Clostridium difficile toxins A and B directly stimulate human mast cells

Clostridium difficile toxins A and B (TcdA and TcdB) are the causative agents of antibiotic-associated pseudomembranous colitis. Mucosal mast cells play a crucial role in the inflammatory processes underlying this disease. We studied the direct effects of TcdA and TcdB on the human mast cell line HMC-1 with respect to degranulation, cytokine release, and the activation of proinflammatory signal pathways. TcdA and TcdB inactivate Rho GTPases, the master regulators of the actin cytoskeleton. The inactivation of Rho GTPases induced a reorganization of the actin cytoskeleton accompanied by morphological changes of cells. The TcdB-induced reorganization of the actin cytoskeleton in HMC-1 cells reduced the number of electron-dense mast cell-specific granules. Accordingly, TcdB induced the release of hexosaminidase, a marker for degranulation, in HMC-1 cells. The actin rearrangement was found to be responsible for degranulation since latrunculin B induced a comparable hexosaminidase release. In addition, TcdB as well as latrunculin B induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 and also resulted in a p38 MAPK-dependent increased formation of prostaglandins D(2) and E(2). The autocrine stimulation of HMC-1 cells by prostaglandins partially contributed to the degranulation. Interestingly, TcdB-treated HMC-1 cells, but not latrunculin B-treated HMC-1 cells, showed a strong p38 MAPK-dependent increase in interleukin-8 release. Differences in the mast cell responses to TcdB and latrunculin B are probably due to the presence of functionally inactive Rho GTPases in toxin-treated cells. Thus, the HMC-1 cell line is a promising model for studying the direct effects of C. difficile toxins on mast cells independently of the tissue context.     

Fatal Adverse Event with Dabigatran in Elderly Patient with Reduced Kidney Function

An elderly man with decreased kidney function was admitted to hospital with gastrointestinal bleeding. After remaining stable for 2 days in hospital, he became haemodynamically unstable and an adverse effect of dabigatran was suspected, but efforts to treat the patient failed and the following morning he passed away. In conjunction with the autopsy, blood samples from his hospital stay were analysed for dabigatran, revealing the highest concentration (6400 ng/mL) apparently reported to date. Supra‐therapeutic dosing was, however, never suspected. Dabigatran is largely excreted through the kidneys. A possible cause of the high dabigatran concentrations could be a rapid decrease in kidney function that seemingly occurred over a period of 2 months, sometime between his initiation of treatment (eGFR 51–55 mL/min/1.73 m²) and subsequent hospital admission (eGFR 31 mL/min/1.73 m²). The increasing dabigatran concentrations in the patient was, however, not apparent to the prescribing doctor, as therapeutic drug monitoring of dabigatran is not recommended in current guidelines and no such analyses were performed. There may be a need to evaluate blood concentrations of dabigatran, in the light of the reported differences in interindividual concentrations, along with the increased risks of thromboembolic events with lower concentrations and major bleeding events with higher concentrations. Functional assays to assess concentrations of dabigatran in blood have been developed and are available in some hospitals to be used in suspected overdoses or before emergency surgeries. Methods to determine concentrations of dabigatran specifically have also been developed and can additionally be used for therapeutic drug monitoring in an outpatient setting, especially in high‐risk individuals.     

The development of caring in the perioperative culture: nurse leaders' perspective on the struggle to retain sight of the patient

This article focuses on Swedish nurse leaders and is aimed at achieving a more complete and differentiated understanding of what constitutes caring in the perioperative culture as well as their knowledge and responsibility for the development of caring. Interviews with open-ended questions were conducted with 10 nurse leaders, in which they described their experiences of developing perioperative caring. The interpretation process was based on Gadamer's philosophy of hermeneutics. The findings indicate that developing a perioperative caring culture is a struggle to retain sight of the patient, a process that includes the following 6 phases: (1) when the nurse leaders understood perioperative caring as a process, the nurse's and patient's shared world became obvious to them; (2) safeguarding the patient's position as a unique human being; (3) safeguarding the nurse's welfare by creating a compassionate atmosphere; (4) promoting an idea means never giving up; (5) attaching importance to being trustworthy; and (6) being involved in a dynamic interaction, comprising communion and reciprocity. The most important goal of nursing leadership is to safeguard the welfare of the suffering patient and the relationship between the nurse leader and nursing staff, based on the motive of caritas derived from the idea of humanistic caring.     

Toward acellular xenogeneic heart valve prostheses: Histological and biomechanical characterization of decellularized and enzymatically deglycosylated porcine pulmonary heart valve matrices

The use of decellularized xenogeneic heart valves might offer a solution to overcome the issue of human valve shortage. The aim of this study was to revise decellularization protocols in combination with enzymatic deglycosylation, in order to reduce the immunogenicity of porcine pulmonary heart valves, in means of cells, carbohydrates, and, primarily, Galα1-3Gal (α-Gal) epitope removal. In particular, the valves were decellularized with sodium dodecylsulfate/sodium deoxycholate (SDS/SD), Triton X-100 + SDS (Tx + SDS), or Trypsin + Triton X-100 (Tryp + Tx) followed by enzymatic digestion with PNGaseF, Endoglycosidase H, or O-glycosidase combined with Neuraminidase. Results showed that decellularization alone reduced carbohydrate structures only to a limited extent, and it did not result in an α-Gal free scaffold. Nevertheless, decellularization with Tryp + Tx represented the most effective decellularization protocol in means of carbohydrates reduction. Overall, carbohydrates and α-Gal removal could strongly be improved by applying PNGaseF, in particular in combination with Tryp + Tx treatment, contrary to Endoglycosidase H and O-glycosidase treatments. Furthermore, decellularization with PNGaseF did not affect biomechanical stability, in comparison with decellularization alone, as shown by burst pressure and uniaxial tensile tests. In conclusion, valves decellularized with Tryp + Tx and PNGaseF resulted in prostheses with potentially reduced immunogenicity and maintained mechanical stability.     

Psychotropic medication in geriatric psychiatric patients: use and unreported use in relation to serum concentrations

Purpose

The aim of this observational study was to describe the type, number, and serum concentration levels of psychotropic drugs in elderly patients, on admission to a geriatric psychiatric inpatient unit. We further wanted to investigate the use and unreported use of psychotropic drugs by analyzing for a broad spectrum of drugs in the serum samples.

Methods

A total of 236 patients were included. Drug use, patient characteristics, and diagnoses were recorded, and serum analysis was performed for a total of 56 psychotropic drugs in 233 of the patients.

Results

Nine out of ten patients (88 %) used one or more psychotropic drugs on admission to hospital; the mean use was 2.8 (95 % confidence interval (CI) 2.6–2.9) drugs. In 25 patients (11 %), drugs reported used were not detected in serum. Unreported use of drugs (serum analysis revealing one or more drugs not reported) was found in 100 patients (43 %). This was more common in younger patients. Psychotropic polypharmacy (use of three or more psychotropic drugs) was found in 109 patients (47 %). Patients with a main diagnosis of affective disorder used the most psychotropic drugs.

Conclusions

Psychotropic drugs are commonly used among geriatric psychiatric patients on admission to hospital. Psychotropic polypharmacy is a major concern among these patients. There was considerable unreported use of drugs within this population, and a low threshold for a broader serum analysis for psychotropic drugs appears indicated.     

Developing a Competency‐based Curriculum in Basic and Clinical Pharmacology – A Delphi Study among Physicians

A new curriculum is planned for the medical school at Lund University, Sweden. Pharmacology, in a broad sense, has been identified as a subject that needs to be strengthened based on needs in the healthcare system. The aim was to identify the competencies in basic and clinical pharmacology that a newly qualified physician needs. Using a modified three‐round Delphi technique, 31 physicians were invited to list necessary competencies (round 1). After content analysis, these panel members classified the list by importance on two occasions (rounds 2 and 3) using a 4‐point scale (4 = necessary, 3 = desirable, 2 = useful, 1 = not necessary). Competencies with the highest ranks based on necessity were retained. Thirty physicians accepted the invitation and 25 (83%) of them completed all three rounds. Round 1 resulted in 258 suggestions, which were subsequently reduced to 95 competencies. Of these 95 competencies, 40 were considered necessary by at least 75% of the panel members. The degree of consensus increased between round 2 and round 3. Using a modified Delphi technique, we identified 40 competencies that could be transferred to learning outcomes for a new curriculum in basic and clinical pharmacology at medical school.