Notes

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Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumour in children. To date, there are no effective chemotherapeutics despite a myriad of clinical trials. PD173212 The intact blood-brain barrier (BBB) is likely responsible for the limited clinical response to chemotherapy. MRI-guided focused ultrasound (MRgFUS) is a promising non-invasive method for treating CNS tumours. Moreover, MRgFUS allows for the temporary and repeated disruption of the BBB. Our group previously reported the feasibility of temporary BBB opening within the normal murine brainstem using MRgFUS following intravenous (IV) administration of microbubbles. In the current study, we set out to test the effectiveness of targeted chemotherapy when paired with MRgFUS in murine models of DIPG. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics tested on patient-derived cell lines. We studied the RCAS/Tv-a model where RCAS-Cre, RCAS-PDGFB, and RCAS-H3.3K27M were used to drive tumourigenesis upon injection in the pons. We also used orthotopically injected SU-DIPG-6 and SU-DIPG-17 xenografts which demonstrated a diffusely infiltrative tumour growth pattern similar to human DIPG. In our study, SU-DIPG-17 xenografts were more representative of human DIPG with an intact BBB. Following IV administration of doxorubicin, MRgFUS-treated animals exhibited a 4-fold higher concentration of drug within the SU-DIPG-17 brainstem tumours compared to controls. Moreover, the volumetric tumour growth rate was significantly suppressed in MRgFUS-treated animals whose tumours also exhibited decreased Ki-67 expression. Herein, we provide evidence for the ability of MRgFUS to enhance drug delivery in a mouse model of DIPG. These data provide critical support for clinical trials investigating MRgFUS-mediated BBB opening, which may ameliorate DIPG chemotherapeutic approaches in children.Boron neutron capture therapy (BNCT) is a tumor selective therapy, the effectiveness of which depends on sufficient 10B delivery to and accumulation in tumors. In this study, we used self-assembling A6K peptide nanotubes as boron carriers and prepared new boron agents by simple mixing of A6K and BSH. BSH has been used to treat malignant glioma patients in clinical trials and its drug safety and availability have been confirmed; however, its contribution to BNCT efficacy is low. A6K nanotube delivery improved two major limitations of BSH, including absence of intracellular transduction and non-specific drug delivery to tumor tissue. Varying the A6K peptide and BSH mixture ratio produced materials with different morphologies-determined by electron microscopy-and intracellular transduction efficiencies. We investigated the A6K/BSH 110 mixture ratio and found high intracellular boron uptake with no toxicity. Microscopy observation showed intracellular localization of A6K/BSH in the perinuclear region and endosome in human glioma cells. The intracellular boron concentration using A6K/BSH was almost 10 times higher than that of BSH. link2 The systematic administration of A6K/BSH via mouse tail vein showed tumor specific accumulation in a mouse brain tumor model with immunohistochemistry and pharmacokinetic study. Neutron irradiation of glioma cells treated with A6K/BSH showed the inhibition of cell proliferation in a colony formation assay. Boron delivery using A6K peptide provides a unique and simple strategy for next generation BNCT drugs.Staphylococcus aureus is a highly virulent pathogen, capable of biofilm formation and responsible for thousands of deaths each year. The prevalence of Methicillin-Resistant S. aureus (MRSA) strains has increased in recent years and thus, the development of new antibiotics has become necessary. Antimicrobial Peptides (AMPs) are effective against a variety of multidrug-resistant bacteria and low levels of resistance have been reported regarding these molecules. Dinoponera quadriceps ant venom (DqV) has been described regarding its effect against S. aureus. In this study, we have evaluated the antibacterial effect of DqV-AMPs, the dinoponeratoxins (DNTxs), against Methicillin-Sensitive and a Methicillin-Resistant S. aureus strains. Our results show DNTx M-PONTX-Dq3a as a potent inhibitor of both strains, being able to prevent biofilm formation at low micromolar range (0.78-3.12 μM). It also showed a short-time effect through membrane disruption. M-PONTX-Dq3a opens up new perspectives for the prevention of biofilm formation through the development of anti-adhesive surface coatings on medical devices, as well as the treatment of resistant strains in skin or soft tissue infections.People with stimulant use disorders are usually underweight. Current accepted knowledge is that they are skinny because stimulants suppress appetite - they eat less. But is it that simple? Here we review the relationship between stimulant use, food intake, metabolism and body weight, and highlight key points that may challenge current knowledge 1) Stimulants interact with the hormonal signals that regulate appetite including ghrelin and leptin, and can produce long-term alterations in the ability to monitor and compensate energy deficits. 2) The diet of people with stimulant use disorders might be characterised by altered nutritional geometry, rather than overall reduction of food intake. 3) Long-term changes in homeostatic signals and nutrient intake can produce metabolic deficits that contribute to unhealthy low weight. Based on this knowledge we advocate for increasing awareness about the nuances of stimulant-related nutritional and metabolic deficits among addiction clinicians, and increased research on the interaction between stimulant use, appetite signaling, and metabolic deficits.
White matter hyperintensities of presumed vascular origin (WMH) are one of the imaging features of cerebral small vessel disease. Controversies persist about the effects of WMH on cognitive dysfunction. This meta-analysis aimed to identify the associations of WMH with risks of cognitive impairment and dementia.

We searched PubMed, EMBASE and Cochrane Library for prospective studies. Primary analyses of cognitive dysfunction and sub-analyses of specific outcomes and study characteristics were conducted using random-effect models.

Thirty-six prospective studies with 19,040 participants were included. WMH at baseline conferred a 14 % elevated risk of cognitive impairment and all-cause dementia (ACD). WMH also conferred 25 % elevated risk of Alzheimer's disease and 73 % elevated risk of vascular dementia. Risk effects of high-grade WMH and continually increasing WMH (in volume or severity) on ACD were revealed. Periventricular WMH conferred a 1.51-fold excess risk for dementia.

WMH were associated with increased risk of cognitive dysfunction and could become a neuroimaging indicator of dementia.
WMH were associated with increased risk of cognitive dysfunction and could become a neuroimaging indicator of dementia.Studies in humans and rodents suggest a critical role for the hippocampal formation in cognition and emotion, but also in the adaptation to stressful events. Successful stress adaptation promotes resilience, while its failure may lead to stress-induced psychopathologies such as depression and anxiety disorders. Hippocampal architecture and physiology is shaped by its strong control of activity via diverse classes of inhibitory interneurons that express typical calcium binding proteins and neuropeptides. Celltype-specific opto- and chemogenetic intervention strategies that take advantage of these biochemical markers have bolstered our understanding of the distinct role of different interneurons in anxiety, fear and stress adaptation. Moreover, some of the signature proteins of GABAergic interneurons have a potent impact on emotion and cognition on their own, making them attractive targets for interventions. In particular, neuropeptide Y is a promising endogenous agent for mediating resilience against severe stress. In this review, we evaluate the role of the major types of interneurons across hippocampal subregions in the adaptation to chronic and acute stress and to emotional memory formation.Current knowledge on the general somatic health and causes of death in Tourette syndrome and chronic tic disorder is very limited. Here, we review the available literature on the topic, while highlighting strengths and weaknesses of the studies conducted to date. These previous works have suggested associations between Tourette syndrome and chronic tic disorder and a range of health conditions, including autoimmune disorders, common allergies and respiratory diseases, sleep difficulties, and metabolic and cardiovascular outcomes. Additionally, the risk of mortality in tic disorders might be higher than that of the general population, but specific causes of death have rarely been studied, except for substance use-related deaths and suicide, which are significantly higher in individuals with Tourette syndrome and chronic tic disorder. Many of these emerging findings require replication and extension but, taken together, they suggest that that it might be sensible to monitor the general health and suicide risk of individuals with Tourette syndrome or chronic tic disorder across the lifespan. We suggest further avenues for research on this topic.The hippocampus is vulnerable to traumatic brain injury (TBI), and hippocampal damage is associated with cognitive deficits that are often the hallmark of TBI. Recent studies have found that TBI induces enhanced neurogenesis in the dentate gyrus (DG) of the hippocampus, and this cellular response is related to innate cognitive recovery. However, cellular mechanisms of the role of DG neurogenesis in post-TBI recovery remain unclear. This study investigated changes in long-term potentiation (LTP) within the DG in relation to TBI-induced neurogenesis. Adult male rats received a moderate TBI or sham injury and were sacrificed for brain slice recordings at 30 or 60 days post-injury. Recordings were taken from the medial perforant path input to DG granule cells in the presence or absence of the GABAergic antagonist picrotoxin, reflecting activity of either all DG granule cells or predominately newborn granule cells, respectively. Measurements of LTP observed in the total granule cell population (with picrotoxin) showed a prolonged impairment which worsened between 30 and 60 days post-TBI. Under conditions which predominantly reflected the LTP elicited in newly born granule cells (no picrotoxin), a strikingly different pattern of post-TBI changes was observed, with a time-dependent cycle of functional impairment and recovery. At 30 days after injury this cell population showed little or no LTP, but by 60 days the capacity for LTP of the newly born granule cells was no different from that of sham controls. The time-frame of LTP improvements in the newborn cell population, comparable to that of behavioral recovery reported previously, suggests the unique functional properties of newborn granule cells enable them to contribute to restorative change following brain injury.Pseudoexfoliation syndrome (PXF) is the most common cause of secondary open angle glaucoma worldwide. Single nucleotide polymorphisms (SNPs) in the gene Lysyl oxidase like 1 (LOXL1) are strongly associated with the development of pseudoexfoliation glaucoma (PXFG). However, these SNPs are also present in 50-80% of the general population, suggestive of other factors being involved in the pathogenesis of PXFG. link3 In this study, we aimed to investigate the influence of epigenetic regulation, specifically DNA methylation, on LOXL1 expression in PXFG using human tenons fibroblasts (HTFs), aqueous humour and serum samples from donors with and without PXFG. LOXL1 expression in HTFs was measured by qPCR and Western Blotting and LOXL1 concentration in aqueous humour was determined by ELISA. Global DNA methylation levels were quantified using an ELISA for 5-methylcytosine. MeDIP assays assessed the methylation status of the LOXL1 promoter region. Expression of methylation-associated enzymes (DNMT1, DNMT3a and MeCP2) were determined by qPCR and inhibited by 0.
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