Abnormal α-synuclein deposits in skin nerves: intra- and inter-laboratory reproducibility.

BACKGROUND AND PURPOSE: Visualization of phosphorylated α-synuclein at serine 129 (p-syn) in skin nerves is a promising test for the in vivo diagnosis of synucleinopathies. Here the aim was to establish the intra- and inter-laboratory reproducibility of measurement of intraneural p-syn immunoreactivity in two laboratories with major expertise (Würzburg and Bologna). METHODS: In total, 43 patients affected by Parkinson's disease (PD 21 patients), dementia with Lewy bodies (DLB 1), rapid eye movement sleep behaviour disorder (RBD 11), multiple system atrophy (MSA-P 4) and small fibre neuropathy (SFN 6) were enrolled. Skin biopsy was performed at the C7 paravertebral spine region and distal skin sites (thigh or leg). The analysis was standardized in both laboratories and carried out blinded on a single skin section double stained with antibodies to p-syn and the pan-axonal marker protein gene product 9.5. Fifty skin sections were randomly selected for the analysis: 25 from C7 and 25 from distal sites. Differently classified sections were re-evaluated to understand the reasons for the discrepancy. RESULTS: The intra-laboratory analysis showed an excellent reproducibility both in Würzburg (concordance of classification 100% of sections; K = 1; P < 0.001) and Bologna (96% of sections; K = 0.92; P < 0.001). Inter-laboratory analysis showed reproducibility in 45 sections (90%; K = 0.8; P < 0.001) and a different classification in five sections, which was mainly due to fragmented skin samples or weak fluorescent signals. CONCLUSIONS: Analysis of p-syn showed excellent inter- and intra-laboratory reproducibility supporting the reliability of this technique. The few ascertained discordances were important to further improve the standardization of this technique.

A rare case of Epstein-Barr virus-associated hepatosplenic smooth muscle tumors after kidney transplantation.

A 27-year old caucasian male was diagnosed 2.7 years after kidney transplantation with Epstein-Barr virus (EBV)-associated smooth muscle tumors in liver and spleen. The reduction in immunosuppression and conversion from tacrolimus to sirolimus did not lead to a regression of the tumors. Additionally, the patient developed a cellular rejection of his renal allograft, which was successfully treated. A combined approach with stereotactic radiofrequency ablation (SRFA) and surgical resection was effective in the treatment of the tumors.

Dysautonomia in prodromal α-synucleinopathy: peripheral versus central autonomic degeneration.

BACKGROUND AND PURPOSE: There is an urgent need for early predictive markers for the course of disease in prodromal α-synucleinopathies such as idiopathic rapid eye movement (REM) sleep behaviour disorder. Autonomic cardiac/vascular dysfunction is a prominent feature in advanced α-synucleinopathies, but its diagnostic value as an early neurodegenerative marker remains unclear. The latter may be complicated since synuclein-mediated neurodegeneration may involve central and peripheral components of the autonomic nervous system. METHODS: The diagnostic value of autonomic symptoms and central and peripheral autonomic markers of blood pressure and heart rate regulation were prospectively evaluated in 20 subjects with idiopathic REM sleep behaviour disorder and 20 age-matched healthy controls. RESULTS: Although subjects with REM sleep behaviour disorder showed no clinical autonomic symptoms, blood pressure (P ≤ 0.035) and heart rate response (P ≤ 0.065) were slightly diminished during orthostatic challenge. Autonomic dysregulation was distinctively reflected in lower resting heart rate (all components, P ≤ 0.05) and blood pressure variability (low frequency component, P ≤ 0.024) indicating peripheral cardiac/vascular denervation. In contrast, baroreflex sensitivity and central cardiac autonomic outflow (sympathovagal balance) were well preserved indicating intact central autonomic regulation. Heart rate variability [very low frequency component, receiver operating characteristic (ROC) area under the curve (AUC) 0.80, P ≤ 0.001] and blood pressure variability (low frequency component ROC AUC 0.73, P ≤ 0.01) but not baroreflex sensitivity and sympathovagal balance showed an excellent diagnostic accuracy in identifying subjects with REM sleep behaviour disorder and healthy controls. CONCLUSIONS: Cardiac/vascular dysfunction in prodromal α-synucleinopathy arises from peripheral rather than from central autonomic degeneration. Autonomic indices encoded in heart rate and blood pressure variability are precise functional markers of early synuclein-mediated neurodegeneration.

The presence of biofilm structures in atherosclerotic plaques of arteries from legs amputated as a complication of diabetic foot ulcers.

OBJECTIVE: Atherosclerosis, rather than microcirculatory impairment caused by endothelial cell dysfunction, is the main driver of circulatory compromise in patients with diabetic limbs. The presence of atherosclerotic plaque at the trifurcation is a significant contributor to amputation of diabetic legs. The presence of bacteria and other microorganisms in atherosclerotic plaque has long been known, however, the cause of chronic inflammation and the role of bacteria/viruses in atherosclerosis have not been studied in detail. The objective of this study was to clarify the cause of the chronic inflammation within atherosclerotic plaques, and determine if any bacteria and/or viruses are involved in the inflammatory pathway. METHOD: This study uses fluorescence microscopy and fluorescence in-situ hybridisation (FISH) to identify components of biofilm in atherosclerotic arteries. These tools are also used to identify individual bacteria, and determine the architectural spatial location within the atherosclerotic plaque where the bacteria can be found. RESULTS: The results indicate that the presence of biofilms in grossly involved arteries may be an important factor in chronic inflammatory pathways of atherosclerotic progression, in the amputated limbs of patients with diabetic foot ulcers and vascular disease. CONCLUSION: While the presence of bacterial biofilm structures in atherosclerotic plaque does not prove that biofilm is the proximate cause of atherosclerosis, it could contribute to the persistent inflammation associated with it. Second, the synergistic relationship between the atherosclerotic infection and the diabetic foot ulcer may ultimately contribute to higher amputation rates in diabetics. DECLARATION OF INTEREST: RAW and RDW have equity interest in PathoGenius, a clinical laboratory using DNA to identify microbes.

[Challenges of aging skin: Care and therapy using the example of venous ulcers]. / Herausforderungen der alternden Haut : Versorgung und Therapie am Beispiel des Ulcus cruris.

BACKGROUND: One of the most significant, and growing, challenges in modern medicine, i.e. the treatment of chronic wounds, is marked by nonuniform data. This concerns both prevalence and incidence of chronic dermatosis, in particular venous ulcers (ulcus cruris), as well as the impact on the health-related quality of life, and practical and economic parameters of the success of different therapies. PURPOSE: The aim of this work is to examine the epidemiology of chronic wounds, in particular age-associated venous ulcers, their impact on health-related quality of life, the treatment regimen, and practical and economic parameters of the success of different therapies. MATERIALS AND METHODS: Performed were analysis of data on the care of venous ulcers in Germany, based on secondary data of Barmer GEK from 2009 and 2012, comparison with data of a NHS Kent Community Health Trust study, and analysis of studies concerning structures, processes and critical success factors for the treatment of chronic wounds, including economic effects. CONCLUSION: Early causal therapy with treatment based on the stage of the wound, consequent goal-oriented interdisciplinary care, and relapse prophylaxis is critical for successful healing of venous ulcers. The costs of treatment significantly correlate with the duration of treatment which can be reduced by up to 60% using guideline-based concepts for the treatment of chronic wounds. Treatment success, in particular with regard to cost-benefit considerations, can be optimized by telemedicine networks of key players who treat chronic wounds.

[Sleep and neurological diseases]. / Schlaf und neurologische Erkrankungen.

Knowledge of the physiology of sleep-wake regulation can contribute to an understanding of the pathophysiology and symptoms of neurological diseases and is helpful for initiating specific therapies for sleep-wake cycle stabilization. Based on historically important observations on the close relationship between sleep and neurological diseases, new insights and developments in selected neurological entities are presented in this review article.

Seasonality in communication and collective decision-making in ants.

The ability of animals to adjust their behaviour according to seasonal changes in their ecology is crucial for their fitness. Eusocial insects display strong collective behavioural seasonality, yet the mechanisms underlying such changes are poorly understood. We show that nest preference by emigrating Temnothorax albipennis ant colonies is influenced by a season-specific modulatory pheromone that may help tune decision-making according to seasonal constraints. The modulatory pheromone triggers aversion towards low-quality nests and enhances colony cohesion in summer and autumn, but not after overwintering-in agreement with reports that field colonies split in spring and reunite in summer. Interestingly, we show that the pheromone acts by downgrading the perceived value of marked nests by informed and naive individuals. This contrasts with theories of collective intelligence, stating that accurate collective decision-making requires independent evaluation of options by individuals. The violation of independence highlighted here was accordingly shown to increase error rate during emigrations. However, this is counterbalanced by enhanced cohesion and the transmission of valuable information through the colony. Our results support recent claims that optimal decisions are not necessarily those that maximize accuracy. Other criteria-such as cohesion or reward rate-may be more relevant in animal decision-making.

How immunosuppressive therapy affects T cells from kidney transplanted patients of different age: the role of latent cytomegalovirus infection.

The average age of patients receiving renal transplantation is increasing as programmes have been established which support the donation of organs from elderly donors to older recipients. Little is known about the effect of immunosuppressive therapy on the immune system of older patients. In this study, T cell function and the composition of the T cell repertoire were analysed in immunosuppressed renal transplant recipients of different age and cytomegalovirus (CMV) status in comparison to age- and CMV-matched controls. Independent of age and CMV status, the production of interleukin (IL)-2 and interferon (IFN)-γ by T cells was decreased in the patient groups and autologous serum from patients was capable of inhibiting the proliferation of CD3⁺ T cells. CXCR5 expression on T cells was increased in patients versus controls reflecting reduced endogenous IL-2 signalling under immunosuppressive therapy. In CMV-seronegative patients kidney transplantation and immunosuppressive therapy did not induce changes in the CD8⁺ T cell pool, but there was a moderate increase in CD4⁺CD28⁻ effector T cells when compared to age-matched controls. In contrast, latent CMV infection triggered a shift from early to late differentiated CD4⁺ and CD8⁺ T cells in patients and controls. This shift was most pronounced in elderly transplant patients under immunosuppressive therapy. In conclusion, our results demonstrate that immunosuppressive therapy following kidney transplantation is effective in patients older than 65 years. Latent CMV infection, however, accelerates age-related changes in the T cell repertoire in elderly people under immunosuppressive therapy. These patients should therefore be monitored with special care.

[Narcolepsy]. / Narkolepsie.

Narcolepsy is a rare sleep disorder. The classical presentation includes the four symptoms excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations. As a model disease with all the transitions from awake to sleeping conditions, non-rapid eye movement (NREM) and rapid eye movement (REM), it plays an important role in neurology and sleep medicine. Patients with narcolepsy possess a reduced number of hypocretin-producing neurons in the hypothalamus and accordingly the hypocretin level in the cerebrospinal fluid is low. The neuropeptide hypocretin (orexin) has functions, such as the regulation of the sleep-wake cycle, the autonomous nerve system, motor system and metabolic processes. The delay in diagnosing narcolepsy is difficult to comprehend in modern medicine. The frequent association with other sleep-wake disorders may be responsible for the delay. Genomewide association studies have subsequently been able to prove that autoimmune mechanisms are responsible for the manifestation of narcolepsy with the HLA association being the most important for susceptibility and protection. Imaging studies have revealed neurodegenerative changes, making a multifactorial etiopathogenesis probable. The frequent occurrence of metabolic disorders has not yet been clarified. Early diagnosis of narcolepsy has the possibility to offer affected persons an adequate medication to lead an almost normal life and the future possibility to cure narcolepsy through immunomodulation therapy.

[REM sleep behavior disorder as a prodromal stage of α-synucleinopathies: symptoms, epidemiology, pathophysiology, diagnosis and therapy]. / REM-Schlaf-Verhaltensstörung als prodromales Stadium von α-Synukleinopathien: Klinik, Epidemiologie, Pathophysiologie, Diagnose und Behandlung.

Rapid eye movement (REM) sleep behavior disorder (RBD) is defined as a parasomnia characterized by loss of REM sleep-associated atonia and the presence of motor activity during dreaming typically presenting with an aggressive dream content. Epidemiological data on the prevalence of RBD are insufficient but it can be idiopathic or symptomatic. A video-audio polysomnography is essential for diagnosis. Clonazepam and melatonin are available as pharmaceutical treatment. Recent studies demonstrated that individuals suffering from idiopathic RBD carry a high specific risk (up to 80 %) for developing a neurodegenerative disorder of the α-synucleinopathy type (e.g. Parkinson's disease, dementia with Lewy bodies and multiple system atrophy) within 10-20 years. The current article provides a short overview of symptoms, epidemiology, pathophysiology, diagnosis and therapy of RBD.

[Obstructive sleep apnea in neurological diseases: specially as a risk factor for stroke]. / Obstruktive Schlafapnoe bei neurologischen Erkrankungen: Speziell als Risikofaktor für Schlaganfall.

Neurological diseases are frequently associated with sleep-related breathing disorders. In contrast patients with obstructive sleep apnea (OSA) suffer more often from cerebrovascular and cardiovascular diseases. Epidemiological studies have shown that OSA is common among patients with stroke, arterial hypertension or cardiovascular disease. In particular apnea-associated arterial hypertension, atrial fibrillation, activation of the sympathetic nervous system, recurrent hypoxemia and vascular inflammatory response should be considered as risk factors for the vascular system. Early diagnosis and treatment of sleep-related breathing disorders in neurological diseases are required to reduce the risk of subsequent cerebrovascular and cardiovascular diseases.

[Consensus paper on the diagnosis and treatment of sleep disordered breathing]. / Konsensuspapier zur Diagnostik und Therapie schlafbezogener Atmungsstörungen bei Erwachsenen.

Diagnosis and treatment of sleep disordered breathing (SDB) undergo substantial changes, both in terms of increasing scientific knowledge and also in terms of patient provision and socio-economic aspects. Increasing evidence shows the relevance of SDB on morbidity and mortality of affected patients. The precise differentiation of different phenotypes of SDBs has improved substantially in recent years. These proceedings influence the approach to the patients suspected of suffering from SDB. The scientific advances on the one hand are facing intentions to simplify diagnostical processes and treatment initiation and intentions to translate duties of physicians to non-medical personnel on the other hand. This consensus paper presents the principals of diagnosis, treatment initiation and provision, including the role of different participants of the healthcare system, and compares different treatment options. Major aspects include the differentiation of the diagnostical process in screening, affirmation of diagnosis and differential diagnosis. In addition, it focusses on the relevance of the pretest probability and describes a therapeutical algorithm.

[The Kleine-Levin syndrome: new aspects of a rare disease]. / Das Kleine-Levin-Syndrom : Neues von einer seltenen Erkrankung.

The Kleine-Levin syndrome (KLS) is a rare disease which can occur one to several times per year. The KLS belongs to the group of hypersomnia of central origin occurring mainly during the second decade of life after infections, sleep deprivation, alcohol consumption or minor trauma. Early manifestation combined with hypersexuality during symptomatic phases can be a predictor for a long course of the disease, which lasts a mean of 1-27 years. Due to the lack of biological markers diagnosis at first manifestation is difficult. The classical trias of hypersomnia, hyperphagia and hypersexuality can only be found in 45 % of patients. The dominant clinical symptoms are hypersomnia with changes in perception and behavior. Subtraction of perfusion studies performed during symptomatic and asymptomatic phases showed decreased perfusion of the left hypothalamus, thalamus, basal ganglia, medial and dorsolateral frontal and temporal regions. In the few patients who had lumbar punctures in both symptomatic and asymptomatic phases hypocretin-1 was moderately to slightly lowered during symptomatic phases. Meta-analyses showed good therapeutic effects of stimulants on the symptom sleepiness. Lithium reduces the frequency and duration of symptomatic phases. Assuming that KLS is underdiagnosed it should be considered as a differential diagnosis in young patients with recurrent hypersomnia.

Validity of biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes: a systematic review.

Novel biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes have been recently identified. We performed a systematic review to assess the validity of biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes in longitudinal studies. The methodological quality of the studies was scored using Standards for Reporting of Diagnostic Accuracy (STARD) criteria and the independent predictive value of the biomarkers beyond conventional risk factors was scored according to the adjustment for these risk factors. Validity of the biomarkers was determined by summarizing the methodological quality and the adjustment score. We identified 15 studies describing 27 biomarkers. Six studies had sufficient methodological quality. These studies identified 13 valid and significant markers for nephropathy in diabetes: serum interleukin 18, plasma asymmetric dimethylarginine; and urinary ceruloplasmin, immunoglobulin G and transferrin were considered valid markers predicting onset of nephropathy. Plasma asymmetric dimethylarginine, vascular cell adhesion molecule 1, interleukin 6, von Willebrand factor and intercellular cell adhesion molecule 1 were considered valid biomarkers predicting progression of nephropathy. Plasma high-sensitivity C-reactive protein, E-selectin, tissue-type plasminogen activator, von Willebrand factor and triglycerides were considered valid markers predicting onset and progression of nephropathy. Several novel biomarkers for prediction of nephropathy in diabetes have been published, which can potentially be applied in clinical practice and research in future. Because of the heterogeneous quality of biomarker studies in this field, a more rigorous evaluation of these biomarkers and validation in larger trials are advocated.

The PTH (1-84)/non-PTH (1-84) ratio is a risk factor for cardiovascular events in hemodialysis patients.

BACKGROUND: We hypothesized that the PTH (1-84)/non-PTH (1-84) ratio (PTH ratio) might help to assess cardiovascular risk in hemodialysis patients. METHODS: In this prospective cohort study 70 prevalent hemodialysis patients were followed up to 4 years. The PTH ratio was determined at baseline. Primary outcomes were cardiovascular events (CVE) and all-cause mortality. Cumulative event-free survival was compared between patients with a ratio < 1 and those with a ratio > 1. The risk-association of the PTH ratio with CVE was examined using an adjusted Multiple Cox Proportional Hazards model. RESULTS: A PTH ratio > 1 was found in 34 patients (49%). During follow-up 26 patients suffered a CVE. Patients with a CVE showed a higher ratio than patients with event-free survival (p = 0.033). In patients with a ratio > 1 a significantly higher number of CVE occurred (53 vs. 22%; p = 0.013), and these patients showed a significantly shorter event-free survival (p = 0.032). In an adjusted Cox-proportional hazards model a higher PTH ratio was found to be independently associated with an elevated risk for CVE (HR = 3.2; 95% CI 1.06 - 13.63; p = 0.04). CONCLUSIONS: A higher PTH (1-84)/non-PTH (1-84) ratio is associated with an increased risk for CVE in hemodialysis patients and might therefore be useful for cardiovascular risk estimation in this population.

The role of UV-irradiation pretreatment on the degradation of 2,4-dichlorophenoxyacetic acid in water.

The degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) in water by the combination process of UV-irradiation, humic acids and activated sludge treatment has been studied. The photoreaction rate of all irradiated samples was lowest for the sample irradiated at 308 nm (the XeCl excilamp) in the absence and in the presence of humic acids, and highest for the sample irradiated at 222 nm (the KrCl excilamp). Photolysis of 2,4-D has been shown to enhance the subsequent microbial degradation.

Aptamer-based modulation of blood coagulation.

Nucleic acid based aptamers are single-stranded oligonucleotide ligands isolated from random libraries by an in-vitro selection procedure. Through the formation of unique three-dimensional structures, aptamers are able to selectively interact with a variety of target molecules and are therefore also promising candidates for the development of anticoagulant drugs. While thrombin represents the most prominent enzymatic target in this field, also aptamers directed against other coagulation proteins and proteases have been identified with some currently being tested in clinical trials. In this review, we summarize recent developments in the design and evaluation of aptamers for anticoagulant therapy and research.

[Frequently occurring sleep disorders]. / Häufige schlafmedizinische Erkrankungen.

Some sleep disorders are frequently found in the general population. The most common include restless legs syndrome, insomnia, and sleep apnea. These sleep disorders are well classified and can easily be diagnosed and treated. Since they are risk factors for cardiovascular and psychiatric disorders, early diagnosis and treatment are essential to prevent these sequelae. The impairments caused by these sleep disorders (e.g., due to daytime sleepiness, sleep disruption, or cognitive deficits) can result in a significant reduction in a person's quality of life. The diagnostic and therapeutic recommendations were taken from the S3 guideline "Nonrestorative sleep/sleep disorders" by the German Sleep Society. The levels of evidence were given according to the recommendations of the Oxford Centre for Evidence-based Medicine.

In-hospital mortality associated factors in elderly patients with invasive mechanical ventilation in the emergency department.

AIMS: To identify factors associated with in-hospital mortality, to estimate the intubation rate and to describe in-hospital mortality in patients over 65 years old with invasive mechanical ventilation (IMV) in the emergency department (ED). METHODS: Retrospective cohort study of patients over 65 years old, who were intubated in an ED of a high complexity hospital between 2016 and 2018. Demographic data, comorbidities, and severity scores on admission were described. Bivariate and multivariate analyses were performed with logistic regression according to mortality and possible confounders. RESULTS: A total of 285 patients with a mean age of 80 years required IMV in the emergency department, for a median of 3 days, and with a mean APACHE II score of 20 points of severity. The IMV rate was .48% (95% CI .43-.54), and 55.44% (158) died. Mortality-associated factors after age and sex adjustment were stroke (OR 2.13; 95% CI 1.21-3.76), chronic kidney failure, (OR 4.,38; 95% CI 1.91-10.04), Charlson index (OR 1.19; 95% CI 1.02-1.38), APACHE II score (OR 1.07; 95% CI 1.02-1.12), and SOFA score (OR 1.14; 95% CI 1.03-1.27). DISCUSSION: Our IMV rate was lower than that stated by Johnson et al. in the United States in 2018 (.59%). In-hospital mortality in our study exceeded that predicted by the APACHE II score (40%) and SOFA (33%). However it was consistent with that reported by Lieberman et al. in Israel and Esteban et al. in the United States. CONCLUSIONS: Although the IMV rate was low in the ED, more than half the patients died during hospitalization. Pre-existing cerebrovascular and renal diseases and high results in the comorbidities index and severity scores on admission were independent factors associated with in-hospital mortality.

Consistent skin α-synuclein positivity in REM sleep behavior disorder - A two center two-to-four-year follow-up study.

OBJECTIVE/METHODS: Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. RESULTS: Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. CONCLUSIONS: Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.