Neuropsychological functions,sleep, and mental health in adults with Klinefelter syndrome

A few studies have examined neuropsychological functions, sleep, and mental health combined in Klinefelter syndrome (KS; 47,XXY). We investigated neuropsychological functions with standard tests, sleep with actigraphy, and self‐reported mental health in 30 men with KS (Mean age = 36.7 years) compared to 21 controls (Mean age = 36.8 years). Men with KS scored significantly lower on mental speed, attention span, working memory, inhibition, and set‐shifting tests, as well as overall IQ (mean effect size difference Cohen's d = 0.79). Men with KS had significantly longer night wakes, with no differences in other sleep variables (mean d = 0.34). Men with KS reported poorer mental health than controls (mean d = 1.16). Regression analyses showed neuropsychological functions explained variance in some sleep domains for men with KS but not for controls. Neuropsychological functions explained variance in some mental health domains for controls. For men with KS, however, verbal IQ was the only significant predictor of mental health. Altogether, men with KS display problems in neuropsychological functions and mental health but do not appear different from controls on most sleep parameters. Our findings indicate that relations between neuropsychological functions, sleep, and mental health differ between men with KS and controls.     

Activation of Islet Autoreactive Na?ve T Cells in Infants Is Influenced by Homeostatic Mechanisms and Antigen-Presenting Capacity

Islet autoimmunity precedes type 1 diabetes onset. We previously found that islet autoimmunity rarely starts before 6 months of age but reaches its highest incidence already at ∼1 year of age. We now examine whether homeostatic expansion and immune competence changes seen in a maturating immune system may account for this marked variation in islet autoimmunity risk in the first year of life. We found naïve proinsulin- and GAD65-responsive T cells in cord blood (CB) of healthy newborns, with highest responses observed in children with type 1 diabetes-susceptible HLA-DRB1/DQB1 genotypes. Homeostatic expansion characteristics with increased IL-7 concentrations and enhanced T-cell responsiveness to IL-7 were observed throughout the first year of life. However, the ability of antigen-presenting cells to activate naïve T cells was compromised at birth, and CB monocytes had low surface expression of CD40 and HLA class II. In contrast, antigen presentation and expression of these molecules had reached competent adult levels by the high incidence age of 8 months. We propose that temporal changes in islet autoimmunity seroconversion in infants are a consequence of the changing balance between homeostatic drive and antigen presentation competence. These findings are relevant for early prevention of type 1 diabetes.Type 1 diabetes is an autoimmune disease resulting from the destruction of insulin-producing pancreatic islet β-cells. The disease is associated with the presence of autoantibodies and antigen-experienced T cells against islet autoantigens (1). Autoreactive T cells can be identified in patients with type 1 diabetes and nondiabetic control subjects (2). Patients have naïve and memory autoantigen-responsive CD4⁺ and CD8⁺ T cells, whereas autoreactive T cells identified in control subjects appear to be confined to the naïve T-cell compartment (3).The presence of autoimmunity against islet antigens is detected by measuring autoantibodies in the blood and it is assumed that seroconversion to islet autoantibody positivity is accompanied by activation of islet autoreactive T cells. Seroconversion is rare prior to 6 months of age but rapidly reaches a peak incidence at ∼1 year of age in genetically susceptible children (4,5). We postulated that a switch from relative protection to susceptibility to islet autoimmunity may be driven by physiological changes in immune competence and homeostatic mechanisms in the first years of life. T cells at birth are mostly naïve, thereby requiring strong signals through the T-cell receptor and costimulation for priming. On the other hand, neonates have active homeostatic mechanisms, including a high cell cycle rate and an increased serum IL-7 concentration favoring clonal expansion (6–8). Here, we compare responsiveness and immune competence of circulating T cells and antigen-presenting cells (APCs) during periods of relative protection (birth) and susceptibility (8 months) to islet autoimmunity. Both periods are characterized by the presence of autoantigen-responsive naïve T cells and T cells that are highly sensitive to homeostatic expansion mechanisms. However, the activation of naïve T cells is compromised at birth and appears fully competent at 8 months of age. We predict, therefore, that the combination of an HLA genotype–determined islet autoreactive naïve T-cell population, homeostatic expansion mechanisms, and immune competence provides a highly favorable environment for islet autoimmunity and, in part, determines the high incidence of seroconversion observed at ∼1 year of age. This has implications for early prevention of islet autoimmunity.     

Molecular-level HLA mismatch is associated with rejection and worsened graft survival in heart transplant recipients – a retrospective study

The aim was to evaluate the association of molecular-level human leukocyte antigen (HLA) mismatching with post-transplant graft survival, rejection, and cardiac allograft vasculopathy (CAV). We retrospectively analyzed all primary cardiac transplant recipients between 01/1984-06/2016. 1167 patients fulfilled inclusion criteria and had HLA typing information available. In 312 donor-recipient pairs, typing at serological split antigen level was available. We used the Epitope MisMatch Algorithm to calculate the number of amino acid differences in antibody-verified HLA eplets (amino acid mismatch load (AAMM)) between donor and recipient. Patients with a higher HLA-DR AAMM load had inferior 1-year graft survival (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01–1.28). The HLA-AB AAMM load showed no impact on graft survival. In the subgroup with available split-level information, we observed an inferior graft survival for a higher HLA-DR AAMM load 3 months after transplantation (HR, 1.22; 95% CI, 1.04–1.44) and a higher risk for rejection for an increasing HLA-AB (HR, 1.70; 95% CI, 1.29–2.24) and HLA-DR (HR, 1.32; 95% CI, 1.09–1.61) AAMM load. No impact on the development of CAV was found. Molecular-level HLA mismatch analysis could serve as a tool for risk stratification after heart transplantation and might take us one step further into precision medicine.     

Attention to affective pictures in closed head injury: event-related brain potentials and cardiac responses

We examined whether closed head injury patients show altered patterns of selective attention to stimulus categories that naturally evoke differential responses in healthy people. Self-reported rating and electrophysiological (event-related potentials [ERPs], heart rate [HR]) responses to affective pictures were studied in patients with mild head injury (n = 20; CT/MRI negative), in patients with predominantly frontal brain lesions (n = 12; CT/MRI confirmed), and in healthy controls (n = 20). Affective valence similarly modulated HR and ERP responses in all groups, but group differences occurred that were independent of picture valence. The attenuation of P3-slow wave amplitudes in the mild head injury group indicates a reduction in the engagement of attentional resources to the task. In contrast, the general enhancement of ERP amplitudes at occipital sites in the group with primarily frontal brain injury may reflect disinhibition of input at sensory receptive areas, possibly due to a deficit in top-down modulation performed by anterior control systems.     

Therapeutic doubt and moral dialogue

This paper aims at analysing the problem of remainder and regret in moral conflicts. Four different approaches are subject of investigation: a moral-theoretical strategy aimed at consistency; a narrative approach of moral coherence and open consensus; Plato's moral methodology of dialogue and aporetic resolution of moral conflicts and finally, an approach deduced from Greek tragedy of emotional resolution of moral conflicts. A central argument is that since there exists no theoretically convincing way of solving the problem of remainder and regret, the attention should instead be directed towards finding alternative ways of coping with this problem. The three last approaches subject of investigation attempt--each in their own way--to do this. Teaching medical ethics to medical students and the burning issue of medical fallibility is used to demonstrate the relevance of these forms of resolution in a medical context.     

X-Nuclei NMR Self-Diffusion Studies in Mesoporous Silica Foam and Microporous MOF CuBTC

A standard X-observe NMR probe was equipped with a z-gradient coil to enable high-sensitivity pulsed field gradient NMR diffusion studies of Li⁺ and Cs⁺ cations of aqueous salt solutions in a high-porosity mesocellular silica foam (MCF) and of CO₂ adsorbed in metal-organic frameworks (MOF). The coil design and the necessary probe modifications, which yield pulsed field gradients of up to ±16.2 Tm^-1, are introduced. The system was calibrated at ²H resonance frequency and successfully applied for diffusion studies at ⁷Li, ²³Na, ¹³C and ¹³³Cs frequencies. Significant reductions of the diffusivities of the cations in LiCl_ac and CsCl_ac solution introduced into MCFs are observed. By comparison of the diffusion behavior with the bulk solutions, a tortuosity of the silica foam of 4.5 ± 0.6 was derived. Single component self-diffusion of CO₂ and CH₄ (measured by ¹H NMR) as well as self-diffusion of the individual components in CO₂/CH₄ mixtures was studied in the MOF CuBTC. The experimental results confirm high mobilities of the adsorbed gases and trends for diffusion separation factors predicted by MD simulations.     

Assessment of P3a and P3b after moderate to severe brain injury.

The purpose of the study was to examine the P3a and P3b components of the event-related brain potential (ERP) in patients sustaining moderate to severe brain injury. Electrophysiological and behavioral responses were recorded in brain injured (N = 18) and healthy control (N = 21) participants performance of an auditory 3-stimulus distractor paradigm. Auditory stimuli consisted of a series of repetitive standard tones (75 ms), occasionally interrupted by equiprobable target (25 ms) and distractor sounds (white noise). Tone duration discrimination accuracy was similar in patients and controls, but patients had prolonged reaction times to targets. The reaction time delay was paralleled by a prolongation of P3b latency to targets in the patient group relative to controls. The stimulus and task dependent modulation of ERP responses in the brain injury group was similar to that of controls in terms of the spatial distribution of ERPs over the scalp. However, the brain injury group had attenuated P3a and P3b amplitudes to distractor and target stimuli, respectively. The electrophysiological data suggest a deficit in the allocation of attentional resources to the processing of deviant stimuli in the brain injury group.     

Stem cell research and the ethics of transparency

Stem cell research represents a field of scientific inquiry subject to intense public and political attention and debate worldwide. There are several reasons for this. First, it is a research endeavor surrounded by great expectations of future therapeutic benefits. Some of these expectations seem to be well founded, while others originate from adult and embryonic research enthusiasts having hyped their case. A second reason why this represents a field of public and political attention relates to deeply felt concerns regarding the moral justifiability of sacrificing potential human lives for research. The aim of this paper is to discuss different ways of making the performance of international embryonic stem cell research more transparent, and of unveiling the need for more open-minded dialog concerning the ethical costs of this research endeavor.     

Coupling of ferredoxin and heterodisulfide reduction via electron bifurcation in hydrogenotrophic methanogenic archaea

In methanogenic archaea growing on H(2) and CO(2) the first step in methanogenesis is the ferredoxin-dependent endergonic reduction of CO(2) with H(2) to formylmethanofuran and the last step is the exergonic reduction of the heterodisulfide CoM-S-S-CoB with H(2) to coenzyme M (CoM-SH) and coenzyme B (CoB-SH). We recently proposed that in hydrogenotrophic methanogens the two reactions are energetically coupled via the cytoplasmic MvhADG/HdrABC complex. It is reported here that the purified complex from Methanothermobacter marburgensis catalyzes the CoM-S-S-CoB-dependent reduction of ferredoxin with H(2). Per mole CoM-S-S-CoB added, 1 mol of ferredoxin (Fd) was reduced, indicating an electron bifurcation coupling mechanism: 2H(2) + Fd(OX) + CoM-S-S-CoB-->Fd(red)(2-) + CoM-SH + CoB-SH + 2H(+). This stoichiometry of coupling is consistent with an ATP gain per mole methane from 4 H(2) and CO(2) of near 0.5 deduced from an H(2)-threshold concentration of 8 Pa and a growth yield of up to 3 g/mol methane.