Subdural spinal haematoma after epidural anaesthesia.

Epidural anaesthesia is widely used in major thoracic and abdominal surgery for postoperative analgesia. Spinal haematoma after epidural anaesthesia in patients without risk factors is very rare. Most of the reported spinal haematomas arose in the epidural space, whereas the subdural localization seen in this case is very uncommon.We report a case of spinal subdural haematoma after difficult and repeated placement of an epidural catheter for postoperative analgesia. As no sensorimotor deficit of the lower limb arose, we refrained from immediate neurosurgical decompression and the patient recovered fully in the course. Nevertheless, any kind of spinal haematoma is a serious complication we should always be aware of. Prompt detection of clinical symptoms such as sensory or motor deficit is most important. Further diagnostic steps and treatment should not be delayed to avoid permanent neurological deficits.

Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2.

Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients' immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies.

Comparing propofol anaesthesia guided by Bispectral Index monitoring and frontal EEG wave analysis with standard monitoring in laparoscopic surgery: protocol for the 'EEG in General Anaesthesia - More Than Only a Bispectral Index' Trial, a multicentre, double-blind, randomised controlled trial.

INTRODUCTION: The use of Bispectral Index (BIS) monitors for assessing depth of sedation has led to a reduction in both the incidence of awareness and anaesthetic consumption in total intravenous anaesthesia. However, these monitors are vulnerable to artefacts. In addition to the processed number, the raw frontal electroencephalogram (EEG) can be displayed as a curve on the same monitor. Anaesthesia practitioners can learn to interpret the EEG in a short tutorial and may be quicker and more accurate thanBIS in assessing anaesthesia depth by recognising EEG patterns. We hypothesise that quality of recovery (QoR) in patients undergoing laparoscopic surgery is better, if propofol is titrated by anaesthesia practitioners able to interpret the EEG. METHODS AND ANALYSIS: This is a multicentre, double-blind (patients and outcome assessors) randomised controlled trial taking place in four Swiss hospitals. Patients aged 18 years or older undergoing laparoscopic procedures with general anaesthesia using propofol and anaesthesia practitioners with more than 2 years experience will be eligible. The primary study outcome is the difference in QoR 24 hours after surgery. Secondary outcomes are propofol consumption, incidence of postoperative nausea and vomiting (PONV) and postoperative delirium.QoR and propofol consumption are compared between both groups using a two-sample t-test. Fisher's exact test is used to compare the incidences of PONV and delirium. A total of 200 anaesthesia practitioners (and 200 patients) are required to have an 80% chance of detecting the minimum relevant difference for the QoR-15 as significant at the 5% level assuming a SD of 20. ETHICS AND DISSEMINATION: Ethical approval has been obtained from all responsible ethics committees (lead committee: Ethikkommission Nordwest- und Zentralschweiz, 16 January 2021). The findings of the trial will be published in a peer-reviewed journal, presented at international conferences, and may lead to a change in titrating propofol in clinical practice. TRIAL REGISTRATION NUMBER: www. CLINICALTRIALS: gov:NCT04105660.

Investigation of Radial Shaft Seal Swelling Using a Special Tribometer and Magnetic Resonance Imaging.

Compatibility between the rubber material of radial shaft seals and the lubricants to be sealed is an important requirement that customers demand of their lubricant suppliers. Among other effects that may result from incompatibility, the penetration of lubricant components into the rubber (swelling) can impair the seal's functionality due to changes in its geometry and mechanical behavior. Typically, the penetration of a lubricant into an elastomer is evaluated after an immersion test using volumetric, gravimetric, and extraction measurements. Due to the small changes that need to be detected, such methods may not be sufficient to obtain meaningful results. In this contribution, we use magnetic resonance imaging (MRI) to investigate swelling on special tribometer samples as well as a radial shaft seal that were previously used in component tests. Several combinations of rubbers and lubricants that have proven to be compatible were tested in addition to combinations with expected incompatibilities in real applications. The results indicate that MRI measurements can be used to quantify the penetration depth and potentially also the velocity with which the lubricant diffuses into the rubber, thereby yielding detailed insights into the swelling process of the seal.

Who can do this procedure? Using entrustable professional activities to determine curriculum and entrustment in anesthesiology - An international survey.

INTRODUCTION: As competency-based curricula get increasing attention in postgraduate medical education, Entrustable Professional Activities (EPAs) are gaining in popularity. The aim of this survey was to determine the use of EPAs in anesthesiology training programs across Europe and North America. METHODS: A survey was developed and distributed to anesthesiology residency training program directors in Switzerland, Germany, Austria, Netherlands, USA and Canada. A convergent design mixed-methods approach was used to analyze both quantitative and qualitative data. RESULTS: The survey response rate was 38% (108 of 284). Seven percent of respondents used EPAs for making entrustment decisions. Fifty-three percent of institutions have not implemented any specific system to make such decisions. The majority of respondents agree that EPAs should become an integral part of the training of residents in anesthesiology as they are universal and easy to use. CONCLUSION: Although recommended by several national societies, EPAs are used in few anesthesiology training programs. Over half of responding programs have no specific system for making entrustment decisions. Although several countries are adopting or planning to adopt EPAs and national societies are recommending the use of EPAs as a framework in their competency-based programs, few are yet using these to make "competence" decisions.

Agonist-induced activation of the S1P receptor 2 constitutes a novel osteoanabolic therapy for the treatment of osteoporosis in mice.

BACKGROUND AND PURPOSE: Osteoporosis is a worldwide epidemic but pharmacological agents to stimulate new bone formation are scarce. We have shown that increasing tissue levels of sphingosine-1-phosphate (S1P) by blocking its degradation by the S1P lyase has pronounced osteoanabolic effect in mouse osteoporosis models by stimulating osteoblast differentiation through the S1P receptor 2 (S1P2). However, S1P lyase inhibitors have side effects complicating potential clinical use. Here, we tested whether direct S1P2 engagement by the S1P2 agonist CYM5520 exerted osteoanabolic potential in estrogen deficiency-induced osteopenia in mice. We compared its efficacy to LX2931, a novel S1P lyase inhibitor currently tested in rheumatoid arthritis. EXPERIMENTAL APPROACH: CYM5520, LX2931 or vehicle were administered to ovariectomized mice for 6 weeks beginning 5 weeks after ovariectomy, Bone mass, cellular composition and mechanical strength were assessed by microCT, histomorphometry and three point bending tests. Plasma markers of bone metabolism were analyzed by ELISA. KEY RESULTS: Therapeutic treatment with CYM5520 and LX2931 clearly increased long bone and vertebral bone mass to impressive 3-5 fold over vehicle in osteopenic ovariectomized mice. As expected, lymphopenia was a side effect of LX2931, whereas none occurred with CYM5520. Consistent with an osteoanabolic effect, CYM5520 increased osteoblast number, osteoid surface and alkaline phosphatase area 2-3 fold over vehicle. Plasma concentrations of the osteoanabolic marker procollagen I C-terminal propeptide were also elevated by CYM5520 and LX2931. LX2931 but not yet CYM5520 increased cortical thickness and mechanical strength without affecting mineral density. CONCLUSION AND IMPLICATIONS: Treatment with a pharmacological S1P2 agonist corrected ovariectomy-induced osteopenia in mice by inducing new bone formation thus constituting a novel osteoanabolic approach to osteoporosis.

Germline-activating mutations in PIK3CD compromise B cell development and function.

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.

Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib.

Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors.

The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and ß isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kδ selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. In vitro, CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. In vivo, CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kδ and PI3Kγδ-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjögren's syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kδ.

Associations Between Impaired Cerebral Blood Flow Autoregulation, Cerebral Oxygenation, and Biomarkers of Brain Injury and Postoperative Cognitive Dysfunction in Elderly Patients After Major Noncardiac Surgery.

BACKGROUND: Increasing evidence links postoperative cognitive dysfunction (POCD) to surgery and anesthesia. POCD is recognized as an important neuropsychological adverse outcome in surgical patients, particularly the elderly. This prospective cohort study aimed to investigate whether POCD is associated with impaired intraoperative cerebral autoregulation and oxygenation, and increased levels of biomarkers of brain injury. METHODS: Study subjects were patients ≥65 years of age scheduled for major noncardiac surgery. Cognitive function was assessed before and 1 week after surgery. POCD was diagnosed if a decline of >1 standard deviation of z-scores was present in ≥2 variables of the test battery. The incidence of POCD 1 week after surgery was modeled as a multivariable function of the index of autoregulation (MxA) and tissue oxygenation index (TOI), adjusting for baseline neuropsychological assessment battery (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery [CERAD-NAB]) total score and the maximum C-reactive protein (CRP) concentration. The biomarkers of brain injury neuron-specific enolase and S100ß protein, age, and level of education were included in secondary multivariable logistic regression analyses. RESULTS: Of the 82 patients who completed the study, 38 (46%) presented with POCD 1 week after surgery. In the multivariable regression analysis, higher intraoperative MxA (odds ratio [OR; 95% confidence interval (CI)], 1.39 [1.01-1.90] for an increase of 0.1 units, P = .08 after Bonferroni adjustment), signifying less effective autoregulation, was not associated with higher odds of POCD. The univariable logistic regression model for MxA yielded an association with POCD (OR [95% CI], 1.44 [1.06-1.95], P = .020). Tissue oxygenation index (1.12 [0.41-3.01] for an increase of 10%, P = 1.0 after Bonferroni adjustment) and baseline CERAD-NAB total score (0.80 [0.45-1.42] for an increase of 10 points, P = .45) did not affect the odds of POCD. POCD was associated with elevated CRP on postoperative day 2 (median [interquartile range]; 175 [81-294] vs 112 [62-142] mg/L, P = .033); however, the maximum CRP value (OR [95% CI], 1.35 [0.97-1.87] for a 2-fold increase, P = .07) had no distinct effect on POCD. CONCLUSIONS: Impairment of intraoperative cerebral blood flow autoregulation is not predictive of early POCD in elderly patients, although secondary analyses indicate that an association probably exists.

Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties.

In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.

Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.

Predicting the occurrence of major adverse cardiac events within 30 days of a vascular surgery: an empirical comparison of the minimum p value method and ROC curve approach using individual patient data meta-analysis.

We aimed to compare the minimum p value method and the area under the receiver operating characteristics (ROC) curve approach to categorize continuous biomarkers for the prediction of postoperative 30-day major adverse cardiac events in noncardiac vascular surgery patients. Individual-patient data from six cohorts reporting B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NTproBNP) were obtained. These biomarkers were dichotomized using the minimum p value method and compared with previously reported ROC curve-derived thresholds using logistic regression analysis. A final prediction model was developed, internally validated, and assessed for its sensitivity to clustering effects. Finally, a preoperative risk score system was proposed. Thresholds identified by the minimum p value method and ROC curve approach were 115.57 pg/ml (p < 0.001) and 116 pg/ml for BNP, and 241.7 pg/ml (p = 0.001) and 277.5 pg/ml for NTproBNP, respectively. The minimum p value thresholds were slightly stronger predictors based on our logistic regression analysis. The final model included a composite predictor of the minimum p value method's BNP and NTproBNP thresholds [odds ratio (OR) = 8.5, p < 0.001], surgery type (OR = 2.5, p = 0.002), and diabetes (OR = 2.1, p = 0.015). Preoperative risks using the scoring system ranged from 2 to 49 %. The minimum p value method and ROC curve approach identify similar optimal thresholds. We propose to replace the revised cardiac risk index with our risk score system for individual-specific preoperative risk stratification after noncardiac nonvascular surgery.

Planarized Intramolecular Charge Transfer: A Concept for Fluorophores with both Large Stokes Shifts and High Fluorescence Quantum Yields.

Fluorophores were successfully used in several areas of chemistry and biochemistry. For many purposes, however, it is necessary that the fluorescence compound features a high fluorescence quantum yield as well as a large Stokes shift. The latter is, for example, achieved by the use of a twisted intramolecular charge-transfer (TICT) compound, which shows a twisted geometry in the excited state. However, the higher the twisting is, the lower becomes in general the fluorescence quantum yield as the resulting emission from the twisted state is forbidden. In order to escape this dilemma, we propose the model of planarized intramolecular charge-transfer (PLICT) states. These compounds are completely twisted in the ground states and planar in the excited states. By means of quantum chemical calculations (time-dependent (TD)-B3LYP and CC2) and experimental studies, we could demonstrate that 1-aminoindole and its derivatives form photoinduced PLICT states. They show both very large Stokes shifts (ν˜ =9000-13 500 cm(-1) , i.e., λ=100-150 nm) and high fluorescence quantum yields. These characteristics and their easy availability starting from the corresponding indoles, make them very attractive for the use as optical switches in various fields of chemistry as well as biological probes.

Monitoring of cerebral blood flow autoregulation in adults undergoing sevoflurane anesthesia: a prospective cohort study of two age groups.

Autoregulation of blood flow is a key feature of the human cerebral vascular system to assure adequate oxygenation and metabolism of the brain under changing physiological conditions. The impact of advanced age and anesthesia on cerebral autoregulation remains unclear. The primary objective of this study was to determine the effect of sevoflurane anesthesia on cerebral autoregulation in two different age groups. This is a follow-up analysis of data acquired in a prospective observational cohort study. One hundred thirty-three patients aged 18-40 and ≥65 years scheduled for major noncardiac surgery under general anesthesia were included. Cerebral autoregulation indices, limits, and ranges were compared in young and elderly patient groups. Forty-nine patients (37 %) aged 18-40 years and 84 patients (63 %) aged ≥65 years were included in the study. Age-adjusted minimum alveolar concentrations of sevoflurane were 0.89 ± 0.07 in young and 0.99 ± 0.14 in older subjects (P < 0.001). Effective autoregulation was found in a blood pressure range of 13.8 ± 9.8 mmHg in young and 10.2 ± 8.6 mmHg in older patients (P = 0.079). The lower limit of autoregulation was 66 ± 12 mmHg and 73 ± 14 mmHg in young and older patients, respectively (P = 0.075). The association between sevoflurane concentrations and autoregulatory capacity was similar in both age groups. Our data suggests that the autoregulatory plateau is shortened in both young and older patients under sevoflurane anesthesia with approximately 1 MAC. Lower and upper limits of cerebral blood flow autoregulation, as well as the autoregulatory range, are not influenced by the age of anesthetized patients. Trial registration ClinicalTrials.gov (NCT00512200).

Predictors of the variability in neuromuscular block duration following succinylcholine: A prospective, observational study.

BACKGROUND: The duration of neuromuscular block (NMB) following succinylcholine administration is characterised by a high interindividual variability. However, this has not yet been quantified in a large sample of surgical patients. The significance of underlying clinical factors is unknown. OBJECTIVE: The objective of this study was to profile the variability in NMB duration following a standard dose of succinylcholine and to investigate contributing clinical and genetic factors. DESIGN: A prospective, observational study. SETTING: Tertiary referral centre. PATIENTS: In a total of 1630 surgical patients undergoing a rapid sequence induction and intubation, clinical risk factors for a prolongation in NMB duration following succinylcholine were assessed. In a subset of 202 patients, additional biochemical and molecular genetic investigations of butyrylcholinesterase were performed. INTERVENTION: A standard 1 mg kg dose of succinylcholine after administration of an induction drug and an opioid. MAIN OUTCOME: NMB duration measured as the time between administration of succinylcholine until reappearance of palpable muscular response to supramaximal transcutaneous ulnar nerve stimulation. RESULTS: NMB varied from 80 s to 44 min with a median duration of 7.3 min. Sixteen percent of patients had NMB duration in excess of 10 min. A multivariable survival model identified physical status, sex, age, hepatic disease, pregnancy, history of cancer and use of etomidate or metoclopramide as independent risk factors for a prolonged NMB. Three novel butyrylcholinesterase variants were identified: p.Ile5Thr; p.Val178Ile; and p.Try231Ser. CONCLUSION: Neuromuscular blockade duration in excess of 10 min occurred in 16% of a general surgical population following a single dose of succinylcholine. The multivariable model of clinical risk factors for prolonged NMB revealed a negative predictive value of 87%, thereby indicating that absence of such risk factors may reliably predict a shorter duration of NMB. In patients with clinical risk factors for a prolonged NMB or with butyrylcholinesterase mutations, an alternative to succinylcholine should be considered.

Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation.

The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. MALT1 promotes signaling by acting as a scaffold, recruiting downstream signaling proteins, as well as by proteolytic cleavage of multiple substrates. However, the relative contributions of these two different activities to T and B cell function are not well understood. To investigate how MALT1 proteolytic activity contributes to overall immune cell regulation, we generated MALT1 protease-deficient mice (Malt1(PD/PD)) and compared their phenotype with that of MALT1 knockout animals (Malt1(-/-)). Malt1(PD/PD) mice displayed defects in multiple cell types including marginal zone B cells, B1 B cells, IL-10-producing B cells, regulatory T cells, and mature T and B cells. In general, immune defects were more pronounced in Malt1(-/-) animals. Both mouse lines showed abrogated B cell responses upon immunization with T-dependent and T-independent Ags. In vitro, inactivation of MALT1 protease activity caused reduced stimulation-induced T cell proliferation, impaired IL-2 and TNF-α production, as well as defective Th17 differentiation. Consequently, Malt1(PD/PD) mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1(PD/PD) animals developed a multiorgan inflammatory pathology, characterized by Th1 and Th2/0 responses and enhanced IgG1 and IgE levels, which was delayed by wild-type regulatory T cell reconstitution. We therefore propose that the pathology characterizing Malt1(PD/PD) animals arises from an immune imbalance featuring pathogenic Th1- and Th2/0-skewed effector responses and reduced immunosuppressive compartments. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and underline its relevance in human health and disease.

Light and chemically driven molecular machines showing a unidirectional four-state switching cycle.

The imitation of macroscopic movements at the molecular level is a key step in the development of nanomachines. The challenge is the synthesis of molecules that are able to transform external stimuli into a direction-controlled mechanical movement. The more complex such motion sequences are, the more difficult is the construction of the corresponding nanomachine. Here, we present a system that demonstrates a unidirectional, four-state switching cycle that bears similar characteristics to the arm movements of a human breaststroke swimmer. Like the latter, the molecules have a torso and two arms. The arms consist of bipyridine units and can be folded and stretched by addition and removal of copper ions. The unidirectional rotation of the arms is achieved by light-induced switching of an azo unit.

Serum anticholinergic activity and postoperative cognitive dysfunction in elderly patients.

BACKGROUND: Cerebral cholinergic transmission plays a key role in cognitive function, and anticholinergic drugs administered during the perioperative phase are a hypothetical cause of postoperative cognitive dysfunction (POCD). We hypothesized that a perioperative increase in serum anticholinergic activity (SAA) is associated with POCD in elderly patients. METHODS: Seventy-nine patients aged >65 years undergoing elective major surgery under standardized general anesthesia (thiopental, sevoflurane, fentanyl, and atracurium) were investigated. Cognitive functions were assessed preoperatively and 7 days postoperatively using the extended version of the CERAD-Neuropsychological Assessment Battery. POCD was defined as a postoperative decline >1 z-score in at least 2 test variables. SAA was measured preoperatively and 7 days postoperatively at the time of cognitive testing. Hodges-Lehmann median differences and their 95% confidence intervals were calculated for between-group comparisons. RESULTS: Of the patients who completed the study, 46% developed POCD. Patients with POCD were slightly older and less educated than patients without POCD. There were no relevant differences between patients with and without POCD regarding gender, demographically corrected baseline cognitive functions, and duration of anesthesia. There were no large differences between patients with and without POCD regarding SAA preoperatively (pmol/mL, median [interquartile range]/median difference [95% CI], P; 1.14 [0.72, 2.37] vs 1.13 [0.68, 1.68]/0.12 [-0.31, 0.57], P = 0.56), SAA 7 days postoperatively (1.32 [0.68, 2.59] vs 0.97 [0.65, 1.83]/0.25 [-0.26, 0.81], P = 0.37), or changes in SAA (0.08 [-0.50, 0.70] vs -0.02 [-0.53, 0.41]/0.1 [-0.31, 0.52], P = 0.62). There was no significant relationship between changes in SAA and changes in cognitive function (Spearman rank correlation coefficient preoperatively of 0.03 [95% CI, -0.21, 0.26] and postoperatively of -0.002 [95% CI, -0.24, 0.23]). CONCLUSIONS: In this panel of patients with low baseline SAA and clinically insignificant perioperative anticholinergic burden, although a relationship cannot be excluded in some patients, our analysis suggests that POCD is probably not a substantial consequence of anticholinergic medications administered perioperatively but rather due to other mechanisms.

Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy.

BACKGROUND: Tissue mast cell numbers are dynamically regulated by recruitment of progenitors from the vasculature. It is unclear whether progenitors are recruited during allergic sensitization and whether recruitment promotes allergic responses. OBJECTIVE: We sought to (1) determine the effect of mast cell recruitment on acute allergic responses and (2) to define the role of phosphoinositide 3-kinase (PI3K) isoforms in sequential steps to allergic responses. METHODS: Gene-targeted mice for PI3Kγ or PI3Kδ or mice treated with isoform-specific PI3K inhibitors (a novel PI3Kγ-specific inhibitor [NVS-PI3-4] and the PI3Kδ inhibitor IC87114) were used to monitor IgE-mediated mast cell recruitment, migration, adhesion by means of intravital microscopy, degranulation, TNF-α release, and subsequent endothelial cell activation in vivo or in bone marrow-derived mast cells. RESULTS: Functional PI3Kγ, but not PI3Kδ, was crucial for mast cell accumulation in IgE-challenged skin, TNF-α release from IgE/antigen-stimulated mast cells, and mast cell/endothelial interactions and chemotaxis. PI3Kγ-deficient bone marrow-derived mast cells did not adhere to the endothelium in TNF-α-treated cremaster muscle, whereas PI3Kδ was not required. Depletion of TNF-α blocked IgE-induced mast cell recruitment, which links tissue mast cell-derived cytokine release to endothelial activation and mast cell recruitment. Interference with mast cell recruitment protected against anaphylaxis and was superior to blockage of tissue mast cell degranulation. CONCLUSIONS: Interference with mast cell recruitment to exacerbated tissues provides a novel strategy to alleviate allergic reactions and surpassed attenuation of tissue mast cell degranulation. This results in prolonged drug action and allows for reduction of drug doses required to block anaphylaxis, an important feature for drugs targeting inflammatory disease in general.