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.

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.

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.

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.

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.

Hyperbaric Oxygen Therapy in Necrotizing Soft Tissue Infections: A Retrospective Study.

Necrotizing soft tissue infection is a severe life-threatening disease correlated with high mortality. Until now, therapeutic concepts include antimicrobial, intensive care and surgical interventions, as well as the application of hyperbaric oxygenation (HBO), which still has a controversial status. Evidence of the therapeutic concept of HBO is, so far, limited to positive experiences in case studies and physiological benefits in animal studies. That is why the HBO therapy method is not yet fully established. In this light, a retrospective data analysis was conducted. The analysis involved 91 intensive care patients in the Clinic for Anesthesiology and Surgical Intensive Care at the University Hospital Halle (Saale) who, because of a necrotizing soft tissue infection, were treated with HBO therapy (period of observation from 2008 to second quarter 2017). Treatment outcome was examined with regard to mortality, complications, time spent in the intensive care unit, and functional limitations. The criteria of therapy relevance, therapy management, and conclusions drawn from the treatment results were evaluated. By examining the result of combining all four categories of treatment, we aim to investigate established guidelines and their practicability. We expect treatment with HBO to have no disadvantages compared with acknowledged treatment concepts. This study considers the success of treatment as a result of complying with optimal therapy. In a contribution to establish coverage use and an inventory of hyperbaric chambers, we also aim to create a national case register, so that patients do not have to depend on long and risky transportations.

Polyunsaturated Fatty Acids Induce ROS Synthesis in Microvascular Endothelial Cells.

In sepsis, endothelial dysfunction is a crucial driver known to limit the survival rate of affected patients. For this, ROS-mediated signaling plays an important role in endothelial communication and functionality. In the management of sepsis, polyunsaturated fatty acids (PUFA) have received increasing attention regarding their anti-inflammatory potential neglecting the oxidative properties of these substances. Therefore, in the present study we examined the capacity of PUFA to interfere with the expression of major ROS-producing enzymes, as well as endothelial ROS production itself. The human microvascular endothelial cells TIME (ATCC number: CRL-4025) were used. Cells were cultured in medium enriched with LNA (C18:3n3), EPA (C20:5n3), DHA (C22:6n3), LA (C18:2n6), or AA (C20:4n6) in concentrations of 15 µM totaling 144 h. Stimulation of cells was performed in the last 24 h of fatty acid supplementation by addition of the cytokines TNF-α + IL-1ß + IFN-γ (5 ng/ml each). Gene expression of eNOS, COX-2, and NOX-4 was evaluated by qPCR. ROS synthesis was analyzed by means of a flow cytometry-based rhodamine 123 assay. Cytokine stimulation was found to differentially affect gene expression of major ROS synthesizing enzymes: eNOS was decreased whereas COX-2 and NOX-4 were increased. As a consequence, cytokine stimulation had no effect on rhodamine accumulation in endothelial cells. PUFA supplementation alone did not affect the gene expression of eNOS, COX-2, and NOX-4. Nevertheless, an increasing action of PUFA on the stimulation-induced reduction in eNOS expression was found. More importantly, the number of rhodamine positive endothelial cells almost doubled following enrichment with the PUFA EPA, DHA or AA. This effect was independent of the stimulation status of the cells but seemed to be related to the number of double bonds of a supplemented fatty acid. Our data warrant further studies to ensure that increased endothelial cell oxidative stress is not boosted by PUFA in septic patients.

Impact of Unsaturated Fatty Acids on Cytokine-Driven Endothelial Cell Dysfunction.

Polyunsaturated fatty acids (PUFA) are reported to exert prophylactic and acute therapeutic effects in diseases linked to endothelial dysfunction. In the present study, the consequences of a PUFA enrichment of endothelial cells (cell line TIME) on cell viability, expression of the cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein 1 (MCP-1), synthesis of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular adhesion molecule 1 (VCAM-1), and production of the coagulation factors plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), and tissue factor (TF) was analyzed in parallel. PUFA of both the n3 and the n6 family were investigated in a physiologically relevant concentration of 15 µM, and experiments were performed in both the presence and the absence of the pro-inflammatory cytokines interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Supplementation of the culture medium with particular fatty acids was found to have a promoting effect on cellular production of the cytokines IL-6, IL-8, GM-CSF, and MCP-1. Further on, PUFA treatment in the absence of a stimulant diminished the percentage of endothelial cells positive for ICAM-1, and adversely affected the stimulation-induced upregulation of VCAM-1. Cell viability and production of coagulation factors were not or only marginally affected by supplemented fatty acids. Altogether, the data indicate that PUFA of either family are only partially able to counterbalance the destructive consequences of an endothelial dysfunction.

Continuous intraoperative monitoring of vagus and recurrent laryngeal nerve function in patients with advanced atrioventricular block.

PURPOSE: Intraoperative neuromonitoring of recurrent laryngeal nerve function after stimulation of the vagus nerve has been embraced as a risk minimization tool in thyroid surgery to prevent recurrent laryngeal nerve injury. Because this technology is increasingly used in an elderly and sicker population, the present study was conducted to determine the safety of this method in patients with second- or third-degree atrioventricular block. METHODS: This study aimed at evaluating the feasibility and safety of continuous intraoperative neuromonitoring (CIONM) in patients with second- or third-degree atrioventricular block. RESULTS: A total of six patients (12 nerves at risk), accounting for 0.3 % of all 1800 patients (3049 nerves at risk) who underwent thyroid surgery during the study period, were found to have second- or third-degree atrioventricular block. All these patients maintained normal systolic and diastolic blood pressures; heart rate; and peripheral arterial oxygen saturation before, during, and after CIONM. No clinically relevant changes in heart rate or blood pressure, cardiac arrhythmia, or other hemodynamically important events were noted despite careful monitoring of these patients. There was no interference between the biphasic waveform of the vocal muscle electromyogram and the spikes generated by the implanted cardiac pacemakers. Outcomes were uneventful with normal vocal fold and parathyroid gland function. CONCLUSIONS: Within the limitations of this series and considering experimental, animal, and human data, continuous IONM of the vagus nerve at ≤2 Hz seems to be reasonably safe. Additional research is warranted to confirm these results in larger groups of patients with advanced atrioventricular block.

Regulation of Expression of Renal Organic Anion Transporters OAT1 and OAT3 in a Model of Ischemia/Reperfusion Injury.

BACKGROUND: Recently, we gained evidence that impairment of rOat1 and rOat3 expression induced by ischemic acute kidney injury (AKI) is mediated by COX metabolites and this suppression might be critically involved in renal damage. METHODS: (i) Basolateral organic anion uptake into proximal tubular cells after model ischemia and reperfusion (I/R) was investigated by fluorescein uptake. The putative promoter sequences from hOAT1 (SLC22A6) and hOAT3 (SCL22A8) were cloned into a reporter plasmid, transfected into HEK cells and (ii) transcriptional activity was determined after model ischemia and reperfusion as a SEAP reporter gen assay. Inhibitors or antagonists were applied with the beginning of reperfusion. RESULTS: By using inhibitors of PKA (H89) and PLC (U73122), antagonists of E prostanoid receptor type 2 (AH6809) and type 4 (L161,982), we gained evidence that I/R induced down regulation of organic anion transport is mediated by COX1 metabolites via E prostanoid receptor type 4. The latter signaling was confirmed by application of butaprost (EP2 agonist) or TCS2510 (EP4 agonist) to control cells. In brief, the latter signaling was verified for the transcriptional activity in the reporter gen assay established. Therein, selective inhibitors for COX1 (SC58125) and COX2 (SC560) were also applied. CONCLUSION: Our data show (a) that COX1 metabolites are involved in the regulation of renal organic anion transport(ers) after I/R via the EP4 receptor and (b) that this is due to transcriptional regulation of the respective transporters. As the promoter sequences cloned were of human origin and expressed in a human renal epithelial cell line we (c) hypothesize that the regulatory mechanisms described after I/R is meaningful for humans as well.

[Multimodal pain management in a patient with atypical cervicogenic headache]. / Patient mit einer atypischen Form zervikogener Kopfschmerzen.

A 45-year-old patient presented with an eight-year history of persistent unilateral headache associated with recurrent episodes of ipsilateral conjunctival injections, eyelid edema and ptosis. Prior ineffective pharmacological treatment strategies included tramadol, non-steroidal anti-inflammatory drugs and triptans. Palpation of right suboccipital trigger points revealed tenderness in the area of the greater occipital nerve and reinforced the symptoms. The diagnosis of cervicogenic headache was confirmed by symptom resolution following right greater occipital nerve blockade. A multimodal treatment strategy (physical therapy, nerve blockade, pharmacological treatment) was chosen and an emphasis was put on optimizing pharmacological pain relief using the opioid analgesic tapentadol and the tricyclic antidepressant amitriptyline as an adjuvant analgesic. Importantly, the patient reported a substantial and consistent pain reduction and considerable quality of life improvement during implementation of the treatment regimen.

Antithrombin III, but not C1 esterase inhibitor reduces inflammatory response in lipopolysaccharide-stimulated human monocytes in an ex-vivo whole blood setting.

In order to examine the immunomodulatory effects of antithrombin III (AT-III) and C1 esterase inhibitor (C1-INH) in human monocytes, we investigated the intracellular expression of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in an ex-vivo laboratory study in a whole blood setting. Heparinized whole blood samples from 23 healthy male and female volunteers (mean age: 27±7years) were pre-incubated with clinically relevant concentrations of AT-III (n=11) and C1-INH (n=12), then stimulated with 0.2 ng/mL lipopolysaccharide (LPS) for 3h. After phenotyping CD14⁺ monocytes, intracellular expression of IL-6, IL-8, and TNF-α was assessed using flow cytometry. In addition, 12 whole blood samples (AT-III and C1-INH, n=6 each) were examined using hirudin for anticoagulation; all samples were processed in the same way. To exclude cytotoxicity effects, 7-amino-actinomycin D and Nonidet P40 staining were used to investigate probes. This study is the first to demonstrate the influence of C1-INH and AT-III on the monocytic inflammatory response in a whole blood setting, which mimics the optimal physiological setting. Cells treated with AT-III exhibited significant downregulation of the proportion of gated CD14⁺ monocytes for IL-6 and IL-8, in a dose-dependent manner; downregulation for TNF-α did not reach statistical significance. There were no significant effects on mean fluorescence intensity (MFI). In contrast, C1-INH did not significantly reduce the proportion of gated CD14⁺ monocytes or the MFI regarding IL-6, TNF-α, and IL-8. When using hirudin for anticoagulation, no difference in the anti-inflammatory properties of AT-III and C1-INH in monocytes occurs. Taken together, in contrast to TNF-α, IL-6 and IL-8 were significantly downregulated in monocytes in an ex-vivo setting of human whole blood when treated with AT-III. This finding implicates monocytes as an important point of action regarding the anti-inflammatory properties of AT-III in sepsis. C1-INH was unable to attenuate the monocytic response, which supports the hypothesis that other cellular components in whole blood (e.g., neutrophils) might be responsible for the known effects of C1-INH in inflammation.

Differential effect of COX1 and COX2 inhibitors on renal outcomes following ischemic acute kidney injury.

BACKGROUND/AIMS: We have previously shown that 1 mg/kg indomethacin improves expression and functionality of renal organic anion transporters Oat1 and Oat3 after renal ischemia and furthermore improves renal outcome after ischemia. As we detected differential effects of COX1 or COX2 inhibitors on organic anion transport after ischemia and reperfusion in culture, we investigated the effect of the SC560 (COX1 inhibitor) and SC58125 (COX2 inhibitor) on expression of Oat1/3 and renal outcome after ischemic acute kidney injury (iAKI). METHODS: iAKI was induced in rats by bilateral clamping of renal arteries for 45 min. SC560 or SC58125 (1 mg/kg each) were given intraperitoneally as soon as reperfusion started. Sham-treated animals served as controls. Oat1/3 were determined by qPCR and Western blot. Glomerular filtration rate (GFR), p-aminohippurate (PAH) clearance and PAH extraction ratio was determined. All parameters were detected 24 h after ischemia. Renal plasma flow was calculated. RESULTS: In clamped animals SC560 (COX1 inhibitor) restored expression of Oat1/3, as well as renal perfusion. Additionally, SC560 substantially improved kidney function as measured by GFR. Application of the COX2 inhibitor SC58125 did not exert these beneficial effects. CONCLUSION: Our study indicates that COX1 inhibitor SC560 applied after ischemia prevents ischemia-induced downregulation of Oat1/3 during reperfusion and has a substantial protective effect on kidney function. Whether and to what particular extent this apparent improvement of function is mechanistically due to beneficial effects on tubular function, renal perfusion or glomerular filtration will be the scope of future studies.

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.

Anesthetic management in patients undergoing hyperthermic chemotherapy.

PURPOSE OF REVIEW: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an important therapeutic option for selected patients with peritoneal surface malignancies. This aggressive multimodality treatment is complex, not only regarding surgical technique, but also regarding anesthesia. The present review represents our experience in anesthetic care. RECENT FINDINGS: Improved prognosis compared with systemic chemotherapy alone has recently been demonstrated for cytoreductive surgery when combined with intraoperative intracavitary hyperthermic chemotherapy. Anesthetic management of HIPEC is further impacted by these developments. In addition to the ambitious, long-lasting surgery, HIPEC causes significant fluid, blood and protein losses, increased intra-abdominal pressure, systemic hyperthermia, and increased metabolic rate, leading to relevant pathophysiological alterations, and therefore represents a challenge for anesthetist and critical care physicians. SUMMARY: Anesthetic management importantly contributes to the containment of the perioperative complications of HIPEC. An appreciation of the technical aspects and physiologic disruptions associated with intra-abdominal HIPEC is critical to ensure effective anesthetic management. Although data on this specialized surgical procedure are scarce, some referral centers have accumulated extensive experience. This article reviews the current knowledge about the anesthesiological and intensive care management of patients undergoing HIPEC. It pinpoints strategies for perioperative monitoring as well as illustrates alterations in hemodynamic, hematopoetic, and fluid hemostasis.

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.

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.