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Perspective reduction in giant mobile or portable arteritis.
BMJ.INTRODUCTION Exposure to poor environmental conditions has been associated with deterioration of physical and mental health, and with reduction of cognitive performance. Environmental conditions may also influence cognitive development of children, but epidemiological evidence is scant. In developed countries, children spend 930 hours per year in a classroom, second only to time spent in their bedroom. Using continuous sensing technology, we investigate the relationship between indoor environmental quality (IEQ) and cognitive performance of school-aged children. The proposed study will result in a better understanding of the effects of environmental characteristics on cognitive performance, thereby paving the way for experimental studies. METHODS AND ANALYSIS A study protocol is presented to reliably measure IEQ in schools. We will monitor the IEQ of 280 classrooms for 5 years, covering approximately 10 000 children. Each classroom in the sample is permanently equipped with a sensor measuring air quality (cardisseminated through peer-reviewed international journals, as well as through conference presentations. In addition, we will exploit ongoing collaboration with project stakeholders and project partners to disseminate information to the target audience. For example, the results will be presented to school boards in the Netherlands, through engagement with the Coalition for Green Schools, as well as to school boards in USA, through engagement with the Center for Green Schools. TRIAL REGISTRATION NUMBER NCT02800616; Results. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.OBJECTIVES Few contemporary studies have examined peer and social drivers of alcohol use during mid-adolescence. We sought to explore young people's perspectives on socio-cultural influences relating to alcohol use behaviour during this period. DESIGN Qualitative research study. METHODS Semi-structured one-to-one (n=25), paired (n=4) or triad (n=1) interviews and one focus group (n=6) were conducted with 30 young people aged 14 to 15 (13 males, 17 females) recruited from 4 schools, and 12 participants (aged 14 to 18, 8 males, 4 females) recruited from two youth groups in an urban centre in the West of England. Nineteen participants abstained from alcohol use, 9 were occasional or moderate drinkers and 14 drank alcohol more regularly. Interviews were audio-recorded, transcribed verbatim and analysed thematically using NVivo V.10, through a lens of social influence and social norms theories. RESULTS Alcohol consumption was associated with being cool, mature and popular, while enabling escape from reality and bohol use during adolescence. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.Homeostatic scaling is a form of synaptic plasticity where individual synapses scale their strengths to compensate for global suppression or elevation of neuronal activity. Apamin purchase This process can be studied by measuring miniature excitatory postsynaptic potential amplitudes and frequencies following the regulation of activity in neuronal cultures. Here we demonstrate a quantitative approach to characterize multiplicative synaptic scaling using immunolabelling of hippocampal neuronal cultures treated with tetrodotoxin or bicuculline to extract scaling factors for various synaptic proteins. This approach allowed us to directly examine the scaling of pre- and postsynaptic scaffolding molecules along with neurotransmitter receptors in primary cultures from mouse and rat hippocampal neurons. We show robust multiplicative scaling of synaptic scaffolding molecules namely, Shank2, PSD95, Bassoon, and AMPA receptor subunits and quantify their scaling factors. We use super-resolution microscopy to calculate scaling factors osolution microscopy, we examine pools of AMPA type glutamatergic receptors, and confirm that they are scaled differentially within functional zones of synapses. Furthermore, we show that the AMPA receptor content within the postsynaptic density and perisynaptic compartments are altered differentially during homeostatic scaling, indicating a differential regulation of receptors within various subsynaptic compartments during homeostatic plasticity. Copyright © 2020 Venkatesan et al.Newly born neurons express high levels of TUBA1A α-tubulin to assemble microtubules for neurite extension and to provide tracks for intracellular transport. In the adult brain, Tuba1a expression decreases dramatically. A mouse that harbors a loss-of-function mutation in the gene encoding TUBA1A (Tuba1aND/+) allows us to ask whether TUBA1A is important for the function of mature neurons. α-tubulin levels are about half of wild type in juvenile Tuba1aND/+ brains, but are close to normal in older animals. In P0 cultured neurons, reduced TUBA1A allows for assembly of less microtubules in axons resulting in more pausing during organelle trafficking. While Tuba1aND/+ mouse behavior is indistinguishable from wild type siblings at weaning, Tuba1aND/+ mice develop adult-onset ataxia. Neurons important for motor function in Tuba1aND/+ remain indistinguishable from wild type with respect to morphology and number and display no evidence of axon degeneration. Tuba1aND/+ neuromuscular junction synapses are the same size as wild type before the onset of ataxia, but are reduced in size in older animals. Together, these data indicate that the TUBA1A-rich microtubule tracks that are assembled during development are essential for mature neuron function and maintenance of synapses over time.Significance Statement Defects in axonal trafficking have been reported in models of movement disorders, but it has been unclear if trafficking defects are coincident or causative. Our results suggest that deficits in TUBA1A αTubulin can cause trafficking defects that impair synaptic maintenance leading to a movement disorder without axon degeneration or impacting myelination or neuron survival. Copyright © 2020 Buscaglia et al.T cell receptor (TCR)-based therapeutic cells and agents have emerged as a new class of effective cancer therapies. These therapies work on cells that express intracellular cancer-associated proteins by targeting peptides displayed on major histocompatibility complex receptors. However, cross-reactivities of these agents to off-target cells and tissues have resulted in serious, sometimes fatal, adverse events. We have developed a high throughput genetic platform (termed "PresentER") that encodes MHC-I peptide minigenes for functional immunological assays and determines the reactivities of TCR-like therapeutic agents against large libraries of MHC-I ligands. In this report, we demonstrated that PresentER could be used to identify the on-and-off targets of T cells and TCR mimic antibodies using in vitro co-culture assays or binding assays. We found dozens of MHC-I ligands that were cross-reactive with two TCR mimic antibodies and two native TCRs and that were not easily predictable by other methods. Copyright ©2020, American Association for Cancer Research.Patients with hematological cancers have improved outcomes after treatment with bispecific antibodies that bind to CD3 on T cells and that redirect T cells towards cancer cells. However, clinical benefit against solid tumors remains to be shown. We made a bispecific antibody that targets both the common prostate tumor-specific antigen PSMA and CD3 (PMSAxCD3) and provide evidence for tumor inhibition in several preclinical solid tumor models. Mice expressing the human extracellular regions of CD3 and PSMA were generated to examine antitumor efficacy in the presence of an intact immune system and PSMA expression in normal tissues. PSMAxCD3 accumulated in PSMA-expressing tissues and tumors as detected by Immuno-PET imaging. Although PSMAxCD3 induced T-cell activation and showed antitumor efficacy in mice with low tumor burden, PSMAxCD3 lost efficacy against larger solid tumors, mirroring the difficulty of treating solid tumors in the clinic. Costimulatory receptors can enhance T-cell responses. We show here that costimulation can enhance the antitumor efficacy of PSMAxCD3. In particular, 4-1BB stimulation in combination with PSMAxCD3 enhanced T-cell activation and proliferation, boosted efficacy against larger tumors, and induced T-cell memory, leading to durable antitumor responses. The combination of CD3 bispecific antibodies and anti-4-1BB costimulation represents a therapeutic approach for the treatment of solid tumors. Copyright ©2020, American Association for Cancer Research.BACKGROUND AND OBJECTIVES Hospital rounds are a traditional vehicle for patient-care delivery and experiential learning for trainees. We aimed to characterize practices and perceptions of rounds in United States nephrology training programs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a national survey of United States nephrology fellows and program directors. Fellows received the survey after completing the 2019 National Board of Medical Examiners Nephrology In-Training Exam. Program directors received the survey at the American Society of Nephrology's 2019 Nephrology Training Program Directors' Retreat. Surveys assessed the structure and perceptions of rounds, focusing on workload, workflow, value for patient care, and fellows' clinical skill-building. Directors were queried about their expectations for fellow prerounds and efficiency of rounds. Responses were quantified by proportions. RESULTS Fellow and program director response rates were 73% (n=621) and 70% (n=55). Most fellows (74%) repofferent frequencies. PODCAST This article contains a podcast at https//www.asn-online.org/media/podcast/CJASN/2020_03_17_CJN.10190819.mp3. Copyright © 2020 by the American Society of Nephrology.PURPOSE Vincristine combined with camptothecin derivatives showed synergy in preclinical pediatric cancer models and the combinations are effective in treatment of childhood solid tumors. We determined whether the synergy between vincristine and irinotecan extends to eribulin, another microtubule inhibitor. EXPERIMENTAL DESIGN Vincristine or eribulin, alone or combined with irinotecan, was studied in 12 xenograft models. Tumor regression and time to event were used to assess antitumor activity. Pharmacodynamic studies and RNA-seq were conducted 24h and 144h after single agent or combination treatment. Effects on vascular development were studied in Matrigel plugs implanted in mice. The interaction between binary combinations was examined in vitro. RESULTS Eribulin combined with irinotecan was more effective than vincristine-irinotecan in 6/12 models. Pharmacodynamic markers induced by eribulin (phospho-histone H3) and irinotecan (γ-H2A.X) were abrogated in combination treated tumors. The predominant RNA-seq signature in combination-treated tumors was activation of the TP53 pathway with increased nuclear TP53. Massive apoptosis was observed 24h only after treatment with the eribulin combination. In vitro, neither combination showed interaction using Combination Index analysis. Eribulin alone and the combination caused alterations in developing vasculature. CONCLUSIONS The eribulin combination is very active in these xenograft models, but not synergistic in vitro. The combination reduced pharmacodynamic markers indicative of single agent mechanisms, but in tumors dramatically activated the TP53 pathway. Although a mechanism for in vivo synergy requires further study, it is possible that eribulin-induced inhibition of microtubule dynamics enhances irinotecan-induced nuclear accumulation of TP53, leading to rapid cell death. Copyright ©2020, American Association for Cancer Research.
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