Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies.

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Psychotic-like experiences in non-clinical subgroups with and without specific beliefs.

BACKGROUND: Assuming a transdiagnostic and extended psychosis phenotype, psychotic-like experiences (PLEs) and psychotic symptoms are on a phenomenological and temporal continuum between clinical and non-clinical populations. Recent research points towards differences in PLE proneness in different subgroups and clinical impact of different PLE subtypes. This study examines the prevalence of PLEs in three groups of individuals with and without specific sets of beliefs aiming to elucidate the question whether proneness to PLEs varies according to traditional versus less traditional supernatural beliefs. METHODS: The anonymized 16-item version of the Prodromal Questionnaire (PQ-16) was used to assess PLEs in three groups including individuals with religious beliefs (RB), belief in esoterism and paranormal phenomena (EB), and those embedded in scientific evidence approach and scepticism towards para-scientific theories (non-believers, NB). Male and female participants between 18 and 90 years were eligible for participation. RESULTS: The sample comprised 159 individuals including 41 RB individuals, 43 EB individuals, and 75 NB individuals. The mean PQ-16 score of the EB individuals (6.86 ± 4.13) was significantly higher compared to NB individuals (3.43 ± 2.99) and to RB individuals (3.38 ± 3.23) with almost twice the score (both p-values < 0.001). There was no significant difference between the PQ-16 scores of the NB group and the RB group (p = 0.935). No significant impact of age (p = 0.330) and gender (p = 0.061) was found on the PQ16-Score. Group affiliation to esoterism was associated with a higher PQ-16 score compared to group affiliation to religious beliefs (p < 0.001) and group affiliation to scepticism (p = 0.011), while the latter two did not differ significantly (p = 0.735). No significant difference was found between the three groups in the degree of distress related to the affirmatively answered PQ-16 items (p = 0.74). CONCLUSION: Under the assumption of a transdiagnostic psychosis phenotype, our findings provide more insight which subgroups within non-clinical samples have a higher likelihood of reporting PLEs.

Semi-automated detection of ungulates using UAV imagery and reflective spectrometry.

In the field of species conservation, the use of unmanned aerial vehicles (UAV) is increasing in popularity as wildlife observation and monitoring tools. With large datasets created by UAV-based species surveying, the need arose to automate the detection process of the species. Although the use of computer learning algorithms for wildlife detection from UAV-derived imagery is an increasing trend, it depends on a large amount of imagery of the species to train the object detector effectively. However, there are alternatives like object-based image analysis (OBIA) software available if a large amount of imagery of the species is not available to develop a computer-learned object detector. The study tested the semi-automated detection of reintroduced Arabian Oryx (O. leucoryx), using the specie's coat sRGB-colour profiles as input for OBIA to identify adult O. leucoryx, applied to UAV acquired imagery. Our method uses lab-measured spectral reflection of hair sample values, collected from captive O. leucoryx as an input for OBIA ruleset to identify adult O. leucoryx from UAV survey imagery using semi-automated supervised classification. The converted mean CIE Lab reflective spectrometry colour values of n = 50 hair samples of adult O. leucoryx to 8-bit sRGB-colour profiles of the species resulted in the red-band value of 157.450, the green-band value of 151.390 and blue-band value of 140.832. The sRGB values and a minimum size permitter were added as the input of the OBIA ruleset identified adult O. leucoryx with a high degree of efficiency when applied to three UAV census datasets. Using species sRGB-colour profiles to identify re-introduced O. leucoryx and extract location data using a non-invasive UAV-based tool is a novel method with enormous application possibilities. Coat refection sRGB-colour profiles can be developed for a range of species and customised to autodetect and classify the species from remote sensing data.

Psychological distress and line-of-duty head injuries in firefighters.

BACKGROUND: Head injuries are common injury in the fire service; however, very little data exist on the risks this may pose to the development of post-traumatic stress disorder (PTSD) and depression in this high-risk population. AIMS: Our study aimed to compare levels of PTSD and depression symptoms in firefighters with a line-of-duty head injury, non-line-of-duty head injury and no head injury. METHODS: In this cross-sectional study, we assessed current PTSD and depression symptoms as well as retrospective head injuries. RESULTS: Seventy-six per cent of the total sample reported at least one head injury in their lifetime. Depression symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to those with no head injury, but not compared to those who sustained a non-line-of-duty head injury. Depression symptoms did not differ between firefighters with a non-line-of-duty head injury and those with no head injury. PTSD symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to both firefighters with no head injury and those with a non-line-of-duty head injury. CONCLUSIONS: We found that firefighters who reported at least one line-of-duty head injury had significantly higher levels of PTSD and depression symptoms than firefighters who reported no head injuries. Our findings also suggest head injuries sustained outside of fire service could have less of an impact on the firefighter's PTSD symptom severity than head injuries that occur as a direct result of their job.

[Intraoperative vascular air embolism : Evidence for risks, diagnostics and treatment]. / Intraoperative vaskuläre Luftembolie : Evidenz bei Risiko, Diagnostik und Therapie.

The entry of gases into the vascular system is called vascular air embolism (VAE). The blocking of the pulmonary circulation by VAE can lead to fulminant right-sided heart failure and cardiocirculatory arrest. A VAE can occur at any time if there is an open connection between the environment and a venous vessel with subatmospheric pressure. This situation occurs during ear nose throat surgery, hip surgery, surgery of the lesser pelvis or breast surgery, if the surgical field is above the level of the heart; however, a VAE can also occur during routine tasks, such as insertion or removal of a central venous catheter or during endoscopic procedures with the insufflation of gas.Because during these procedures VAE is not the main focus of the anesthesia or surgery personnel, in such situations its sudden unexpected occurrence can have severe consequences. In contrast, in cardiac surgery or neurosurgery the risk of intraoperative VAE is much better known. In procedures with a higher risk of a clinically relevant VAE, a patent foramen ovale should be ruled out by preoperative transesophageal echocardiography (TEE). Intraoperatively TEE is the most sensitive procedure not only to detect a VAE but also to visualize the clinical expression, e.g. acute right heart overload.The avoidance of an initial and repeated air embolism is the primary measure to minimize the incidence and severity of VAE.Intraoperatively the following measures should be undertaken: excellent communication between anesthesia and surgery personnel with predetermined actions, maintenance of normal volume, patient positioning with minimal difference in height between heart and head, state of the art surgical technique with closure of potential air entry sites, sufficient detection of air by TEE, repeated jugular vein compression during neurosurgery, intraoperative Trendelenburg positioning of the patient during persisting or clinically evident VAE, differentiated adjustment of ventilatory settings and catecholamine treatment, aspiration of the blood-air mixture (air lock) at the junction of the superior vena cava and right atrium through a large bore central venous line and keeping check of the coagulation status.

Mechanical dissipation via image potential states on a topological insulator surface.

Joule energy loss due to resistive heating is omnipresent in today's electronic devices whereas quantum-mechanical dissipation is largely unexplored. Here, we experimentally observe a suppression of the Joule dissipation in Bi2Te3 due to topologically protected surface states. Instead, a different type of dissipation mechanism is observed by pendulum atomic force microscopy, which is related to single-electron tunnelling resonances into image potential states that are slightly above the Bi2Te3 surface. The application of a magnetic field leads to the breakdown of the topological protection of the surface states and restores the expected Joule dissipation process. Nanomechanical energy dissipation experienced by the cantilever of the pendulum atomic force microscope provides a rich source of information on the dissipative nature of the quantum-tunnelling phenomena on the topological insulator surface, with implications for coupling a mechanical oscillator to the generic quantum material.

Effect of subinhibitory exposure to quaternary ammonium compounds on the ciprofloxacin susceptibility of Escherichia coli strains in animal husbandry.

BACKGROUND: Quaternary ammonium compound based disinfectants are commonly used in pig and poultry husbandry to maintain farm hygiene. However, studies have shown that subinhibitory concentrations of these disinfectants may increase antibiotic resistance. Investigation of antibiotic susceptibility is usually assessed via the microbroth dilution method, although this conventional culture-based technique only provides information on the bacteriostatic activity of an antimicrobial agent. Therefore, experiments were performed to investigate the effect of prior benzalkonium chloride (BKC) exposure on the viability of subsequent ciprofloxacin (CIP) treated Escherichia coli. RESULTS: Following CIP treatment, bacterial cell counts were significantly higher after exposure to a subinhibitory BKC concentration than without BKC exposure. The flow cytometric results suggested a BKC-dependent onset of membrane damage and loss of membrane potential. CONCLUSION: Our results indicate a lower bactericidal effect of CIP treatment on BKC-exposed E. coli isolates compared to unexposed E. coli isolates.

Repeated disinfectant use in broiler houses and pig nursery units does not affect disinfectant and antibiotic susceptibility in Escherichia coli field isolates.

BACKGROUND: Disinfectants are frequently used in animal production to reduce or eliminate the load of infectious agents and parasites in buildings and equipment associated with the housing or transportation of animals. There are growing concerns that the use of disinfectants would select for resistance to antibiotics and disinfectants. The aim of this study was to determine the effect of repeated use of different disinfectants on the disinfectant and antibiotic susceptibility under practical conditions in a broiler and pig pilot farm. Therefore, the susceptibility of Escherichia coli (E. coli) to 14 antibiotics and 4 disinfectants was monitored over a one-year period. RESULTS: High (20-50%) to very high (> 50%) resistance levels for ampicillin, sulfamethoxazole, trimethoprim and tetracycline were observed in both animal production types. Disinfectant susceptibility did not change over time and did not depend on the used disinfection product. Compared to in-use concentrations of formaldehyde, benzalkoniumchloride and a peracetic acid - hydrogen peroxide formulation, all E. coli strains remained susceptible indicating that the use of disinfectants did not select for disinfectant resistance. Moreover, no association could be found between the use of disinfectants and antibiotic resistance. CONCLUSIONS: These findings suggest that repeated use of disinfectants in agricultural environments does not select for antibiotic resistance nor does it reduce disinfectant susceptibility.

Current good manufacturing practices-compliant manufacture and measurement of biotin-labeled red blood cells.

BACKGROUND: Red blood cells (RBCs) can be labeled with N-hydroxysuccinimidobiotin (sulfo-NHS-biotin), which binds to cell surface proteins under aqueous conditions. Biotinylated RBCs can be safely infused and detected in peripheral blood samples using flow cytometry, using a fluorochrome-conjugated streptavidin (SA) detection reagent. Biotinylated RBCs have been used to track survival of transfused RBCs, and have applications in optimizing RBC storage and in understanding donor genetic, environmental and disease factors affecting RBC products. METHODS: We have developed a closed-system, current good manufacturing practices (cGMP)-compliant procedure for biotinylation of RBCs and a quantitative flow cytometric assay to estimate the dose of cell-bound biotin delivered to the patient. Resulting products were characterized for variability, sterility, endotoxin, hemolysis, total dose of cell-bound biotin and stability. RESULTS: The density of biotin-labeling increased as a log-linear function of sulfo-NHS-biotin-labeling concentration, with greater variability at lower concentrations. The upper estimates of biotin doses in the average product (mean RBC content = 5.55 × 1011) were 9.8 and 73.0 µg for products labeled at 3 and 15 µg sulfo-NHS-biotin/mL of total reaction mixture (27 and 135 nmol/mL packed RBCs), respectively. All products were negative for bacterial and fungal growth at 14 days and were below the limit of endotoxin detection. Biotinylated RBCs were stable in vitro for up to 50 days after labeling. DISCUSSION: We have validated a closed-system procedure for biotinylating RBCs for investigational use. A standard operating procedure is presented in sufficient detail for implementation in a cGMP-compliant cell-processing facility.

Improved quantitative detection of biotin-labeled red blood cells by flow cytometry.

BACKGROUND: Biotin-labeled red blood cells (BioRBC) can be tracked after transfusion, providing a convenient and safe way to measure RBC survival in vivo. RBC survival is of interest for determining optimal blood storage conditions and for assessing the impact of genetic and biologic variants in blood donors on the survival of transfused RBCs. Here we present an improved, platform-independent assay for quantifying biotin on BioRBC. This approach is also useful for detecting BioRBC in peripheral blood samples as rare events. STUDY DESIGN AND METHODS: We optimized the signal-to-noise ratio of the detecting reagent (phycoerythrin-conjugated streptavidin [SA-PE]) by determining the SA-PE concentration yielding the greatest separation index between BioRBC and unlabeled RBCs. We calibrated the fluorescence intensity measurements to molecules of equivalent soluble fluorochrome (MESF), a quantitative metric of fluorochrome binding and therefore of biotin bound per RBC. We then characterized the limit of blank and limit of quantification (LoQ) for BioRBC labeled at different densities. RESULTS: Biotin-labeled RBCs at sulfo-NHS-biotin concentrations of 3 to 30 µg/mL (27-271 nmol/mL RBCs) ranged from approximately 32,000 to 200,000 MESF/RBC. The LoQ ranged from one in 274,000 to one in 649,000, depending on biotin-labeling density. CONCLUSION: Increased sensitivity to detect BioRBC may facilitate tracking over longer periods and/or reduction of the BioRBC dose. Total RBC-bound biotin dose has been shown to correlate with the likelihood of developing antibodies to BioRBC. Lowering the dose of labeled cells may help avoid this eventuality.

Alcohol use and mental health symptoms in female firefighter recruits.

BACKGROUND: Limited research suggests that female firefighters report problem drinking at higher rates than the general population. AIMS: To identify longitudinal drinking patterns in female firefighters, make comparisons to male firefighters and examine problem drinking in relation to post-traumatic stress disorder (PTSD) and depression. METHODS: Study participants included 33 female and 289 male firefighter recruits, who were assessed over their first 3 years of fire service. RESULTS: Female firefighters consumed increasing numbers of drinks per week, with a median of 0.90 drinks per week at baseline, and 1.27 drinks in year 3. Female firefighters reported binge drinking at high rates, with nearly half binging at least once per year across all time points (44-74%). The percentage that reported binge drinking three or more times per month doubled over the course of the study (from 9% to 18%). Overall, males reported higher rates of binge drinking and a greater number of drinks per week; however, binge drinking rates among females increased over time and became comparable to rates of binge drinking among males. A greater percentage of female than male firefighters met the criteria for problem drinking by year 1. Problem drinking was associated with screening positive for PTSD at year 1 and depression at year 2, but not with occupational injury. CONCLUSIONS: Over time, female firefighters reported increasing amounts of drinking, more frequent binge drinking and more negative consequences from drinking. These findings along with existing literature indicate female firefighters change their drinking in the direction of their male counterparts.

Proteomic Profiling of Native Unpassaged and Culture-Expanded Mesenchymal Stromal Cells (MSC).

Human culture-expanded mesenchymal stromal cells (MSC) are being considered for multiple therapeutic applications because of their regenerative and anti-inflammatory properties. Although a large number of MSC can be propagated from a small initial sample, several lines of evidence indicate that MSC lose their immunosuppressive and regenerative potency aftaer multiple passages. In this report, we use the FACSCAP Lyoplate proteomic analysis system to detect changes in cell surface protein expression of CD45- /CD31- /CD34- /CD73+ /CD105+ stromal cells in unpassaged bone marrow (BM) and through 10 serial culture passages. We provide for the first time a detailed characterization of native unpassaged BM MSC (0.08% of BM mononuclear cells) as well as the changes that occur during the initial expansion. Adipogenic and osteogenic differentiative potential was determined though the serial passages and correlated with immunophenotypic changes and senescence. Among the most prominent were striking decreases in Fas ligand, CD98, CD205, and CD106, accompanied by a gain in the expression of CD49c, CD63, CD98, and class 1 and class 2 major histocompatibility complex (MHC) molecules. Other molecules that are down-modulated with later passage include CD24, CD54, CD59, CD243/P-glycoprotein, and CD273/PD-L2. Early senescence, as defined by the loss of replicative capacity occurring with the loss of differentiative capacity, increase in CDKN2A p16, and increased time to confluence, was accompanied by loss of the motility-associated metalloproteinase CD10 and the proliferation-associated transferrin receptor CD71. Among the strongest statistical associations were loss of MAC-inhibitory protein/CD59, loss of ICAM-1/CD54, and increase in CDKN2A as a function of increasing passage, as well as increased CD10 expression with adipogenic and osteogenic capacities. The data provide a clear set of markers that can be used to assess MSC quality. We suggest that clinically relevant numbers of highly functional low passage MSC can be manufactured starting with large quantities of BM, which are readily available from cadaveric organ donors.

Flow cytometric detection of most proteins in the cell surface proteome is unaffected by trypsin treatment.

Flow cytometry is often performed on adherent cells or solid tissues that have been released from their growth substrate or disaggregated by enzymatic digestion. Although detection of strongly expressed cell surface proteins following such procedures indicates that many survive treatment with proteolytic enzymes, applications such as cell surface proteomics involve assessment of the expression of more than 200 proteins and it is important to know how to interpret negative results. To address this problem, we performed flow cytometry-based cell surface proteomic analysis on two non-adherent cell lines, THP1 and K562, after mock and authentic trypsin treatment, according to a widely used protocol to remove adherent cells (0.25% trypsin, 2.21 mM EDTA, 37°C, 5 min). In a single screening experiment, we examined the effect of treatment on mean fluorescence intensity and on the percent of positive cells and determined the false negative rate. Of 164 determinations that were ≥20% positive after mock treatment, 13 (7.9%) were <20% positive after trypsin treatment. Four proteins were chosen for time-course studies (performed in triplicate), confirming initial sensitivity results but revealing significant variability in the magnitude of the trypsin effect. When trypsin sensitivity of individual proteins was examined as a function of the number of predicted high probability extracellular trypsin cleavage sites, we found that the markers that yielded false negatives all had high numbers of sites (>30), but even so, the majority of proteins with high numbers of trypsin sites could still be detected after mild trypsin treatment. We conclude that the great majority of cell surface proteins can be detected after mild trypsin treatment, but that negative results should not be over-interpreted, due to the possibility of false negatives.

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

OBJECTIVES: To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease. METHODS: We identified children with genetically confirmed POLG disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age-related reference ranges and to non-POLG patients presenting with status epilepticus. RESULTS: Forty-one patients with POLG disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non-epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5-hydroxyindoleacetic acid levels. CONCLUSIONS: Children with POLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.

Correction to: Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

Due to a typesetting error the wrong Table 2 was used. The correct Table 2 is shown here.

Flow Cytometry Is a Powerful Tool for Assessment of the Viability of Fungal Conidia in Metalworking Fluids.

Fungal contamination of metalworking fluids (MWF) is a dual problem in automated processing plants because resulting fungal biofilms obstruct cutting, drilling, and polishing machines. Moreover, some fungal species of MWF comprise pathogens such as Fusarium solani Therefore, the development of an accurate analytical tool to evaluate conidial viability in MWF is important. We developed a flow cytometric method to measure fungal viability in MWF using F. solani as the model organism. To validate this method, viable and dead conidia were mixed in several proportions and flow was cytometrically analyzed. Subsequently, we assessed the fungicidal activity of two commercial MWF using flow cytometry (FCM) and compared it with microscopic analyses and plating experiments. We evaluated the fungal growth in both MWF after 7 days using quantitative PCR (qPCR) to assess the predictive value of FCM. Our results showed that FCM distinguishes live from dead conidia as early as 5 h after exposure to MWF, whereas the microscopic germination approach detected conidial viability much later and less accurately. At 24 h, microscopic analyses of germinating conidia and live/dead analyses by FCM correlated well, although the former consistently underestimated the proportion of viable conidia. In addition, the reproducibility and sensitivity of the flow cytometric method were high and allowed assessment of the fungicidal properties of two commercial MWF. Importantly, the obtained flow cytometric results on viability of F. solani conidia at both early time points (5 h and 24 h) correlated well with fungal biomass measurements assessed via a qPCR methodology 7 days after the start of the experiment.IMPORTANCE This result shows the predictive power of flow cytometry (FCM) in assessing the fungicidal capacity of MWF formulations. It also implies that FCM can be implemented as a rapid detection tool to estimate the viable fungal load in an industrial processing matrix (MWF).

Adipose Stem Cell Function Maintained with Age: An Intra-Subject Study of Long-Term Cryopreserved Cells.

Background: The progressive decline in tissue mechanical strength that occurs with aging is hypothesized to be due to a loss of resident stem cell number and function. As such, there is concern regarding use of autologous adult stem cell therapy in older patients. To abrogate this, many patients elect to cryopreserve the adipose stromal-vascular fraction (SVF) of lipoaspirate, which contains resident adipose stem cells (ASC). However, it is not clear yet if there is any clinical benefit from banking cells at a younger age. Objectives: We performed a comparative analysis of SVF composition and ASC function from cells obtained under GMP conditions from the same three patients with time gap of 7 to 12 years. Methods: SVF, cryobanked under good manufacturing practice (GMP) conditions, was thawed and cell yield, viability, and cellular composition were assessed. In parallel, ASC proliferation and efficiency of tri-lineage differentiation were evaluated. Results: The results showed no significant differences existed in cell yield and SVF subpopulation composition within the same patient between harvest procedures 7 to 12 years apart. Further, no change in proliferation rates of cultured ASCs was found, and expanded cells from all patients were capable of tri-lineage differentiation. Conclusions: By harvesting fat from the same patient at two time points, we have shown that despite the natural human aging process, the prevalence and functional activity of ASCs in an adult mesenchymal stem cell, is highly preserved. Level of Evidence: 5.

Corticosteroid-Binding Globulin: A Review of Basic and Clinical Advances.

Corticosteroid-binding globulin (CBG, transcortin) is the primary cortisol binding protein. It is a non-inhibitory serine protease inhibitor, capable of conformational change from a high cortisol-binding affinity form to a low affinity form upon cleavage of its reactive centre loop by various proteases, such as neutrophil elastase. The burgeoning inflammatory role of CBG applies to acute, severe inflammation where depletion is associated with mortality, and to chronic inflammation where defects in cortisol delivery may perpetuate inflammation. Naturally occurring human mutations influence a wide range of CBG properties and point toward a role in hitherto unexplained chronic musculoskeletal pain and fatigue disorders as well as potentially affecting fertility outcomes including offspring gender. In vitro and knock-out animal models of CBG propose a role for CBG in cortisol transport to the brain, providing a foundation for understanding the human observations in those with CBG mutations and sex differences in stress-related mood and behaviour. Finally, CBG measurement has a practical role in the estimation of free cortisol, useful in clinical circumstances where CBG levels or cortisol binding affinity is reduced. Taken together, novel data suggest a role for cortisol in targeted cortisol delivery, with implications in acute and chronic inflammation, as well as roles in metabolism and neurocognitive function, implying that CBG is a multifaceted component in the mechanisms of hypothalamic-pituitary-adrenal axis related homeostasis.

Strategies to enhance rational use of antibiotics in hospital: a guideline by the German Society for Infectious Diseases.

INTRODUCTION: In the time of increasing resistance and paucity of new drug development there is a growing need for strategies to enhance rational use of antibiotics in German and Austrian hospitals. An evidence-based guideline on recommendations for implementation of antibiotic stewardship (ABS) programmes was developed by the German Society for Infectious Diseases in association with the following societies, associations and institutions: German Society of Hospital Pharmacists, German Society for Hygiene and Microbiology, Paul Ehrlich Society for Chemotherapy, The Austrian Association of Hospital Pharmacists, Austrian Society for Infectious Diseases and Tropical Medicine, Austrian Society for Antimicrobial Chemotherapy, Robert Koch Institute. MATERIALS AND METHODS: A structured literature research was performed in the databases EMBASE, BIOSIS, MEDLINE and The Cochrane Library from January 2006 to November 2010 with an update to April 2012 (MEDLINE and The Cochrane Library). The grading of recommendations in relation to their evidence is according to the AWMF Guidance Manual and Rules for Guideline Development. CONCLUSION: The guideline provides the grounds for rational use of antibiotics in hospital to counteract antimicrobial resistance and to improve the quality of care of patients with infections by maximising clinical outcomes while minimising toxicity. Requirements for a successful implementation of ABS programmes as well as core and supplemental ABS strategies are outlined. The German version of the guideline was published by the German Association of the Scientific Medical Societies (AWMF) in December 2013.