Therapy of disseminated nocardiosis with recombinant Interferon Gamma-1b

Nocardiosen sind seltene Erkrankungen die durch einige Arten der bakteriellen Gattung Nocardia hervorgerufen werden. Insbesondere in einer disseminierten Verlaufsform weist die Erkrankung ein hohes Mortalitätsrisiko auf. Die Arbeit von Derungs et al. stellt einen adjuvanten Therapieansatz der Erkrankung vor und behandelt die Frage, inwiefern die Einbeziehung der Pathologie des Wirts (host-directed therapy) den Therapieerfolg der Nocardiose verbessern kann. Die konventionelle antibiotische Therapie der Erkrankung adressiert den Krankheitserreger. Mit der additiven Gabe von rekombinantem Interferon Gamma 1b soll zusätzlich eine Modifikation von krankheitsbedingenden Wirtsfaktoren erreicht werden. Dabei sind methodologische Herausforderungen zu berücksichtigen, die sich bei wissenschaftlich abgesicherten Therapien seltener Erkrankungen stellen. Die Aussagekraft der Untersuchung ist primär durch die niedrige Fallzahl und eine fehlende klinische Kontrollgruppe begrenzt. Vor dem Hintergrund des allgemein reduzierten Evidenzniveaus aller Therapieoptionen der disseminierten Nocardiose liefert sie eine Rationale zur Komplementierung der aktuell vorherrschenden Behandlungsstrategien. Limitierte Behandlungserfolge bei der konventionellen Therapie disseminierter Nocardiosen stehen einerseits in einem engen Zusammenhang mit der komplexen und dynamischen Taxonomie der Gattung der Erreger. Andererseits ist dafür die Immunpathologie des Wirts von großer Bedeutung. Die Arbeit demonstriert einen innovativen Therapieansatz auf Basis der beschriebenen Fälle und in Rückgriff auf die Pathophysiologie der Erkrankung.Nocardiosis is a rare disease caused by some species of the bacterial genus Nocardia. Especially disseminated manifestation of the disease has a high mortality risk. The work of Derungs et al. presents an adjuvant therapeutic approach to disseminated Nocardiosis and addresses the question to what extent host-directed therapy is able to improve therapeutic results. While conventional antibiotic therapy of the disease addresses the pathogen, additive administration of recombinant interferon gamma 1b aims to alter disease-causing host factors. Methodological challenges that arise with science-based therapies for rare diseases need to be taken into account. The validity of the study is primarily limited by the low number of cases and the lack of a clinical control group. Against the background of the generally limited level of evidence of all therapy options for disseminated nocardiosis, it provides a rationale for complementing the currently prevailing treatment strategies. On the one hand, limited treatment successes in the conventional therapy of disseminated nocardiosis are closely related to the complex and dynamic taxonomy of the genus of the pathogen. On the other hand, the immunopathology of the host is of great importance. The work demonstrates an innovative therapeutic approach based on the cases described and in recourse to the pathophysiology of the disease

Symptoms, toxicities, and analytical results for a patient after smoking herbs containing the novel synthetic cannabinoid MAM-2201

We report a case of intoxication by the synthetic cannabinoid MAM-2201 ([1-(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl)-methanone). A 31-year-old man smoked about 300mg of a herbal blend. He experienced an acute transient psychotic state with agitation, aggression, anxiety, and vomiting associated with a sympathomimetic syndrome. MAM-2201 was detected and quantified in a plasma sample using liquid chromatography-tandem mass spectrometry (LC-MS-MS). The level was 49ng/ml 1h after smoking. The use of other drugs was analytically excluded. The presence of MAM-2201 was confirmed in the herbal blend using gas chromatography-mass spectrometry (GC-MS) and LC-high resolution MS. This is the first description of an analytically confirmed intoxication and of the determination of MAM-2201 in human blood plasm

SCCER JA-RED - Analysis of initial case and identification of potential use for renewables and waste heat at the building and district level - Deliverable 1.1.1

This deliverable summarizes the current situation of all relevant aspects for the future planning and optimization of the local energy system at the demonstrator site of this Joint Activity (Rolle and Mont-sur-Rolle VD). The two communities are analyzed in terms of settlement structure, buildings, renewable energy potential and waste heat. The analysis of the settlement structure yields areas that will require special attention during planning and implementation of future changes to the local energy system – for environmental, social or technical reasons. Furthermore, it lays out existing structures, like road networks, electrical and gas-grids. The analysis of buildings shows that fossil fuels are the predominantly used source of heating energy in Rolle and Mont-sur-Rolle. Hence there is a large potential for the reduction of greenhouse gas emission. A fast simulation model to calculate time series for heating and electricity demands had been developed. This models allowed us to generate time series for each of the 1650 houses in less than 1 hour. Exemplary results for individual buildings are presented in this deliverable. These models will be an essential component in achieving the next milestones of this Joint Activity and will enable practitioners to use time-resolved demand curves in their planning processes. In the last part of this deliverable, the potential for renewable energy generation is analyzed. Estimations for thermal energy that can be provided by locally available wood, Lake Geneva and geothermal probes, as well as, estimations of the wind energy and PV potential lead us to the conclusion that the current energy demand could be entirely covered using renewable sources. Hence this deliverable prepared the basis for the next steps of developing the energy concept for Rolle and Mont-sur-Rolle

Symptoms, toxicities, and analytical results for a patient after smoking herbs containing the novel synthetic cannabinoid MAM-2201

We report a case of intoxication by the synthetic cannabinoid MAM-2201 ([1-(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl)-methanone). A 31-year-old man smoked about 300 mg of a herbal blend. He experienced an acute transient psychotic state with agitation, aggression, anxiety, and vomiting associated with a sympathomimetic syndrome. MAM-2201 was detected and quantified in a plasma sample using liquid chromatography-tandem mass spectrometry (LC–MS–MS). The level was 49 ng/ml 1 h after smoking. The use of other drugs was analytically excluded. The presence of MAM-2201 was confirmed in the herbal blend using gas chromatography–mass spectrometry (GC–MS) and LC–high resolution MS. This is the first description of an analytically confirmed intoxication and of the determination of MAM-2201 in human blood plasma

Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease

In Alzheimer's disease (AD), cerebral arteries, in contrast to cerebral microvessels, show both cerebral amyloid angiopathy- (CAA) dependent and -independent vessel wall pathology. However, it remains unclear whether CAA-independent vessel wall pathology affects arterial function thereby chronically reducing cerebral perfusion, and if so which mechanisms mediate this effect. To this end, we assessed the ex vivo vascular function of the basilar artery and a similar-sized peripheral artery (femoral artery) in the Swedish-Arctic (SweArc) transgenic AD mouse model at different disease stages. Further, we used quantitative immunohistochemistry to analyze CAA, endothelial morphology, and molecular pathways pertinent to vascular relaxation. We found that endothelium-dependent, but not smooth muscle-dependent vasorelaxation was significantly impaired in basilar and femoral arteries of 15-month-old SweArc mice compared to that of age-matched wildtype (WT) and 6-month-old SweArc mice. This impairment was accompanied by significantly reduced levels of cyclic GMP (cGMP), indicating a reduced nitric oxide (NO) bioavailability. However, no age- and genotype-related differences in oxidative stress as measured by lipid peroxidation were observed. Although parenchymal capillaries, arterioles, and arteries showed abundant CAA in the 15-month-old SweArc mice, no CAA or changes in endothelial morphology were detected histologically in the basilar and femoral artery. Thus, our results suggest that in this AD mouse model dysfunction of large intracranial, extracerebral arteries important for brain perfusion is mediated by reduced NO bioavailability rather than by CAA. This finding supports the growing body of evidence highlighting the therapeutic importance of targeting the cerebrovasculature in AD

Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke

Aim: Constitutive genetic deletion of the adaptor protein p66Shc was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66Shc gene regulation in human ischaemic stroke. Methods and Results: Ischaemia/reperfusion brain injury was induced by performing a transient middle cerebral artery occlusion surgery on wild-type mice. After the ischaemic episode and upon reperfusion, small interfering RNA targeting p66Shc was injected intravenously. We observed that post-ischaemic p66Shc knockdown preserved blood-brain barrier integrity that resulted in improved stroke outcome, as identified by smaller lesion volumes, decreased neurological deficits, and increased survival. Experiments on primary human brain microvascular endothelial cells demonstrated that silencing of the adaptor protein p66Shc preserves claudin-5 protein levels during hypoxia/reoxygenation by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and reactive oxygen species production. Further, we found that in peripheral blood monocytes of acute ischaemic stroke patients p66Shc gene expression is transiently increased and that this increase correlates with short-term neurological outcome. Conclusion: Post-ischaemic silencing of p66Shc upon reperfusion improves stroke outcome in mice while the expression of p66Shc gene correlates with short-term outcome in patients with ischaemic stroke

Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-β and tau pathology in iPSC-derived neurons from sporadic Alzheimer's disease patients

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and increased production of reactive oxygen species (ROS) has been described in postmortem brain samples and animal models. However, these observations were made at a late stage of disease and the inability to examine an early, presymptomatic phase in human neurons impeded our understanding of cause or consequence of mitochondrial dysfunction in AD. We used human induced pluripotent stem cell-derived neuronal cells (iN cells) from sporadic AD (SAD) patients and healthy control subjects (HCS) to show aberrant mitochondrial function in patient-derived cells. We observed that neuronal cultures from some patients produced more ROS and displayed higher levels of DNA damage. Furthermore, patient-derived cells showed increased levels of oxidative phosphorylation chain complexes, whereas mitochondrial fission and fusion proteins were not affected. Surprisingly, these effects neither correlated with Aβ nor phosphorylated and total tau levels. Synaptic protein levels were also unaffected in SAD iN cells. The results of this study give new insights into constitutional metabolic changes in neurons from subjects prone to develop Alzheimer's pathology. They suggest that increased ROS production may have an integral role in the development of sporadic AD prior to the appearance of amyloid and tau pathology. Keywords: Alzheimer's disease, Induced pluripotent stem cells, Induced neuronal cells, Sporadic AD, Mitochondria, A