Non-canonical function of ADAM10 in presynaptic plasticity.

A Disintegrin And Metalloproteinase 10 (ADAM10) plays a pivotal role in shaping neuronal networks by orchestrating the activity of numerous membrane proteins through the shedding of their extracellular domains. Despite its significance in the brain, the specific cellular localization of ADAM10 remains not well understood due to a lack of appropriate tools. Here, using a specific ADAM10 antibody suitable for immunostainings, we observed that ADAM10 is localized to presynapses and especially enriched at presynaptic vesicles of mossy fiber (MF)-CA3 synapses in the hippocampus. These synapses undergo pronounced frequency facilitation of neurotransmitter release, a process that play critical roles in information transfer and neural computation. We demonstrate, that in conditional ADAM10 knockout mice the ability of MF synapses to undergo this type of synaptic plasticity is greatly reduced. The loss of facilitation depends on the cytosolic domain of ADAM10 and association with the calcium sensor synaptotagmin 7 rather than ADAM10's proteolytic activity. Our findings unveil a new role of ADAM10 in the regulation of synaptic vesicle exocytosis.

The synergism of cytosolic acidosis and reduced NAD+/NADH ratio is responsible for lactic acidosis-induced vascular smooth muscle cell impairment in sepsis.

BACKGROUND: During sepsis, serve vascular dysfunctions lead to life-threatening multiple organ failure, due to vascular smooth muscle cells (VSMC) impairments, resulting in vasoplegia, hypotension and hypoperfusion. In addition, septic patients have an altered cell metabolism that leads to lactic acidosis. Septic patients suffering from lactic acidosis have a high risk of mortality. In addition, septic survivors are at risk of secondary vascular disease. The underlying mechanisms of whether and how lactic acidosis leads to the changes in VSMCs is not well understood. The aim of this study was to comprehensively investigate the effect of lactic acidosis on VSMCs and additionally compare the effects with those induced by pure acidosis and sodium lactate. METHODS: Primary human aortic smooth muscle cells (HAoSMCs) were treated for 48 h with lactic acidosis (LA_pH 6.8), hydrochloric acid (HCl_pH 6.8), sodium lactate (Na+-lactate_pH 7.4) and the respective controls (ctrl._pH 7.4; hyperosmolarity control: mannitol_pH 7.4) and comparatively analyzed for changes in (i) transcriptome, (ii) energy metabolism, and (iii) phenotype. RESULTS: Both types of acidosis led to comparable and sustained intracellular acidification without affecting cell viability. RNA sequencing and detailed transcriptome analysis revealed more significant changes for lactic acidosis than for hydrochloric acidosis, with lactate being almost ineffective, suggesting qualitative and quantitative synergism of acidosis and lactate. Bioinformatic predictions in energy metabolism and phenotype were confirmed experimentally. Lactic acidosis resulted in strong inhibition of glycolysis, glutaminolysis, and altered mitochondrial respiration which reduced cellular ATP content, likely due to increased TXNIP expression and altered NAD+/NADH ratio. Hydrochloric acidosis induced significantly smaller effects without changing the NAD+/NADH ratio, with the ATP content remaining constant. These metabolic changes led to osteo-/chondrogenic/senescent transdifferentiation of VSMCs, with the effect being more pronounced in lactic acidosis than in pure acidosis. CONCLUSIONS: Overall, lactic acidosis exerted a much stronger effect on energy metabolism than pure acidosis, whereas lactate had almost no effect, reflecting the qualitative and quantitative synergism of acidosis and lactate. As a consequence, lactic acidosis may lead to acute functional impairments of VSMC, sustained perturbations of the transcriptome and cellular dedifferentiation. Moreover, these effects may contribute to the acute and prolonged vascular pathomechanisms in septic patients.

Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases.

Neurodegenerative protein conformational diseases (PCDs), such as Alzheimer's, Parkinson's, and Huntington's, are a leading cause of death and disability worldwide and have no known cures or effective treatments. Emerging evidence suggests a role for the gut microbiota in the pathogenesis of neurodegenerative PCDs; however, the influence of specific bacteria on the culprit proteins associated with each of these diseases remains elusive, primarily due to the complexity of the microbiota. In the present study, we employed a single-strain screening approach to identify human bacterial isolates that enhance or suppress the aggregation of culprit proteins and the associated toxicity in Caenorhabditis elegans expressing Aß1-42, α-synuclein, and polyglutamine tracts. Here, we reveal the first comprehensive analysis of the human microbiome for its effect on proteins associated with neurodegenerative diseases. Our results suggest that bacteria affect the aggregation of metastable proteins by modulating host proteostasis rather than selectively targeting specific disease-associated proteins. These results reveal bacteria that potentially influence the pathogenesis of PCDs and open new promising prevention and treatment opportunities by altering the abundance of beneficial and detrimental microbes.

Pain management in surgical intensive care patients: A retrospective observational research.

Sepsis and septic shock are the most common causes of death in non-cardiac surgical intensive care units (ICU). Adequate analgesia is essential to achieve positive outcomes. There were differences in pain management between patients with and without sepsis or septic shock. The release of inflammatory mediators, especially cytokines, in sepsis or septic shock decreases the pain threshold. Septic intensive care patients probably require higher doses of opioids than do non-septic patients. A retrospective observational study was carried out in an anesthesiologic intensive care unit from January 1, 2014 to June 30, 2016. Patients were divided into 4 groups according to the following criteria: sepsis ("yes/no" and communication ability "yes/no"). After adjusting for the number of cases using the pairing method, a total of 356 patients were recruited. The endpoint of our study was defined as the "total opioid dose". Statistical evaluations were performed using t tests and 2-factor analysis of variance. There was a significant difference in opioid doses between communicative and non-communicative ICU patients F(1, 352) = 55.102, P < .001). This effect was observed in the ICU patients with and without sepsis. The mean sufentanil dose was significantly higher in non-communicative patients than in communicative patients group (E(1, 352) = 51.435, P < .001, partial ƞ2 = 0.144). The effect of higher opioid- (F(1, 352) = 1.941, P = .161) and sufentanil (F(1, 352) = 1.798, P = .342) requirement was not statistically significant due to sepsis. The hypothesis that sepsis decreases the pain threshold could not be proven in this study. The effect of a higher opioid requirement is not directly caused by sepsis but by communication ability. Furthermore, we were able to show through our investigations and especially through the data of the pain recording instruments that the septic and non-septic intensive care patients receive sufficient pain therapy treatment in our ICU. Regular pain evaluations should be performed on patients in the ICUs who are able to communicate and those who are not.

Direct and indirect effects of tubulin post-translational modifications on microtubule stability: Insights and regulations.

Microtubules (MTs) mediate various cellular functions such as structural support, chromosome segregation, and intracellular transport. To achieve this, the pivotal properties of MTs have to be changeable and tightly controlled. This is enabled by a high variety of tubulin posttranslational modifications, which influence MT properties directly, via altering the MT lattice structurally, or indirectly by changing MT interaction partners. Here, the distinction between these direct and indirect effects of MT PTMs are exemplified by acetylation of the luminal α-tubulin K40 resulting in decreased rigidity of MTs, and by MT detyrosination which decreases interaction with depolymerizing proteins, thus causing more stable MTs. We discuss how these PTMs are reversed and regulated, e.g. on the level of enzyme transcription, localization, and activity via various signalling pathways including the conventional calcium-dependent proteases calpains and how advances in microscopy techniques and development of live-sensors facilitate the understanding of MT PTM interaction and effects.

Caldendrin and myosin V regulate synaptic spine apparatus localization via ER stabilization in dendritic spines.

Excitatory synapses of principal hippocampal neurons are frequently located on dendritic spines. The dynamic strengthening or weakening of individual inputs results in structural and molecular diversity of dendritic spines. Active spines with large calcium ion (Ca2+ ) transients are frequently invaded by a single protrusion from the endoplasmic reticulum (ER), which is dynamically transported into spines via the actin-based motor myosin V. An increase in synaptic strength correlates with stable anchoring of the ER, followed by the formation of an organelle referred to as the spine apparatus. Here, we show that myosin V binds the Ca2+ sensor caldendrin, a brain-specific homolog of the well-known myosin V interactor calmodulin. While calmodulin is an essential activator of myosin V motor function, we found that caldendrin acts as an inhibitor of processive myosin V movement. In mouse and rat hippocampal neurons, caldendrin regulates spine apparatus localization to a subset of dendritic spines through a myosin V-dependent pathway. We propose that caldendrin transforms myosin into a stationary F-actin tether that enables the localization of ER tubules and formation of the spine apparatus in dendritic spines.

Analysis of 30 anaesthesia-related deaths in Germany between 2006 and 2015: An analysis of a closed claims database.

BACKGROUND: Anaesthesiology is one of the safest fields in medicine today in relation to mortality. Deaths directly because of anaesthesia have fortunately now become rare exceptions. Nevertheless, important findings can still be drawn from the rare deaths that still occur. OBJECTIVE: The aim of this study was to identify and analyse the causes of deaths related to anaesthesia alone over a 10-year period. DESIGN: Retrospective structured analysis of a database of medical liability claims. SETTING: Hospitals at all levels of care in Germany. PATIENTS: The database of a large insurance broker included data for 81 413 completed liability claims over the 10-year period from 2006 to 2015. Among 1914 cases associated with anaesthetic procedures, 56 deaths were identified. Of these, 30 clearly involved anaesthesia (Edwards category 1) and were included in the evaluation. INTERVENTIONS: None (retrospective database analysis). MAIN OUTCOME MEASURES: Causes of anaesthesia-related death identified from medical records, court records, expert opinions and autopsy reports. RESULTS: The 30 deaths were analysed in detail at the case and document level. They included high proportions of 'potentially avoidable' deaths, at 86.6%, and what are termed 'never events', at 66.7%. Problems with the airway were the cause in 40% and problems with correct monitoring in 20%. In addition, communication problems were identified as a 'human factor' in 50% of the cases. CONCLUSION: The majority of the anaesthesia-related deaths investigated could very probably have been avoided with simple anaesthesiological measures if routine guidelines had been followed and current standards observed. Actions to be taken are inferred from these results, and recommendations are made. In future, greater care must be taken to ensure that the level of safety already achieved in anaesthesiology can be maintained despite demographic developments and increasing economic pressures.

Cardiogenic shock with highly complicated course after influenza A virus infection treated with vva-ECMO and Impella CP (ECMELLA): a case report.

BACKGROUND: The value of mechanical circulatory support (MCS) in cardiogenic shock, especially the combination of the ECMELLA approach (Impella combined with ECMO), remains controversial. CASE PRESENTATION: A previously healthy 33-year-old female patient was submitted to a local emergency department with a flu-like infection and febrile temperatures up to 39 °C. The patient was tested positive for type-A influenza, however negative for SARS-CoV-2. Despite escalated invasive ventilation, refractory hypercapnia (paCO2: 22 kPa) with severe respiratory acidosis (pH: 6.9) and a rising norepinephrine rate occurred within a few hours. Due to a Horovitz-Index < 100, out-of-centre veno-venous extracorporeal membrane oxygenation (vv-ECMO)-implantation was performed. A CT-scan done because of anisocoria revealed an extended dissection of the right vertebral artery. While the initial left ventricular function was normal, echocardiography revealed severe global hypokinesia. After angiographic exclusion of coronary artery stenoses, we geared up LV unloading by additional implantation of an Impella CP and expanded the vv-ECMO to a veno-venous-arterial ECMO (vva-ECMO). Clinically relevant bleeding from the punctured femoral arteries resulted in massive transfusion and was treated by vascular surgery later on. Under continued MCS, LVEF increased to approximately 40% 2 days after the initiation of ECMELLA. After weaning, the Impella CP was explanted at day 5 and the vva-ECMO was removed on day 9, respectively. The patient was discharged in an unaffected neurological condition to rehabilitation 25 days after the initial admission. CONCLUSIONS: This exceptional case exemplifies the importance of aggressive MCS in severe cardiogenic shock, which may be especially promising in younger patients with non-ischaemic cardiomyopathy and potentially reversible causes of cardiogenic shock. This case impressively demonstrates that especially young patients may achieve complete neurological restoration, even though the initial prognosis may appear unfavourable.

Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses.

Members of the SH3- and ankyrin repeat (SHANK) protein family are considered as master scaffolds of the postsynaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this proof-of-principle study, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3 and demonstrate that both mutant proteins indeed show distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and distal structural disturbances result in altered synaptic targeting and changes of protein turnover at synaptic sites in rat primary hippocampal neurons.

Treatment effects of palliative care consultation and patient contentment: A monocentric observational study.

ABSTRACT: Palliative care is a central component of the therapy in terminally ill patients. During treatment in non-palliative departments this can be realized by consultation.To analyze the change in symptom burden during palliative care consultation.In this observational study, we enrolled all cancer cases (n = 163) receiving inpatient treatment for 2015 to 2018 at our institution. We used the MDASI-questionnaire (0 = 'not present' and 10 = "as bad as you can imagine") and the FAMCARE-6 (1 = very satisfied, 5 = very dissatisfied) to analyze the treatment effect and patient satisfaction, respectively.We examined the association of symptom burden and patient satisfaction using Spearman-correlation. Comparing mean values, we applied the Wilcoxon-test and one-way ANOVA.An improvement in MDASI-core-items after treatment completion was significant (P < .05) in 14/18 symptoms. The change in perception of pain showed the strongest improvement (median: 5 to 3). Initially the MDASI-items "activity" (median = 8) and emotional distress (median = 5 and 6) were viewed as especially incriminating. There was no evidence for a correlation between patients' age, the type of diagnosis and time since diagnosis.The analysis of FAMCARE-6 patient contentment was lower or equal to two in all of the six items. There was a weak negative association between the change in symptom burden of psycho-emotional items "distress/feeling upset" (P = .006, rSp = -0,226), "sadness" and patient satisfaction in FAMCARE-6.A considerable improvement of the extensive symptom burden particularly of pain relief was achieved by integrating palliative consultation in clinical practice.

Mid-German Sepsis Cohort (MSC): a prospective observational study of sepsis survivorship.

PURPOSE: The Mid-German Sepsis Cohort (MSC) aims to investigate mid-term and long-term functional disabilities in sepsis survivors from intensive care unit (ICU) discharge until 1 year after. Secondary, post-acute mortality and morbidity, health-related quality of life and healthcare utilisation will be investigated. PARTICIPANTS: The MSC comprises adult (aged ≥18 years) patients who were treated for (severe) sepsis or septic shock on ICU. The participants were recruited between 15 April 2016 and 30 November 2018 from five German centres. Three thousand two hundred and ten patients with sepsis were identified, of which 1968 survived their ICU stay and were eligible for enrolment in the follow-up cohort. Informed consent for follow-up assessment was provided by 907 patients (46.1% of eligible patients). FINDINGS TO DATE: The recruitment of the participants for follow-up assessments and the baseline data collection is completed. Incidence of sepsis was 116.7 patients per 1000 ICU patients. In this cohort profile, we provide an overview of the demographics and the clinical characteristics of both the overall sepsis cohort and the ICU survivors who provided informed consent for follow-up assessment (907 out of 1968 ICU survivors (46.1%)). FUTURE PLANS: The follow-ups are conducted 3, 6 and 12 months after ICU discharge. Another yearly follow-up up to 5 years after ICU discharge is pursued. Several cooperation and satellite projects were initiated. This prospective cohort offers a unique resource for research on long-term sequelae of sepsis survivors. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS00010050).

SATB2-LEMD2 interaction links nuclear shape plasticity to regulation of cognition-related genes.

SATB2 is a schizophrenia risk gene and is genetically associated with human intelligence. How it affects cognition at molecular level is currently unknown. Here, we show that interactions between SATB2, a chromosomal scaffolding protein, and the inner nuclear membrane protein LEMD2 orchestrate the response of pyramidal neurons to neuronal activation. Exposure to novel environment in vivo causes changes in nuclear shape of CA1 hippocampal neurons via a SATB2-dependent mechanism. The activity-driven plasticity of the nuclear envelope requires not only SATB2, but also its protein interactor LEMD2 and the ESCRT-III/VPS4 membrane-remodeling complex. Furthermore, LEMD2 depletion in cortical neurons, similar to SATB2 ablation, affects neuronal activity-dependent regulation of multiple rapid and delayed primary response genes. In human genetic data, LEMD2-regulated genes are enriched for de novo mutations reported in intellectual disability and schizophrenia and are, like SATB2-regulated genes, enriched for common variants associated with schizophrenia and cognitive function. Hence, interactions between SATB2 and the inner nuclear membrane protein LEMD2 influence gene expression programs in pyramidal neurons that are linked to cognitive ability and psychiatric disorder etiology.

Contribution of ambient noise and hyperbaric atmosphere to olfactory and gustatory function.

INTRODUCTION: Taste and smell are important for occupational performance and quality of life. Previous studies suggested that the function of these senses might be influenced by ambient pressure and noise. This knowledge would be helpful for divers, submarine crews, or mine workers. The present study aimed to investigate the effects of noise and hyperbaric pressure on olfactory and gustatory functions. METHODS: This prospective controlled study included 16 healthy male divers. Inside a hyperbaric chamber, participants performed olfactory and gustatory function tests at sea level pressure and at 2 bar pressure. The olfaction threshold, and the discrimination and identification of odorants were measured with validated ´Sniffin sticks´. Taste identification and the gustation threshold scores were examined with validated filter paper strips. Tests were performed under two conditions: noise reduction (silence) and white noise stimulation presented at 70 dB sound pressure level. RESULTS: The results showed that normobaric and hyperbaric ambient pressures did not significantly affect olfactory or gustatory function. Moreover, noise had no relevant impact on taste or odor sensation. The odor identification score was not influenced in hyperbaric conditions, and the odor threshold score was not influenced by ambient noise or both barometric conditions. The only taste modality affected by hyperbaric conditions was the sensitivity to salty taste, but it was not significant. CONCLUSION: We concluded that hyperbaric and noisy environments have no influence on gustatory and olfactory function. From a practical point of view, the influence of pressure in moderate hyperbaric occupations should be negligible.

Necrotizing fasciitis caused by the treatment of chronic non-specific back pain.

BACKGROUND: Chronic back pain is a multifactorial disease that occurs particularly in adults and has many negative effects on the quality of daily life. Therapeutic strategies are often multimodal and designed for a long-term therapy period. In some cases, one option is joint infiltration or intrathecal injection with local anaesthetics. An adverse effect of this intervention may be necrotic fasciitis, a disease with high mortality and few therapeutic options. CASE PRESENTATION: This case shows a 53-year-old female patient who developed necrotic fasciitis after infiltrations of the sacroiliac joint and after epidural-sacral and intrathecal injections. CONCLUSION: Thanks to early and aggressive surgical intervention, antibiotic treatment and hyperbaric oxygenation, she survived this serious complication and was able to return to life.

Cytoskeletal makeup of the synapse: Shaft versus spine.

The ability of neurons to communicate and store information depends on the activity of synapses which can be located on small protrusions (dendritic spines) or directly on the dendritic shaft. The formation, plasticity, and stability of synapses are regulated by the neuronal cytoskeleton. Actin filaments together with microtubules, neurofilaments, septins, and scaffolding proteins orchestrate the structural organization of both shaft and spine synapses, enabling their efficacy in response to synaptic activation. Synapses critically depend on several factors, which are also mediated by the cytoskeleton, including transport and delivery of proteins from the soma, protein synthesis, as well as surface diffusion of membrane proteins. In this minireview, we focus on recent progress made in the field of cytoskeletal elements of the postsynapse and discuss the differences and similarities between synapses located in the spines versus dendritic shaft.

[Red Flags and Shock Symptoms]. / «Red Flags¼ und Schocksymptome.

Red Flags and Shock Symptoms Abstract. The term 'red flags' is often used in emergency medicine. However, there is no clear medical definition in German for 'red flag'. In most cases, 'red flags' are warning symptoms that indicate a potentially harmful threat to a patient's health. This article wants to explain and define the term 'red flags'. Red flags are explained in emergency medicine and especially in shock in the context of their basic pathophysiological causes. The aim is to improve the understanding of the timely recognition and the exact interpretation of these warning symptoms in the preclinical environment, in order to immediately start a sufficient therapy.

[Medical Cannabis-Related Relapse in a Patient with a History of Alcohol Abuse]. / Alkoholrückfall nach medizinisch indizierter Cannabistherapie.

HISTORY AND CLINICAL FINDINGS: In this report, a 60-year old patient with a history of mixed nociceptive and neuropathic chronic pain after successful removal of oral squamous cell cancer is described who received outpatient pain treatment in our clinic. Moreover, the patient presented with a history of alcohol abuse as well as anorexia and weight loss. EXAMINATIONS AND DIAGNOSIS: The patient was in reduced general condition and cachectic nutritional status. In addition, he suffered from oral pain that radiated to both ears and a related loss of appetite. TREATMENT: In the light of progressive cachexia, we started regular medical cannabis (Sativex®, contains i. e. delta-9-tetrahydrocannabinol and cannabidiol). Despite good initial tolerability, medical cannabis was stopped early due to alcohol relapse of the patient. After termination of medical cannabis, the patient regained control of alcohol consumption and achieved sobriety. CONCLUSIONS: We suggest that medical cannabis only be prescribed with particular caution in patients with a history of alcohol abuse.

[Safety of Pharmacotherapy in Emergencies]. / Sichere Pharmakotherapie im Notfall.

Safety of Pharmacotherapy in Emergencies Abstract. Emergency pharmacotherapy is one of the most commonly used medical procedures. At the same time, pharmacotherapy in an emergency is always a potentially dangerous action. Medication errors are even among the most frequently registered errors in medicine. Due to the special circumstances in emergency medicine, special precautions are required to ensure the safety of drug therapy. In addition to the important background information, this article presents procedures that are recognized and applicable in daily routine to increase safety in pharmacotherapy.

Rotational Thromboelastometry for Assessing Bleeding Complications and Factor XIII Deficiency in Cardiac Surgery Patients.

We aimed to detect alterations and deficits in hemostasis during cardiac surgery with cardiopulmonary bypass (CPB) using point-of-care-supported coagulation analysis (rotational thromboelastometry, impedance aggregometry), in addition to single factor assays for the measurement of fibrinogen (FI) and factor XIII (FXIII) levels. Forty-one patients scheduled for elective cardiac surgery with CPB were enrolled in this observational study. Perioperative measurement (pre-, postheparin, 30-minutes before the end of bypass, 1-hourpostoperatively) of standard laboratory variables, additional rotational thromboelastometry (ROTEM; International GmbH, Munich, Germany), Multiplate analysis (Roche, Switzerland), and an assay of FXIII activity were performed as well as the collection of epidemiological data and blood loss. The FI and FXIII levels as well as the measured ROTEM and Multiplate parameters correlated weakly with the blood loss. Clotting time and maximum clot firmness (MCF) of the intrinsically activated ROTEM showed a good correlation (rCT-INTEM = 0.378; P < .05, rMCF-INTEM = 0.305; P < .05) with postoperative drainage loss, suggesting a dependence of blood loss on the initial intrinsic activity. Additionally, perioperative FI or FIBTEM levels and the FXIII levels correlated with each other. Intrinsically activated ROTEM showed a good correlation with postoperative drainage loss, thus suggesting a dependence of blood loss on the initial intrinsic activity and therefore facilitating clinicians to assess postoperative bleeding complications. Based on the FI level or the MCFFIBTEM measured by ROTEM, it may also be possible to assess the FXIII concentration. Especially in chronically ill and massive bleeding cardiac surgery patients with significantly decreased FXIII levels, the knowledge of FXIII deficiency may help clinicians to treat coagulation disorders more adequately.