Increased compensatory kidney workload results in cellular damage in a short time porcine model of mixed acidemia – Is acidemia a ‘first hit’ in acute kidney injury?

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

The Prodromal Microbiome

Non peer reviewe

Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation

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

Bacterial Metabolites Mirror Altered Gut Microbiota Composition in Patients with Parkinson's Disease

Increasing evidence is supporting the hypothesis of α-synuclein pathology spreading from the gut to the brain although the exact etiology of Parkinson's disease (PD) is unknown. Furthermore, it has been proposed that inflammation, via the gastrointestinal tract, potentially through infections, may contribute to α-synuclein pathogenesis, and thus to the risk of developing PD. Recently, many studies have shown that PD patients have an altered microbiota composition compared to healthy controls. Inflammation in the gut might drive microbiota alterations or vice versa. Many studies focused on the detection of biomarkers of the etiology, onset, or progression of PD however also report metabolites from bacterial origin. These metabolites might reflect the bacterial composition and as well play an important role in immune homeostasis, ultimately affecting the progression of PD. Besides the bacterial metabolites, pharmacological treatment of PD might play a crucial role during the progression and thus treatment of the disease on the immune system. This review aims to establish a link between the microbial composition with the observed alterations of bacterial metabolites and their impact on the immune system, which could have influential effect in onset, progression and etiology of PD

The nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behavior disorder.

BACKGROUND: Increasing evidence connects the gut microbiota and the onset and/or phenotype of Parkinson's disease (PD). Differences in the abundances of specific bacterial taxa have been reported in PD patients. It is, however, unknown whether these differences can be observed in individuals at high risk, for example, with idiopathic rapid eye movement sleep behavior disorder, a prodromal condition of alpha-synuclein aggregation disorders including PD. OBJECTIVES: To compare microbiota in carefully preserved nasal wash and stool samples of subjects with idiopathic rapid eye movement sleep behavior disorder, manifest PD, and healthy individuals. METHODS: Microbiota of flash-frozen stool and nasal wash samples from 76 PD patients, 21 idiopathic rapid eye movement sleep behavior disorder patients, and 78 healthy controls were assessed by 16S and 18S ribosomal RNA amplicon sequencing. Seventy variables, related to demographics, clinical parameters including nonmotor symptoms, and sample processing, were analyzed in relation to microbiome variability and controlled differential analyses were performed. RESULTS: Differentially abundant gut microbes, such as Akkermansia, were observed in PD, but no strong differences in nasal microbiota. Eighty percent of the differential gut microbes in PD versus healthy controls showed similar trends in idiopathic rapid eye movement sleep behavior disorder, for example, Anaerotruncus and several Bacteroides spp., and correlated with nonmotor symptoms. Metagenomic sequencing of select samples enabled the reconstruction of genomes of so far uncharacterized differentially abundant organisms. CONCLUSION: Our study reveals differential abundances of gut microbial taxa in PD and its prodrome idiopathic rapid eye movement sleep behavior disorder in comparison to the healthy controls, and highlights the potential of metagenomics to identify and characterize microbial taxa, which are enriched or depleted in PD and/or idiopathic rapid eye movement sleep behavior disorder. (c) 2017 International Parkinson and Movement Disorder Society

Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes

Influence of different intensive care therapy concepts on CVVH haemocompatibility with respect to the coagulation system

Hintergrund: Die akut reduzierte Hämokompatibilität durch frühes Filterversagen limitiert als häufige Komplikation den erfolgreichen Einsatz extrakorporaler Systeme, wie der kontinuierlich veno-venösen Hämofiltration (CVVH). Neben adversen Eigenschaften künstlicher Oberflächen werden Gerinnungsstörungen im Kontext zugrundeliegender Erkrankungen als ursächlich angesehen. Über die Interaktion therapiekonzeptbedingter Einflüsse, wie lungenprotektiver Beatmung mit tolerierter Azidämie, Infusion hyperchlorämischer Lösungen, Pufferstrategien, Antikoagulation mit einer CVVH im Hinblick auf die Gerinnungsfunktion ist bisher wenig bekannt. Eine durch lungenprotektive Beatmungstherapie assoziierte Azidose bedarf darüber hinaus einer ventilationsunabhängigen Korrektur. Methodik: Durch Kombination aus Säureinfusion (je 0,2 M Milchsäure/Salzsäure) und niedrigen Beatmungsvolumina (6-8 ml.kg-1) wurde in gesunden anästhesierten Schweinen die Aufrechterhaltung einer gemischten Azidämie (pH 7,2) etabliert. Zusätzlich zur Azidämie wurde in einer weiteren Gruppe eine Hypoxämie (pH 7,2; PaO2<70 mmHg) induziert. Zur forcierten Blut-System-Interaktion wurde eine CVVH für drei Stunden mit Filtrat-Rezirkulation betrieben. Eine anschließende Azidosekorrektur erfolgte mittels THAM-Puffer und CVVH im Standardmodus. Die Heparinisierung (60 IU.kg-1.h-1) erfolgte ACT basiert. Ergebnisse: Die Azidämie zeigte pro- und antikoagulatorischen Einfluss auf die plasmatische Gerinnungsfunktion. Im Vergleich zum pH 7,4 führte Azidämie zu erhöhten Aktivierungsmarkern, Thrombozyten- und Fibrinogenverlusten. Die Filterfunktion und Blutflussraten unterschieden sich nach 5 Stunden Filterlaufzeit noch nicht, eine Azidämie assoziierte höhere Anzahl an verstopften Filterkapillaren deutete sich jedoch bereits an. THAM 8 mmol.kg-1.h-1, prädilutorisch appliziert, ermöglichte eine rasche Azidosekorrektur und wies eine signifikant geringere Anzahl verstopfter Filterkapillaren auf, voraussichtlich auf der Basis einer günstigeren Hämorheologie im Filter durch die prädilutorische pH-Korrektur. Diskussion: Eine Azidämie bedingte Interaktion mit der CVVH-Hämokompatibilität und Gerinnungsfunktion konnte gezeigt werden. Zur Optimierung des Nutzen-Risiko- Verhältnisses für den Intensivpatienten unter CVVH sollte der interaktive Einfluss einzelner Therapievariablen im Sinne einer verbesserten „Begleittherapie“ zukünftig systematisch evaluiert werden.Background: Reduced haemocompatibility and early filter failure are frequent complications during extracorporeal organ therapy with continuous venovenous haemofiltration (CVVH). Beyond adverse effects of artificial surfaces, coagulation disorders diyplay the main reason of filter blockage. Still, little is known about the impact of therapy dependent factors (lung protective ventilation strategies with permissive hypercapnia/acidaemia, infusion therapy with hyperchloraemic solutions, buffer strategies, anticoagulation) and a CVVH-circuit with respect to the coagulation system. Acidaemia through lung protective ventilations strategy needs to be corrected independent from ventilation. Methods: Acidaemia (pH 7,2) was induced by infusion of an acid solution (0,2 M of lactic acid and HCL) and combination of low tidal volume ventilation (6-8 mL.kg-1). One group underwent additional hypoxaemia (pH 7,2; PaO2<70 mmHg). CVVH was operated with reinfusion of the filtrate to the venous line for 3 hours based on standardized heparinization (60 IU.kg-1.h-1). Correction of acidaemia was performed with predilutional application of THAM buffer in the CVVH open mode. Results: Acidaemia led to a contradictory pattern with respect to the plasmatic haemostasis. Compared to the control group with PH 7,4 acidaemia was associated with elevated markers of coagulation activation, loss of platelets and a decrease in fibrinogen concentration. Filter function did not differ between groups, but a tendency for higher rates of filter blockage was found. Predilutional THAM application with 8 mmol.kg-1.h-1 successfully corrected acidaemia and reduced filter blockage presumably due to improved haemorheology. Discussion: We could show that there is an interaction of acidaemia with the CVVH haemocompatibility with respect to the coagulation system. Further studies are needed to systematically clarify the overall influence of the accompanying therapy