Bisphenol A and Reproductive Health: Update of Experimental and Human Evidence, 2007–2013

Background: In 2007, an expert panel reviewed associations between bisphenol A (BPA) exposure and reproductive health outcomes. Since then, new studies have been conducted on the impact of BPA on reproduction.Objective: In this review, we summarize data obtained since 2007, focusing on a) findings from human and animal studies, b) the effects of BPA on a variety of reproductive end points, and c) mechanisms of BPA action.Methods: We reviewed the literature published from 2007 to 2013 using a PubMed search based on keywords related to BPA and male and female reproduction.Discussion: Because BPA has been reported to affect the onset of meiosis in both animal and in vitro models, interfere with germ cell nest breakdown in animal models, accelerate follicle transition in several animal species, alter steroidogenesis in multiple animal models and women, and reduce oocyte quality in animal models and women undergoing in vitro fertilization (IVF), we consider it an ovarian toxicant. In addition, strong evidence suggests that BPA is a uterine toxicant because it impaired uterine endometrial proliferation, decreased uterine receptivity, and increased implantation failure in animal models. BPA exposure may be associated with adverse birth outcomes, hyperandrogenism, sexual dysfunction, and impaired implantation in humans, but additional studies are required to confirm these associations. Studies also suggest that BPA may be a testicular toxicant in animal models, but the data in humans are equivocal. Finally, insufficient evidence exists regarding effects of BPA on the oviduct, the placenta, and pubertal development.Conclusion: Based on reports that BPA impacts female reproduction and has the potential to affect male reproductive systems in humans and animals, we conclude that BPA is a reproductive toxicant.Citation: Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. 2014. Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect 122:775–786; http://dx.doi.org/10.1289/ehp.1307728     

A broadly-protective vaccine against meningococcal disease in sub-Saharan Africa based on Generalized Modules for Membrane Antigens (GMMA)

Introduction

Neisseria meningitidis causes epidemics of meningitis in sub-Saharan Africa. These have mainly been caused by capsular group A strains, but W and X strains are increasingly contributing to the burden of disease. Therefore, an affordable vaccine that provides broad protection against meningococcal disease in sub-Saharan Africa is required.

Methods

We prepared Generalized Modules for Membrane Antigens (GMMA) from a recombinant serogroup W strain expressing PorA P1.5,2, which is predominant among African W isolates. The strain was engineered with deleted capsule locus genes, lpxL1 and gna33 genes and over-expressed fHbp variant 1, which is expressed by the majority of serogroup A and X isolates.

Results

We screened nine W strains with deleted capsule locus and gna33 for high-level GMMA release. A mutant with five-fold increased GMMA release compared with the wild type was further engineered with a lpxL1 deletion and over-expression of fHbp. GMMA from the production strain had 50-fold lower ability to stimulate IL-6 release from human PBMC and caused 1000-fold lower TLR-4 activation in Human Embryonic Kidney cells than non-detoxified GMMA. In mice, the GMMA vaccine induced bactericidal antibody responses against African W strains expressing homologous PorA and fHbp v.1 or v.2 (geometric mean titres [GMT] = 80,000–200,000), and invasive African A and X strains expressing a heterologous PorA and fHbp variant 1 (GMT = 20–2500 and 18–5500, respectively). Sera from mice immunised with GMMA without over-expressed fHbp v.1 were unable to kill the A and X strains, indicating that bactericidal antibodies against these strains are directed against fHbp.

Conclusion

A GMMA vaccine produced from a recombinant African N. meningitidis W strain with deleted capsule locus, lpxL1, gna33 and overexpressed fHbp v.1 has potential as an affordable vaccine with broad coverage against strains from all main serogroups currently causing meningococcal meningitis in sub-Saharan Africa.     

Learning curve of medical students in ultrasound-guided simulated nerve block

Background

Good hand-eye coordination is a prerequisite for safe ultrasound-guided peripheral nerve blocks. However, new skills have to be acquired when compared to the traditional nerve stimulation technique. We tested and mathematically described the learning curve of these skills in inexperienced ultrasound users employing a simple phantom of a peripheral nerve.

Methods

A simple phantom made from a piece of spaghetti to simulate a nerve, within a starch core and embedded in gelatine was used for ultrasound-guided simulation of a peripheral nerve block. Eighteen medical students who were novices to ultrasound were enrolled. Serial time to successful injection was measured. Quality of injection was rated by two independent observers.

Results

Time to successful injection improved from a median of 66.5 s (49.5–90) for the first trial to 37 s (23.5–53.5) for the 11th trial. A plateau of 30 s was reached for t _1/2 after 2.7 trials and 4 × t _1/2 after 7.8 trials when described as first-order exponential decay. Time to successful injection was significantly shortened after 5 trials. Quality of injection with numbers of trials followed a sigmoidal shape with 50 % of maximum quality after 3.6 trials and a plateau after 8.5 trials. Likewise, a significant improved quality of injection was reached after 5 trials.

Conclusion

Based on our mathematical analyses of the learning curve, inexperienced ultrasound users can improve their hand-eye coordination within 5 subsequent trials in a simple model of a peripheral nerve block.     

Safety and tolerance of a new extensively hydrolyzed rice protein-based formula in the management of infants with cow’s milk protein allergy

Guidelines recommend the use of extensively hydrolyzed cow’s milk protein-based formulas (eHF) in the treatment of infants with cow’s milk protein allergy (CMPA). Extensively hydrolyzed rice protein infant formula (eRHF) has recently become available and could offer a valid alternative. A prospective trial was performed to evaluate the hypo-allergenicity and safety of a new eRHF in infants with a confirmed CMPA. Patients were fed the study formula for 6 months. Clinical tolerance of the eRHF was evaluated with a symptom-based score (SBS) and growth (weight and length) was monitored. Forty infants (mean age, 3.4 months; range, 1–6 months) with CMPA confirmed by a food challenge were enrolled. All infants tolerated the eRHF and the SBS significantly decreased as of the first month of intervention. Moreover, the eRHF allowed a catch-up to normal weight gain as of the first month as well as a normalization of the weight-for-age, weight-for length, and BMI z-scores within the 6-month study period. Conclusion: In accordance with current guidelines, this eRHF was tolerated by more than 90 % of children with proven CMPA with a 95 % confidence interval. This eRHF is an adequate and safe alternative to cow milk-based eHF.     

The bioequivalence of fixed‐dose combination tablets of bisoprolol and ramipril and its drug‐drug interaction potential

Chronic antihypertensive treatment often includes combination of two or more therapies with complementary mechanism of action targeting different blood pressure (BP) control system. If available, these components are recommended to be administered as a fixed‐dose combination (FDC) to reduce tablet burden, improve adherence and thus BP control. A combination of ramipril (RAMI) and bisoprolol (BISO) is one of the options used in clinical practice and is supported by therapeutic guidelines. The clinical program for a novel BISO/RAMI FDC consisted of two randomized, open‐label, bioequivalence (BE) studies and one drug‐drug interaction (DDI) study. The BE was examined between two FDC strengths of BISO/RAMI (10/10 and 10/5 mg) and the individual reference products administered concomitantly at respective doses after a single oral dose under fasting conditions. In both BE studies, 64 healthy subjects were randomized according to a two‐way crossover design. The DDI study evaluated a potential pharmacokinetic (PK) interaction between BISO 10 mg and RAMI 10 mg following their single or concomitant administrations in 30 healthy subjects under fasting condition. BE for BISO/RAMI 10/5 mg and absence of a clinically relevant PK DDI between BISO and RAMI was demonstrated as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for area under the concentration time curve (AUC) and maximum concentration (C_max) remained within the acceptance range of 80.00 to 125.00%. However, BE for BISO/RAMI 10/10 mg was not demonstrated, as the lower bound of the 90% CI of C_max for RAMI was outside the acceptance range of BE. Both drugs administered alone or combined were well‐tolerated. No PK interaction was observed between BISO and RAMI/ramiprilat, since the co‐administration of BISO and RAMI 10 mg single doses resulted in comparable rate and extent of absorption for BISO and RAMI when compared to their individual products.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Bisoprolol (BISO) and ramipril (RAMI) have both well‐characterized pharmacokinetic (PK) properties, however, clinical studies for this fixed‐dose combination (FDC) are limited and as per our knowledge, a potential of PK drug‐drug interactions (DDIs) between both compounds has not been evaluated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The clinical program was focused on the evaluation of bioequivalence (BE) for two strengths of novel FDCs containing BISO/RAMI in comparison with their free‐combinations and evaluation of potential PK interaction between BISO and RAMI.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

An absence of PK interaction between BISO and RAMI has been demonstrated in the DDI study. The BE studies provided information about in vivo behavior of the FDC, as well as additional PK, and statistical and safety data for BISO and RAMI.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

FDC containing BISO and RAMI may reduce tablet burden, improve adherence to treatment, and blood pressure control in patients with hypertension. The administration of BISO and RAMI is not associated with a risk of PK interaction between both compounds.     

Dyskinesia Matters

Levodopa-induced dyskinesia (LID) represents a significant source of discomfort for people with Parkinson's disease (PD). It negatively affects quality of life, it is associated with both motor and nonmotor fluctuations, and it brings an increased risk of disability, balance problems, and falls. Although the prevalence of severe LID appears to be lower than in previous eras (likely owing to a more conservative use of oral levodopa), we have not yet found a way to prevent the development of this complication. Advanced surgical therapies, such as deep brain stimulation, ameliorate LID, but only a minority of PD patients qualify for these interventions. Although some have argued that PD patients would rather be ON with dyskinesia than OFF, the deeper truth is that patients would very much prefer to be ON without dyskinesia. As researchers and clinicians, we should aspire to make that goal a reality. To this end, translational research on LID is to be encouraged and persistently pursued. © 2019 International Parkinson and Movement Disorder Society