Effects of vitamin supplementation on inflammatory markers and psychological wellbeing among distressed women: a randomized controlled trial.

BACKGROUND: Multivitamins are a popular supplement taken to promote physical and mental health. During periods of stress, they may have a protective role for health and wellbeing, although the current evidence of their efficacy is mixed. OBJECTIVE: To determine whether multivitamin supplementation impacts psychological and inflammatory markers of women who are experiencing psychological distress. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: An 8-week randomized controlled trial was conducted to assess changes in both psychological state and pro-inflammatory markers of patients receiving multivitamins or placebo. The sample comprised women who reported elevated psychological distress in the previous 4 weeks. MAIN OUTCOME MEASURES: Psychological state was assessed using Spielberger's State-Trait Personality Inventory to assess anxiety, curiosity, depression and anger. Pro-inflammatory markers comprised interleukin (IL)-1ß, IL-5, IL-6, tumour necrosis factor (TNF)-α and TNF-ß. RESULTS: Improvements across time were observed for all psychological measures and cytokines, except IL-5, but were independent of the active intervention. Only TNF-ß demonstrated a significant differential change between groups over the course of the intervention, in favour of multivitamin supplementation (active group mean rank decreased from 11.1 to 7.1; placebo group mean rank decreased from 8.9 to 7.8). CONCLUSION: The results suggest that administration of multivitamins was not effective in improving psychological state. However, some evidence supported the positive impact of multivitamin supplementation on pro-inflammatory cytokine profiles of women currently experiencing stress.

Treatment for mitochondrial disorders.

BACKGROUND: Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. They present with central and peripheral neurological features usually in association with other organ involvement including the eye, the heart, the liver, and kidneys, diabetes mellitus and sensorineural deafness. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and premature death. Vitamin supplements, pharmacological agents and exercise therapy have been used in isolated cases and small clinical trials, but the efficacy of these interventions is unclear. OBJECTIVES: To determine whether there is objective evidence to support the use of current treatments for mitochondrial disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched September 2003), the Cochrane Central Register of Controlled Trials, MEDLINE (January 1966 to October 3 2003), EMBASE (January 1980 to October 3 2003) and the European Neuromuscular Centre (ENMC) clinical trials register, and contacted experts in the field. SELECTION CRITERIA: We included randomised controlled trials (including crossover studies) and quasi-randomised trials comparing pharmacological treatments, and non-pharmacological treatments (vitamins and food supplements), and physical training in individuals with mitochondrial disorders. The primary outcome measures included an improvement in muscle strength and/or endurance, or neurological clinical features. Secondary outcome measures included quality of life assessments, biochemical markers of disease and negative outcomes. DATA COLLECTION AND ANALYSIS: Details of the number of randomised patients, treatment, study design, study category, allocation concealment and patient characteristics were extracted. Analysis was based on intention to treat data. We planned to use meta-analysis, but this did not prove necessary. MAIN RESULTS: Six hundred and seventy-eight abstracts were reviewed, and six fulfilled the entry criteria. Two trials studied the effects of co-enzyme Q10 (ubiquinone), one reporting a subjective improvement and a significant increase in a global scale of muscle strength, but the other trial did not show any benefit. Two trials used creatine, with one reporting improved measures of muscle strength and post-exercise lactate, but the other reported no benefit. One trial of dichloroacetate showed an improvement in secondary outcome measures of mitochondrial metabolism, and one trial using dimethylglycine showed no significant effect. AUTHORS' CONCLUSIONS: There is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches.

The effect of propofol on airway pressures generated by magnetic stimulation of the phrenic nerves.

OBJECTIVES: To assess the effect of propofol on the change in airway pressure produced by diaphragmatic contraction. DESIGN AND SETTING: Prospective, controlled study in patients anaesthetised with propofol in a university hospital. PATIENTS AND METHODS: We stimulated the phrenic nerves before and immediately after induction of anaesthesia in 11 subjects, using a pair of 43-mm mean diameter double magnetic coils and measured the change in airway pressure at the mouth (TwPmo) produced by the resulting diaphragmatic contraction. Supramaximality of stimulation was confirmed with electromyogram and pressure measurements. We recorded the change in Resting End Expiratory Position (REEP) using a spirometer. We applied an approximate correction for the effect of lung volume on the amplitude of twitch pressure produced by diaphragmatic contraction. INTERVENTION: Following the initial stimulations, the patients were anaesthetised with a propofol infusion. Once stable, repeat measurements were made. MEASUREMENTS AND RESULTS: Following induction, REEP fell by mean 0.3 l standard deviation (SD) 0.2 l. TwPmo fell by mean 14.2% SD 14.0% ( P = 0.01), mean 22.3% SD 11.7% corrected ( P < 0.001). Twitch transdiaphragmatic pressure fell by 18.1% and 20.0% (25.8% and 27.7% corrected) in two further subjects studied with oesophageal and gastric balloon catheters. CONCLUSION: Propofol does reduce the effectiveness with which diaphragmatic contraction produces changes of pressure in the airway.

Genotoxicity evaluation of wood-derived and vegetable oil-derived stanol esters.

Plant stanol esters from wood and vegetable oil sources were tested for genotoxicity in bacterial (Salmonella typhimurium) and mammalian cell (L5178Y) gene mutation assays and in a mammalian cell chromosome aberration assay (CHO cells). The two stanol ester formulations were tested separately at doses up to the limit of solubility, with and without the addition of an Aroclor-induced rat liver microsome metabolic activation system (S9 mix). All tests were performed in duplicate and gave negative results for both wood and vegetable oil stanol ester formulations. Thus, plant stanol esters are not genotoxic under the conditions of exposure tested.

Short-term tests of estrogenic potential of plant stanols and plant stanol esters.

To test for potential estrogenic activity of plant stanols and plant stanol esters, two short-term tests were performed. These were the E-screen test, which measures a substance's ability to induce proliferation of estrogen-responsive human breast adenocarcinoma (MCF-7) cells in culture, and an in vivo test, which measures uterotrophic activity in immature female rats fed the test substance. Four samples of vegetable oil-derived stanols (containing 88-99% stanols) were tested in the E-screen test, and one sample of wood-derived and one of vegetable oil-derived stanol fatty acid esters were tested in the in vivo test. In the E-screen test, the positive control substance, 17beta-estradiol, at 100 pM, produced a statistically significant, 11.6-fold increase in cell proliferation, as measured by sulforhodamine B staining. None of the stanol preparations produced any increase in cell proliferation when tested at 1, 10, and 100 microM. The highest dose of each stanol sample was associated with microscopic evidence of cytotoxicity and crystalline precipitation in the culture dishes. In the in vivo test, the positive control compound, diethylstilbestrol, produced a significant, dose-related increase in absolute and relative uterus weight in young female rats (17 days old at the start of treatment) fed the compound at 5, 10, and 20 ppb in the diet for 4 days. Neither of the two stanol ester preparations caused any significant change in absolute or relative uterus weight when fed at a concentration of 8.3% in the diet for 4 days. Thus, under the conditions of testing used, neither the free stanols nor the stanol fatty acid ester preparations showed evidence of estrogenic or uterotrophic activity.

13-week oral toxicity study with stanol esters in rats.

Plant sterols and their saturated derivatives, known as stanols, reduce serum cholesterol when consumed in amounts of approximately 2 g per day. Stanol fatty acid esters have been developed as a highly fat-soluble form that may lower cholesterol more effectively than stanols. Stanol esters occur naturally in human diets, but at levels far below those known to lower cholesterol. The present study was conducted to assess the safety of stanol esters upon subchronic ingestion at levels comparable to or exceeding those recommended for lowering cholesterol. Two stanol fatty acid ester preparations, wood-derived stanol esters and vegetable oil-derived stanol esters, were fed to groups of 20 male and 20 female Wistar rats for 13 weeks, at dietary concentrations of 0, 0.2, 1, and 5% total stanols (equivalent to 0, 0.34, 1.68, and 8.39% wood-derived stanol esters and 0, 0.36, 1.78, and 8.91% vegetable oil-derived stanol esters). Both preparations were well tolerated as evidenced by the absence of clinical changes or major abnormalities in growth, food and water consumption, ophthalmoscopic findings, routine hematological and clinical chemistry values, renal concentrating ability, composition of the urine, appearance of the feces, estrus cycle length, organ weights, gross necropsy findings, and histopathological findings. Plasma cholesterol and phospholipids were slightly decreased in males fed the stanol esters. In both sexes, plasma levels of plant sterols were decreased whereas those of stanols tended to increase. Fecal excretion of sterols, including cholesterol, and stanols was markedly increased in the stanol ester groups. Compared to controls, male rats fed stanol esters showed somewhat lower liver weights and more pronounced glycogen depletion. These hepatic changes were considered to reflect an altered nutritional condition and not a pathological condition. Plasma levels of vitamin E, vitamin K1, and, to a lesser extent, vitamin D were decreased in males and females fed the high-dose diets. Hepatic levels of vitamins E and D showed similar changes (vitamin K1 in the liver was not determined). For both preparations, the mid-dose level (1% total stanols in the diet) was a no-observed-adverse-effect level. This dietary level provided approximately 0.5 g total stanols/kg body wt/day.

Developmental toxicity study of vegetable oil-derived stanol fatty acid esters.

In a standard developmental toxicity study, a mixture of vegetable oil-derived stanol fatty acid esters was administered in the diet to groups of 28 mated female HsdCpb:WU Wistar rats at concentrations that provided 0, 1, 2.5, and 5% total stanols (equivalent to 0, 1.75, 4.38, and 8.76% plant stanol esters). Test diets were adjusted with rapeseed oil to maintain an equivalent caloric content of fatty acids at each of the treatment levels. The treatment period extended from day 0 to 21 of gestation. No compound-related toxicity or clinical effects were seen in any of the treated groups. No statistically significant differences were seen in body weights or body weight gain in the low- or mid-dose groups, although slight but statistically significant decreases in mean body weight relative to controls were seen at gestation days 7 and 14 in the high-dose group. The decreases in body weight in the high-dose group may be attributable to the virtual lack of absorption of the dietary stanols. Body weight gains were equivalent to controls throughout the study except for a statistically significant decrease seen only in the 0- to 7-day gestation period in the high-dose group. No significant effects were seen on food consumption in terms of g/rat/day, but a slight, statistically significant increase was seen in the mid-dose group during gestation days 7-14. A significant increase was seen in the high-dose group during the 7- to 21-day period of gestation. Reproductive performance was not affected by the treatment. There were no statistically significant differences in uterine weight, placental weight, fetal weight, number of fetuses, number of implantation sites, number of corpora lutea, and early/late resorptions between the treated and control groups. In addition, there was no biologically meaningful effect on fetal sex ratio. Visceral and skeletal examinations did not show any significant increases in the incidence of malformations, anomalies, or variations that were considered to be treatment related. Dietary plant (8.76% plant stanol esters) stanol esters at concentrations up to 5% total stanols were concluded to have no adverse effects on reproduction or development.

A systematic review comparing continuity of midwifery care with standard maternity services.

OBJECTIVE: To review randomised controlled trials of alternative maternity services characterised by continuity of midwifery care. METHODS: A systematic review of randomised controlled trials, analysed on an intention to treat basis, in which the study intervention was characterised by a midwife or small group of midwives providing care from early pregnancy to the postnatal period (defined as that provided on the postnatal ward); and the controls by standard maternity care as practised in the place where the trial was conducted. The seven trials identified included 9148 women. Main outcome measures were interventions during labour, maternal outcomes and infant outcomes. RESULTS: The alternative models with continuity of midwifery care were associated with less use of obstetric interventions during labour (eg, induction, augmentation of labour, electronic fetal monitoring, obstetric analgesia, instrumental vaginal delivery and episiotomy). However, the caesarean section rate did not differ statistically between the trial groups (OR 0.91; 95% CI 0.78 to 1.05). The lower episiotomy rate in the alternative models of care (OR 0.69; 95% CI 0.61 to 0.77) was associated with a significantly higher rate of perineal tears in the pooled alternative groups (OR 1.15; 95% CI 1.05 to 1.26). The percentage of intact perineums was very similar for the two groups (OR 1.11; 95% CI 1.00 to 1.24). There was no maternal death, and rates of maternal complications based on unpooled estimates did not show any statistically significant differences. The proportion of babies with an Apgar score < 7 at five minutes after the birth was approximately the same in the pooled alternative groups as in the control groups (OR 1.13 95% CI 0.69 to 1.84). Admission to intensive care or special care baby unit was similar (OR 0.86; 95% CI 0.71 to 1.04). The difference in perinatal deaths was bordering on statistical significance (OR 1.60; 95% CI 0.99 to 2.59). CONCLUSION: Continuity of midwifery care is associated with lower intervention rates than standard maternity care. No statistically significant differences were observed in maternal and infant outcomes. However, more research is necessary to make definite conclusions about safety, for the infant as well as for the mother. This review illustrates the variation in the different models of alternative and standard maternity care, and thus the problems associated with pooling data from different trials.

Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice.

PURPOSE: To characterize ocular abnormalities associated with iris atrophy in DBA/2J mice and to determine whether mice of this strain develop elevated intraocular pressure (IOP) and glaucoma. METHODS: Different approaches, including slit-lamp biomicroscopy, ophthalmoscopic examination, ultrasound backscatter microscopy, and histology were used to examine the eyes of DBA/2J mice ranging from 2 to 30 months old. IOP was measured in DBA/2J mice of different ages. RESULTS: DBA/2J mice were found to develop pigment dispersion, iris transillumination, iris atrophy, anterior synechias, and elevated IOP. IOP was elevated in most mice by the age of 9 months. These changes were followed by the death of retinal ganglion cells, optic nerve atrophy, and optic nerve cupping. The prevalence and severity of these lesions increased with age. Optic nerve atrophy and optic nerve cupping was present in the majority of mice by the age of 22 months. CONCLUSIONS: DBA/2J mice develop a progressive form of secondary angle-closure glaucoma that appears to be initiated by iris atrophy and the associated formation of synechias. This mouse strain represents a useful model to evaluate mechanisms of pressure-related ganglion cell death and optic nerve atrophy, and to evaluate strategies for neuroprotection.

Randomised, controlled trial of efficacy of midwife-managed care.

BACKGROUND: Midwife-managed programmes of care are being widely implemented although there has been little investigation of their efficacy. We have compared midwife-managed care with shared care (ie, care divided among midwives, hospital doctors, and general practitioners) in terms of clinical efficacy and women's satisfaction. METHODS: We carried out a randomised controlled trial of 1299 pregnant women who had no adverse characteristics at booking (consent rate 81.9%). 648 women were assigned midwife-managed care and 651 shared care. The research hypothesis was that compared with shared care, midwife-managed care would produce fewer interventions, similar (or more favourable) outcomes, similar complications, and greater satisfaction with care. Data were collected by retrospective review of case records and self-report questionnaires. Analysis was by intention to treat. FINDINGS: Interventions were similar in the two groups or lower with midwife-managed care. For example, women in the midwife-managed group were less likely than women in shared care to have induction of labour (146 [23.9%] vs 199 [33.3%]; 95% CI for difference 4.4-14.5). Women in the midwife-managed group were more likely to have an intact perineum and less likely to have had an episiotomy (p = 0.02), with no significant difference in perineal tears. Complication rates were similar. Overall, 32.8% of women were permanently transferred from midwife-managed care (28.7% for clinical reasons, 3.7% for non-clinical reasons). Women in both groups reported satisfaction with their care but the midwife-managed group were significantly more satisfied with their antenatal (difference in mean scores 0.48 [95% CI 0.41-0.55]), intrapartum (0.28 [0.18-0.37]), hospital-based postnatal care (0.57 [0.45-0.70]), and home-based postnatal care (0.33 [0.25-0.42]). INTERPRETATION: We conclude that midwife-managed care for healthy women, integrated within existing services, is clinically effective and enhances women's satisfaction with maternity care.

The effect of valproate on blood metabolite concentrations in spontaneously diabetic, ketoacidotic, BB/E Wistar rats.

Valproate is an effective anticonvulsant which is rarely associated with hepatotoxicity. It has profound effects on the intermediary metabolism of isolated rat hepatocytes. In this paper the effect of valproate on blood metabolite concentrations in spontaneously diabetic BB/E rats has been studied. Valproate causes a marked fall in blood ketone body concentrations and a smaller fall in blood glucose concentrations following either oral or intraperitoneal administration. Valproate may have a role in the treatment of patients with "brittle" diabetes.

Metabolic changes in fed rats caused by chronic administration of ethyl 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate, a new hypoglycaemic compound.

Ethyl 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA) is strongly hypoglycaemic in fasted normal and diabetic rats [H. P. O. Wolf, K. Eistetter and G. Ludwig, Diabetologia 22, 456 (1982)]. POCA was fed for 12 weeks to rats on a standard low-fat (3%) diet at levels of 0.05% and 0.2% to give daily intakes of about 50 and 200 mg/per kg body-wt respectively. This is much more than effective hypoglycaemic doses in fasted rats (5-10 mg/kg body-wt). The animals appeared healthy but they had slightly decreased rates of weight gain compared with the controls. POCA caused a 15% increase in the weight of the myocardium and accumulation of lipid in the liver. Chronic administration of POCA did not cause any large changes in water-soluble blood metabolite concentrations, although VLDL-triacylglycerol and both VLDL and HDL cholesterol concentrations were lowered. There were only small changes in some metabolites of the glycolytic and gluconeogenic pathways and the citrate cycle in liver and skeletal muscle. ATP concentrations were maintained in all groups. There were 2- to 3-fold increases in the total content of CoA and of carnitine and their acylated forms. POCA-feeding caused small decreases in LPL activities in heart and had variable effects in adipose tissue. POCA was also fed to a few rats on a high fat (30%) diet for 4 weeks. Only small changes in blood, liver and muscle metabolite concentrations were found, except for large increases in the liver CoA and carnitine contents. It was concluded that POCA does not cause large perturbations of glucose homeostasis, or acute toxic effects, during 12 weeks administration to normal animals at high dose levels. The very-long term importance of accumulation of lipid in liver; increase in myocardial weight; and also of hepatic peroxisomal proliferation [A. J. Bone, H. S. A. Sherratt, D. M. Turnbull and H. Osmundsen, Biochem. biophys. Res. Commun. 104, 708 (1982)] cannot yet be determined. The possible use of POCA and related compounds in the chemotherapy of diabetes merits further investigation.

Anorexia nervosa, liquorice and hypokalaemic myopathy.

A patient with a past history of anorexia nervosa developed a hypokalaemic myopathy following a 'flu-like illness. Although she was apparently in remission from anorexia nervosa, the diet was found to be markedly abnormal with an excessive ingestion of liquorice and a low potassium salt intake. The clinical features and investigations, including muscle biopsy, are described. The patient is compared, with 2 reported cases of liquorice-induced myopathy, and the relationship between anorexia nervosa, liquorice and hypokalaemic myopathy is discussed.

Cis-platinum(II) diamine dichloride causes mutation, transformation, and sister-chromatid exchanges in cultured mammalian cells.

The anti-tumor agent cis-platinum(II) diamine dichloride caused dose-dependent toxicity in V79 Chinese hamster cells and in secondary Syrian hamster embryo cells. Chromosome aberrations were induced and positive dose--response relationships were observed for induction of sister-chromatid exchanges and 6-thioguanine-resistant mutations in V79 cells and morphologic transformation of secondary Syrian hamster embryo cells. The findings suggest that this chemical is a potential human carcinogen.

Sister chromatid exchange and chromosome aberration analysis with the use of several carcinogens and noncarcinogens.

Several chemical carcinogens and noncarcinogens were tested for their ability to induce sister chromatid exchanges (SCE) and structural chromosome aberrations in cultured V79-4 Chinese hamster cells. All of the direct-acting carcinogens induced a large increase in SCE frequency. Two chemicals, which are mutagenic in microorganisms but whose carcinogenicity is poorly documented, also increased the frequency of SCE. Carcinogenic polycyclic hydrocarbons caused an increased incidence of SCE only when a metabolizing feeder layer was used, whereas no increase was observed with noncarcinogenic polycyclic hydrocarbons. The other noncarcinogens also did not influence the SCE frequency. Although some chemicals increased the frequency of structural chromosome aberrations, no correlation was found between the frequencies of SCE and aberrations.