The Role of BDNF/TrkB Signaling in Acute Amphetamine-Induced Locomotor Activity and Opioid Peptide Gene Expression in the Rat Dorsal Striatum

Exposure to psychostimulants increases brain-derived neurotrophic factor (BDNF) mRNA and protein levels in the cerebral cortex and subcortical structures. Because BDNF is co-localized with dopamine and glutamate in afferents to the striatum of rats, it may be co-released with those neurotransmitters upon stimulation. Further, there may be an interaction between the intracellular signaling cascades activated by dopamine, glutamate, and TrkB receptors in medium spiny striatal neurons. In the present study, the effect of acute amphetamine administration on TrkB phosphorylation, as an indirect indicator of activation, and striatal gene expression, was evaluated. In Experiment 1, 15 min or 2 h after a single saline or amphetamine (2.5 mg/kg, i.p.) injection, the caudate–putamen (CPu), nucleus accumbens (NAc), and dorsomedial prefrontal cortex (dmPFC) were extracted and processed for phospho (p)-TrkB immunoreactivity. Immunoprecipitation analyses indicated that neither the tyrosine phosphorylation (p-Tyr) or autophosphorylation sites of TrkB (706) were changed in NAc, CPu, or dmPFC 15 min after amphetamine administration. In contrast, p-Tyr and the PLCγ phosphorylation site of TrkB (816) were increased in the NAc and CPu 2 h after amphetamine. In Experiment 2, intra-striatal infusion of the tyrosine kinase inhibitor, K252a, increased amphetamine-induced vertical activity but not total distance traveled. In addition, K252a inhibited amphetamine-induced preprodynorphin, but not preproenkephalin, mRNA expression in the striatum. These data indicate that acute amphetamine administration induces p-TrkB activation and signaling in a time- and brain region-dependent manner and that TrkB/BDNF signaling plays an important role in amphetamine-induced behavior and striatal gene expression

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Identification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease

Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-naïve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making

Governing towards sustainability - conceptualizing modes of governance

There is a growing scientific debate regarding the suitability of certain modes of governance for promoting sustainable development (SD). However, thus far there is neither agreement on ways to meaningfully distinguish and understand governance modes nor a foundation of the aspects to be chosen for this endeavor. In order to overcome this conceptual vagueness, this paper presents a meta-framework for a sound conceptualization of governance modes. Founded on a reinterpretation of the discourse ´from government to governance´, we argue that only a multi-dimensional approach giving consideration to political processes (politics), institutional structures (polity) and policy content (policy) adequately captures the complexity of governance phenomena. We furthermore highlight possible key features for exploring these dimensions and compare three recently published frameworks for modes of governance. By offering a sound conceptual clarification of governance modes, we facilitate both their meaningful differentiation and a more systematic understanding of their inherent complexity. In so doing, we inform both theoretical and empirical research on governance for SD. We pave the way not only for making more differentiated theoretical statements on the relationship between governance modes and SD but also for empirically exploring this relationship on a profound basis