Prodromal or mild Alzheimer's disease: Influence of neuropsychiatric symptoms and premordid personality on caregivers' burden.

OBJECTIVE: In Alzheimer's disease (AD), the burden on caregivers is influenced by various factors, including the stage of disease progression and neuropsychiatric symptoms (NPS). To date, there has been limited research examining how patient's premorbid personality could affect this burden. The objective of this study was to investigate the impact of both premorbid personality and NPS in individuals with prodromal to mild AD on their caregivers' burden. METHOD: One hundred eighty participants with prodromal or mild AD drown from the PACO (in French: Personnalité Alzheimer COmportement) cohort were included. Personality was assessed by the Revised NEO Personality Inventory (NEO-PI-R). Neuropsychiatric symptoms were measured with the short version of the Neuropsychiatric Inventory (NPI-Q), and caregiver burden was evaluated with the Zarit burden scale. Relationships between personality, Neuro-Psychiatric Inventory (NPI) scores, and caregiver burden were determined using multivariate linear regressions controlled for age, sex, educational level, and Mini Mental State Examination. RESULTS: The total NPI score was related to increased burden (beta = 0.45; p < 0.001). High level of neuroticism (beta = 0.254; p = 0.003) et low level of conscientiousness (beta = - 0.233; p = 0.005) were associated higher burden. Extraversion (beta = -0.185; p = 0.027) and conscientiousness (beta = -0.35; p = 0.006) were negatively associated with burden. In contrast, neuroticism, openness and agreeableness were not correlated with burden. When adjusted on total NPI score, the relationship between extraversion and conscientiousness didn't persist. CONCLUSION: Our results suggest that premorbid personality of patients with prodromal to mild Alzheimer influence caregivers's burden, with a protective effect of a high level of extraversion and conscientiousness.

Review: cellularity in bone marrow autografts for bone and fracture healing.

The use of autografts, as primary cell and tissue source, is the current gold standard approach to treat critical size bone defects and nonunion defects. The unique mixture of the autografts, containing bony compartments and bone marrow (BM), delivers promising results. Although BM mesenchymal stromal cells (BM-MSCs) still represent a major target for various healing approaches in current preclinical research and respective clinical trials, their occurrence in the human BM is typically low. In vitro expansion of this cell type is regulatory challenging as well as time and cost intensive. Compared with marginal percentages of resident BM-MSCs in BM, BM mononuclear cells (BM-MNCs) contained in BM aspirates, concentrates, and bone autografts represent a readily available abundant cell source, applicable within hours during surgical procedures without the need for time-consuming and regulatory challenging cell expansion. This benefit is one reason why autografting has become a clinical standard procedure. However, the exact anatomy and cellularity of BM-MNCs in humans, which is strongly correlated to their unique mode of action and wide application range remains to be elucidated. The aim of this review was to present an overview of the current knowledge on these specific cell types found in human BM, emphasize the contribution of BM-MNCs in bone healing, highlight donor site dependence, and discuss limitations in the current isolation and subsequent characterization procedures. Hereby, the most recent and relevant examples of human BM-MNC cell characterization, flow cytometric analyses, and findings are summarized, with a strong focus on bone therapy.

Vitamin D Metabolites: Analytical Challenges and Clinical Relevance.

Recent research activities have provided new insights in vitamin D metabolism in various conditions. Furthermore, substantial progress has been made in the analysis of vitamin D metabolites and related biomarkers, such as vitamin D binding protein. Liquid chromatography tandem mass spectrometric (LC-MS/MS) methods are capable of accurately measuring multiple vitamin D metabolites in parallel. Nevertheless, only 25(OH)D and the biologically active form 1,25(OH)2D are routinely measured in clinical practice. While 25(OH)D remains the analyte of choice for the diagnosis of vitamin D deficiency, 1,25(OH)2D is only recommended in a few conditions with a dysregulated D metabolism. 24,25(OH)2D, free and bioavailable 25(OH)D, and the vitamin D metabolite ratio (VMR) have shown promising results, but technical pitfalls in their quantification, limited clinical data and the lack of reference values, impede their use in clinical practice. LC-MS/MS is the preferred method for the measurement of all vitamin D related analytes as it offers high sensitivity and specificity. In particular, 25(OH)D and 24,25(OH)2D can accurately be measured with this technology. When interpreted together, they seem to provide a functional measure of vitamin D metabolism beyond the analysis of 25(OH)D alone. The determination of VDBP, free and bioavailable 25(OH)D is compromised by unresolved analytical issues, lacking reference intervals and insufficient clinical data. Therefore, future research activities should focus on analytical standardization and exploration of their clinical value. This review provides an overview on established and new vitamin D related biomarkers including their pathophysiological role, preanalytical and analytical aspects, expected values, indications and influencing conditions.

Role of Vitamin K in Bone and Muscle Metabolism.

Vitamin K, a cofactor for the γ-glutamyl carboxylase enzyme, is required for the post-translational activation of osteocalcin and matrix Gla protein, which play a key role in bone and muscle homeostasis. In vivo and in vitro models for osteoporosis and sarcopenia suggest the vitamin K could exert a positive effect in both conditions. In bone, it increases osteoblastogenesis, whilst decreases osteoclast formation and function. In muscle, it is associated with increased satellite cell proliferation and migration and might play a role in energy metabolism. Observational trials suggest that high levels of vitamin K are associated with increased bone mineral density and reduced fracture risk. However, interventional studies for vitamin K supplementation yielded conflicting results. Clinical trials in sarcopenia suggest that vitamin K supplementation could improve muscle mass and function. One of the main limitations on the vitamin K studies are the technical challenges to measure its levels in serum. Thus, they are obtained from indirect sources like food questionnaires, or levels of undercarboxylated proteins, which can be affected by other environmental or biological processes. Although current research appoints to a beneficial effect of vitamin K in bone and muscle, further studies overcoming the current limitations are required in order to incorporate this supplementation in the clinical management of patients with osteosarcopenia.

Immune and stem cell compartments of acetabular and femoral bone marrow in hip osteoarthritis patients.

OBJECTIVE: Hip osteoarthritis (OA) affects all components of the osteochondral unit, leading to bone marrow (BM) lesions, and unknown consequences on BM cell functionality. We analyzed the cellular composition in OA-affected acetabula compared to proximal femur shafts obtained of hip OA patients to reveal yet not explored immune and stem cell compartments. DESIGN: Combining flow cytometry, cellular assays and transcription analyses, we performed extensive ex vivo phenotyping of acetabular BM cells from 18 hip OA patients, comparing them with their counterparts from patient-matched femoral shaft BM samples. Findings were related to differences in skeletal sites and age. RESULTS: Acetabular BM had a greater frequency of T-lymphocytes, non-hematopoietic cells and colony-forming units fibroblastic potential than femoral BM. The incidence of acetabular CD45+CD3+ T-lymphocytes increased (95% CI: 0.1770 to 0.0.8416), while clonogenic hematopoietic progenitors declined (95% CI: -0.9023 to -0.2399) with age of patients. On the other side, in femoral BM, we observed higher B-lymphocyte, myeloid and erythroid cell frequencies. Acetabular mesenchymal stromal cells (MSCs) showed a senescent profile associated with the expression of survival and inflammation-related genes. Efficient osteogenic and chondrogenic differentiation was detected in acetabular MSCs, while adipogenesis was more pronounced in their femoral counterparts. CONCLUSION: Our results suggest that distinctions in BM cellular compartments and MSCs may be due to the influence of the OA-stressed microenvironment, but also acetabular vs femoral shaft-specific peculiarities cannot be excluded. These results bring new knowledge on acetabular BM cell populations and may be addressed as novel pathogenic mechanisms and therapeutic targets in OA.

Increased Ion Temperature and Neutron Yield Observed in Magnetized Indirectly Driven D_{2}-Filled Capsule Implosions on the National Ignition Facility.

The application of an external 26 Tesla axial magnetic field to a D_{2} gas-filled capsule indirectly driven on the National Ignition Facility is observed to increase the ion temperature by 40% and the neutron yield by a factor of 3.2 in a hot spot with areal density and temperature approaching what is required for fusion ignition [1]. The improvements are determined from energy spectral measurements of the 2.45 MeV neutrons from the D(d,n)^{3}He reaction, and the compressed central core B field is estimated to be ∼4.9 kT using the 14.1 MeV secondary neutrons from the D(T,n)^{4}He reactions. The experiments use a 30 kV pulsed-power system to deliver a ∼3 µs current pulse to a solenoidal coil wrapped around a novel high-electrical-resistivity AuTa_{4} hohlraum. Radiation magnetohydrodynamic simulations are consistent with the experiment.

Development and characterization of a predictive microCT-based non-union model in Fischer F344 rats.

INTRODUCTION: Non-unions remain a clinical problem and are characterised by the failure to heal after a defined period of time. Current preclinical non-union models apply a wide variety of techniques to diminish intrinsic healing potential deviating from the clinical situation. The aim of this study was to develop and characterise a non-union model in rats using internal plate fixation without the need for additional healing insults, whereby bone healing can be longitudinally assessed using microCT. It was hypothesized that healing/non-unions can be accurately predicted at early time points by microCT. MATERIALS AND METHODS: Female, skeletally mature Fischer F344 rats received a 2 mm or 1 mm femoral osteotomy, stabilized with either a 2 mm thick plate or a 1.25 mm thick plate. Healing was monitored by microCT over 14 weeks and histological analysis at euthanasia. The mechanical environment was characterised using finite element (FE) modelling and biomechanical testing. RESULTS: The majority of animals receiving the 2 mm thick plate displayed poor healing responses in both the 2 mm and 1 mm defect size groups. Bone and cartilage formation were markedly improved using the 1.25 mm thick plate. MicroCT could accurately predict bone forming capacity at early time points (3-4 weeks). CONCLUSIONS: The 2 mm thick plating system confers poor healing responses in female Fischer F344 rats, comparable to atrophic non-unions. By reducing plate thickness to increase interfragmentary strain within the defect site healing is improved, leading to borderline healing situations or increased abundance of cartilage tissue present in the defect site with ultimate failure to bridge the defect (hypertrophic non-union). Furthermore, microCT can reliably identify delayed/non-healing animals within 4 weeks, thereby allowing their selective targeting for the testing of novel, clinically relevant treatment strategies in different clinical situations aimed at restoring impaired bone healing.

Intranasal oxytocin has sympathoexcitatory effects on vascular tone in healthy males.

Oxytocin appears to be involved in the neuroendocrine regulation of sympathetic blood pressure (BP) homeostasis. In animals, intracerebral administration of oxytocin induces BP-relevant sympathetic activation. In humans, central nervous effects of oxytocin on BP regulation remain unclear. Intranasal administration supposedly delivers oligopeptides such as oxytocin directly to the brain. We investigated the effects of intranasal oxytocin on sympathetic vascular baroreflex function in humans using microneurographic techniques. In a balanced, double-blind crossover design, oxytocin or placebo was administered intranasally to 12 lean, healthy males (age 25 ± 4 yr). Muscle sympathetic nerve activity (MSNA) was assessed microneurographically before (presubstance), 30-45 min (postsubstance I), and 105-120 min (postsubstance II) after oxytocin administration. Baroreflex was challenged via graded infusions of vasoactive drugs, and correlation of BP with MSNA and heart rate (HR) defined baroreflex function. Experiments were conducted in the afternoon after a 5-h fasting period. After oxytocin, resting MSNA (burst rate and total activity) showed significant net increases from pre to postsubstance II compared with placebo [Δincrease = +4.3 ± 1.2 (oxytocin) vs. +2.2 ± 1.4 bursts/min (placebo), ANOVA; P < 0.05; total activity = 184 ± 11.5% (oxytocin) vs. 121 ± 14.3% (placebo), ANOVA; P = 0.01). This was combined with a small but significant net increase in resting diastolic BP, whereas systolic and mean arterial BP or HR as well as baroreflex sensitivity at vasoactive drug challenge were not altered. Intranasally administered oxytocin induced vasoconstrictory sympathoactivation in healthy male humans. The concomitant increase of diastolic BP was most likely attributable to increased vascular tone. This suggests oxytocin-mediated upward resetting of the vascular baroreflex set point at centers superordinate to the mere baroreflex-feedback loop.

The EU chemicals strategy for sustainability: in support of the BfR position.

The EU chemicals strategy for sustainability (CSS) asserts that both human health and the environment are presently threatened and that further regulation is necessary. In a recent Guest Editorial, members of the German competent authority for risk assessment, the BfR, raised concerns about the scientific justification for this strategy. The complexity and interdependence of the networks of regulation of chemical substances have ensured that public health and wellbeing in the EU have continuously improved. A continuous process of improvement in consumer protection is clearly desirable but any initiative directed towards this objective must be based on scientific knowledge. It must not confound risk with other factors in determining policy. This conclusion is fully supported in the present Commentary including the request to improve both, data collection and the time-consuming and bureaucratic procedures that delay the publication of regulations.

Decision making under uncertainty in a quasi realistic binary decision task - An fMRI study.

Approaching real life decision making through Quasi Realistic Decision Making may increase the ecological validity of decision making experiments. This could help narrow the gap between laboratory settings and observations in real world contexts and thus allow for generalization of laboratory results to everyday life. A binary decision task with quasi realistic context and stimuli was created to investigate neural processing of certain and uncertain decision making, using functional Magnetic Resonance Imaging. On the basis of behavioral data (consistency of decisions in identical contexts), trials with uncertain and certain decision making were identified. This allowed for comparing uncertain and certain conditions, and contrasting each condition with a low level baseline (i.e., between trial fixation dot). A Conjunction analysis between contrasts of uncertainty versus baseline and certainty versus baseline indicated a large overlap of neural network recruitment distributed in bilateral middle frontal, medial frontal, inferior parietal, occipito-temporal, and medio-temporal areas, and the cingulate cortex. While basic neural processing principles in uncertain and certain contexts were comparable, the direct contrast revealed activation foci in middle cingulate and in frontal and parietal areas. The quasi realistic approach revealed a common network for decision making which is modulated by uncertainty.

[COVID-19 pandemic: structured expansion of ventilation capacities using home respirators]. / COVID-19-Pandemie: strukturierte Erweiterung von Beatmungskapazitäten mithilfe von Heimrespiratoren.

Due to the current COVID-19 pandemic there is a need for a rapid increase in intensive care and ventilation capacities. Delivery times for additional intensive care respirators are currently not foreseeable. An option to increase ventilation capacities not only for COVID-19, but for all patients requiring mechanical ventilation is to use home respirators. Home respirators are turbine respirators, so they can usually be operated without high-pressure oxygen connections and can therefore also be used in areas outside the classical intensive care medical infrastructure. Due to their limited technical features, home respirators are not suitable for the treatment of severely affected patients but can be used for weaning after respiratory improvement, which means that intensive care respirators are available again more quickly. Respiratory therapists are specially trained nurses or therapists in the field of out of hospital ventilation and can independently use home ventilation respirators, for example for weaning in the intensive care unit. Thus, they relieve intensive care nursing staff in the pandemic. Due to the COVID-19 pandemic medical students from the Oldenburg University are currently being trained in operating home respirators to provide basic support in the hospital if necessary.

Approaches to mimic the complexity of the skeletal mesenchymal stem/stromal cell niche in vitro.

Mesenchymal stem/stromal cells (MSCs) are an essential element of most modern tissue engineering and regenerative medicine approaches due to their multipotency and immunoregulatory functions. Despite the prospective value of MSCs for the clinics, the stem cells community is questioning their developmental origin, in vivo localization, identification, and regenerative potential after several years of far-reaching research in the field. Although several major progresses have been made in mimicking the complexity of the MSC niche in vitro, there is need for comprehensive studies of fundamental mechanisms triggered by microenvironmental cues before moving to regenerative medicine cell therapy applications. The present comprehensive review extensively discusses the microenvironmental cues that influence MSC phenotype and function in health and disease - including cellular, chemical and physical interactions. The most recent and relevant illustrative examples of novel bioengineering approaches to mimic biological, chemical, and mechanical microenvironmental signals present in the native MSC niche are summarized, with special emphasis on the forefront techniques to achieve bio-chemical complexity and dynamic cultures. In particular, the skeletal MSC niche and applications focusing on the bone regenerative potential of MSC are addressed. The aim of the review was to recognize the limitations of the current MSC niche in vitro models and to identify potential opportunities to fill the bridge between fundamental science and clinical application of MSCs.

[Polypharmacy after Discharge from Hospital: An Analysis Using Data of the Statutory Health Insurance (AOK) of Saxony-Anhalt]. / Polypharmazie in der nachstationären Versorgung: Eine Analyse mit Daten der AOK Sachsen-Anhalt.

INTRODUCTION AND AIM: The growing number of people suffering from chronic diseases and multimorbidity is associated with an increased risk of polypharmacy. The aims of the study are to estimate the prevalence of polypharmacy and to analyse its determinants in the transition from in- to outpatient care. Furthermore, we estimate the risk of a potential inappropriate medication (PIM) and its determinants. METHODS: The analyses are based on the data of a German statutory health insurance (AOK Saxony-Anhalt) of the third quarter of 2009. The analyses include all insured persons aged 60 years and older who were discharged from hospital within the study period and had filled at least one prescription at the pharmacy (n=21 041). After the analysis of prevalence rates of polypharmacy within 30 days after discharge from hospital, we used binary logistic regression models to estimate the effect of determinants of polypharmacy and PIM. In addition, interaction effects between the number of diseases and the number of practitioners involved in the therapy were calculated. RESULTS: Our analyses show a significant effect of the number of diseases and the number of practitioners on the risk of polypharmacy. Furthermore, patients who are treated with 5 or more drugs have a significantly higher risk of a PIM prescription. The interaction model illustrates a disproportional rise of polypharmacy risk in women with multiple chronic conditions with an increase in the number of doctors treating them. CONCLUSION: The results suggest that polypharmacy is not a result of increasing morbidity alone. Furthermore, the remarkable effect of the number of physicians treating a patient points to an unsolved problem in communication and coordination in outpatient pharmacotherapy and shows the need for centralized medication monitoring.

Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy.

The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.

IκB kinase inhibition as a potential treatment of osteoarthritis - results of a clinical proof-of-concept study.

OBJECTIVE: This publication summarizes the clinical development of the compound SAR113945, an IκB kinase inhibitor injected intra-articularly in a slow-release formulation to treat patients with symptomatic osteoarthritis (OA) of the knee. RESULTS: In vitro experiments demonstrated a specific inhibition of the IκB kinase complex. Profiling of SAR113945 on kinases, enzymes and ion channels supported the initiation of a clinical development. Cellular assay systems also revealed an inhibition in the synthesis of interleukin 1ß, tumor necrosis factor α (TNFα) and the prostaglandin E2 (PGE2). In vivo studies demonstrated positive effects of SAR113945 on thermal and mechanical hyperalgesia and even showed superiority in comparison with triamcinolone. Pharmacokinetic measurements showed a sustained release of dissolved SAR113945 locally supporting a comparably high exposure in the knee joint combined with a low systemic exposure. Three phase 1 studies with a dose-escalating design confirmed safety and tolerability of SAR113945. In those studies SAR113945 showed a positive trend on the WOMAC scores. The proof-of-concept or phase 2a study failed to show any effect in the overall group of recruited study participants for the primary endpoint, the WOMAC pain subscore at day 56, but showed a statistically significant difference in a subgroup of patients who had presented with effusion at baseline. CONCLUSION: Inhibiting the NFκB signaling pathway is an attractive method to treat patients with signs and symptoms of OA. The preclinical work and the results of the phase 1 studies appeared promising for a full clinical development, however, the proof-of-concept study failed to show efficacy in a larger patient sample size.

Distinct phasic and sustained brain responses and connectivity of amygdala and bed nucleus of the stria terminalis during threat anticipation in panic disorder.

BACKGROUND: Panic disorder (PD) patients are constantly concerned about future panic attacks and exhibit general hypersensitivity to unpredictable threat. We aimed to reveal phasic and sustained brain responses and functional connectivity of the amygdala and the bed nucleus of the stria terminalis (BNST) during threat anticipation in PD. METHODS: Using functional magnetic resonance imaging (fMRI), we investigated 17 PD patients and 19 healthy controls (HC) during anticipation of temporally unpredictable aversive and neutral sounds. We used a phasic and sustained analysis model to disentangle temporally dissociable brain activations. RESULTS: PD patients compared with HC showed phasic amygdala and sustained BNST responses during anticipation of aversive v. neutral stimuli. Furthermore, increased phasic activation was observed in anterior cingulate cortex (ACC), insula and prefrontal cortex (PFC). Insula and PFC also showed sustained activation. Functional connectivity analyses revealed partly distinct phasic and sustained networks. CONCLUSIONS: We demonstrate a role for the BNST during unpredictable threat anticipation in PD and provide first evidence for dissociation between phasic amygdala and sustained BNST activation and their functional connectivity. In line with a hypersensitivity to uncertainty in PD, our results suggest time-dependent involvement of brain regions related to fear and anxiety.

Attached and Suspended Denitrifier Communities in Pristine Limestone Aquifers Harbor High Fractions of Potential Autotrophs Oxidizing Reduced Iron and Sulfur Compounds.

Oxygen and nitrate availability as well as the presence of suitable organic or inorganic electron donors are strong drivers of denitrification; however, the factors influencing denitrifier abundance and community composition in pristine aquifers are not well understood. We explored the denitrifier community structure of suspended and attached groundwater microorganisms in two superimposed limestone aquifer assemblages with contrasting oxygen regime in the Hainich Critical Zone Exploratory (Germany). Attached communities were retrieved from freshly crushed parent rock material which had been exposed for colonization in two groundwater wells (12.7 and 48 m depth). Quantitative PCR and amplicon pyrosequencing of nirK and nirS genes encoding copper-containing or cytochrome cd1 heme-type nitrite reductase, respectively, and of bacterial 16S ribosomal RNA genes showed a numerical predominance of nirS-type denitrifiers in both attached and suspended groundwater communities and a dominance of nirS-type denitrifiers closely related to the autotrophic thiosulfate- and hydrogen-oxidizing Sulfuritalea hydrogenivorans and the iron- and sulfide-oxidizing Sideroxydans lithotrophicus ES-1. Potential rates of nitrate reduction in association with exposed crushed rock material were higher with an inorganic electron donor (thiosulfate) compared to an organic electron donor (fumarate/acetate) in the upper aquifer assemblage but similar in the lower, oxic aquifer. Our results have clearly demonstrated that groundwater from pristine limestone aquifers harbors diverse denitrifier communities which appear to selectively attach to rock surfaces and harbor a high potential for nitrate reduction. Our findings suggest that the availability of suitable inorganic versus organic electron donors rather than oxygen availability shapes denitrifier communities and their potential activity in these limestone aquifers.

Addiction: an underestimated problem in psoriasis health care.

BACKGROUND: Psoriasis is a disease of enormous socio-economic impact. Despite approval of numerous highly efficient and costly therapies, a minor proportion of severely affected patients actually receives sufficient treatment. OBJECTIVE: To investigate whether addictions are associated with psoriasis and to develop evidence-based recommendations for dermatologists in their daily clinical practice in order to improve medical assessment of psoriasis and patients' quality of life. PATIENTS AND METHODS: Psoriasis patients at the University Department of Dermatology were asked to fill out a paper-based self-reported anonymous questionnaire with 92 questions of validated screening tests for the six most common addictions in Germany (alcohol, nicotine, drugs and illegal drugs, gambling, food). Body weight and height as well as current Psoriasis Area and Severity Index (PASI) were documented as well. RESULTS: Between October 2015 and February 2016, 102 patients (65 males, 37 females; mean age 49.7 years (SD 13.4), range 18-83 years) participated in the study. Fifty-seven of the 102 patients showed addictive behaviour. Of these, 23.8% were high-risk drinkers, 41% regular smokers, 11% at risk of drug abuse, 4.1% at risk of food dependency and 19% compulsive gamblers. Compared with the general population, these results are significantly higher for alcohol abuse (P < 0.005), nicotine (P < 0.001) and gambling (P < 0.001). Body mass index was significantly higher in the study population (P < 0.001). CONCLUSION: Addictions and gambling are more prevalent in patients with psoriasis compared with the general population. Respective screening measures are recommended in daily practice for doctors treating psoriasis patients, and PeakPASI is suggested as a score to document patients' lifetime highest PASI. Parallel to new drug approvals and even more detailed insights into the pathomechanism of psoriasis, public health strategies and interdisciplinary approaches are essential for a general sustained psoriasis treatment.

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus.

In Staphylococcus aureus, metabolism is intimately linked with virulence determinant biosynthesis, and several metabolite-responsive regulators have been reported to mediate this linkage. S. aureus possesses at least three members of the RpiR family of transcriptional regulators. Of the three RpiR homologs, RpiRc is a potential regulator of the pentose phosphate pathway, which also regulates RNAIII levels. RNAIII is the regulatory RNA of the agr quorum-sensing system that controls virulence determinant synthesis. The effect of RpiRc on RNAIII likely involves other regulators, as the regulators that bind the RNAIII promoter have been intensely studied. To determine which regulators might bridge the gap between RpiRc and RNAIII, sarA, sigB, mgrA, and acnA mutations were introduced into an rpiRc mutant background, and the effects on RNAIII were determined. Additionally, phenotypic and genotypic differences were examined in the single and double mutant strains, and the virulence of select strains was examined using two different murine infection models. The data suggest that RpiRc affects RNAIII transcription and the synthesis of virulence determinants in concert with σ(B), SarA, and the bacterial metabolic status to negatively affect virulence.

Sialylation of anti-histone immunoglobulin G autoantibodies determines their capabilities to participate in the clearance of late apoptotic cells.

The Fc portion of immunoglobulin (Ig)G harbours a single glycosylation site. Glycan sialylation is critical for structure and for certain effector functions of IgG. Anti-histone IgG of patients with systemic lupus erythematosus is reportedly responsible for the recruitment of polymorphonuclear cells (PMN) to the clearance of apoptotic cells. Autoantibodies decorating secondary necrotic cells (SNEC) induce proinflammatory responses after activation of blood-borne phagocytes. Analysing the sialylation status of affinity-purified anti-histone IgG in patients with systemic lupus erythematosus (SLE), we demonstrated that the anti-histone IgG was contained preferentially in the non-sialylated fraction. In functional ex-vivo phagocytosis studies, non-sialylated anti-SNEC IgG directed SNEC preferentially into PMN but did not change their cytokine secretion profiles. In contrast, sialylated IgG reduced the phagocytosis by monocytes of SNEC. Moreover, the sialylated anti-SNEC IgG was not simply anti-inflammatory, but switched the cytokine secretion profiles from interleukin (IL)-6/IL-8 to tumour necrosis factor (TNF)-α/IL-1ß. Here we describe how different sialylation statuses of IgG autoantibodies contribute to the complex inflammatory network that regulates chronic inflammation.