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Carbodiimides and pyridines form reversible adducts that slowly deliver carbodiimide "fuels" to out-of-equilibrium reaction networks, slowing activation kinetics and elongating transient state lifetimes. More-nucleophilic pyridines give more adduct under typical conditions. This approach can be used to extend the lifetimes of transient polymer hydrogels.

Nucleotide-induced conformational changes in motor proteins are key to many important cell functions. Inspired by this biological behavior, we report a simple chemically fueled system that exhibits carbodiimide-induced geometry changes. Bridging via transient anhydride formation leads to a significant reduction of the twist about the biaryl bond of substituted diphenic acids, giving a simple molecular clamp. The kinetics are well-described by a simple mechanism, allowing structure-property effects to be determined. The kinetic parameters can be used to derive important characteristics of the system such as the efficiencies (anhydride yields), maximum anhydride concentrations, and overall lifetimes. Transient diphenic anhydrides tolerate steric hindrance ortho to the biaryl bond but are significantly affected by electronic effects, with electron-deficient substituents giving lower yields, peak conversions, and lifetimes. The results provide useful guidelines for the design of functional systems incorporating diphenic acid units.

Transient changes in molecular geometry are key to the function of many important biochemical systems. Here, we show that diphenic acids undergo out-of-equilibrium changes in dihedral angle when reacted with a carbodiimide chemical fuel. Treatment of appropriately functionalized diphenic acids with EDC ( N -(3-(dimethylamino)propyl)- N '-ethylcarbodiimide hydrochloride) yields the corresponding diphenic anhydrides, reducing the torsional angle about the biaryl bond by ∼45°, regardless of substitution. In the absence of steric resistance, the reaction is well-described by a simple mechanism; the resulting kinetic parameters can be used to derive important properties of the system, such as yields and lifetimes. The reaction tolerates steric hindrance ortho to the biaryl bond, although the competing formation of (transient) byproducts complicates quantitative analysis.

Tamoxifen has been a very effective treatment for breast cancer for several decades, however, at the same time increases the risk of endometrial cancer, especially after prolonged exposure. In addition, tamoxifen has been associated with a higher proportion of unfavorable uterine tumor subtypes (carcinosarcomas and serous adenocarcinomas) with worse survival. We investigated whether endometrial tumors, which developed after prolonged tamoxifen treatment for breast cancer, are genetically different from endometrial tumors without preceding tamoxifen exposure. Array CGH was used on archival formalin-fixed paraffin embedded endometrial tumors to determine genomic aberrations. We compared the genomic profiles of 52 endometrial tumors from breast cancer patients after long-term (>or=2 years) tamoxifen use (endometrioid adenocarcinomas, n = 26; carcinosarcomas, n = 14; and serous adenocarcinomas, n = 12) with endometrial tumors from unexposed breast cancer patients (n = 45). Genomic profiles were correlated with tamoxifen exposure, tumor subtypes, and histopathological characteristics of the endometrial tumors. The common uterine corpus cancers of the endometrioid subtype show few genomic aberrations. Tumors with many genomic aberrations were in general ER-negative. In contrast, carcinosarcomas and serous adenocarcinomas showed many aberrations; however, they were indistinguishable from each other. Tumors that developed after prolonged tamoxifen use did not show more or different aberrations than unexposed tumors. This was true for all tumor subtypes. Thus, endometrial carcinomas that develop after prolonged tamoxifen use cannot be distinguished from nonusers on basis of their tumor genomic profile.

Tamoxifen increases the risk of uterine corpus cancer. Since only few, mostly small, studies have examined prognosis of uterine corpus cancer following tamoxifen, we conducted a large retrospective cohort study to further investigate this. We examined histopathologic and immunohistochemical characteristics of 332 patients with uterine corpus cancer following breast cancer, according to tamoxifen use. Survival was examined in the same patients combined with 309 patients from a previous study with updated follow-up. Histological review of all cancers was performed. Long-term tamoxifen users showed a higher proportion of non-endometrioid tumors than non-users (32.7% vs. 17.4%, P=0.004), especially serous adenocarcinomas and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed (20.0% vs. 11.3%, P=0.049). Within FIGO stage I, both short-term and long-term tamoxifen users showed a higher proportion of tumors limited to the endometrium than non-users (35.7% vs. 22.9%, P=0.049 and 0.004 respectively). Uterine corpus cancers in long-term tamoxifen users were more often steroid receptor-negative (ERalpha, PRA and PRB, P<0.05) and P53-positive (P=0.015). Three-year uterine corpus cancer-specific survival was worse for long-term tamoxifen users than for non-users (82% vs. 93% P=0.0001). The survival difference remained after adjustment for histopathologic and immunohistochemical characteristics (hazard ratio (HR) for >or=2 years tamoxifen=2.4; 95% CI=1.2-4.6). In conclusion, this large study clearly shows that tamoxifen-associated tumors have less favorable histological features and a worse survival. Our results can be applied when weighing risks and benefits of tamoxifen versus other hormonal agents used in the prevention and treatment of breast cancer.

The aim of this study was to establish a population-based incidence of severe acute maternal morbidity (SAMM) in hypertensive pregnancies and to assess if substandard care was unique to cases of SAMM and mortality or whether it was apparent in uncomplicated pregnancies as well. The population-based incidence of hypertension was 12%. Using defined criteria for SAMM, the incidence of SAMM was 3/1000 deliveries. The MMR was 42/100000 deliveries, i.e. SAMM is seven times greater than the mortality. Substandard care was similar in cases of SAMM and mortality and uncomplicated hypertensive patients. Audit of SAMM is informative, can be conducted more frequently, and in small sample population groups. It also allows interviews of patients, hence problems of inefficient documentation is obviated.

Objective: To assess whether severe acute maternal morbidity (SAMM, 'near misses') can be used as a surrogate of an analysis of maternal deaths to describe the pattern of severe maternal disease and avoidable factors related to it., Design: Prospective, descriptive study., Setting: A SAMM and maternal mortality audit was conducted in three clearly defined geographical areas, consisting of rural and urban settings in South Africa., Population: Indigent black African pregnant women., Method: Cases of SAMM and maternal deaths were collected in the areas and a comparison was made of the disease profiles and avoidable factors, missed opportunities and substandard care., Main Outcome Measures: The proportion of primary obstetric causes and avoidable factors in women with SAMM and maternal deaths, and the mortality indices of the primary obstetric causes of death and organ system dysfunction., Results: A total of 423 women with SAMM and 128 maternal deaths were collected over two years. Demographic factors were similar between the groups except that significantly more maternal deaths had not attended any antenatal care. The primary obstetric causes of SAMM and maternal death did not correlate. The four most common causes of SAMM were complications of hypertension (27.2%), postpartum haemorrhage (18.0%), antepartum haemorrhage (12.8%) and abortion (11.3%), whereas the four most common causes of maternal death were non-pregnancy related sepsis (26.6%), complications of hypertension (23.4%), pre-existing medical disease (14.1%) and abortion (10.9%). The types of avoidable factors were similar between both groups although administrative factors occurred significantly more frequently in the maternal death group as did poor problem identification and monitoring., Conclusion: Review of SAMM gives a different disease pattern to that obtained from maternal death audits. However, in diagnosing inadequacies in the health system, similar information was obtained.

Objective: To investigate the effect of chronic oxygen therapy in fetuses with absent end diastolic flow in the umbilical artery assessed by doppler analysis at 24-30 weeks of gestation., Design: A double-blind, randomised control trial was performed with patients blindly allocated to receive humidified oxygen or humidified air., Setting: A tertiary referral hospital in South Africa., Participants: Thirty-two women who presented between 24 and 30 weeks of gestation with a confirmed finding of absent end diastolic flow in the umbilical artery., Methods: After randomisation patients were allocated to receive a 40% mixture of humidified oxygen or humidified air from uniform coloured gas cylinders which were marked either 'a' or 'b' All women received betamethasone from 27 weeks of gestation on a weekly basis. Cardiotocographs were used from 28 weeks of gestation; after 28 weeks of gestation an amniocentesis was considered to confirm fetal maturity. Women were expected to breath the allocated gas continuously apart from meals and visits to the toilet., Main Outcome Measures: Survival of the fetus was the main outcome measure with secondary outcome measures documenting improvement in the fetal condition in utero., Results: There were 16 women randomised to receive oxygen and 16 to receive air. There were nine survivors in the oxygen group (56.3%) and six in the air group (37.5%) (relative risk 1.5, 95% confidence interval 0.7-3.2). There was a nonsignificant increase in mean birthweight in the oxygen group (858.3 grammes vs 774.4 grammes) and a nonsignificant increase in mean duration of treatment in the oxygen group (12.8 days vs 10.4 days)., Conclusion: This study did not demonstrate that chronic oxygen therapy provides any benefits to compromised fetuses between 24 and 30 weeks of gestation. Larger studies with sufficient power are necessary to assess whether oxygen therapy can reduce perinatal mortality by a clinically useful amount in this group of patients.

The incidence of acute renal failure in pregnancy has decreased. This decrease is less marked in developing countries in which resources are more scarce. The clinical diagnosis of acute renal failure is crude due to the variability of clinical signs and the late occurrence of basic biochemical abnormalities. Obstetric and gynaecological diseases are found among the traditional pre-renal, intra-renal and post-renal causes of acute renal failure. The cornerstone of management is the identification of high-risk cases and the prevention of acute renal failure by maintaining intravascular volume. The evidence for the efficacy of other prophylactic medical interventions, such as the use of loop diuretics, mannitol, low-dose dopamine and others, is poor. Management of established acute renal failure includes restoration of intravascular volume, treatment of any reversible causes, especially pregnancy complications such as pre-eclampsia, strict fluid balance and correction of any electrolyte abnormality or metabolic acidosis. Dialysis is a supportive measure until the kidneys recover., (Copyright 2001 Harcourt Publishers Ltd.)

The purpose of this study was (i) to compare a range of stress-related personality traits, including defense and coping mechanisms, of migraine patients (n = 23) with those of tension headache patients (n = 18) and dermatologically afflicted, but otherwise healthy, controls (n = 22), and (ii) to compare their state anxiety and other moods before, during, and after the presentation of a psychological stressor (mental arithmetic). For all three groups, mental arithmetic induced a significant increase in state anxiety and mood disturbance, followed by a subsequent decrease during recovery. Migraine patients were not found to have a higher disposition for anxiety, depression, or rigidity than tension headache patients or controls. Between the headache groups no differences in the use of defense and coping mechanisms were found. Compared to the control group, however, both migraine patients and tension headache patients were more inclined to use internally focused defense mechanisms and less inclined to seek social support when confronted with a problem. The psychological reaction of migraine patients to mental stress hardly differed from tension headache and control subjects. Compared to the control subjects, however, both groups of headache patients exhibited a diminished recovery from feelings of vigour, depression, and fatigue due to the stress induced. It is suggested that this distinct psychological reaction to stress of headache patients versus healthy control subjects is related to the more internally focused defense style of the headache sufferers. Thus, in contrast to previous results, this study does not present evidence of a migraine personality. It suggests the development of specific personality characteristics as a consequence of suffering from episodic headache.

Objective: To test the application of a clinical definition of severe acute maternal morbidity., Design: A one-year prospective descriptive multi-centre study., Setting: Kalafong and Pretoria Academic hospitals, catering for the delivery of indigent women in the Pretoria Health Region., Methods: A 'near-miss' describes a patient with an acute organ system dysfunction, which if not treated appropriately, could result in death. The case notes of women fitting this definition and all maternal deaths were analysed and compared., Outcome Measure: Determine the primary obstetric factors and the organ systems that failed. Identification of episodes of sub-standard care and missed opportunities. Results One hundred and forty-seven near misses and 30 maternal deaths were identified. The commonest reasons for a near-miss were: emergency hysterectomy in 42 women (29%); severe hypotension in 40 (27%); and pulmonary oedema in 24 (16%). The most common initiating obstetric conditions were hypertension in 38 women (26%); haemorrhage in 38 (26%); and abortion or puerperal sepsis in 29 (20%). The primary obstetric factors amongst the maternal deaths were: hypertension (33%); sepsis (27%); and maternal medical diseases (17%) in 10, 8 and 5 women respectively. Sub-standard care was identified in 82 cases. Breakdown in the health care administration was identified in 33, and patient-orientated missed opportunities on 34 occasions., Conclusion: The definition of severe acute maternal morbidity identified nearly five times as many cases as maternal death. This definition allows for an effective audit system of maternal care because it is clinically based, the definition is robust and the cases identified reflect the pattern of maternal death.

This study aimed at the combined assessment of the serotonergic and sympathetic nervous system reactions of migraine patients before, during, and after the induction of mental stress in order to detect the possible role of these reactions in inducing a migraine attack. The responses to mental stress of the migraine patients were compared to a group of patients suffering from tension headache and a control group. Activation of the sympathoadrenomedullary system due to mental stress was successfully induced in the migraine patients (n = 23), in the tension headache patients (n = 18), and in the control group (n = 22). The results of this study present evidence of increased cardiovascular activity in migraine patients as compared to nonmigraineurs. However, no evidence was found of a specific serotonergic, sympathoadrenomedullary, or cerebrovascular response of migraine patients to mental stress as compared to nonmigraineurs.

Objective: To assess the effect of low dose dopamine on the urine output in postpartum pre-eclamptic or eclamptic women with oliguria., Design: A double blind, randomised controlled study., Setting: The high care area of the labour ward in a teaching hospital., Sample: Forty postpartum pre-eclamptic women with oliguria, defined as < 30 mL/hour, who have not responded to a 300 mL crystalloid fluid challenge., Intervention: Dopamine was infused at a rate of 1 to 5 microg/kg per minute, or sterile water was given as placebo in the same dilution., Main Outcome Measure: Urine output, blood pressure and pulse was measured for six hours before and for six hours after the intervention., Results: Women who received dopamine (344 mL over 6 hours) showed a clinically and statistically significant (P = 0.0014, Mann-Whitney U test) higher median urine output compared with those receiving placebo (135 mL over 6 hours) for the duration of therapy. The respective 95% confidence intervals were 212.3 to 712.7 mL compared with 73.8 to 244.7 mL. No differences in blood pressure or pulse were found between the two groups., Conclusions: The use of low dose dopamine in a labour setting improved urine output in postpartum pre-eclamptic women with oliguria who had not responded to a single fluid challenge without a detrimental effect on the blood pressure or pulse.

In medical genetics, several systems are used to classify and code genetic disorders for the purpose of automated registration. In the Netherlands, a genetic diagnosis code system has been developed that links a unique four-digit code to a principal description and all current synonyms. The main goal of this coding system is to enable nationwide uniformity of coding, without losing access to information stored in the past, identified by the ICD/BPA code (the International Classification of Diseases as adapted by the British Paediatric Association) and/or the MIM code (McKusick's classification in Mendelian Inheritance in Man). To this effect, the Dutch diagnosis code is cross-referenced with the 2 pre-existing classification systems. Developments in medical genetics make regular updates of all coding systems necessary. In the Netherlands, new diagnosis codes are assigned centrally to preserve uniformity and distributed periodically to all 8 clinical genetic centers. Diagnosis codes are assigned in numerical order of inclusion, enabling quick and easy updates. It is possible to include subclassifications of disorders according to pattern of inheritance, gene location, and gene mutations and to cover all disorders and disorder subtypes which are not clearly distinguished by the 2 pre-existing classification systems. The architecture of the coding system is suitable for international use. It offers a practical solution for clinical geneticists in need of a coding system suitable for clinical use. The use of the diagnosis code will also facilitate reliable comparison of data and nationwide genetic epidemiological studies.

Objective: To establish the antihypertensive properties of intravenous nimodipine used to treat eclamptic patients. To assess the effects of intravenous nimodipine on oxygen delivery and consumption., Design: A prospective observational study., Setting: The Maternity Centre Obstetric Intensive Care Unit, Groote Schuur Hospital., Participants: Four unselected patients presenting with proteinuric hypertension and seizures., Methods: Haemodynamic observations were obtained by a radial artery catheter and right heart catheterisation with a pulmonary artery flow directed thermodilution catheter. Observations were obtained prior to and after the administration of nimodipine., Results: A significant reduction in mean arterial pressure occurred in all patients after administration of nimodipine. This was due to a significant reduction in systemic vascular resistance. Neither oxygen delivery to the tissues nor peripheral oxygen consumption changed significantly during nimodipine infusion. No adverse effects related to the use of nimodipine were documented., Conclusions: Nimodipine is an effective vasodilator. There may be a role for nimodipine as a single agent for the management of eclampsia.

The functional connections between corticospinal neurones and motor units of the monkey's hand muscles were investigated by constructing cross-correlograms of activity recorded from pyramidal tract neurones and from single motor units in the contralateral thenar muscles during performance of a precision grip between thumb and index finger. Only those neurones which produced postspike facilitation of the surface-recorded electromyogram (EMG) of these muscles were selected for analysis. Positive correlations were observed for 11/15 selected neurones, and the form of the correlation was suggestive of monosynaptic action. Corticospinal cells which produced a correlation peak often did so with all concurrently-sampled motor units.