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M Marek,1 M Grobe-Einsler,1 JR Bedarf,1 B Wabbels,2 S Paus1 1Department of Neurology, University of Bonn, Bonn, Germany; 2Department of Ophthalmology, University of Bonn, Bonn, Germany Background: Sexual dysfunction is a frequent, yet underrated, symptom of neurological disease. While knowledge of non-motor comorbidity in focal dystonia is growing rapidly, there is no information on the prevalence of sexual dysfunction in cervical dystonia (CD) or blepharospasm (BL). Methods: In this controlled study, we examined sexual dysfunction in 65 patients with CD and 54 patients with BL by the Arizona Sexual Experience Scale, a validated self-rating scale. Results: Sexual dysfunction was significantly higher in CD patients (45%) than in controls (24%), and frequent in BL (39%). Interestingly, variables of dystonia such as disease duration or severity did not influence sexuality; yet, 23% of CD patients ascribed worsening of their sexual life to dystonia. Symptoms of depression were identified as the most important predictors for sexual dysfunction, followed by age, and personal status (single). Conclusion: Our observations establish sexual dysfunction as a frequent non-motor symptom in CD and BL that is perceived as a burden. It should be considered when investigating patients with adult-onset focal dystonia. Keywords: dystonia, cervical dystonia, blepharospasm, sexual dysfunction, depression

Janis Rebecca Bedarf,1 Sied Kebir,1,2 Joan Philipp Michelis,1,3 Bettina Wabbels,4 Sebastian Paus1 1Department of Neurology, University of Bonn, Bonn, 2Department of Neurology, University of Essen, Essen, Germany; 3Movement Disorders Center, Department of Neurology, Bern University Hospital, Bern, Switzerland; 4Department of Ophthalmology, University of Bonn, Bonn, Germany Abstract: Depression is the most important nonmotor symptom in blepharospasm (BL). As facial expression influences emotional perception, summarized as the facial feedback hypothesis, we investigated if patients report fewer depressive symptoms if injections of botulinum neurotoxin (BoNT) include the “grief muscles” of the glabellar region, compared to treatment of orbicularis oculi muscles alone. Ninety BL patients were included, half of whom had BoNT treatment including the frown lines. While treatment pattern did not predict depressive symptoms overall, subgroup analysis revealed that in male BL patients, BoNT injections into the frown lines were associated with remarkably less depressive symptoms. We hypothesize that in BL patients presenting with dystonia of the eyebrow region, BoNT therapy should include frown line application whenever justified, to optimize nonmotor effects of BoNT denervation. Keywords: botulinum neurotoxin, blepharospasm, depression, facial feedback, frown lines, grief muscles

Background: Recent studies suggested the existence of (poly-)microbial infections in human brains. These have been described either as putative pathogens linked to the neuro-inflammatory changes seen in Parkinson's disease (PD) and Alzheimer's disease (AD) or as a "brain microbiome" in the context of healthy patients' brain samples., Methods: Using 16S rRNA gene sequencing, we tested the hypothesis that there is a bacterial brain microbiome. We evaluated brain samples from healthy human subjects and individuals suffering from PD (olfactory bulb and pre-frontal cortex), as well as murine brains. In line with state-of-the-art recommendations, we included several negative and positive controls in our analysis and estimated total bacterial biomass by 16S rRNA gene qPCR., Results: Amplicon sequencing did detect bacterial signals in both human and murine samples, but estimated bacterial biomass was extremely low in all samples. Stringent reanalyses implied bacterial signals being explained by a combination of exogenous DNA contamination (54.8%) and false positive amplification of host DNA (34.2%, off-target amplicons). Several seemingly brain-enriched microbes in our dataset turned out to be false-positive signals upon closer examination. We identified off-target amplification as a major confounding factor in low-bacterial/high-host-DNA scenarios. These amplified human or mouse DNA sequences were clustered and falsely assigned to bacterial taxa in the majority of tested amplicon sequencing pipelines. Off-target amplicons seemed to be related to the tissue's sterility and could also be found in independent brain 16S rRNA gene sequences., Conclusions: Taxonomic signals obtained from (extremely) low biomass samples by 16S rRNA gene sequencing must be scrutinized closely to exclude the possibility of off-target amplifications, amplicons that can only appear enriched in biological samples, but are sometimes assigned to bacterial taxa. Sequences must be explicitly matched against any possible background genomes present in large quantities (i.e., the host genome). Using close scrutiny in our approach, we find no evidence supporting the hypothetical presence of either a brain microbiome or a bacterial infection in PD brains. Video abstract.

The gut microbiota is emerging as an important modulator of neurodegenerative diseases, and accumulating evidence has linked gut microbes to Parkinson's disease (PD) symptomatology and pathophysiology. PD is often preceded by gastrointestinal symptoms and alterations of the enteric nervous system accompany the disease. Several studies have analyzed the gut microbiome in PD, but a consensus on the features of the PD-specific microbiota is missing. Here, we conduct a meta-analysis re-analyzing the ten currently available 16S microbiome datasets to investigate whether common alterations in the gut microbiota of PD patients exist across cohorts. We found significant alterations in the PD-associated microbiome, which are robust to study-specific technical heterogeneities, although differences in microbiome structure between PD and controls are small. Enrichment of the genera Lactobacillus, Akkermansia, and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent PD gut microbiome alterations. This dysbiosis might result in a pro-inflammatory status which could be linked to the recurrent gastrointestinal symptoms affecting PD patients.

Acute kidney injury (AKI) corrupts the outcome of about 50% of all critically ill patients. We investigated the possible contribution of the pathology acidemia on the development of AKI. Pigs were exposed to acidemia, acidemia plus hypoxemia or a normal acid-base balance in an experimental setup, which included mechanical ventilation and renal replacement therapy to facilitate biotrauma caused by extracorporeal therapies. Interestingly, extensive histomorphological changes like a tubular loss of cell barriers occurred in the kidneys after just 5 hours exposure to acidemia. The additional exposure to hypoxemia aggravated these findings. These 'early' microscopic pathologies opposed intra vitam data of kidney function. They did not mirror cellular or systemic patterns of proinflammatory molecules (like TNF-α or IL 18) nor were they detectable by new, sensitive markers of AKI like Neutrophil gelatinase-associated lipocalin. Instead, the data suggest that the increased renal proton excretion during acidemia could be an 'early' first hit in the multifactorial pathogenesis of AKI., Competing Interests: All authors declare no further competing interests, especially concerning employment, consultancy, patents, products in development or marketed products. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The vast majority of Parkinson's disease (PD) cases are of sporadic origin and despite extensive research in recent years, the etiology still remains unclear. Several current case control studies are aiming to characterize a putative PD-specific composition of the gut microbiome, reflecting the potential relevance of microbiota in the pathogenesis of PD. Although methodologies and cohort sizes differed, the currently available studies showed reproducible or consistent results in terms of PD-specific alterations to the intestinal bacteria. By applying metagenomic sequencing procedures, it is even possible to distinguish PD cases from healthy individuals at a very early disease stage by means of individually modified microbiota. Among others, microbiota that are associated with an altered intestinal barrier or immune function, such as Akkermansia, Lactobacillus, Faecalibacterium and Prevotella were significantly over-represented or under-represented. There may even be a prodromal microbiome, as a comparable microbial shift is also found in patients with rapid eye movement (REM) sleep behavior disorder (RBD), a risk factor for the later development of synucleinopathies, such as PD.

Background: Parkinson's disease (PD) presently is conceptualized as a protein aggregation disease in which pathology involves both the enteric and the central nervous system, possibly spreading from one to another via the vagus nerves. As gastrointestinal dysfunction often precedes or parallels motor symptoms, the enteric system with its vast diversity of microorganisms may be involved in PD pathogenesis. Alterations in the enteric microbial taxonomic level of L-DOPA-naïve PD patients might also serve as a biomarker., Methods: We performed metagenomic shotgun analyses and compared the fecal microbiomes of 31 early stage, L-DOPA-naïve PD patients to 28 age-matched controls., Results: We found increased Verrucomicrobiaceae (Akkermansia muciniphila) and unclassified Firmicutes, whereas Prevotellaceae (Prevotella copri) and Erysipelotrichaceae (Eubacterium biforme) were markedly lowered in PD samples. The observed differences could reliably separate PD from control with a ROC-AUC of 0.84. Functional analyses of the metagenomes revealed differences in microbiota metabolism in PD involving the ẞ-glucuronate and tryptophan metabolism. While the abundances of prophages and plasmids did not differ between PD and controls, total virus abundance was decreased in PD participants. Based on our analyses, the intake of either a MAO inhibitor, amantadine, or a dopamine agonist (which in summary relates to 90% of PD patients) had no overall influence on taxa abundance or microbial functions., Conclusions: Our data revealed differences of colonic microbiota and of microbiota metabolism between PD patients and controls at an unprecedented detail not achievable through 16S sequencing. The findings point to a yet unappreciated aspect of PD, possibly involving the intestinal barrier function and immune function in PD patients. The influence of the parkinsonian medication should be further investigated in the future in larger cohorts.

Background: Epilepsia partialis continua (EPC) is defined as continuous myoclonic jerking of a body part of cortical origin and often resembles a movement disorder. Unfortunately, anti-epileptic therapy is frequently ineffective. Currently, the effect of botulinum neurotoxin (BoNT) therapy in EPC is controversial., Methods: We analyzed case histories, treatment protocols, and video documentation of 5 patients with EPC, who received BoNT therapy in our movement disorders unit. The Unified Myoclonus Rating Scale was used to document treatment effects., Results: In all patients, BoNT treatment significantly reduced severity and frequency of myoclonus and led to pronounced improvement of speech and arm utilization, regardless of etiology or duration of EPC., Conclusion: BoNT represents a safe, effective treatment in EPC, offering long-term abatement of myoclonus. The substantial functional profit may hint at mechanisms beyond local impairment of neuromuscular transmission, such as modulation of maladaptive cortical plasticity, as observed in dystonia and poststroke spasticity.

Experimental data indicate that hypercapnic adidosis has anti-inflammatory effects. These anti-inflammatory effects may even be a beneficial property in case of low tidal volume ventilation with consecutive hypercapnic acidosis. It is unclear whether these anti-inflammatory effects predominate in critically ill patients who suffer from multiple pro- and anti-inflammatory insults like extracorporeal organ support (pro-inflammatory), metabolic acidosis (pro- and anti-inflammatory), as well as hypoxia (pro-inflammatory). Eighteen pigs were randomized into three groups, mechanically ventilated and connected to a continuous veno-venous hemofiltration (CVVH) as pro-inflammatory insult. A reference group with normal acid-base state obtained normoventilation; a normoxemic acidemia group obtained normoxemic, mixed acidemia due to infusion of lactic and hyperchloremic acid and low tidal volume ventilation, and in a hypoxemic acidemia group the mixed acidemia was paralleled by hypoxemia. Lung histology including pulmonary leukocyte invasion, blood gases, blood cell counts, and hemodynamics were examined. The histological examination of the lungs of acidemic pigs showed a suppressed invasion of leukocytes and thinner alveolar walls compared with normoventilated and with hypoxemic pigs. Enhanced congestion and alveolar red blood cells (RBCs) combined with an increase of the pulmonary artery pressure were observed in acidemic pigs in comparison with the reference group. Normoxemic acidemia reduced the pro-inflammatory reaction to the CVVH and mechanical ventilation in the ventilated lung areas in the form of pulmonary leukocyte invasion. However, this did not result in reduced scores for lung injury. Instead, an increased score for criteria which represent lung injury (congestion and alveolar RBCs) was observed in acidemic pigs., (© 2013 Wiley Periodicals, Inc. and International Center for Artificial Organs and Transplantation.)

Intensive therapy demanding diseases (organ failure or sepsis) are assumed to be the etiology behind a decreased biocompatibility of extracorporeal systems for renal replacement therapy (RRT). There are also potential interactions between different components of the overall therapy. Volume substitutes are known to influence hemorheology and coagulation. To define a potential net effect of volume substitutes on the hemocompatibility of an RRT, we chose an animal model without interfering pathophysiologies. According to the problem of early filter failure and coagulation disorders in critically ill patients, we focused on the hypothesized interaction between RRT and different volume substitutes with respect to blood cell counts, coagulation parameters and required heparin dose. Forty-eight pigs were assigned to four groups of fluid therapy with either normal saline (NaCl), 6%HES130kD/0.4 (HES130), 6%HES200kD/0.5 (HES200) or 4%gelatin (GEL). Six pigs of each fluid group underwent continuous venovenous hemofiltration (CVVH), the remaining six served as the control group. Anticoagulation was performed with continuous heparin infusion. CVVH was run in a recirculation-mode for 4.5 h to force hemocompatibility reactions, thereafter in a standard-mode for 2 h. During the CVVH-treatment GEL reduced platelet counts and fibrinogen concentration and additionally lowered ATIII levels. Heparin requirements did not differ between different volume substitutes or CVVH and control groups. Severe pathophysiologies are not the only reason for a reduced hemocompatibility of CVVH treatment. Interaction of a particular volume substitute with CVVH should be considered when interpreting study results and evolving new strategies., (© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.)

In intensive care medicine, convection-based apheresis is of growing interest. Applying extracorporeal systems in the critically ill patient can cause severe complications like nosocomial infections and bleeding, which can be worsened or even initialized by the anticoagulation protocol used. Furthermore, the filter modules (hemo- and plasmafilters) often tend to a fast blockage. A decrease in sieving performance due to membrane fouling may be tolerable for some time, but the complete blockage of high percentages of hollow fibers, which is named "clotting," often requires the immediate exchange of the filter. Extracorporeal detoxification and high clearance renal replacement regimes both require high blood flow and filtration rates. As a consequence, filter clotting and anticoagulation-associated bleeding are the most sensitive aspects in these applications. We were interested in the paradox phenomenon of the parallel occurrence of intra vitam bleeding and filter clotting in critically ill patients. Through stepwise investigations based on in vitro and animal experiments, we identified a stasis of blood flow followed by blood cell sedimentation and aggregation ("clogging") as the main factor of hollow fiber blockage in hemo- and plasma filters. As a result, various aspects which increase the risk of stasis inside the hollow fibers were investigated, for example, patient's hemorheology, configuration of an extracorporeal treatment system including interaction of catheter features with the filtration procedure, and basic therapeutic approaches such as colloidal volume substitutes and tolerated acidosis. Finally, an etiological triad for the blockage of hollow fibers due to filter clogging and consecutive filter failure was formed., (© 2013, Copyright the Authors. Artificial Organs © 2013, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Exhausting physical exercise and insufficient nutritional intake impairing immunological and neuro-endocrine pathways are the most discussed issues in research on overtraining syndrome (OTS). Interestingly, depletion of the total body sodium (Na(+))-content which occurs in case of various diseases with completely different aetiologies is associated with a symptom pattern strikingly comparable to overreaching (OR) and/or OTS. The transient dilution based hyponatraemia gained attention due to its impact on reduced performance and the death of various endurance athletes. But the stepwise depletion of the total body (tissue) Na(+)-content is a completely different pathophysiology and is still relatively unknown. That is because depleted tissue Na(+)-content is hard to detect. The complex, dominant mechanisms for the maintenance of plasma homeostasis are concealing the Na(+)-depletion in the tissues quite successfully in a stage when symptoms already may be prominent. Furthermore, we are all programmed to think about sedentary people who are rather at risk to have a salt (Na(+)) intake which is far too high. But either, competitive top athletes and engaged recreational athletes have high losses of electrolytes with sweat and might be prone to a stepwise Na(+)-depletion. All the more because they also try to have a balanced, health sodium reduced diet. One person of our research group who is used to a rather low sodium-nutrition repeatedly experienced OR-(short term-OTS)-symptoms when training loads of recreational sport activities were increasing. Getting aware about identical symptoms between OR and total body Na(+)-depletion in another professional context the decision for a self experiment was settled. Under a given training protocol changing symptoms under low sodium-nutrition were recorded. When OR-like symptoms became prominent the training loads were maintained but stringent Na(+)-substitution was performed instead of the usually recommended resting period. As experienced before, typical symptoms such as sleeping disorders, harassed feeling, high diuresis, thirst and increasing blood pressure developed within 2 weeks with the increased training loads and the usual low Na(+)-nutrition. This was before plasma sodium decreased below the physiological range. High Na(+)-substitution instead of a resting period enabled the recovery from OR symptoms within some days. Out of various articles we choose and report some interesting further medical phenomenon where our hypothesis of Na(+)-depletion as a trigger mechanism might give new ideas for identifying pathophysiological mechanisms. The hypothesis: Tissue Na(+)-depletion triggers OR- and OTS- development via the renin-angiotensin-aldosterone system which initiate at first a stimulation and then exhaustion of the sympathetic system., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Continuous veno-venous hemofiltration (CVVH) and mixed acidemia often occur simultaneously in critically ill patients. In a previous study in non-acidemic pigs we found that colloids and CVVH interact specifically with respect to hemodynamic stability, with favorable effects for 6% HES 130/0.4 versus 4% gelatine (GEL) infusion. In a porcine model, we investigated whether these colloid-type associated differences are still dominant under acidemic conditions., Methods: We utilized 5 groups, a non-acidemic reference group receiving HES130 and CVVH; two acidemic groups receiving HES130 infusion (one with and one without CVVH); and two acidemic groups receiving GEL infusion (one with and one without CVVH). Mixed acidemia (pH ~7.20) was established by low tidal volume ventilation and acid infusion. Stable acidemia/CVVH application was maintained for 3 hours. Hemodynamics and blood gases were recorded., Results: Mixed acidemia led to a significant decrease in MAP and increase in MPAP in all groups. CVVH led to a further decrease in MAP but improved MPAP. During CVVH, HES130 ensured significantly higher MAP, Hb, and DO2 values than GEL infusion. In the groups without CVVH these differences between HES 130/0.4 and GEL were not observed., Conclusions: As in a previous study in non-acidemic pigs, we found a colloid-specific influence of HES130 versus GEL on hemodynamics during CVVH under acidemia. Again, HES130 infusion may lead to favorable effects. In contrast, acidemia without CVVH application was dominant over the impact of a respective colloid. The application of a CVVH seems to be an important trigger for the overall circulatory response to a particular colloid.

Background: Reduced haemocompatibility and early filter failure during continuous venovenous haemofiltration (CVVH) can be attributed to various aspects from filter engineering to rheological problems. Still, little is known about the impact of acidaemia and hypoxaemia on the haemocompatibility of a CVVH. In a porcine model, we investigated blood and coagulation parameters, filter performance and blockage of filter capillaries to assess the impact of acidaemia and hypoxaemia on haemocompatibility., Methods: Pigs were assigned to three groups (n = 6). One group received mixed acidaemia (pH 7.2) by acid infusion (0.2 M of lactic acid and 0.2 M HCl diluted in normal saline) and low tidal volume ventilation (6-8 mL/kg(-)(1)), one group underwent an additional hypoxaemia (pH 7.2; PaO(2) < 70 mmHg) and another was treated with normal saline and normoventilation (control group; pH 7.4). To accelerate biocompatibility reactions, CVVH was operated with reinfusion of the filtrate to the venous line for 3 h based on standardized heparinization., Results: Acidaemia led to a contradictory pattern with respect to prothrombin time (prolongation), activated partial thrombin time and activated clotting time (acceleration). In comparison to normal pH homeostasis, acidaemia led to increasing activation markers such as terminal complement complex marker sC5b-9, thrombin-anti-thrombin complexes (TAT) and D-dimers. Additional hypoxaemia intensified activation with regard to TAT and complement complex marker sC5b-9. Platelet counts suffered from acidaemia and a tendency for higher rates of blocked hollow fibres was found., Conclusion: Acidaemia led to deteriorated haemocompatibility reactions to a CVVH circuit. The coagulation pattern developed towards complications for the coagulatory state.

Purpose: Hypoxemia and acidemia (hypoxemia/acidemia) are serious complications in the critically ill and often occur in unstable patients exposed to extracorporeal organ support. Still, little is known about the biocompatibility interactions of hypoxemia/acidemia with extracorporeal circuits (ECC). Existing animal models often include the release of mediator cascades (sepsis-, lung injury models) or are based on small laboratory animals. We established a porcine model of hypoxemia/acidemia without an underlying disease and further challenged the situation with an extracorporeal circuit (ECC)., Methods: Hypoxemia/acidemia were induced (3.5 h) and maintained (3 h) in anesthetized pigs (40 kg) by a stepwise reduction in oxygenation, infusion of 0.4 mol.l⁻¹ lactic and hydrochloric acid and by low tidal volume ventilation, targeting an PaO₂ < 70 mmHg, SvO₂ < 65%, pH ~ 7.2. Venovenous hemofiltration (CVVH) operated in recirculation mode without volume exchange was chosen to prove the suitability of the model for studies on ECCs under clinical conditions (ECC group, n=6). Another 6 animals underwent the same protocol except for the CVVH (reference group, n=6)., Results: The median PaO₂ during hypoxemia/acidemia was 62 mmHg, the median SvO₂ was 38%, and the median pH was 7.22. Hypoxemia/acidemia was successfully induced and maintained for 6.5 h in all pigs. CVVH could be performed for 3 h with blood flow rates up to 300 ml.min⁻¹ and filtrate rates up to 60 ml.min⁻¹., Conclusions: Our model provides hypoxemia/acidemia with blood gas values comparable to critically ill adult patients for several hours, during which it is possible to perform CVVH. Thus, it enables research on the biocompatibility reactions of extracorporeal circuits under intensive care conditions.