The Parkinson's disease variant rs356182 regulates neuronal differentiation independently from alpha-synuclein.

One of the most significant risk variants for Parkinson's disease (PD), rs356182, is located at the PD-associated locus near the alpha-synuclein (α-syn) encoding gene, SNCA. SNCA-proximal variants, including rs356182, are thought to function in PD risk through enhancers via allele-specific regulatory effects on SNCA expression. However, this interpretation discounts the complex activity of genetic enhancers and possible non-conical functions of α-syn. Here we investigated a novel risk mechanism for rs356182. We use CRISPR-Cas9 in LUHMES cells, a model for dopaminergic midbrain neurons, to generate precise hemizygous lesions at rs356182. The PD-protective (A/-), PD-risk (G/-) and wild-type (A/G) clones were neuronally differentiated and then compared transcriptionally and morphologically. Among the affected genes was SNCA, whose expression was promoted by the PD-protective allele (A) and repressed in its absence. In addition to SNCA, hundreds of genes were differentially expressed and associated with neurogenesis and axonogenesis-an effect not typically ascribed to α-syn. We also found that the transcription factor FOXO3 specifically binds to the rs356182 A-allele in differentiated LUHMES cells. Finally, we compared the results from the rs356182-edited cells to our previously published knockouts of SNCA and found only minimal overlap between the sets of significant differentially expressed genes. Together, the data implicate a risk mechanism for rs356182 in which the risk-allele (G) is associated with abnormal neuron development, independent of SNCA expression. We speculate that these pathological effects manifest as a diminished population of dopaminergic neurons during development leading to the predisposition for PD later in life.

Role of smooth muscle activation in the static and dynamic mechanical characterization of human aortas.

Experimental data and a suitable material model for human aortas with smooth muscle activation are not available in the literature despite the need for developing advanced grafts; the present study closes this gap. Mechanical characterization of human descending thoracic aortas was performed with and without vascular smooth muscle (VSM) activation. Specimens were taken from 13 heart-beating donors. The aortic segments were cooled in Belzer UW solution during transport and tested within a few hours after explantation. VSM activation was achieved through the use of potassium depolarization and noradrenaline as vasoactive agents. In addition to isometric activation experiments, the quasistatic passive and active stress-strain curves were obtained for circumferential and longitudinal strips of the aortic material. This characterization made it possible to create an original mechanical model of the active aortic material that accurately fits the experimental data. The dynamic mechanical characterization was executed using cyclic strain at different frequencies of physiological interest. An initial prestretch, which corresponded to the physiological conditions, was applied before cyclic loading. Dynamic tests made it possible to identify the differences in the viscoelastic behavior of the passive and active tissue. This work illustrates the importance of VSM activation for the static and dynamic mechanical response of human aortas. Most importantly, this study provides material data and a material model for the development of a future generation of active aortic grafts that mimic natural behavior and help regulate blood pressure.

Review of Systemic Mock Circulation Loops for Evaluation of Implantable Cardiovascular Devices and Biological Tissues.

CLINICAL IMPACT: On needs-based ex vivo monitoring of implantable devices or tissues/organs in cardiovascular simulators provides new insights and paves new paths for device prototypes. The insights gained could not only support the needs of patients, but also inform engineers, scientists and clinicians about undiscovered aspects of diseases (during routine monitoring). We analyze seminal and current work and highlight a variety of opportunities for developing preclinical tools that would improve strategies for future implantable devices. Holistically, mock circulation loop studies can bridge the gap between in vivo and in vitro approaches, as well as clinical and laboratory settings, in a mutually beneficial manner.

Crosslinking Vinyl-Addition Polynorbornenes via Difunctional Diazirines to Generate Low Dielectric-Constant and Low Dielectric-Loss Thermosets.

Thermosets having low dielectric constant (Dk < 3) and low dielectric dissipation factor (Df < 0.003), high glass transition temperature (Tg > 150 °C), and good adhesion to copper are desirable for the low loss layers of the copper clad laminates (CCL) in next generation printed circuit boards. Three different difunctional diazirines are evaluated for both thermal and photochemical crosslinking of a high Tg vinyl-addition polynorbornene resin: poly(5-hexyl-1-norbornene) (poly(HNB)). The substrate polymer, crosslinked by the carbenes generated from the activated diazirines, forms thermosets with Dk < 2.3 and Df < 0.001 at 10 GHz depending on the identity of the diazirine and the loading. The Dk and Df values for one composition are stable for 1600 h at 125 °C in air and for 1400 h at 85 °C and 85% relative humidity, suggesting good long-term reliability of this thermoset. Adhesion of poly(HNB) to copper can be enhanced by priming the copper surface with a diazirine prior to high temperature lamination; peel strength values of greater than 7.5 N cm-1 are achieved. Negative-tone photopatterning of poly(HNB) with diazirines upon exposure to 365 nm light is demonstrated.

[From the practice of monitoring SARS-CoV-2 test sites in the city of Cologne]. / Aus der Praxis der Überwachung der SARS-CoV-2-Teststellen im Stadtgebiet Köln.

In spring 2021, a law for the nationwide opening of test centers in Germany was passed. The local health department fulfilled the task of monitoring the test centers that subsequently opened throughout Cologne regarding the infectious and hygienic risks. Inspections were carried out using structured checklists. A retrospect evaluation of the identified deficiencies was run for the period between March 15 and July 31, 2021. In 84% of the cases, hygienic deficiencies were found when the test sites were inspected for the first time. 35% of the test sites were closed immediately, most of them temporarily. These first results provide information on frequent and important hygienic problems of the rapid set up of test sites and important advice for avoiding those and thus protecting employees and test persons.

[Test Concept of the City of Cologne for Critical Infrastructure (KRITIS) during the First Wave of the COVID-19 Pandemic]. / Testkonzept der Stadt Köln für die Kritische Infrastruktur (KRITIS) in der ersten Welle der Corona-Pandemie.

BACKGROUND: At the beginning of the COVID-19 pandemic, the Public Health Department of the City of Cologne established preferential testing for critical infrastructure (KRITIS) personnel. The aim of this study was to retrospectively analyze this concept. METHODS: Test results as well as demographic and job-related data from March to April 2020 were collected and descriptively analyzed using a specially developed software. KRITIS personnel who tested positive were systematically interviewed over the phone. RESULTS: 1521 individuals were tested, of whom 896 (59%) were from the healthcare sector, particularly from the nursing professions (35%). Testing and consultation services were also utilized by employees of non-profit organizations (8%), administration (7%), fire department (11%), and police (4%). KRITIS personnel who tested positive suspected increased risk from contacts at the workplace (58%), mostly without adequate protection (85%). Of those surveyed, 83% rated the KRITIS concept as 'good' or 'very good'. Processes at the testing center were rated as 'good' or 'very good' by 89%, while 47% rated phone support as 'good' or 'very good', and 30% as 'sufficient' or poor. Free comments showed that frequent phone contact from the Public Health Department was perceived as positive and even more often as negative interindividually. Communication and advice were positively highlighted, while lack of competence and coordination were criticized. The respondents criticized the comparatively lower provision of testing services for family members, for example, due to limited resources. CONCLUSION: With the KRITIS concept, the Public Health Department of Cologne developed and implemented an offer for system-relevant professional groups that was intensively used and mostly assessed as positive. This concept can be used as a blueprint for other pandemics.

[Medical clinical diagnostics for indoor mould exposure - Update 2023 (AWMF Register No. 161/001)]. / Medizinisch klinische Diagnostik bei Schimmelpilzexposition in Innenräumen ­ Update 2023 (AWMF-Register-Nr. 161/001).

This article is an abridged version of the updated AWMF mould guideline "Medical clinical diagnostics in case of indoor mould exposure - Update 2023", presented in July 2023 by the German Society of Hygiene, Environmental Medicine and Preventive Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin, GHUP), in collaboration with German and Austrian scientific medical societies, and experts. Indoor mould growth is a potential health risk, even if a quantitative and/or causal relationship between the occurrence of individual mould species and health problems has yet to be established. There is no evidence for a causal relationship between moisture/mould damage and human diseases, mainly because of the ubiquitous presence of fungi and hitherto inadequate diagnostic methods. Sufficient evidence for an association between moisture/mould damage and the following health effects has been established for: allergic respiratory diseases, allergic rhinitis, allergic rhino-conjunctivitis, allergic bronchopulmonary aspergillosis (ABPA), other allergic bronchopulmonary mycosis (ABPM), aspergilloma, Aspergillus bronchitis, asthma (manifestation, progression, exacerbation), bronchitis (acute, chronic), community-acquired Aspergillus pneumonia, hypersensitivity pneumonitis (HP; extrinsic allergic alveolitis (EEA)), invasive Aspergillosis, mycoses, organic dust toxic syndrome (ODTS) [workplace exposure], promotion of respiratory infections, pulmonary aspergillosis (subacute, chronic), and rhinosinusitis (acute, chronically invasive, or granulomatous, allergic). In this context the sensitizing potential of moulds is obviously low compared to other environmental allergens. Recent studies show a comparatively low sensitization prevalence of 3-22,5 % in the general population across Europe. Limited or suspected evidence for an association exist with respect to atopic eczema (atopic dermatitis, neurodermatitis; manifestation), chronic obstructive pulmonary disease (COPD), mood disorders, mucous membrane irritation (MMI), odor effects, and sarcoidosis. (iv) Inadequate or insufficient evidence for an association exist for acute idiopathic pulmonary hemorrhage in infants, airborne transmitted mycotoxicosis, arthritis, autoimmune diseases, cancer, chronic fatigue syndrome (CFS), endocrinopathies, gastrointestinal effects, multiple chemical sensitivity (MCS), multiple sclerosis, neuropsychological effects, neurotoxic effects, renal effects, reproductive disorders, rheumatism, sick building syndrome (SBS), sudden infant death syndrome, teratogenicity, thyroid diseases, and urticaria.The risk of infection posed by moulds regularly occurring indoors is low for healthy persons; most species are in risk group 1 and a few in risk group 2 (Aspergillus fumigatus, A. flavus) of the German Biological Agents Act (Biostoffverordnung). Only moulds that are potentially able to form toxins can be triggers of toxic reactions. Whether or not toxin formation occurs in individual cases is determined by environmental and growth conditions, water activity, temperature and above all the growth substrates.In case of indoor moisture/mould damage, everyone can be affected by odor effects and/or mood disorders.However, this is not an acute health hazard. Predisposing factors for odor effects can include genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for mood disorders may include environmental concerns, anxiety, condition, and attribution, as well as various diseases. Risk groups to be protected particularly regarding infection risk are immunocompromised persons according to the classification of the German Commission for Hospital Hygiene and Infection Prevention (Kommission für Krankenhaushygiene und Infektionsprävention, KRINKO) at the Robert Koch-Institute (RKI), persons suffering from severe influenza, persons suffering from severe COVID-19, and persons with cystic fibrosis (mucoviscidosis); with regard to allergic risk, persons with cystic fibrosis (mucoviscidosis) and patients with bronchial asthma must be protected. The rational diagnostics include the medical history, physical examination, and conventional allergy diagnostics including provocation tests if necessary; sometimes cellular test systems are indicated. In the case of mould infections, the reader is referred to the specific guidelines. Regarding mycotoxins, there are currently no useful and validated test procedures for clinical diagnostics. From a preventive medical point of view, it is important that indoor mould infestation in relevant magnitudes cannot be tolerated for precautionary reasons.For evaluation of mould damage in the indoor environment and appropriate remedial procedures, the reader is referred to the mould guideline issued by the German Federal Environment Agency (Umweltbundesamt, UBA).

Galectin-3, Acute Kidney Injury and Myocardial Damage in Patients With Acute Heart Failure.

BACKGROUND: Galectin-3, a biomarker of inflammation and fibrosis, can be associated with renal and myocardial damage and dysfunction in patients with acute heart failure (AHF). METHODS AND RESULTS: We retrospectively analyzed 790 patients with AHF who were enrolled in the AKINESIS study. During hospitalization, patients with galectin-3 elevation (> 25.9 ng/mL) on admission more commonly had acute kidney injury (assessed by KDIGO criteria), renal tubular damage (peak urine neutrophil gelatinase-associated lipocalin [uNGAL] > 150 ng/dL) and myocardial injury (≥ 20% increase in the peak high-sensitivity cardiac troponin I [hs-cTnI] values compared to admission). They less commonly had ≥ 30% reduction in B-type natriuretic peptide from admission to last measured value. In multivariable linear regression analysis, galectin-3 was negatively associated with estimated glomerular filtration rate and positively associated with uNGAL and hs-cTnI. Higher galectin-3 was associated with renal replacement therapy, inotrope use and mortality during hospitalization. In univariable Cox regression analysis, higher galectin-3 was associated with increased risk for the composite of death or rehospitalization due to HF and death alone at 1 year. After multivariable adjustment, higher galectin-3 levels were associated only with death. CONCLUSIONS: In patients with AHF, higher galectin-3 values were associated with renal dysfunction, renal tubular damage and myocardial injury, and they predicted worse outcomes.

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice.

BACKGROUND: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear. METHODS: We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16-20 weeks. RESULTS: DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs. CONCLUSION: We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.

Alpha-synuclein negatively controls cell proliferation in dopaminergic neurons.

As researchers grapple with the mechanisms and implications of alpha-synuclein (α-syn) in neuropathology, it is often forgotten that the function(s) of α-syn in healthy cells remain largely elusive. Previous work has relied on observing α-syn localization in the cell or using knockout mouse models. Here, we address the specific role of α-syn in human dopaminergic neurons by disrupting its gene (SNCA) in the human dopaminergic neuron cell line, LUHMES. SNCA-null cells were able to differentiate grossly normally and showed modest effects on gene expression. The effects on gene expression were monodirectional, resulting primarily in the significant decrease of expression for 401 genes, implicating them as direct, or indirect positive targets of α-syn. Gene ontological analysis of these genes showed enrichment in terms associated with proliferation, differentiation, and synapse activity. These results add to the tapestry of α-syn biological functions. SIGNIFICANCE STATEMENT: The normal functions of α-syn have remained controversial, despite its clear importance in Parkinson's Disease pathology, where it accumulates in Lewy bodies and contributes to neurodegeneration. Its name implies synaptic and nuclear functions, but how it participates at these locations has not been resolved. Via knock-out experiments in dopaminergic neurons, we implicate α-syn as a functional participant in synapse activity and in proliferation/differentiation, the latter being novel and provide insight into α-syn's role in neuronal development.

[Basic Knowledge of Hygiene in Voluntary Disaster Control Using - German Red Cross in the Rhein-Erft District as an Example]. / Hygienisches Grundwissen im ehrenamtlichen Katastrophenschutz ­Am Beispiel des Deutschen Roten Kreuzes im Rhein-Erft-Kreis .

Full-time workers in the rescue service are often exposed to a risk of infection. The volunteers of the German disaster control (Katastrophenschutz; KatS) are exposed to a similar risk of infection when they are deployed. The aim of this study was to investigate the hygiene status of the two operational units of the German Red Cross (Deutsches Rotes Kreuz; DRK) in the Rhein-Erft District (Rhein-Erft-Kreis; REK). The 66 volunteers of the two operational units (Einsatzeinheiten; EE) "NRW BM 05" and "NRW BM 02" were assessed by means of a written questionnaire. The results showed that they had good general knowledge of hygiene.There were, however, deficits in the knowledge of specific diseases and some multi-resistant pathogens. In general, perceived risk varied greatly, and was often above 5 on a scale from 1-10, where "1" stands for no perceived risk and "10" for high perceived risk. Thus, there is a certain "concern" about getting an infection in action. Appropriate training courses are needed to optimize this situation in the future.

[Spreading Dynamics of the Alpha and Beta Virus Variants of SARS-CoV-2 at the Beginning of Their Appearance in the City of Cologne in January and February 2021]. / Ausbreitungsdynamik der Alpha- und Beta-Virusvarianten von SARS-CoV-2 zum Beginn ihres Auftretens in der Stadt Köln im Januar und Februar 2021.

BACKGROUND AND AIM OF THE STUDY: Constantly changing virus variants of the novel coronavirus SARS-CoV-2 pose major challenges to the healthcare system. The aim of the present study was to analyse major outbreaks of the alpha and beta variants in Cologne in order to enable effective and rapid response to new virus variants in future pandemics as well as to derive targeted measures to combat the pandemic. METHODS: In the observation period from January 22 to February 23, 2021, all individuals testing positive for SARS-CoV-2 and their contact persons who were reported to the Cologne Public Health Department were interviewed by employees of the Public Health Department over the telephone. On the one hand, these data formed the basis for the epidemiological and descriptive comparison of the alpha and beta variants to the previously dominant wild type. On the other hand, they were also the basis for the graphical processing of clusters formed by the two virus variants in the form of so-called timelines. For the present work, all clusters with ≥10 individuals were taken into account for the period under consideration. RESULTS: Of the 3780 individuals that tested positive for SARS-CoV-2 in Cologne during the observation period, 818 cases were due to the virus variants alpha and beta. The alpha versus the beta variant spread quickly in Cologne despite strict non-pharmaceutical interventions. As part of the cluster analysis, five major outbreak were identified in Cologne during the observation period. The alpha variant clusters included two daycare centers and one monastery, while the beta variant clusters included a communal accommodation for refugees and an old people's and nursing home. With the help of cluster analysis, the core role of the spread of the virus variants examined was shown, especially in the context of the home setting. In addition, a high proportion of cases of unknown infection site/contact was found for the wild type and alpha variant. CONCLUSION: Cluster analyses are an extremely useful tool in the determination of infection sites/contacts and transmission paths as well as in determining existing protective measures and hygiene concepts. Since clusters are to be regarded as the most unfavorable spread scenario, cluster analyses provide important suggestions for modifying further action for both this, as well as for future pandemics.

Numerical analysis of the impact of cytoskeletal actin filament density alterations onto the diffusive vesicle-mediated cell transport.

The interior of a eukaryotic cell is a highly complex composite material which consists of water, structural scaffoldings, organelles, and various biomolecular solutes. All these components serve as obstacles that impede the motion of vesicles. Hence, it is hypothesized that any alteration of the cytoskeletal network may directly impact or even disrupt the vesicle transport. A disruption of the vesicle-mediated cell transport is thought to contribute to several severe diseases and disorders, such as diabetes, Parkinson's and Alzheimer's disease, emphasizing the clinical relevance. To address the outlined objective, a multiscale finite element model of the diffusive vesicle transport is proposed on the basis of the concept of homogenization, owed to the complexity of the cytoskeletal network. In order to study the microscopic effects of specific nanoscopic actin filament network alterations onto the vesicle transport, a parametrized three-dimensional geometrical model of the actin filament network was generated on the basis of experimentally observed filament densities and network geometries in an adenocarcinomic human alveolar basal epithelial cell. Numerical analyzes of the obtained effective diffusion properties within two-dimensional sampling domains of the whole cell model revealed that the computed homogenized diffusion coefficients can be predicted statistically accurate by a simple two-parameter power law as soon as the inaccessible area fraction, due to the obstacle geometries and the finite size of the vesicles, is known. This relationship, in turn, leads to a massive reduction in computation time and allows to study the impact of a variety of different cytoskeletal alterations onto the vesicle transport. Hence, the numerical simulations predicted a 35% increase in transport time due to a uniformly distributed four-fold increase of the total filament amount. On the other hand, a hypothetically reduced expression of filament cross-linking proteins led to sparser filament networks and, thus, a speed up of the vesicle transport.

Differences in Collagen Fiber Diameter and Waviness between Healthy and Aneurysmal Abdominal Aortas.

Collagen plays a key role in the strength of aortic walls, so studying micro-structural changes during disease development is critical to better understand collagen reorganization. Second-harmonic generation microscopy is used to obtain images of human aortic collagen in both healthy and diseased states. Methods are being developed in order to efficiently determine the waviness, that is, tortuosity and amplitude, as well as the diameter, orientation, and dispersion of collagen fibers, and bundles in healthy and aneurysmal tissues. The results show layer-specific differences in the collagen of healthy tissues, which decrease in samples of aneurysmal aortic walls. In healthy tissues, the thick collagen bundles of the adventitia are characterized by greater waviness, both in the tortuosity and in the amplitude, compared to the relatively thin and straighter collagen fibers of the media. In contrast, most aneurysmal tissues tend to have a more uniform structure of the aortic wall with no significant difference in collagen diameter between the luminal and abluminal layers. An increase in collagen tortuosity compared to the healthy media is also observed in the aneurysmal luminal layer. The data set provided can help improve related material and multiscale models of aortic walls and aneurysm formation.

Potential Utility of Cardiorenal Biomarkers for Prediction and Prognostication of Worsening Renal Function in Acute Heart Failure.

BACKGROUND: Multiple different pathophysiologic processes can contribute to worsening renal function (WRF) in acute heart failure. METHODS AND RESULTS: We retrospectively analyzed 787 patients with acute heart failure for the relationship between changes in serum creatinine and biomarkers including brain natriuretic peptide, high sensitivity cardiac troponin I, galectin 3, serum neutrophil gelatinase-associated lipocalin, and urine neutrophil gelatinase-associated lipocalin. WRF was defined as an increase of greater than or equal to 0.3 mg/dL or 50% in creatinine within first 5 days of hospitalization. WRF was observed in 25% of patients. Changes in biomarkers and creatinine were poorly correlated (r ≤ 0.21) and no biomarker predicted WRF better than creatinine. In the multivariable Cox analysis, brain natriuretic peptide and high sensitivity cardiac troponin I, but not WRF, were significantly associated with the 1-year composite of death or heart failure hospitalization. WRF with an increasing urine neutrophil gelatinase-associated lipocalin predicted an increased risk of heart failure hospitalization. CONCLUSIONS: Biomarkers were not able to predict WRF better than creatinine. The 1-year outcomes were associated with biomarkers of cardiac stress and injury but not with WRF, whereas a kidney injury biomarker may prognosticate WRF for heart failure hospitalization.

Severely destructive unilateral wrist arthritis as a rare variant of rheumatoid arthritis: analysis of clinical and imaging features.

OBJECTIVES: Rheumatoid arthritis (RA) is a common autoimmune disease typically affecting joints symmetrically. A small number of patients develop unilateral and severely destructive wrist arthritis (DWA). The objective of our study was to characterise patients with this type of affection. METHODS: This was a retrospective cohort study of RA patients with positive RF/anti-CCP antibodies. Clinical characteristics, including, age, gender, disease duration, dexterity, occupational history, smoking status, and the number of prescribed DMARDs were recorded. Conventional radiographs were evaluated using the modified Sharp/van der Heijde scoring (mSS) method. RESULTS: We analysed our laboratory database of 1247 patients and identified 559 patients with a clinical diagnosis of RA. For 395 of the patients, radiographs of the hands were available for evaluation. 25 patients had extensive unilateral DWA, corresponding to a prevalence of 6.3% (25 of 395 patients). 11 patients were excluded due to incomplete data. Of the remaining 14 patients, 13 were female with a median age of 61 (33-83) years, and median disease duration of 18 (1-33) years. 8 of 11 (72.7%) patients were smokers; in three, smoking status was not known. 80% with known dexterity developed unilateral DWA in the dominant hand. Total mSS was significantly higher on the affected side (39, interquartile range 35.25-46.25) versus non-affected (13, IQR 3-23). MSS were not different if the carpal bones were excluded from scoring. Side of involvement (left vs. right), or dominant versus non-dominant hand, did not result in a different mSS. CONCLUSIONS: Unilateral DWA is a rare variant of RA which predominantly affects women who smoke.

Association of Testosterone Levels and Steroid 5-Alpha-Reductase 2 Polymorphisms with Opioid Craving.

BACKGROUND/AIMS: Opioid dependence is a severe disease which is associated with a high risk of relapse, even in cases of successful withdrawal therapy. Studies have shown alterations of the hypothalamic-pituitary-gonadal axis in opioid-dependent patients, such as decreased testosterone serum levels in affected males. Sex hormones and the steroid 5-alpha-reductase 2 (SRD5A2) V89L polymorphism are associated with craving during alcohol withdrawal, but little is known about their impact on symptomatology of opioid dependence. METHODS: In this study, we analyzed 2 independent male cohorts of opioid-dependent patients for possible alterations in testosterone serum levels compared to non-opioid-dependent controls. In one of the cohorts, we additionally investigated associations of testosterone serum levels and 3 SRD5A2 polymorphisms with symptoms of opioid dependence, measured by the Heroin Craving Questionnaire (HCQ). RESULTS: In the patient groups, we found significantly decreased testosterone serum levels compared to the control groups. Furthermore, we found significant associations of both the testosterone serum levels and the SRD5A2 V89L polymorphism with opioid craving assessed by the HCQ. CONCLUSION: Our data show a possible role of testosterone metabolism in opioid dependence, which may be relevant for the establishment of future treatment strategies.

Brain volume changes after long-term injectable opioid treatment: A longitudinal voxel-based morphometry study.

Clinical research has demonstrated the efficacy of injectable opioid treatment for long-term, treatment-refractory opioid-dependent patients. It has been hypothesized that compulsive drug use is particularly associated with neuroplasticity changes in the networks corresponding to withdrawal/negative affect and preoccupation/anticipation rather than binge/intoxication. However, as yet, no study has investigated the effect of long-term opioid treatment on key regions within these networks. Magnetic resonance imaging (MRI) was used to assess brain volumes changes during long-term (approximately 9 years) injectable opioid agonist treatment with diacetylmorphine (DAM) in 22 patients with opioid use disorder. Voxel-based morphometry was applied to detect volumetric changes within the networks of binge/intoxication (ventral/dorsal striatum, globus pallidus and thalamus), withdrawal/negative affect (amygdala and ventral striatum) and preoccupation/anticipation (hippocampus, orbitofrontal and anterior cingulate cortex). The relationships between significant volume changes and features of opioid use disorder were tested using Pearson correlation. Long-term opioid agonist treatment was associated with the enlargement of the right caudate nucleus, which was related to the duration of opioid use disorder. In contrast, reduced volume in the right amygdala, anterior cingulate cortex and orbitofrontal cortex were found that were related to opioid dose, onset of opioid consumption and state anxiety. These findings suggest that long-term opioid agonist treatment is related to structural changes in key brain regions underlying binge/intoxication, withdrawal/negative affect and preoccupation/anticipation, suggesting sustained interaction between these systems.

An active approach of pressure waveform matching for stress-based testing of arteries.

BACKGROUND: Arterial compliance assists the cardiovascular system with three key roles: (i) storing up to 50% of the stroke volume; (ii) ensuring blood flow during diastole; (iii) dampening pressure oscillations through arterial distension. In mock circulation loops (MCLs), arterial compliance was simulated either with membrane, spring, or Windkessel chambers. Although they have been shown to be suitable for cardiac device testing, their passive behavior can limit stress-based testing of arteries. Here we present an active compliance chamber with a feedback control of variable compliance as part of an MCL designed for biomechanical evaluation of arteries under physiological waveforms. MATERIALS AND METHODS: The chamber encloses a piston that changes the volume via a cascaded controller when there is a difference between the real-time pressure and the physiological reference pressure with the aim to equilibrate both pressures. RESULTS: The experimental results showed repeatable physiological waveforms of aortic pressure in health (80-120 mm Hg), systemic hypertension (90-153 mm Hg), and heart failure reduced ejection fraction (78-108 mm Hg). Statistical validation (n = 20) of the function of the chamber is presented against compared raw data. CONCLUSION: We demonstrate that the active compliance chamber can track the actual pressure of the MCL and balance it in real time (every millisecond) with the reference values in order to shape the given pressure waveform. The active compliance chamber is an advanced tool for MCL applications for biomechanical examination of stented arteries and for preclinical evaluation of vascular implants.

Calreticulin Deficiency Disturbs Ribosome Biogenesis and Results in Retardation in Embryonic Kidney Development.

Nephrogenesis is driven by complex signaling pathways that control cell growth and differentiation. The endoplasmic reticulum chaperone calreticulin (Calr) is well known for its function in calcium storage and in the folding of glycoproteins. Its role in kidney development is still not understood. We provide evidence for a pivotal role of Calr in nephrogenesis in this investigation. We show that Calr deficiency results in the disrupted formation of an intact nephrogenic zone and in retardation of nephrogenesis, as evidenced by the disturbance in the formation of comma-shaped and s-shaped bodies. Using proteomics and transcriptomics approaches, we demonstrated that in addition to an alteration in Wnt-signaling key proteins, embryonic kidneys from Calr-/- showed an overall impairment in expression of ribosomal proteins which reveals disturbances in protein synthesis and nephrogenesis. CRISPR/cas9 mediated knockout confirmed that Calr deficiency is associated with a deficiency of several ribosomal proteins and key proteins in ribosome biogenesis. Our data highlights a direct link between Calr expression and the ribosome biogenesis.