female allografts: Delta CrCl from 106.8 +/- 13.2 mL/min to 114.4 +/- 11.4 mL/min (35.6% increase) and 71.8 +/- 7.4 to 89.5 +/- 11.3 mL/min (24.7% increase), respectively, and Delta SCr from 90.1 +/- 5.4 micromol/L to 73.6 +/- 6.6 micromol/L (17.8% decrease) and 99.8 +/- 9.7 micromol/L to 78.0 +/- 5.7 micromol/L (13.5% decrease), respectively. Differences between the two groups did not reach statistical significance. CONCLUSIONS: Donor gender and/or age do not appear to influence the gestational renal response in kidney transplant recipients.

Pre-eclampsia as a multi-system disease.

Pre-eclampsia cannot be defined precisely by clinical signs which are just readily detectable secondary features of the primary abnormality within the uterus. The multisystem sequelae could be thought of as a secondary maternal adaptation, with the large variation in clinical presentation reflecting variable susceptibility of maternal target organs. The changes may be characteristic of pre-eclampsia but are not specific and therefore reflect a process rather than a discrete disease entity. Because the pathogenesis is so controversial it is not surprising that views on management differ so much.

Detecting premalignant cervical lesions. Contribution of screening colposcopy to cytology.

The combination of parallel cytology and screening colposcopy was found to increase the detection of premalignant cervical lesions from 8.2% in a group of patients (based on cytology alone) to 15.3% in that group (based on the combination). The combination of the two methods used in parallel increased the sensitivity, negative predictive value and efficiency of cervical cancer screening over cytology alone while having only a small negative impact on the positive predictive value of a positive test. The addition of screening colposcopy to cytology produces a significant improvement over current uniphasic screening protocols.

Comparative study of operative laparoscopy versus laparotomy. Analysis of the financial impact.

A matched case study was performed comparing the financial impact of substituting laparoscopy for laparotomy. Laparoscopy was substantially less costly to the patient and her employer while more profitable for the hospital.

Plasma oxytocin during third stage of labour: comparison of natural and active management.

The incidences of postpartum haemorrhage and retained placenta have decreased with the use of synthetic oxytocin and controlled cord traction. Whether such treatment is valuable is open to question because of the lack of clinical and physiological studies. The physiological effects of synthetic oxytocin on plasma concentrations of oxytocin and events during delivery were assessed. Plasma oxytocin concentration was determined in serial samples during the late second stage and throughout the third stage of labour in 25 women. Ten women received combined ergotamine and synthetic oxytocin intramuscularly and 15 were not treated. The geometric mean plasma oxytocin concentration significantly increased in the women given oxytocin when measured before and after delivery of the fetal anterior shoulder (3.1 (SD 2.0) pmol/l before and 15.9 (2.7) pmol/l after). Six of the women who did not receive treatment showed a significant increase in geometric mean plasma oxytocin concentration before and after delivery of the fetal shoulder (3.2 (2.0) pmol/l before and 6.4 (2.0) pmol/l after) and nine did not show an increase (geometric mean 2.4 (3.1) pmol/l before and 2.2 (2.2) pmol/l after). Of these nine women, two had an abnormal third stage of delivery; one woman had a postpartum haemorrhage and one required manual removal of the placenta. As it is impossible to predict which women will show a rise in the plasma concentration of endogenous oxytocin, intramuscular oxytocin should be given routinely.