The aetiology of post-traumatic stress following childbirth: a meta-analysis and theoretical framework

There is evidence that 3.17% of women report posttraumatic stress disorder (PTSD) after childbirth. This meta-analysis synthesizes research on vulnerability and risk factors for birth-related PTSD and refines a diathesis-stress model of its etiology. Systematic searches were carried out on PsychInfo, PubMed, Scopus and Web of Science using PTSD terms crossed with childbirth terms. Studies were included if they reported primary research that examined factors associated with birth-related PTSD measured at least one month after birth. 50 studies (N=21,429) from 15 countries fulfilled inclusion criteria. Pre-birth vulnerability factors most strongly associated with PTSD were depression in pregnancy (.51), fear of childbirth (.41), poor health or complications in pregnancy (r = .38), and a history of PTSD (.39) and counselling (.32). Risk factors in birth most strongly associated with PTSD were negative subjective birth experiences (.59), having an operative birth (assisted vaginal or caesarean, .48), lack of support (-.38), and dissociation (.32). After birth, PTSD was associated with poor coping and stress (.30), and was highly comorbid with depression (.60). Moderator analyses showed that the effect of poor health or complications in pregnancy was more apparent in high-risk samples. The results of this meta-analysis are used to update a diathesis-stress model of the etiology of postpartum PTSD and can be used to inform screening, prevention and intervention in maternity care

Characterization of two bacterial multi-flavinylated proteins harboring multiple covalent flavin cofactors

In recent years, studies have shown that a large number of bacteria secrete multi-flavinylated proteins. The exact roles and properties, of these extracellular flavoproteins that contain multiple covalently anchored FMN cofactors, are still largely unknown. Herein, we describe the biochemical and structural characterization of two multi-FMN-containing covalent flavoproteins, SaFMN3 from Streptomyces azureus and CbFMN4 from Clostridiaceae bacterium. Based on their primary structure, these proteins were predicted to contain three and four covalently tethered FMN cofactors, respectively. The genes encoding SaFMN3 and CbFMN4 were heterologously coexpressed with a flavin transferase (ApbE) in Escherichia coli, and could be purified by affinity chromatography in good yields. Both proteins were found to be soluble and to contain covalently bound FMN molecules. The SaFMN3 protein was studied in more detail and found to display a single redox potential (-184 mV) while harboring three covalently attached flavins. This is in line with the high sequence similarity when the domains of each flavoprotein are compared. The fully reduced form of SaFMN3 is able to use dioxygen as electron acceptor. Single domains from both proteins were expressed, purified and crystallized. The crystal structures were elucidated, which confirmed that the flavin cofactor is covalently attached to a threonine. Comparison of both crystal structures revealed a high similarity, even in the flavin binding pocket. Based on the crystal structure, mutants of the SaFMN3-D2 domain were designed to improve its fluorescence quantum yield by changing the microenvironment of the isoalloxazine moiety of the flavin cofactor. Residues that quench the flavin fluorescence were successfully identified. Our study reveals biochemical details of multi-FMN-containing proteins, contributing to a better understanding of their role in bacteria and providing leads to future utilization of these flavoprotein in biotechnology.</p

Substrate Induced Movement of the Metal Cofactor between Active and Resting State

Regulation of enzyme activity is vital for living organisms. In metalloenzymes, far-reaching rearrangements of the protein scaffold are generally required to tune the metal cofactor's properties by allosteric regulation. Here structural analysis of hydroxyketoacid aldolase from Sphingomonas wittichii RW1 (SwHKA) revealed a dynamic movement of the metal cofactor between two coordination spheres without protein scaffold rearrangements. In its resting state configuration (M$^{2+}$$_R$), the metal constitutes an integral part of the dimer interface within the overall hexameric assembly, but sterical constraints do not allow for substrate binding. Conversely, a second coordination sphere constitutes the catalytically active state (M$^{2+}$$_A$) at 2.4 Å distance. Bidentate coordination of a ketoacid substrate to M$^{2+}$$_A$ affords the overall lowest energy complex, which drives the transition from M$^{2+}$$_R$ to M$^{2+}$$_A$. While not described earlier, this type of regulation may be widespread and largely overlooked due to low occupancy of some of its states in protein crystal structures

The diagnostic strength of the 24-h pad test for self-reported symptoms of urinary incontinence in pregnancy and after childbirth

The clinical impact of incontinence in pregnancy and after childbirth is growing because some studies report the efficacy of physiotherapy in pregnancy and because obstetric choices are supposed to have significant impact on post-reproductive urinary function (Goldberg et al. in Am J Obstet Gynecol 188:1447–1450, 2003). Thus, the need for objective measurement of urinary incontinence in pregnancy is growing. Data on pad testing in pregnancy are lacking. We assessed the clinical relevance of the 24-h pad test during pregnancy and after childbirth, compared with data on self-reported symptoms of urinary incontinence and visual analogue score. According to the receiver operating characteristic curve, the diagnostic value of pad testing for measuring (severity of) self-reported incontinence during pregnancy is not of clinical relevance. However, for the purposes of research, pad tests, combined with subjective/qualitative considerations, play a critical role in allowing comparisons across studies, quantifying the amount of urine loss and establishing a measure of severity

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents

Background: Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist. Objectives: The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations. Methods: Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n = 8), and German pediatric patients in a therapeutic drug monitoring service (n = 22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM®). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages. Results: In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th–75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 µg/L [56.0–180.5 µg/L]) than in non-responders (58.0 µg/L [14.9–105.5 µg/L]), although non-significant (p = 0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders. Conclusions: Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100–400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account

Use of alternative and complementary medicine in menopause

Objectives: To review the clinical evidence available for the treatment of menopausal symptoms with alternative and complementary medicine. Methods: The MEDLINE, PREMEDLINE and COCHRANE electronic databases for the years 1980–2002 were searched for articles concerning soy products, black cohosh, dong quai, acupuncture, ginseng and evening primrose oil. Studies pertaining to menopausal vasomotor symptoms, lipid profiles and bone mineral densities of postmenopausal women were included. The data from clinical trials were reviewed. Results: Soy isoflavones slightly decrease total cholesterol and LDL levels. The clinical significance of this small change is yet to be determined. The synthetic isoflavone derivative ipriflavone increases bone mineral density in healthy peri‐ and postmenopausal women with moderate bone mineral densities. Although earlier reports have claimed that soy is beneficial for the improvement of vasomotor symptoms, recent data do not support this claim. There are insufficient data on the other alternative therapies for treating menopausal symptoms at this time. Conclusion: Alternative and complementary medicine may play a role in the management of menopause, however, well‐designed large studies are still needed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135146/1/ijgo195.pd

Exercise Training in Pregnancy for obese women (ETIP): study protocol for a randomised controlled trial

<p/> <p>Background</p> <p>Both maternal pre-pregnancy obesity and excessive gestational weight gain are increasing in prevalence and associated with a number of adverse pregnancy outcomes for both mother and child. Observational studies regarding physical activity in pregnancy have found reduced weight gain in active mothers, as well as reduced risk of adverse pregnancy outcomes. There is however a lack of high quality, randomized controlled trials on the effects of regular exercise training in pregnancy, especially those with a pre-pregnancy body mass index (BMI) at or above 30 kg/m².</p> <p>Methods</p> <p>We are conducting a randomised, controlled trial in Norway with two parallel arms; one intervention group and one control group. We will enroll 150 previously sedentary, pregnant women with a pre-pregnancy BMI at or above 30 kg/m². The intervention group will meet for organized exercise training three times per week, starting in gestation week 14 (range 12-16). The control group will get standard antenatal care. The main outcome measure will be weight gain from baseline to delivery. Among the secondary outcome measures are changes in exercise capacity, endothelial function, physical activity level, body composition, serum markers of cardiovascular risk, incontinence, lumbopelvic pain and cardiac function from baseline to gestation week 37 (range 36-38). Offspring outcome measures include anthropometric variables at birth, Apgar score, as well as serum markers of inflammation and metabolism in cord blood.</p> <p>Discussion</p> <p>The results of this trial will provide knowledge about effects of regular exercise training in previously sedentary, obese pregnant women. If the program proves effective in reducing gestational weight gain and adverse pregnancy outcomes, such programs should be considered as part of routine pregnancy care for obese women.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01243554">NCT01243554</a></p

Hot or not? Discovery and characterization of a thermostable alditol oxidase from Acidothermus cellulolyticus 11B

We describe the discovery, isolation and characterization of a highly thermostable alditol oxidase from Acidothermus cellulolyticus 11B. This protein was identified by searching the genomes of known thermophiles for enzymes homologous to Streptomyces coelicolor A3(2) alditol oxidase (AldO). A gene (sharing 48% protein sequence identity to AldO) was identified, cloned and expressed in Escherichia coli. Following 6xHis tag purification, characterization revealed the protein to be a covalent flavoprotein of 47 kDa with a remarkably similar reactivity and substrate specificity to that of AldO. A steady-state kinetic analysis with a number of different polyol substrates revealed lower catalytic rates but slightly altered substrate specificity when compared to AldO. Thermostability measurements revealed that the novel AldO is a highly thermostable enzyme with an unfolding temperature of 84 °C and an activity half-life at 75 °C of 112 min, prompting the name HotAldO. Inspired by earlier studies, we attempted a straightforward, exploratory approach to improve the thermostability of AldO by replacing residues with high B-factors with corresponding residues from HotAldO. None of these mutations resulted in a more thermostable oxidase; a fact that was corroborated by in silico analysis