Trends in rates of natural conceptions among Danish women born during 1960-1984

STUDY QUESTION The aim of the study was to analyse trends in the rate of natural conceptions (RNC) among birth cohorts of women born during the period 1960-1984. SUMMARY ANSWER In this nationwide study of Danish-born female cohorts born during the period 1960-1984, we found a gradual decline in the RNC with successive birth cohorts. WHAT IS KNOWN ALREADY Our results confirm the findings from a previous study on trends in RNC among native Danish women. STUDY DESIGN, SIZE, DURATION This is a register-based cohort study. Our data set included 803 435 native Danish women born in 1960-1984, of whom 68.2% had conceived at least one child as of 1 January 2008, by which time the follow-up was terminated. PARTICIPANTS/MATERIALS, SETTING, METHODS Data from Danish national registers were linked at the individual level using unique personal numbers assigned at birth to each resident. We analysed the data for the cohorts of native Danish women born in 1960-1984 and resident in Denmark in 2008. For these cohorts, we estimated the RNC per woman, defined as the mean number of live births minus live births after assisted reproductive technology (ART) plus the mean number of induced abortions. Births, abortions and births after ART were partly projected for the younger cohorts who had not finished their reproductive years before 2008. In addition, we looked at trends in hormonal contraception use. MAIN RESULTS In the main projection scenario, the RNC gradually declined with successive cohorts from 2.39 among women born in 1960 to 2.15 among women born in 1984, with stable values of 2.15-2.16 projected in the youngest cohorts analysed, 1979-1984. The projected decline was a consequence of a decrease in induced abortion rates and an increase in the use of ART among the younger cohorts. Furthermore, we projected a cohort increase in the share of women without natural conceptions. LIMITATIONS, REASONS FOR CAUTION A considerable portion of the results was based on projections, which involve uncertainty, especially concerning the results for women born in 1980 and later. In addition, information on IUI could not be included, which led to underestimation of the frequency of births after ART treatment. WIDER IMPLICATIONS OF THE FINDINGS The results of our study contribute new insights to the research field of declining fertility rates in Europe and many other parts of the world. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from Kirsten and Freddy Johansens Foundation and the European Commission project 'Developmental effects of environment on reproductive health' (grant no. 212844). None of the funding sources had any involvement in the study.     

Strong and sustained effector function of memory‐ versus naïve‐derived T cells upon T‐cell receptor RNA transfer: Implications for cellular therapy

Current protocols used to select CMV‐specific T cells for adoptive immunotherapy focus on virus‐specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem‐cell transplantation (HSCT) from CMV‐seronegative donors. Here, we redirected T cells of CMV‐seronegative donors with a human genetically engineered TCR recognizing an HLA‐A*0201‐binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non‐viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naïve‐derived T‐cell subsets were both efficiently transfected by TCR‐RNA, memory‐derived T cells showed much stronger levels of HLA‐A*0201‐restricted cytolytic activity to CMV‐infected fibroblasts and maintained acquired function for 5–10 days. In addition to redirection of CD8⁺ cytotoxic T cells, TCR‐RNA transfection was capable of redirecting CD4⁺ T cells into potent Ag‐specific Th cells that efficiently triggered maturation of DCs. Our data suggest that memory rather than naïve‐derived T cells are the preferred subset for transient TCR expression by RNA electroporation, providing more efficient and sustained virus‐specific CD4⁺ and CD8⁺ T‐cell function. CMV TCR‐RNA may represent a suitable therapeutic ‘off‐the‐shelf’ reagent to be used in severe CMV infections of HSCT patients when endogenous CMV‐specific T‐cell immunity is insufficient.     

HIV-1 mRNA electroporation of PBMC: a simple and efficient method to monitor T-cell responses against autologous HIV-1 in HIV-1-infected patients

Efficient monitoring of HIV-1-specific T-cells is crucial for the development of HIV-1 vaccines and immunotherapies. Currently, mainly peptides and vaccinia vectors are used for detection of HIV-1-specific cytotoxic T-lymphocytes (CTL), however, as HIV-1 is a variable virus, it is unknown to what extent the T-cell response against the autologous virus is under- or overestimated by using antigens from heterologous viral strains. Therefore, we established a new method for immunomonitoring of CTL using electroporation of peripheral blood mononuclear cells (PBMC) with mRNA derived from autologous viral strains. From six HIV-1-infected patients virus derived mRNA was produced after PCR-based cloning of autologous gag (n=5) and/or nef genes (n=3) from plasma and electroporated into PBMC from patients and healthy donors. Electroporation of PBMC with mRNA resulted in efficient protein expression with good induction of γ-interferon (γ-IFN) release by specific T-cells comparable to peptide pools and better than recombinant vaccinia viruses. Three mRNA encoded autologous Gag proteins and one autologous mRNA encoded Nef protein were better recognized by autologous PBMC in comparison to heterologous mRNA encoded Gag or Nef proteins (SF2 or HXB2). However, in one case each, mRNA encoded autologous Gag or Nef, respectively, was recognized less efficiently due to the presence of CTL escape mutations. In summary, electroporation of PBMC with mRNA is a very efficient, easy and rapid method for immunomonitoring of HIV-1-specific T-cell responses against autologous viral strains. Our data demonstrate that patients' CTL responses against autologous viral strains may be under- or overestimated by using antigens from heterologous viral strains.     

Human investigations into the exercise pressor reflex

During exercise, neural input from skeletal muscles reflexly maintains or elevates blood pressure (BP) despite a maybe fivefold increase in vascular conductance. This exercise pressor reflex is illustrated by similar heart rate (HR) and BP responses to electrically induced and voluntary exercise. The importance of the exercise pressor reflex for tight cardiovascular regulation during dynamic exercise is supported by studies using pharmacological blockade of lower limb muscle afferent nerves. These experiments show attenuation of the increase in BP and cardiac output when exercise is performed with attenuated neural feedback. Additionally, there is no BP response to electrically induced exercise with paralysing epidural anaesthesia or when similar exercise is evoked in paraplegic patients. Furthermore, BP decreases when electrically induced exercise is carried out in tetraplegic patients. The lack of an increase in BP during exercise with paralysed legs manifests, although electrical stimulation of muscles enhances lactate release and reduces muscle glycogen. Thus, the exercise pressor reflex enhances sympathetic activity and maintains perfusion pressure by restraining abdominal blood flow, while brain, skin and muscle blood flow may also become affected because the reflex 'resets' arterial baroreceptor modulation of vascular conductance, making BP the primarily regulated cardiovascular variable during exercise.     

Sleep EEG alterations: effects of different pulse-modulated radio frequency electromagnetic fields

Previous studies have observed increases in electroencephalographic power during sleep in the spindle frequency range (approximately 11–15 Hz) after exposure to mobile phone‐like radio frequency electromagnetic fields (RF EMF). Results also suggest that pulse modulation of the signal is crucial to induce these effects. Nevertheless, it remains unclear which specific elements of the field are responsible for the observed changes. We investigated whether pulse‐modulation frequency components in the range of sleep spindles may be involved in mediating these effects. Thirty young healthy men were exposed, at weekly intervals, to three different conditions for 30 min directly prior to an 8‐h sleep period. Exposure consisted of a 900‐MHz RF EMF, pulse modulated at 14 Hz or 217 Hz, and a sham control condition. Both active conditions had a peak spatial specific absorption rate of 2 W kg^?1. During exposure subjects performed three different cognitive tasks (measuring attention, reaction speed and working memory), which were presented in a fixed order. Electroencephalographic power in the spindle frequency range was increased during non‐rapid eye movement sleep (2nd episode) following the 14‐Hz pulse‐modulated condition. A similar but non‐significant increase was also observed following the 217‐Hz pulse‐modulated condition. Importantly, this exposure‐induced effect showed considerable individual variability. Regarding cognitive performance, no clear exposure‐related effects were seen. Consistent with previous findings, our results provide further evidence that pulse‐modulated RF EMF alter brain physiology, although the time‐course of the effect remains variable across studies. Additionally, we demonstrated that modulation frequency components within a physiological range may be sufficient to induce these effects.     

Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice

Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6-/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6-/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD.     

Many putative endocrine disruptors inhibit prostaglandin synthesis

Background

Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics.

Objectives and Methods

Using cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption.

Results

We found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator–activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes.

Conclusion

Our findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades.     

Electrophysiological effects of semantic context in picture and word naming

Recent language production studies have started to use electrophysiological measures to investigate the time course of word selection processes. An important contribution with respect to this issue comes from studies that have relied on an effect of semantic context in the semantic blocking task. Here we used this task to further establish the empirical pattern associated with the effect of semantic context, and whether the effect arises during output processing. Electrophysiological and reaction time measures were co-registered while participants overtly named picture and word stimuli in the semantic blocking task. The results revealed inhibitory reaction time effects of semantic context for both words and pictures, and a corresponding electrophysiological effect that could not be interpreted in terms of output processes. These data suggest that the electrophysiological effect of semantic context in the semantic blocking task does not reflect output processes, and therefore undermine an interpretation of this effect in terms of word selection.     

Interventions to safeguard system effectiveness during periods of emergency department crowding

This article summarizes the proceedings of a breakout session, "Interventions to Safeguard System Effectiveness," at the 2011 Academic Emergency Medicine consensus conference, "Interventions to Assure Quality in the Crowded Emergency Department." Key definitions fundamental to understanding the effectiveness of emergency care during periods of emergency department (ED) crowding are outlined. Next, a proposed research agenda to evaluate interventions directed at improving emergency care effectiveness is outlined, and the paper concludes with a prioritization of those interventions based on breakout session participant discussion and evaluation.