Cognitive Deficits in Executive and Language Functions Predict Postoperative Delirium.

OBJECTIVES: Postoperative delirium (POD) remains the most common complication in older adults, with cognitive impairment being the main risk factor. Patients with mild cognitive impairment, in particular, have much to lose from delirium; despite this, their cognitive impairment might be clinically overlooked. Understanding which cognitive domains are particularly predictive in this regard may improve the sensitivity of preoperative testing and allow for a more targeted application of resource-intensive measures to prevent delirium in the perioperative period. The authors conducted this study with the aim of identifying the most indicative cognitive domains. DESIGN: A secondary analysis of a randomized controlled trial. SETTING: At a single center, the University Medical Centre Hamburg in Hamburg, Germany. PARTICIPANTS: Patients ≥60 years without major neurocognitive disorders (dementia, Mini-Mental State Examination score ≤23) scheduled for cardiovascular surgery. MEASUREMENTS AND MAIN RESULTS: Preoperative neuropsychologic testing and delirium screening were performed twice daily until postoperative day 5. A multiple logistic regression model was applied to determine the predictive ability of test performances for the development of delirium. RESULTS: A total of 541 patients were included in the analysis; the delirium rate was 15.6%. After controlling for confounders, only low performance within the Trail Making Test B/A (odds ratio [OR] = 1.32; 95% CI: 1.05-1.66) and letter fluency (OR = 0.66; 95% CI: 0.45-0.96) predicted a particularly high risk for delirium development. The discriminative ability of the final multiple logistic regression model to predict POD had an area under the curve of 0.786. CONCLUSIONS: Impairment in the cognitive domains of executive function and language skills associated with memory, inhibition, and access speed seem to be particularly associated with the development of delirium after surgery in adults ≥65 years of age without apparent preoperative neurocognitive impairment.

Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo.

Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.

Comparison of the '4-item assessment test' and 'nursing delirium screening scale' delirium screening tools on non-intensive care unit wards: A prospective mixed-method approach.

BACKGROUND: In elderly patients following surgery, postoperative delirium (POD) is the most frequent complication and is associated with negative outcomes. The 2017 European Society of Anaesthesiology guideline on POD aims to improve patient care by implementing structured delirium prevention, diagnosis and treatment. However, these recommendations, especially systematic delirium screening, are still incompletely adopted in clinical practice. The aim of this study was to evaluate the feasibility and acceptance of validated delirium screening tools and to identify barriers to their implementation on nonintensive care unit wards. METHODS: Screening rates, as well as practicability, acceptance and the interprofessional handling of positive results, were assessed for each group. Screening rates were calculated as a percentage of the total potential testing episodes completed (up to 15 per patient). Patients were considered eligible when aged 65 years and above. Barriers and motivating factors were assessed in a mixed method approach by utilising questionnaires and focus group discussions. INTERVENTION: In a 3-month phase, a guideline-compliant screening protocol involving screening for POD three times daily for 5 days following surgery was introduced in five wards: both the 4-item assessment test (4AT) and the nursing delirium screening scale (NuDESC) were used. Before commencing the study and again after 6 weeks, medical staff of the respective wards underwent a 45 min training session. RESULTS: Of a total of 3183 potential testing episodes, 999 (31.4%) were completed, with more NuDESC observational tests (43%) than 4AT bedside tests completed (20%). The 4AT was considered more difficult to integrate into daily working routines, it took longer to administer, and nurses felt uncomfortable conducting the screening (53 vs. 13%). Screening results indicating delirium were often not discussed within the team (47%), and nurses felt that often such results were not taken seriously by physicians (54%). CONCLUSION: The observational NuDESC showed a higher completion rate than the bedside 4AT, although overall testing rates were low. The necessary time needed to conduct the screening, the negative reactions by patients, insufficient team communication and a lack of initiation of any therapy were identified as major barriers in the implementation of the guideline-compliant screening protocol. For all staff, further education and awareness of the importance of POD diagnosis and treatment might improve the screening rates. The NuDesc received better results concerning acceptance, practicability and introduction into daily work routine, leading to higher screening rates compared with the 4AT. The latter instrument, which was intended to be used rather selectively or when POD is suspected, might therefore not be suitable for guideline-compliant regular and repeated screening for POD.

Pharmaceutical management of elderly high-risk patients in perioperative settings (PHAROS): protocol of a pilot sequential intervention study.

INTRODUCTION: With increasing age, the risk of complications after surgery rises in elderly patients. Furthermore, the prevalence of multimorbidity and polypharmacy rises with age, making this elderly population especially vulnerable for drug-related problems and posing an additional risk for postoperative complications. Still, only few studies have concentrated on investigating how medication safety can be improved in these patients. The aim of this pilot study is to examine the impact of a comprehensive intervention (interprofessional systematic medication therapy management) on medication appropriateness in elderly polymedicated, multimorbid patients during hospital stay for elective surgery. METHODS AND ANALYSIS: This pilot study will include a total number of 140 patients. Surgical high-risk patients ≥65 years taking more than five chronic systemic drugs will be recruited consecutively for 9 months in the control group capturing usual care regarding medication history and in-hospital medication therapy management without any study intervention. Recruitment of the intervention group will be conducted for another 9 months. The intervention consists of the following components: an additional medication history by a hospital pharmacist before admission, a subsequent medication review, optimisation of the long-term medication and recommendations to the patient's general practitioner. A follow-up will be performed 3 months after surgery. As the primary study outcome, medication appropriateness will be measured using the Medication Appropriateness Index.Secondary outcomes are postoperative complications, incidence and frequency of adverse drug reactions and potentially inappropriate medication in the elderly, satisfaction with inpatient and outpatient care, medication reconciliation and health-related quality of life. Multivariable analyses will be used to analyse all quantitative research questions. ETHICS AND DISSEMINATION: Ethics approval was obtained by the medical ethics committee of the Medical Chamber of Hamburg (study ID: PV5754). Data will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: The study is registered at www.drks.de: DRKS00014621.

Analysis of purine receptor expression and functionality in alveolar epithelial cells.

Despite its fundamental role in providing an extensive surface for gas exchange, the alveolar epithelium (AE) serves as an immunological barrier through, e.g., the release of proinflammatory cytokines and secretion of surfactant to prevent alveolar collapse. Thus, AE is important for sustaining lung homeostasis. Extracellular ATP secreted by alveolar epithelial cells (AECs) is involved in physiological and pathological conditions and acts mainly through the activation of purine receptors (P2Rs). When studying P2R-mediated processes, primary isolated type II AECs (piAECs) still represent the gold standard in in vitro research, although their preparation is time-consuming and requires the sacrifice of many animals. Hence, cultivated immortalized and tumor-derived AEC lines may constitute a valuable alternative. In this work, we examined P2R expression and functionality in piAECs, in immortalized and tumor-derived AEC lines with the purpose of gaining a better understanding of purinergic signaling in different cell systems and assisting researchers in the choice of a suitable cell line with a certain P2R in demand. We combined mRNA and protein analysis to evaluate the expression of P2R. For pharmacological testing, we conducted calcium ([Ca2+]) measurements and siRNA receptor knockdown. Interestingly, the mRNA and protein levels of P2Y2, P2Y6, and P2X4 were detected on all cell lines. Concerning functionality, P2XR could be narrowed to L2 and piAECs while P2YR were active in all cell lines.

Improvement of perioperative care of the elderly patient (PeriAge): protocol of a controlled interventional feasibility study.

INTRODUCTION: Geriatric patients have a pronounced risk to suffer from postoperative complications. While effective risk-specific perioperative measures have been studied in controlled experimental settings, they are rarely found in routine healthcare. This study aims (1) to implement a multicomponent preoperative and intraoperative intervention, and investigate its feasibility, and (2) exploratorily assess the effectiveness of the intervention in routine healthcare. METHODS AND ANALYSIS: Feasibility and exploratory effectiveness of the intervention will be investigated in a monocentric, prospective, non-randomised, controlled trial. The intervention includes systematic information for patients and family about measures to prevent postoperative complications; preoperative screening for frailty, malnutrition, strength and mobility with nutrient supplementation and physical exercise (prehabilitation) as needed. Further components focus on potentially inadequate medication, patient blood-management and carbohydrate loading prior to surgery, retainment of orientation aids in the operating room and a geriatric anaesthesia concept. Data will successively be collected from control, implementation and intervention groups. Patients aged 65+ with impending surgery will be included. A sample size of 240, n=80 per group, is planned. Assessments will take place at inclusion and 2, 30 and 180 days after surgery. Mixed-methods analyses will be performed. Exploratory effectiveness will be assessed using mixed segmented regressions. The primary endpoint is functional status. Secondary endpoints include cognitive performance, health-related quality of life, length of inpatient stay and occurrence of postoperative complications. Feasibility will be assessed through semi-structured interviews with staff and patients and quantitative analyses of the data quality, focussing on practicability, acceptance, adoption and fidelity to protocol. ETHICS AND DISSEMINATION: The study will be carried out in accordance with the Helsinki Declaration and to principles of good scientific practice. The Ethics Committee of the Medical Association Hamburg, Germany, approved the protocol (study ID: PV5596). Results will be disseminated in scientific journals and healthcare conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03325413.

The P2-receptor-mediated Ca2+ signalosome of the human pulmonary endothelium - implications for pulmonary arterial hypertension.

Dysfunction of the pulmonary endothelium is associated with most lung diseases. Extracellular nucleotides modulate a plethora of endothelial functions in the lung such as vessel integrity, vasodilatation, inflammatory, and thrombotic responses as well as survival and DNA repair, mostly via Ca2+ signaling pathways. However, a comprehensive analysis of the molecular components of the underlying P2 receptor-mediated Ca2+ signaling pathways in the lung has not been conducted so far. Therefore, our aim was to identify the principal P2 receptor Ca2+ signalosome in the human pulmonary endothelium and investigate potential dysregulation in pulmonary vascular disease. Comparative transcriptomics and quantitative immunohistochemistry were performed on publicly available RNA sequencing and protein datasets to identify the specific expression profile of the P2-receptor Ca2+ signalosome in the healthy human pulmonary endothelium and endothelial cells (EC) dysfunctional due to loss of or defective bone morphogenetic protein receptor (BMPR2). Functional expression of signalosome components was tested by single cell Ca2+ imaging. Comparative transcriptome analysis of 11 endothelial cell subtypes revealed a specific P2 receptor Ca2+ signalosome signature for the pulmonary endothelium. Pulmonary endothelial expression of the most abundantly expressed Ca2+ toolkit genes CALM1, CALM2, VDAC1, and GNAS was confirmed by immunohistochemistry (IHC). P2RX1, P2RX4, P2RY6, and P2YR11 showed strong lung endothelial staining by IHC, P2X5, and P2Y1 were found to a much lesser extent. Very weak or no signals were detected for all other P2 receptors. Stimulation of human pulmonary artery (HPA) EC by purine nucleotides ATP, ADP, and AMP led to robust intracellular Ca2+ signals mediated through both P2X and P2Y receptors. Pyrimidine UTP and UDP-mediated Ca2+ signals were generated almost exclusively by activation of P2Y receptors. HPAEC made dysfunctional by siRNA-mediated BMPR2 depletion showed downregulation of 18 and upregulation of 19 P2 receptor Ca2+ signalosome genes including PLCD4, which was found to be upregulated in iPSC-EC from BMPR2-mutant patients with pulmonary arterial hypertension. In conclusion, the human pulmonary endothelium expresses a distinct functional subset of the P2 receptor Ca2+ signalosome. Composition of the P2 receptor Ca2+ toolkit in the pulmonary endothelium is susceptible to genetic disturbances likely contributing to an unfavorable pulmonary disease phenotype found in pulmonary arterial hypertension.

De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans.

The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.

Streptococcus pneumoniae inhibits purinergic signaling and promotes purinergic receptor P2Y2 internalization in alveolar epithelial cells.

Bacterial pneumonia is a global health challenge that causes up to 2 million deaths each year. Purinergic signaling plays a pivotal role in healthy alveolar epithelium. Here, we used fluorophore-based analysis and live-cell calcium imaging to address the question of whether the bacterial pathogen Streptococcus pneumoniae directly interferes with purinergic signaling in alveolar epithelial cells. Disturbed purinergic signaling might result in pathophysiologic changes like edema formation and atelectasis, which are commonly seen in bacterial pneumonia. Purine receptors are mainly activated by ATP, mediating a cytosolic calcium response. We found that this purinergic receptor P2Y2-mediated response is suppressed in the presence of S. pneumoniae in A549 and isolated primary alveolar cells in a temperature-dependent manner. Downstream inositol 3-phosphate (IP3) signaling appeared to be unaffected, as calcium signaling via protease-activated receptor 2 remained unaltered. S. pneumoniae-induced suppression of the P2Y2-mediated calcium response depended on the P2Y2 phosphorylation sites Ser-243, Thr-344, and Ser-356, which are involved in receptor desensitization and internalization. Spinning-disk live-cell imaging revealed that S. pneumoniae induces P2Y2 translocation into the cytosol. In conclusion, our results show that S. pneumoniae directly inhibits purinergic signaling by inducing P2Y2 phosphorylation and internalization, resulting in the suppression of the calcium response of alveolar epithelial cells to ATP, thereby affecting cellular integrity and function.

Postoperative Nausea and Vomiting Following Craniotomy: Risk Factors and Complications in Context of Perioperative High-dose Dexamethasone Application.

INTRODUCTION: Postoperative nausea and vomiting (PONV) is common in patients after craniotomy and may lead to severe postoperative complications. The aim of this study was to identify risk factors and postoperative complications associated with PONV in the context of perioperative high-dose dexamethasone administration. PATIENTS AND METHODS: In this prospective single-center study, all patients planned for elective craniotomy for supra- and infratentorial lesions were eligible to be included. Any PONV in a 24-hour period after craniotomy was recorded and analyzed with regard to time to postoperative complications and the administration of perioperatively administered high-dose dexamethasone. RESULTS: The overall PONV rate of 421 patients during a 9-month period was 18.1% (76 patients). Multivariate analysis revealed a significant association of PONV with female sex, infratentorial localization, age, and history of PONV. There was no association between PONV and postoperative complications such as intracranial hemorrhage, cerebrospinal fluid (CSF) leaks, or pneumonia. Perioperative administration of high-dose dexamethasone for prophylactic prevention of edema was the only significant risk factor for postoperative complications (odds ratio [OR]: 3.34; confidence interval [CI], 1.39-8.05; p < 0.01) with a highly significant association with the occurrence of CSF leaks (OR: 6.85; CI, 1.62-29.05; p < 0.01). CONCLUSION: The low PONV rate of 18.1% in this study may be the result of the frequent perioperative administration of high-dose dexamethasone for the prevention of edema. Our data indicate that perioperative high-dose dexamethasone is significantly associated with CSF leaks and can therefore not be recommended on a regular basis.

The Perioperative Care of Older Patients.

BACKGROUND: Elderly patients are a growing and vulnerable group with an elevated perioperative risk. Perioperative treatment pathways that take these patients' special risks and requirements into account are often not implemented in routine clinical practice. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, the AWMF guideline database, and the Cochrane database for guidelines from Germany and abroad, meta-analyses, and Cochrane reviews. RESULTS: The care of elderly patients who need surgery calls for an interdisciplinary, interprofessional treatment concept. One component of this concept is preoperative preparation of the patient ("prehabilitation"), which is best initiated before hospital admission, e.g., correction of deficiency states, optimization of chronic drug treatment, and respiratory training. Another important component consists of pre-, intra-, and postoperative measures to prevent delirium, which can lower the frequency of this complication by 30-50%: these include orientation aids, avoidance of inappropriate drugs for elderly patients, adequate analgesia, early mobilization, short fasting times, and a perioperative nutrition plan. Preexisting cognitive impairment predisposes to postoperative delirium (odds ratios [OR] ranging from 2.5 to 4.5). Frailty is the most important predictor of the postoperative course (OR: 2.6-11). It follows that preoperative assessment of the patient's functional and cognitive status is essential. CONCLUZION: The evidence-based and guideline-consistent care of elderly patients requires not only close interdisciplinary, interprofessional, and cross-sectoral collaboration, but also the restructuring and optimization of habitual procedural pathways in the hospital. Elderly patients' special needs can only be met by a treatment concept in which the entire perioperative phase is considered as a single, coherent process.

Determinants of Perioperative Outcome in Frail Older Patients.

BACKGROUND: Older patients are undergoing surgery in increasing numbers. Frailty is a key risk factor associated with higher rates of complications and mortality, longer hospital stays, and functional impairment. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, including guidelines from Germany and abroad. RESULTS: Many studies have been published on the assessment of frailty and its consequences, but the scientific investigation of this topic and the clinical utility of the findings are made more difficult by the lack of a uniform definition and of uniform instruments for assessment. Some definitions of frailty include only physical aspects, while others encompass cognitive, emotional, and social factors as well. Despite this variability, the assessment of frailty enables better estimation of the perioperative risk so that the patient can be optimally prepared for the operation. Especially for frail elderly patients, an interdisciplinary approach is called for over the entire perioperative treatment period. CONCLUSION: In the future, the definition of frailty will need to be standardized so that this parameter can be properly assessed and investigated in comparative studies.

Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function.

BACKGROUND: In acute respiratory distress syndrome (ARDS), pulmonary perfusion failure increases physiologic dead space ventilation (VD/VT), leading to a decline of the alveolar CO2 concentration [CO2]iA. Although it has been shown that alveolar hypocapnia contributes to formation of atelectasis and surfactant depletion, a typical complication in ARDS, the underlying mechanism has not been elucidated so far. METHODS: In isolated perfused rat lungs, cytosolic or mitochondrial Ca2+ concentrations ([Ca2+]cyt or [Ca2+]mito, respectively) of alveolar epithelial cells (AECs), surfactant secretion and the projected area of alveoli were quantified by real-time fluorescence or bright-field imaging (n=3-7 per group). In ventilated White New Zealand rabbits, the left pulmonary artery was ligated and the size of subpleural alveoli was measured by intravital microscopy (n=4 per group). Surfactant secretion was determined in the bronchoalveolar lavage (BAL) by western blot. RESULTS: Low [CO2]iA decreased [Ca2+]cyt and increased [Ca2+]mito in AECs, leading to reduction of Ca2+-dependent surfactant secretion, and alveolar ventilation in situ. Mitochondrial inhibition by ruthenium red or rotenone blocked these responses indicating that mitochondria are key players in CO2 sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO2 to the inspiratory gas inhibited these responses. CONCLUSIONS: Accordingly, we provide evidence that alveolar hypocapnia leads to a Ca2+ shift from the cytosol into mitochondria. The subsequent decline of [Ca2+]cyt reduces surfactant secretion and thus regional ventilation in lung regions with high VD/VT. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO2 application.

[Why and How Should I Assess Frailty? A Guide for the Preoperative Anesthesia Clinic]. / Warum und wie sollte ich Frailty erfassen? ­ ein Ansatz für die Anästhesieambulanz.

Introduction: Frailty is a condition of decreased physiological reserves seen in approx. one third of elderly anesthesiological patients, and affecting many aspects of treatment as well as outcome. Although there are over 60 measurement instruments, frailty assessment is still poorly implemented. Understanding why and how to assess frailty is key to its implementation in preoperative anesthesia clinics. Method: After presenting the impact of perioperative frailty and the benefits of an early diagnosis on health related quality of life, we present an overview of the most important tools that can be used in the preoperative frailty assessment. Results: Early diagnosis offer several optimization opportunities for the perioperative period. The most efficient frailty assessment tools are presented and discussed, including physical, cognitive, and psychosocial aspects. Conclusion: Frailty assessments vary immensely in terms of required time, equipment, and expertise. We recommend at least one test for each domain of frailty, so as to obtain a more holistic view of the patient's physiological reserve. The implementation of an adequate and consistent preoperative frailty assessment has the potential to improve patient safety as well as short and long term outcomes.

IDH3 mediates apoptosis of alveolar epithelial cells type 2 due to mitochondrial Ca2+ uptake during hypocapnia.

In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (VD/VT) correlating with mortality. High VD/VT results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.

[Preoperative Evaluation and Arrangements: The Elderly Patient]. / Präoperative Vorbereitung und Evaluation: der ältere Patient.

With a constantly growing portion of elderly within our population and the advances of modern medicine, surgery on aged and very aged patients has become a daily hospital routine. Due to the physical and mental features of ageing these patients face special perioperative risks. They display a higher rate of complications, morbidity and cognitive deficits which might in the end lead to persisting need of care. Even in the healthy elderly, most organ functions are "physiologically" instable or deficient and the homeostasis of health and disease is fragile. The preoperative evaluation of the aged patient has to be extended towards risk factors and pathologic pre-conditions which derive especially from high age and are so far not determined by a mere "fit-for-anaesthesia?" EVALUATION: This includes assessment of frailty and functional status as well as the evaluation of pre-existing cognitive deficits, malnutrition and polypharmacy. Prevention of postoperative cognitive deficits and delirium is an important goal of medical therapy and requires i. a. omission of benzodiazepines, BIS-controlled anaesthesia, focus on patient's comfort and orientation and inclusion of close relatives and confidants in all processes. Considering all this, an elderly patient might require more time than usually given to be well prepared for anaesthesia, surgery and the postoperative course. The altered physiology and the special risk profile of the aged patient demand special attention and time throughout the perioperative phase. With an increasing number of elderly presenting for surgery, it is likely that more age-adapted structures and processes become implemented in our hospitals.

In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis.

Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of "transient receptor potential vanilloid-4" (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF-κB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF.

The Selective JAK1/3-Inhibitor R507 Mitigates Obliterative Airway Disease Both With Systemic Administration and Aerosol Inhalation.

BACKGROUND: The efficacy of selective Janus kinase 1/3 inhibitor R507 to prevent obliterative airway disease was analyzed in preclinical airway transplantation models. METHODS: Orthotopic trachea transplantations were performed between Lewis donors and Brown Norway rat recipients. Oral everolimus (4 mg/kg once per day) or oral respective inhaled R507 (60 mg/kg twice per day, each) was used for immunosuppression. Grafts were retrieved after 6 or 60 days. Toxicity and anti-inflammatory effects of R507 were analyzed on human airway epithelial cells. RESULTS: In 6-day animals, oral and inhaled R507 more potently diminished mononuclear graft infiltration than everolimus and preserved ciliated pseudostratified columnar respiratory epithelium. Everolimus and R507 similarly suppressed systemic cellular and humoral immune activation. In untreated rats, marked obliterative airway disease developed over 60 days. Oral and inhaled R507 was significantly more effective in reducing airway obliteration and preserved the morphology of the airway epithelium. Luciferase-positive donors revealed that a substantial amount of smooth muscle cells within the obliterative tissue was of donor origin. Only everolimus but not R507, adversely altered kidney function and lipid profiles. The R507 aerosol did not show airway toxicity in vitro but effectively suppressed activation of inflammatory signaling pathways induced by IL-1ß. CONCLUSIONS: The Janus kinase 1/3 inhibitor R507 is a very well-tolerated immunosuppressant that similarly diminished obliterative airway disease with systemic or inhaled administration.

Dexamethasone PONV prophylaxis alters the hypothalamic-pituitary-adrenal axis after transsphenoidal pituitary surgery.

BACKGROUND: Postoperative nausea and vomiting (PONV) is common after general anesthesia and are reported by approximately 20% to 25% of all patients and up to 39% of patients undergoing neurosurgical procedures. The most common standard prophylaxis is a single application of 4 mg of dexamethasone before initiating anesthesia. Dexamethasone is known to suppress adreno-corticotroph hormone and cortisol levels. The objective was to find out whether this prophylaxis has an effect on the postoperative levels of cortisol in patients undergoing transsphenoidal pituitary surgery, and therefore simulates pituitary deficiency. PATIENTS AND METHODS: A retrospective analysis of the files of 136 consecutive patients who were operated during a course of 6 months were included. Nineteen patients with a known history of PONV received a standard dose of 4 mg of dexamethasone perioperatively. Blood tests were drawn at the first postoperative day and were compared with blood tests of patients who had no history of PONV and therefore received no prophylaxis. RESULTS: Patients who were treated with a dexamethasone PONV prophylaxis showed no significant changes in cortisol levels; preoperative median of 93 µg/L (range, 39 to 427) and a postoperative median of 87 µg/L (range, 10 to 733; P=0.798) opposed to patients who did not receive such treatment; preoperative cortisol 114 µg/L (range, 10 to 387) and postoperative levels of 273 µg/L (range, 10 to 1352; P<0.001). CONCLUSIONS: As early postoperative blood checks of the cortisol levels yield important information about potential pituitary sufficiency after transsphenoidal surgery, the probability that dexamethasone PONV prophylaxis suppresses postoperative cortisol levels should be considered.