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Abstract: Background: Raised concentrations of endotoxin (lipopolysaccharides, LPS) have been demonstrated in patients with chronic heart failure (CHF). Tolerance of monocytes to LPS can be induced by negative feedback mechanism through LPS itself, resulting in a downregulation of cytokine response to LPS challenge. As endotoxin desensitization has also been suggested for CHF, we investigated the response to LPS challenge in CHF patients. Methods: We prospectively studied 100 patients with CHF (62±13 years) and 21 controls (58±10 years, LVEF 60±3%). HLA-DR expression and TNFα generation of monocytes after ex vivo stimulation by LPS (stimulation with LPS 50 and 500 pg/ml) were determined. 46 CHF patients were in NYHA class II (LVEF 29±8%) and 54 in NYHA class III (LVEF 27±7%). Results: HLA-DR expression in controls (25,837±7915 ABS/cell) was comparable to CHF NYHA II patients (23,720±8488 ABS/cell, n.s.), but lower in patients classified NYHA III (20,327±5073 ABS/cell, p <0.01). Stimulated TNFα production ex vivo was higher in CHF NYHA III (LPS 50: 437±284; LPS 500: 946±500 pg/ml, each p <0.05) and CHF NYHA II (LPS 50: 397±277; LPS 500: 933±483 pg/ml, each p <0.05) compared to controls (LPS 50: 315±134; LPS 500: 715±339 pg/ml). Conclusions: In chronic heart failure TNFα generation capacity increases while HLA-DR expression decreases compared to controls. Thus patients with CHF display enhanced susceptibility to inflammatory stimuli. [Copyright &y& Elsevier]

Die vorliegende Arbeit beschreibt die Reaktion von Triplett‐Disauerstoff mit den porphyrinogenen Calix[4]pyrrolatoaluminaten hin zu Alkylperoxidoaluminaten mit hoher Selektivität. Multikonfigurationsquantenchemische Berechnungen beleuchten den spinverbotenen Prozess. Ungeachtet einer vernachlässigbaren Spin‐Bahn‐Kopplungskonstante wird die Interkombination (intersystem crossing) durch die Entartung des Singulett‐ und Triplett‐Zustands sowie durch spinvibronische Kopplung ermöglicht. Die gebildeten Peroxide sind stabil gegenüber externen Substraten, gehen allerdings eine beispiellose oxidative Pyrrol‐α‐Spaltung mittels einer durch Ligand‐Aromatisierung/‐dearomatisierung initiierten Spaltung der O‐O‐σ‐Bindung ein. Ein detaillierter Vergleich der Calix[4]pyrrolatoaluminate mit disauerstoffbezogener Enzymologie liefert Einblicke in die Arbeitsweise von metall‐ und cofaktorfreien Enzymen. Diese Zusammenhänge bekräftigen die Wichtigkeit von strukturellem Zwang und Element‐Ligand‐Kooperativität für die Funktionen des aeroben Lebens. [ABSTRACT FROM AUTHOR]

The present work describes the reaction of triplet dioxygen with the porphyrinogenic calix[4]pyrrolato aluminates to alkylperoxido aluminates in high selectivity. Multiconfigurational quantum chemical computations disclose the mechanism for this spin‐forbidden process. Despite a negligible spin–orbit coupling constant, the intersystem crossing (ISC) is facilitated by singlet and triplet state degeneracy and spin–vibronic coupling. The formed peroxides are stable toward external substrates but undergo an unprecedented oxidative pyrrole α‐cleavage by ligand aromatization/dearomatization‐initiated O−O σ‐bond scission. A detailed comparison of the calix[4]pyrrolato aluminates with dioxygen‐related enzymology provides insights into the ISC of metal‐ or cofactor‐free enzymes. It substantiates the importance of structural constraint and element–ligand cooperativity for the functions of aerobic life. [ABSTRACT FROM AUTHOR]

A concise synthetic route towards a new family of phosphorus‐containing polycyclic aromatic hydrocarbons starting from the versatile acridophosphine has been established. The structural and optoelectronic properties of these compounds were efficiently modulated through derivatization of the phosphorus center. X‐ray crystallographic analysis, UV/Vis spectroscopic, and electrochemical studies supported by DFT calculations identified the considerable potential of these scaffolds for the development of organophosphorus functional materials with tailored properties upon further functionalization. [ABSTRACT FROM AUTHOR]

Background: The SARS-CoV-2/COVID-19 pandemic necessitates a rapid reorganization of the hospital procedures. The establishment of centers dedicated to COVID-19 treatment and care also necessitates preparation of the surgical departments for the forthcoming emergency interventions for infected patients and patients with an unclear infection status. This article summarizes the evidence on standards for personal protective equipment for personnel in the central emergency admission department and in the operations area as well as restructuring measures for the procedures in the operations area in a COVID-plus area. Method: A systematic literature search was carried out. Results: The grey area of unknown infected and potential transmitters of SARS-CoV-2/COVID-19 is high. Patients with an unclear infection status or who are highly suspected of having an infection should be classified as infectious until the contrary can be proven. The protection of personnel in healthcare professions against infections is of particular importance. The supply of adequate personal protective equipment in a risk-stratified form can substantially influence the success of combating the pandemic. Most operations must be assessed as aerosol-forming procedures and necessitate the maximum protection of personnel working directly on the patient. Particular attention should be paid to obligatory hygiene regulatory measures for protection against contamination during the reorganization in the operations area and on the transport routes between the wards. Conclusion: The correct personal protective equipment considering the occupational safety helps to sustainably protect personnel from infections. Reorganizational measures in the operating room are urgently indicated for potential aerosol-forming procedures in infected patients or patients with an unclear infection status. The current dynamic situation necessitates a high level of flexibility as well as reassessment and adaptation of the measures at short intervals. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinases (MMPs) virtually degrade all components of the extracellular matrix and are mainly expressed in tissues following inflammation or remodeling. Increased expression of certain MMPs in sputum and bronchoalveolar lavage of patients with cystic fibrosis (CF) is related to impaired lung function. We investigated whether a panel of serum MMPs is associated with both, impairment of pulmonary function and occurrence of pulmonary exacerbations (PEx) in adult patients with CF. Methods: Serum concentrations of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, and TIMP-1 were determined by ELISA in 54 adult CF patients. PEx was defined based on a score established by Rosenfeld in 2001. MMP-1, MMP-8, MMP-9 and TIMP-1 were assessed in 7 CF patients with PEx before and after systemic antibiotic therapy. Results: Of the 54 CF patients, PEx was diagnosed in 16 different CF patients. Compared to healthy controls, MMP-1, MMP-8, and MMP-9, serum levels were elevated in CF patients and correlated with PEx. MMP-8 expression was associated with impaired lung function. For MMP-2, we observed a decreased expression and an association of MMP-2 decline with PEx. Antibiotic treatment of CF patients with PEx led to a decrease of MMP-1, MMP-8 and active MMP-9 protein concentration. Conclusions: Increased serum expression of certain MMPs is associated with occurrence of PEx and impaired lung function in CF. Hence, these MMPs might serve as surrogate markers for PEx. [Copyright &y& Elsevier]

Abstract: Background: During cardiac arrest the paramount goal of basic life support (BLS) is the oxygenation of vital organs. Current recommendations are to combine chest compressions with ventilation in a fixed ratio of 30:2; however the optimum compression/ventilation ratio is still debatable. In our study we compared four different compression/ventilation ratios and documented their effects on the return of spontaneous circulation (ROSC), gas exchange, cerebral tissue oxygenation and haemodynamics in a pig model. Methods: Study was performed on 32 pigs under general anaesthesia with endotracheal intubation. Arterial and central venous lines were inserted. For continuous cerebral tissue oxygenation a Licox® PtiO2 probe was implanted. After 3min of cardiac arrest (ventricular fibrillation) animals were randomized to a compression/ventilation-ratio 30:2, 100:5, 100:2 or compressions-only. Subsequently 10min BLS, Advanced Life Support (ALS) was performed (100%O2, 3 defibrillations, 1mg adrenaline i.v.). Data were analyzed with 2-factorial ANOVA. Results: ROSC was achieved in 4/8 (30:2), 5/8 (100:5), 2/8 (100:2) and 0/8 (compr-only) pigs. During BLS, PaCO2 increased to 55mmHg (30:2), 68mmHg (100:5; p =0.0001), 66mmHg (100:2; p =0.002) and 72mmHg (compr-only; p <0.0001). PaO2 decreased to 58mmg (30:2), 40mmHg (100:5; p =0.15), 43mmHg (100:2; p =0.04) and 26mmHg (compr-only; p <0.0001). PtiO2 baseline values were 12.7, 12.0, 11.1 and 10.0mmHg and decreased to 8.1mmHg (30:2), 4.1mmHg (100:5; p =0.08), 4.3mmHg (100:2; p =0.04), and 4.5mmHg (compr-only; p =0.69). Conclusions: During BLS, a compression/ventilation-ratio of 100:5 seems to be equivalent to 30:2, while ratios of 100:2 or compressions-only detoriate peripheral arterial oxygenation and reduce the chance for ROSC. [Copyright &y& Elsevier]

: ObjectivesThe goal of this study was to determine if brain natriuretic peptide (BNP) levels are associated with exercise capacity in patients with chronic heart failure (HF).: BackgroundPlasma levels of BNP are increased subject to the degree of systolic and diastolic left ventricular dysfunction in patients with chronic HF. Exercise testing is useful to assess functional capacity and prognosis in chronic HF.: MethodsWe prospectively studied 70 consecutive patients with chronic HF (60.3 ± 10.4 years, 51 men) referred for cardiopulmonary exercise testing. Resting BNP was obtained after 10 min of supine rest before symptom-limited bicycle exercise testing.: ResultsIn patients with chronic HF, BNP levels correlated with oxygen uptake (VO2), both at anaerobic threshold (VO2AT: r = −0.54, p < 0.001) and peak exercise (peak VO2: r = −0.56, p < 0.001). Impairment of ventilatory efficiency (EqCO2: r = 0.43, p < 0.001) and maximum exercise level (W % predicted: r = −0.44, p < 0.05) correlated less well with BNP. There was a significant inverse correlation between left ventricular ejection fraction and BNP (r = −0.50, p < 0.05). Brain natriuretic peptide discriminated well chronic HF patients with a peak VO2 <10 ml/min/kg (area under the receiver operating characteristic [ROC] 0.93) or <14 ml/min/kg (area under the ROC 0.72). A BNP >316 pg/ml was associated with a risk ratio of 6.8 (95% confidence interval, 2.3 to 19.8) for a reduced exercise capacity with a peak VO2 <14 ml/min/kg.: ConclusionsBrain natriuretic peptide is clearly associated with exercise capacity in chronic HF. Brain natriuretic peptide levels show a significant correlation with the impairment of VO2 at peak exercise and anaerobic threshold. Brain natriuretic peptide is able to differentiate between chronic HF patients with moderately and severely impaired exercise capacity. [Copyright &y& Elsevier]

Recent advances in understanding how neuronal activity shapes developing brain circuits increasingly rely on G i/o -dependent inhibitory chemogenetic tools (G i -DREADDs). However, their mechanisms of action and efficacy in neurons with immature G i/o signaling are elusive. Here, we express the G i -DREADD hM4Di in glutamatergic telencephalic neurons and analyze its impact on CA1 pyramidal neurons in neonatal mice. Using acousto-optic two-photon Ca 2+ imaging, we report that activation of hM4Di leads to a complete arrest of spontaneous synchrony in CA1 in vitro . We demonstrate that hM4Di does not cause somatic hyperpolarization or shunting but rather mediates presynaptic silencing of glutamatergic neurotransmission. In vivo , inhibition through hM4Di potently suppresses early sharp waves (eSPWs) and discontinuous oscillatory network activity in CA1 of head-fixed mice before eye opening. Our findings provide insights into the role of G i/o signaling in synchronized activity in the neonatal hippocampus and bear relevance for applying chemogenetic silencing at early developmental stages., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Aromaticity in organic molecules is well defined, but its role in metal-only rings remains controversial. Here we introduce a supramolecular stabilization approach of a cationic {Bi 4 } rhomboid within the symmetric charge sphere of two bowl-shaped dianionic calix[4]pyrrolato indinates. Crystallographic and spectroscopic characterization, quantum chemical analysis and magnetically induced ring currents indicate σ-aromaticity in the formally tetracationic 16-valence electron [Bi 4 ] 4+ ring. Computational screening for other p-block elements identifies the planar rhomboid as the globally preferred structure for 16-valence electron four-atomic clusters. The aromatic [Bi 4 ] 4+ is isoelectronic to the [Al 4 ] 4- , a motif previously observed as antiaromatic in Li 3 [Al 4 ] - in the gas phase. Thus, subtle factors such as charge isotropy seem to decide over aromaticity or antiaromaticity, advising for caution in debates based on the Hückel model-a concept valid for second-row elements but less deterministic for the heavier congeners., (© 2024. The Author(s).)

Objectives: A timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both cancer and RMD, we analysed if a metabolic signature can indicate paraneoplasia (PN) or reveal concomitant cancer in patients with RMD., Methods: Metabolic alterations in the sera of rheumatoid arthritis (RA) patients with (n=56) or without (n=52) a history of invasive cancer were quantified by nuclear magnetic resonance analysis. Metabolites indicative of cancer were determined by multivariable regression analyses. Two independent RA and spondyloarthritis (SpA) cohorts with or without a history of invasive cancer were used for blinded validation. Samples from patients with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, non-invasive (NI) precancerous lesions and non-melanoma skin cancer and systemic lupus erythematosus and samples prior to the development of malignancy were used to test the model performance., Results: Based on the concentrations of acetate, creatine, glycine, formate and the lipid ratio L1/L6, a diagnostic model yielded a high sensitivity and specificity for cancer diagnosis with AUC=0.995 in the model cohort, AUC=0.940 in the blinded RA validation cohort and AUC=0.928 in the mixed RA/SpA cohort. It was equally capable of identifying cancer in patients with PN. The model was insensitive to common demographic or clinical confounders or the presence of NI malignancy like non-melanoma skin cancer., Conclusions: This new set of metabolic markers reliably predicts the presence of cancer in arthritis or PN patients with high sensitivity and specificity and has the potential to facilitate a rapid and correct diagnosis of malignancy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tactile sensation and vision are often both utilized for the exploration of objects that are within reach though it is not known whether or how these two distinct sensory systems combine such information. Here in mice, we used a combination of stereo photogrammetry for 3D reconstruction of the whisker array, brain-wide anatomical tracing and functional connectivity analysis to explore the possibility of tacto-visual convergence in sensory space and within the circuitry of the primary visual cortex (VISp). Strikingly, we find that stimulation of the contralateral whisker array suppresses visually evoked activity in a tacto-visual sub-region of VISp whose visual space representation closely overlaps with the whisker search space. This suppression is mediated by local fast-spiking interneurons that receive a direct cortico-cortical input predominantly from layer 6 neurons located in the posterior primary somatosensory barrel cortex (SSp-bfd). These data demonstrate functional convergence within and between two primary sensory cortical areas for multisensory object detection and recognition., (© 2024. The Author(s).)

Introduction: Since the beginning of the pandemic in spring 2020, inpatient healthcare has been under enormous burden, which is reflected especially in overworked staff, imprecise bed planning and/or data transfer. According to the recommendation of the Science Council, university clinics should play a controlling role in regional healthcare and act in conjunction with surrounding hospitals and practices., Methods: In September 2021, 31 representatives from 18 university hospitals were invited to a hybrid Delphi study with a total of 4 survey rounds to discuss criteria for effective inpatient care in a pandemic situation, which were extracted from previous expert interviews. Criteria that were classified as very important/relevant by≥75% of the participants in the first round of the survey (consensus definition) were then further summarized in 4 different small groups. In a third Delphi round, all participants came together again to discuss the results of the small group discussions. Subsequently, these were prioritized as Optional ("can"), Desirable ("should") or Necessary ("must") recommendations., Results: Of the invited clinical experts, 21 (67.7%) participated in at least one Delphi round. In an online survey (1st Delphi round), 233 criteria were agreed upon and reduced to 84 criteria for future pandemic management in four thematic small group discussions (2nd Delphi round) and divided into the small groups as follows: "Crisis Management and Crisis Plans" (n=20), "Human Resources Management and Internal Communication" (n=16), "Regional Integration and External Communication" (n=24) and "Capacity Management and Case & Care" (n=24). In the following group discussion (3rd Delphi round), the criteria were further modified and agreed upon by the experts, so that in the end result, there were 23 essential requirements and recommendations for effective inpatient care in a pandemic situation., Conclusion: The results draw attention to key demands of clinical representatives, for example, comprehensive digitization, standardization of processes and better (supra) regional networking in order to be able to guarantee needs-based care even under pandemic conditions. The present consensus recommendations can serve as guidelines for future pandemic management in the inpatient care sector., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Mechanically interlocked structures, such as catenanes and rotaxanes, are fascinating synthetic targets and some are used for molecular switches and machines. Today, the vast majority of catenated structures are built upon macrocycles and only a very few examples of three-dimensional shape-persistent organic cages forming such structures have been reported. However, the catenation in all these cases was based on a thermodynamically favoured π-π-stacking under certain reaction conditions. Here, we show that catenane formation can be induced by adding methoxy or thiomethyl groups to one of the precursors during the synthesis of chiral [8 + 12] imine cubes, giving dimeric and trimeric catenated organic cages. To elucidate the underlying driving forces, we reacted 11 differently 1,4-disubstituted terephthaldehydes with a chiral triamino tribenzotriquinacene under various conditions to study whether monomeric cages or catenated cage dimers are the preferred products. We find that catenation is mainly directed by weak interactions derived from the substituents rather than by π-stacking., (© 2022. The Author(s).)

Spontaneous correlated activity is a universal hallmark of immature neural circuits. However, the cellular dynamics and intrinsic mechanisms underlying network burstiness in the intact developing brain are largely unknown. Here, we use two-photon Ca 2+ imaging to comprehensively map the developmental trajectories of spontaneous network activity in the hippocampal area CA1 of mice in vivo. We unexpectedly find that network burstiness peaks after the developmental emergence of effective synaptic inhibition in the second postnatal week. We demonstrate that the enhanced network burstiness reflects an increased functional coupling of individual neurons to local population activity. However, pairwise neuronal correlations are low, and network bursts (NBs) recruit CA1 pyramidal cells in a virtually random manner. Using a dynamic systems modeling approach, we reconcile these experimental findings and identify network bi-stability as a potential regime underlying network burstiness at this age. Our analyses reveal an important role of synaptic input characteristics and network instability dynamics for NB generation. Collectively, our data suggest a mechanism, whereby developing CA1 performs extensive input-discrimination learning prior to the onset of environmental exploration., Competing Interests: JG, VR, MM, OW, CG, SK, KH, KK No competing interests declared, (© 2022, Graf, Rahmati et al.)

Objectives: Rheumatic immune-related adverse events (irAE) such as (poly)arthritis in patients undergoing immune checkpoint inhibitor (ICI) treatment pose a major clinical challenge. ICI therapy improves CD8 + T cell (CD8) function, but CD8 contributes to chronic inflammation in autoimmune arthritis (AA). Thus, we investigated whether immune functional and metabolic changes in CD8 explain the development of musculoskeletal irAE in ICI-treated patients., Methods: Peripheral CD8 obtained from ICI-treated patients with and without arthritis irAEs and from AA patients with and without a history of malignancy were stimulated in media containing 13 C-labelled glucose with and without tofacitinib or infliximab. Changes in metabolism, immune-mediator release, expression of effector cell-surface molecules and inhibition of tumour cell growth were quantified., Results: CD8 from patients with irAE showed significantly lower frequency and expression of cell-surface molecule characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and proinflammatory immune mediators compared with CD8 from ICI patients who did not develop irAE. This was accompanied by a higher glycolytic rate and ATP production. Gene-expression analysis of pre-ICI-treated CD8 revealed several differentially expressed transcripts in patients who later developed arthritis irAEs. In vitro tofacitinib or infliximab treatment did not significantly change the immune-metabolic profile nor the capacity to release cytolytic mediators that inhibit the growth of the human lung cancer cell line H838., Conclusions: Our study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE has a distinct immune-effector and metabolic profile from those that remain irAE free. This specific irAE profile overlaps with the one observed in CD8 from AA patients and may prove useful for novel therapeutic strategies to manage ICI-induced irAEs., Competing Interests: Competing interests: KB: Consultancy and/or speaker fees and/or travel reimbursements: Abbvie, Bristol Myers Squibb (BMS), Gilead/Galapagos, Janssen, Merck Sharp & Dohme (MSD), Mundipharma, Novartis, Pfizer, Roche, Viatris, UCB. Scientific support: Medical Faculty of University of Heidelberg, Rheumaliga Baden-Württemberg e.V., AbbVie, Novartis. MMSC: Scientific support: Novartis, Pfizer. JCH: honoraria: BMS, MSD, Novartis, Roche, Pierre Fabre, Sanofi, Almirall; consultant or advisory role: MSD, Pierre Fabre, Sunpharma; Scientific support: BMS; Travel support: Pierre Fabre. PC: honoraria: Roche, Takeda, Gilead, AstraZeneca, Novartis; scientific support: Roche, Takeda, Amgen, Merck, AstraZeneca, Novartis; travel support: AstraZeneca, Merck, Janssen, Daiichi Sankyo, Takeda, Novartis, Elli Lilly; data safety monitoring and/or advisory board: Pfizer, Chugai, Boehringer Ingelheim, Roche. JG: honoraria: Galapagos; travel support: Elli Lilly. HML: Scientific funding: Abbvie, Novartis, Pfizer, Roche; consulting fees and honoraria: Abbvie, AstraZeneca, Actelion, Amgen, Bayer Vital, Boehringer Ingelheim, BMS, Celgene, GlaxoSmithKline (GSK), Galapagos, Janssen, Elli Lilly, Medac, MSD, Novartis, Pfizer, Roche, Sanofi, UCB; travel support: Abbvie, AstraZeneca, Boehriner Ingelheim, BMS, Celgene, GSK, Gilead, Janssen, Elli Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB; data safety monitoring and/or advisory board: Abbvie, AstraZeneca, Amgen, Boehriner Ingelheim, BMS, Celgene, GSK, Gilead, Janssen, Elli Lilly, Medac, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

8-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds' antimycobacterial properties are described. Reactions of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one and the clinical drug candidate BTZ043 with the Grignard reagent CH 3 MgBr afford the corresponding dearomatized stable 4,5-dimethyl-5H- and 4,7-dimethyl-7H-benzo[e][1,3]thiazines. These methine compounds are structurally characterized by X-ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non-planar 4H-benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH 3 ) 2 S ⋅ BH 3 . Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis, as proven by in vitro growth inhibition assays., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical, and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in vitro excitatory actions of γ-aminobutyric acid (GABA) and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics, and behavioral performance are subtle. Our data reveal a neural network function of NKCC1 in hippocampal glutamatergic neurons in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development., Competing Interests: The authors declare no competing interest.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The SARS-CoV-2 pandemic poses major challenges for the entire medical care system. Especially in university institutions as maximum care providers, a higher exposure to potentially infectious patients or actual COVID-19 patients is to be expected. In a short period of time, an operational concept had to be developed regarding the current hygiene recommendations of the Robert Koch Institute (RKI), the leading medical societies and the internal hospital hygiene plan. Here, patient safety and employee protection are equally important.In cooperation with the Institute for Medical Microbiology and Hospital Hygiene and the occupational medical service, interventions were defined to develop solutions to minimize the COVID-19 transmission risk for examiners and patients despite limited diagnostic and equipment resources. For this purpose, an operational concept was developed, consisting of various individual actions, e. g. the reduction of outpatient treatment to emergencies, life-threatening diseases and urgent aftercare, a double triage of patients and the introduction of treatment teams.The newly developed operational concept was successfully implemented within a few days. After the initial rollout and several "hygiene inspections" only minor improvements to the concept were necessary. All measures were documented in the internal quality handbook and are accessible to all employees. Since the SARS-CoV-2 pandemic is a dynamic process with regular changes in the development and information status, the operational concept is regularly reviewed for validity and adjusted as necessary., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

The SARS-CoV‑2 pandemic poses major challenges for the entire medical care system. Especially in maximum care clinical facilities, a higher exposure to potentially infectious patients or positively tested COVID-19 patients is to be expected. A hospital facility concept was developed in the Department of Ophthalmology, Goethe University, Frankfurt am Main, Germany with the aim of achieving maximum patient safety with maximum employee protection. The current infection control hygiene recommendations of the Robert Koch Institute (RKI), the leading specialist association, were taken into consideration along with the existing hospital hygiene plan of the University Hospital Frankfurt am Main. Incorporated into the developmental process were the Institute for Medical Microbiology and Hospital Hygiene, the occupational medical service department and the board of the University Hospital Frankfurt am Main. The operational concept with individualized measures ensures that (i) the care of outpatients; (ii) the performance of outpatient operations; (iii) and the care of admitted patients and patients undergoing surgery are also guaranteed during the COVID-19 pandemic. All measures have been documented in writing in the clinic's internal quality manual and are thus accessible to all employees. The concept is regularly checked for functionality, so-called stress tests and hygiene inspections are carried out and improvements are made as necessary.

For pilots and doctors, as well as a variety of other professions the knowledge of human performance limitations is essential, especially in critical situations. Crew resource management was developed in the 1980s in the aviation industry in order to ensure systematic training and support in such instances. Just recently, the value is recognized not only in other high reliability organizations but also in medicine., (© Georg Thieme Verlag Stuttgart · New York.)

The demographic trend of industrialized societies is also reflected in commercial airlines' passengers: passengers are older nowadays and long-haul flights are routine mode of transport despite considerable chronic and acute medical conditions. Moreover, duration of non-stop flight routes and the number of passengers on board increase. Thus, the probability of a medical incident during a particular flight event increases, too.Due to international regulations minimum standards for medical equipment on board, and first aid training of the crews are set. However, it is often difficult to assess whether a stopover at a nearby airport can improve the medical care of a critically ill passenger. Besides flight operations and technical aspects, the medical infrastructure on the ground has to be considered carefully.Regardless of the amount of experience of a physician medical emergencies on board an aircraft usually represent a particular challenge. This is mainly due to the unfamiliar surroundings, the characteristics of the cabin atmosphere, the often existing cultural and language barriers and legal liability concerns., (© Georg Thieme Verlag Stuttgart · New York.)

The need for inter-hospital transports over long distances aboard air ambulances or airlines has increased in recent years, both in the civil as well as the military sector. More often severely ill intensive care patients with multiple organ failure and appropriate supportive care (e.g. mechanical ventilation, catecholamines, dialysis, cardiac assist devices) are transported by air. Despite the fact that long-haul intensive care transports by air ambulance and airlines via Patient Transport Compartment (PTC) are considered established modes of transport they always provide a number of challenges. Both modes of transport have distinct logistical and medical advantages and disadvantages. These-as well as the principal risks of an air-bound long-haul intensive care transport -have to be included in the risk assessment and selection of means of transport. Very often long-haul intensive care transports are a combination of air ambulance and scheduled airlines utilizing the PTC., (© Georg Thieme Verlag Stuttgart · New York.)

Air travel has become a natural part of modern life. Both the environment, they take place in and the physical changes humans are exposed to must not be underestimated. Changes of pressure and volume of gases in higher altitudes induce specific physiological reactions, whereas limitations to compensate need to be acknowledged. It is the artificial environment of the aircraft cabin that allows travel in usual flight levels. Nevertheless, mild hypoxia and its sequeale have to be considered., (© Georg Thieme Verlag Stuttgart · New York.)

Background: One in every 10 000 to 40 000 passengers on commercial aircraft will have a medical incident while on board. Many physicians are unaware of the special features of the cabin atmosphere, the medical equipment available on airplanes, and the resulting opportunities for medical intervention., Methods: A selective literature search was performed and supplemented with international recommendations and guidelines and with data from the Lufthansa registry., Results: Data on in-flight medical emergencies have been collected in various ways, with varying results; it is generally agreed, however, that the more common incidents include gastrointestinal conditions (diarrhea, nausea, vomiting), circulatory collapse, hypertension, stroke, and headache (including migraine). Data from the Lufthansa registry for the years 2010 and 2011 reveal the rarity of cardiopulmonary resuscitation (mean: 8 cases per year), death (12 cases per year), childbirth (1 case per year), and psychiatric incidents (81 cases per year). If one assumes that one medical incident arises for every 10 000 passengers, and that there are 400 passengers on board each flight, then one can calculate that the probability of experiencing at least one medical incident reaches 95% after 24 intercontinental flights., Conclusion: An in-flight medical emergency is an exceptional event for the physician and all other persons involved. Physician passengers can act more effectively if they are aware of the framework conditions, the available medical equipment, and the commonly encountered medical conditions.

Background: This study was performed to evaluate the metabolic effects of a single oral dose of 8 mg dexamethasone in women undergoing hysterectomy., Methods: Ninety non-diabetic women undergoing abdominal hysterectomy were randomised to receive 8 mg dexamethasone or placebo 2 h before surgery. Patients' perioperative care was standardised (fasting from midnight before surgery, balanced anaesthesia using propofol, fentanyl, remifentanil, cisatracurium, desflurane in oxygen/air). At five defined time points after drug administration (approximately 2, 4, 6, 10 and 14 h), blood samples were drawn under fasting conditions to measure blood glucose and free (non-esterified) fatty acids (NEFA). Data were analysed using analysis of variance for repeated measures., Results: Data of 82 patients (dexamethasone: 44 and placebo: 38) were eligible for analysis. There was a statistically significant increase in blood glucose in both groups (P = 0.008). This increase was more pronounced in patients receiving dexamethasone (interaction term: P = 0.02) with maximum values at 6 h after surgery (or approximately 10 h after dexamethasone administration). There were 36 patients (placebo: 9 = 24% and dexamethasone: 27 = 61%) presenting with elevated glucose concentrations (>7 mmol l⁻¹) and 11 patients (placebo: 2 = 5% and dexamethasone: 9 = 20%) with hyperglycaemia (>8.5 mmol l⁻¹). There were no statistically significant changes in the plasma concentrations of NEFA during the perioperative period., Conclusion: Amounts of dexamethasone frequently used for prophylaxis of post-operative nausea and vomiting can cause short-lasting hyperglycaemia in the post-operative period, but no relevant alterations in fat metabolism. Thus, the benefits of administering corticosteroids should be weighed against the potential side-effects of short-lasting hyperglycaemia.

The structure of the title compound, [Zn(4)(C(40)H(24)N(8))(4)]·8C(3)H(7)NO·3H(2)O, has been redetermined at 100 K. The redetermination is of significantly higher precision and gives further insight into the disorder of pyridyl groups and solvent mol-ecules. The mol-ecules of (5,10,15,20-tetra-4-pyridyl-porphyrinato)zinc(II) (ZnTPyP) form homomolecular cyclic tetra-mers by coordination of a peripheral pyridyl group to the central Zn atom of an adjacent symmetry-related mol-ecule. The tetra-mer so formed exhibits mol-ecular S(4) symmetry and is located about a crystallographic fourfold rotoinversion axis. Severely disordered dimethyl-formamide and water mol-ecules are present in the crystal, the contributions of which were omitted from refinement. Inter-molecular C-H⋯N hydrogen bonding is observed.

Resistance to antibiotics and the directly related proportion of multiresistant bacterial pathogens (MRP) is increasing continuously. This applies particularly for intensive care units. The most relevant MRP are methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended spectrum ss-lactamase formers (ESBL), multiresistant pseudomonades and Acinetobacter species. According to WHO the world is in danger of entering a so-called "post-antibiotic era", in which it is no longer possible to treat the causes of infectious diseases with antibiotics. The reasons for this development are considered to be the increased morbidity of patients as well as the too frequent, too long-enduring and often inappropriate usage of antimicrobial substances. But also the increasing number of invasive measures and interventions as well as the still existing inadequate maintenance of hygiene standards and the inadequate establishment of non-medicamentous measures (e.g. hand disinfection) for infection prophylaxis play a significant role., (Georg Thieme Verlag Stuttgart. New York.)

Unlabelled: Bone marrow (BM)-derived stem cells and CD34(+) fibrocytes are associated with fibrogenesis in several organs. In an Abcb4(-/-) mouse model for sclerosing cholangitis alpha-smooth muscle actin-positive (alpha-SMA(+)) myofibroblasts are thought to play a pivotal role in hepatic fibrogenesis. The aim of this study was 2-fold: (1) to demonstrate that the origin of an important fibrogenetic cell population is the BM; and (2) to investigate whether transplantation of BM (BM-Tx) affects liver function, staging, and grading. Surrogate markers for fibrogenesis and regulation of hepatic stellate cells (HSC) as well as progenitor-cell-derived fibrocytes in liver tissue were analyzed by quantitative real-time polymerase chain reaction (PCR) and immunohistology. After lethal irradiation of recipient mice, BM-Tx was carried out by way of tail vein injection of BM cells from marker protein donors (green fluorescent protein, GFP(+)) or Abcb4(-/-) mice as control (syngeneic Tx). Parameters of liver function were assessed serologically and histologically. Activated HSC of alpha-SMA(+)/CRP2(+) phenotype were expressed in approximately 50% of proliferating bile ducts, whereas fibrotic liver parenchyma showed no expression thereof. Epithelial mesenchymal transfer (EMT) was visualized in the areas of proliferating bile ducts. The hematopoietic origin of CD34(+) fibrocytes was demonstrated immunohistologically in livers of BM chimeric mice. These CD34(+) cells infiltrated hepatic lobules from portal fields and developed a desmin(+) phenotype expressing collagen type I in fibrotic parenchyma as well as in vitro after isolation by magnetic cell separation. Transplantation of GFP(+)/Abcb4(+) BM improved liver function and staging compared with sham transplantation, but no significant differences were noticed among allogeneic and syngeneic Tx., Conclusion: The present study is the first to identify that both BM-derived fibrocytes and HSC are involved in biliary fibrogenesis in Abcb4(-/-) mice. Our data suggest that changes in immunity subsequent to BM-Tx may alter hepatic fibrosis.

It is estimated for the year 2006 that around 500,000 to 600,000 nosocomial infections occurred in Germany and that among these 10,000 to 15,000 patients died of the infection. Nosocomial infections in general lengthen the duration of hospitalisation by on average 4 days - with associated extra costs of 4000 to 20,000 Euro per case. About a third of all infections acquired in hospital are considered to be avoidable. However, the classification of an infection as nosocomial does not automatically mean that a causal relationship exists between a medical intervention and the occurrence of the infection. Also a nosocomial infection is not a synonym for medical or nursing errors. The first epidemiological report of the EU emphasises the health-political and health-economical significance of nosocomial infections and classifies the increasing number of infections acquired in hospitals as a most important danger - even higher than the threats of pandemic influenza and HIV., ((c) Georg Thieme Verlag Stuttgart New York.)

The pathophysiological mechanisms of thioacetamide (TAA)-induced hepatic fibrogenesis are not yet fully understood. In particular, the role of hepatic stellate cells (HSCs) remains unclear. We therefore examined proliferation and transdifferentiation of HSC as well as the underlying molecular mechanisms in TAA-induced fibrosis. Hepatic fibrogenesis was induced in mice by addition of TAA to drinking water. Liver damage was determined by assessment of alanine aminotransferase and aspartate aminotransferase levels, and measurement of collagen deposition. Additionally, expression patterns of alpha-smooth muscle actin, glial fibrillary acidic protein (GFAP, specific hepatic biomarker for HSC), cysteine- and glycine-rich protein 2 (CRP2, specific marker of HSC transdifferentiation), tissue inhibitor of metalloproteinases-1, matrix metalloproteinase-9 (MMP-9), interleukins (IL-1beta, IL-6), platelet-derived growth factors (PDGF-B, PDGF-D) , tumor necrosis factor (TNF)-alpha, and (transforming growth factor (TGF)-beta1 were assessed by real-time PCR. Transcription of GFAP and CRP2 were transiently upregulated during TAA-induced fibrogenesis (punctum maxima (p.m.) week 10 for GFAP and week 14 for CRP2). Similar transient expression patterns were demonstrated for IL-1beta, IL-6, TGF-beta1, and PDGF-B (p.m. week 12) whereas TNF-alpha and PDGF-D continuously increased with ongoing liver injury. In particular, not only neutrophil granulocytes, but also macrophages and leukocytes served as a major source for MMP-9 expression. GFAP and CRP2 expression patterns demonstrated transiently increased HSC-activation during TAA-induced hepatic fibrogenesis. The rate of increase of transcription of GFAP correlated best with PDGF-B, whereas CRP2 levels correlated with PDGF-B, PDGF-D, and IL-1beta expression. This study demonstrates for the first time that transiently increased activation patterns of HSC are observed in toxically induced hepatic fibrosis. Thus, TAA in drinking water is an effective and elegant model to induce reproducible states of liver fibrosis without parenchymal damage in mice.

Both, obligatory non-invasive hemodynamic monitoring and adjunctive hemodynamic monitoring need to be considered perioperatively. Patient as well as surgical requirements may contribute to the decision making process. Effectiveness and quality of the perioperative patient monitoring solely depends on the knowledge and awareness of the anesthesist with regard to the potentials and limitations of the applied monitoring.

Besides adequate and early antimicrobial therapy, goal-directed haemodynamic in-terventions are crucial for survival of severe sepsis and septic shock. Although cardiac output often is restored in the early phase of sepsis syndrome significant left- and right ventricular impairment may already be present. Clinical presentation, invasive blood pressure tracing and echocardiographic evaluation are pivotal for early recognition, diagnosis and monitoring of therapeutic interventions.

Although validated instruments are readily available for structured outcome assessment, this has been rarely employed in German intensive care units yet. Analysis of the effectiveness or efficiency of intensive care medicine without systematic assessment of outcomes and underlying structures and processes is impossible. Detailed knowledge of outcomes is mandatory, when continuous quality improvement is warranted. In the future, German intensive care units should implement regular outcome assessment to allow objective comparisons considering the particular case mix. Evidence-based guidelines may facilitate both, development of objectives, and assessment of outcomes. Owing to the advancement of medicine regular updates of guidelines are mandatory. Moreover, targets for the quality assessment need to be adjusted accordingly. This finally leads toward a continuous quality improvement process.

Brain natriuretic peptide (BNP) has been established as a new and reliable laboratory marker for chronic heart failure (CHF). BNP is a neurohormone secreted by the cardiac ventricles in response to volume expansion and pressure overload. It is released as N-terminal pro-brain natriuretic peptide and then Korrelaenzymatically cleaved into the NT fragment and the immunoreactive BNP. BNP promotes vasodilatation, natriuresis, diuresis, and inhibits the renin-angiotensin- aldosterone system. BNP values depend on sex, age, renal function, and the assay used. BNP exhibits a high sensitivity and specificity for the diagnosis of CHF. BNP determination improves the differential diagnosis of acute dyspnea. Normal BNP levels are found, if dyspnea is caused by pulmonary disease, pathologic BNP values are typical of a cardiac disorder. In CHF, BNP levels can be used as a reliable independent predictor of cardiac death or deterioration of cardiac functional status at follow-up. As a general screening test for CHF, BNP is of limited value due to a substantial number of false positive test results, which lead to further cardiac diagnostic testing. BNP is helpful for the assessment of the success of CHF therapy in acute cardiac decompensation and outpatients. An individually tailored CHF therapy with serial determination of BNP opens up new perspectives for a more objective and effective treatment of CHF patients.

Background and Purpose: The "Therapeutic Intervention Scoring System" (TISS) and the simplified version TISS-28 obtain the therapeutic workload in the critically ill and may be used for outcome prediction. The feasibility and applicability regarding cost analysis and outcome prediction of TISS and TISS-28 have been assessed in 303 consecutive medical patients staying longer than 24 h in the intensive care unit (ICU)., Patients and Methods: The mean age of the enrolled patients was 62 +/- 12 years, 216 (71%) patients were male, length of ICU stay 3.7 +/- 4.7 days, and SAPS II (Simplified Acute Physiology Score) 26 +/- 13 points. The overall mortality was 44 patients (14.5%) with 25 patients (8.3%) dying while on the ICU., Results: The data collection process for TISS took significantly longer than for TISS-28. On the day of admission, the correlation of TISS and TISS-28 was excellent (r(2) = 0.91; p < 0.001). The discriminatory power as assessed by the area under the receiver operating characteristic (ROC) curve was satisfactory for TISS (0.79 +/- 0.04), TISS-28 (0.76 +/- 0.04), and SAPS II (0.77 +/- 0.04) with regard to outcome prediction. Patient-specific costs per TISS-28 point amounted to 36 euros.--and were significantly higher than the 25 euros.--calculated per TISS point. Staff costs (42%) were the most prominent cost-generating factor, and patient-specific costs contributed two thirds to the total ICU costs. There was no association of severity of illness or number of organ failure and costs. Only the length of ICU stay correlated strongly with the costs of the individual patients during the ICU stay (r(2) = 0.79; p < 0.001)., Conclusion: The faster data collection process as well as the uniformity of the system are strong clinical and scientific advantages of the TISS-28. In addition, TISS-28 is capable of calculating individual costs in an acceptable time frame. Therefore TISS-28 serves as a valuable tool for quality assurance and cost analysis purposes in the medical ICU.