Non-calyceal excitatory inputs mediate low fidelity synaptic transmission in rat auditory brainstem slices

Principal neurons of the medial nucleus of the trapezoid body (MNTB) receive a synaptic input from a single giant calyx terminal that generates a fast-rising, large excitatory postsynaptic current (EPSC), each of which are supra-threshold for postsynaptic action potential generation. Here, we present evidence that MNTB principal neurons receive multiple excitatory synaptic inputs generating slow-rising, small EPSCs that are also capable of triggering postsynaptic action potentials but are of non-calyceal origin. Both calyceal and non-calyceal EPSCs are mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-d-aspartate (NMDA) receptor activation; however, the NMDA receptor-mediated response is proportionally larger at the non-calyceal synapses. Non-calyceal synapses generate action potentials in MNTB principal neurons with a longer latency and a lower reliability than the large calyceal input. They constitute an alternative low fidelity synaptic input to the fast and secure relay transmission via the calyx of Held synapse.     

Multinational study in children and adolescents with newly diagnosed type 1 diabetes: association of age,ketoacidosis, HLA status,and autoantibodies on residual beta‐cell function and glycemic control 12 months after diagnosis

HB Mortensen, PGF Swift, RW Holl, P Hougaard, L Hansen, H Bjoerndalen, CE de Beaufort, M Knip. Multinational study in children and adolescents with newly diagnosed type 1 diabetes: association of age, ketoacidosis, HLA status, and autoantibodies on residual beta‐cell function and glycemic control 12 months after diagnosis. Objective: To identify predictors of residual beta‐cell function and glycemic control during the first 12 months after the diagnosis of type 1 diabetes (T1D). Subjects and Methods: Clinical information and blood samples were collected from 275 children. HbA1c, antibodies, HLA typing and mixed meal‐stimulated C‐peptide levels 1, 6, and 12 months after diagnosis were analyzed centrally. Results: Mean age at diagnosis was 9.1 yr. DKA with standard bicarbonate <15 mmol/L was associated with significantly poorer residual beta‐cell function 1 (p = 0.004) and 12 months (p = 0.0003) after diagnosis. At 12 months, the decline in stimulated C‐peptide levels compared with the levels at 1 month was 69% in the youngest age group and 50% in patients 10 yr and above (p < 0.001). Stimulated C‐peptide at 12 months was predicted by younger age (p < 0.02) and bicarbonate levels at diagnosis (p = 0.005), and by stimulated C‐peptide (p < 0.0001), postmeal blood glucose (p = 0.0004), insulin antibodies (IA; p = 0.02) and glutamic acid decarboxylase antibodies (GADA; p = 0.0004) at 1 month. HbA1c at 12 months was predicted by HbA1c at diagnosis (p < 0.0001), GADA at 1 month (p = 0.01), and non‐white Caucasian ethnicity (p = 0.002). Conclusions: Younger age, ketoacidosis at diagnosis, and IA and GADA 1 month after diagnosis were the strongest explanatory factors for residual beta‐cell function at 12 months. Glycemic control at 12 months was influenced predominantly by ethnicity, HbA1c at diagnosis, and GADA at 1 month.     

Barriers and facilitators of shared decision making in acutely ill inpatients with schizophrenia—Qualitative findings from the intervention group of a randomised‐controlled trial

BackgroundShared decision making (SDM) is appreciated as a promising model of communication between clinicians and patients. However, in acute mental health settings, its implementation is still unsatisfactory.ObjectiveThe aim of this study is to examine barriers and facilitators of SDM with acutely ill inpatients with schizophrenia.DesignA qualitative interview study was performed.Setting and ParticipantsThe analysis is based on interviews with participants (patients and staff members) of the intervention group of the randomised‐controlled SDM^PLUS trial that demonstrated a significant improvement of SDM measures for patients with schizophrenia on acute psychiatric wards.Main Variables StudiedInterviews addressed treatment decisions made during the current inpatient stay. The interviews were analysed using qualitative content analysis.ResultsA total of 40 interviews were analysed and 131 treatment decisions were identified. According to the interviewees, SDM had taken place in 29% of the decisions, whereas 59% of the decisions were made without SDM. In 16%, a clear judgement could not be made. Barriers and facilitators of SDM were categorised into patient factors, clinician factors, setting factors and others. Clinicians mostly reported patient factors (e.g., symptoms) as barriers towards SDM, which were not mirrored on the patients'' side. Facilitators included patient as well as clinician behaviour during consultations.ConclusionEven in the context of a successful SDM intervention, the implementation of SDM for patients in the very acute stages of schizophrenia is often not possible. However, strong facilitators for SDM have also been identified, which should be used for further implementation of SDM.Patient or Public ContributionDuring the development of the study protocol, meetings with user representatives were held.     

New caryophyllene derivatives from Betula litwinowii

Four new caryophyllene derivatives-14-hydroxy-4, 5-dihydro-beta-caryophyllene (1), 14-acetoxy-4, 5-dihydro-beta-caryophyllene (2), 4, 5-dihydro-beta-caryophyllene-14-al (3), and caryophylla-8(14)-en-5-one (4)-are reported from the essential oil of Betula litwinowii. Compounds 1-4 were characterized by MS and 1D and 2D NMR analyses and chemical transformations. The antibacterial and antifungal activity of 1 is also reported.     

Microbial transformations of the antimelanoma agent betulinic acid

Microbial transformation studies of the antimelanoma agent betulinic acid (1) were conducted. Screening experiments showed a number of microorganisms capable of biotransforming 1. Three of these cultures, Bacillus megaterium ATCC 14581, Cunninghamella elegans ATCC 9244, and Mucor mucedo UI-4605, were selected for preparative scale transformation. Bioconversion of 1 with resting-cell suspensions of phenobarbital-induced B. megaterium ATCC 14581 resulted in the production of the known betulonic acid (2) and two new metabolites: 3beta,7beta-dihydroxy-lup-20(29)-en-28-oic acid (3) and 3beta,6alpha, 7beta-trihydroxy-lup-20(29)-en-28-oic acid (4). Biotransformation of 1 with growing cultures of C. elegans ATCC 9244 produced one new metabolite characterized as 1beta,3beta, 7beta-trihydroxy-lup-20(29)-en-28-oic acid (5). Incubation of 1 with growing cultures of M. mucedo UI-4605 afforded metabolite 3. Structure elucidation of all metabolites was based on NMR and HRMS analyses. In addition, the antimelanoma activity of metabolites 2-5 was evaluated against two human melanoma cell lines, Mel-1 (lymph node) and Mel-2 (pleural fluid).     

Development of antibiotics and the future of marine microorganisms to stem the tide of antibiotic resistance

Antibiotics remain essential tools in the control of infectious diseases. With the emergence of new diseases, resistant forms of diseases such as tuberculosis and malaria, as well as the emergence of multidrug-resistant bacteria, it has become essential to develop novel antibiotics. Development of the existing antibiotics involved three strategies, including discovery of new target sites, modification of existing antibiotic structures, and the identification of new resources for novel antibiotics. Marine microorganisms have clearly become an essential new resource in the discovery of new antibiotic leads.