Search

Burkitt lymphoma is a highly aggressive B cell non-Hodgkin's lymphoma characterised by translocation of

Purpose To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2019. Materials and methods The Critical Care Pharmacotherapy Literature Update (CCPLU) Group screened 36 journals monthly for impactful articles and reviewed 113 articles during 2019 according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. Results Articles with a 1A grade, including three clinical practice guidelines, six meta-analyses, and five original research trials are reviewed here from those included in the monthly CCPLU. Clinical practice guidelines on the use of polymyxins and antiarrhythmic drugs in cardiac arrest as well as meta-analyses on antipsychotic use in delirium, stress ulcer prophylaxis (SUP), and vasoactive medications in septic shock and cardiac arrest were summarized. Original research trials evaluated delirium, sedation, neuromuscular blockade, SUP, anticoagulation reversal, and hemostasis. Conclusion This clinical review and expert opinion provides summary and perspectives of clinical practice impact on influential critical care pharmacotherapy publications in 2019.

Advancing Health Equity Through Innovations and Technology This year’s summit was unique given the COVID-19 pandemic: a major global outbreak that has imposed severe restrictions in all aspects of our life. At the outset, we were faced with three mutually exclusive options. First option was to cancel the summit in its entirety: this was the easiest and most obvious choice once the COVID-19 pandemic forced a near total lockdown all over the country with unprecedented disruptions of normal daily activities as the disease announced its thunderous touchdown on United States (US) soil. It was also the most-logical response faced with uncertainty regarding summit logistics and expected poor attendance due to the raging pandemic. Second option was to conduct a digital summit restricted to local audiences at Baylor College of Medicine: this option entailed implementing a virtual summit with attendance restricted to participants from our institution only. It sounded like a reasonable choice but that would impede the presence of diversity of topics, perspectives, insights and experiential learning opportunities, which are what render the summit exciting and worth attending. And finally, the last option was to conduct a digital unrestricted summit open to all interested audiences throughout the US. The conduct of a virtual summit open to all participants from around the country was initially considered daunting given the likelihood of amplified technical problems associated with an array of internet access differentials around the country, which would require a strong Information Technology (IT) presence throughout the sessions. Nonetheless, the attractiveness of going national with a virtual summit, despite the pandemic and logistical challenges, slowly gained converts and became the dominant choice. The response and level of participation in this first virtual summit showed an unanticipated surge despite the increase in registration fees to cover IT costs. This year, we had attendees from all regions of the US as well as from the United Kingdom. The range of topics was quite diverse encompassing health disparities in relation to cancers, nutrition, musculo-skeletal disorders, amputation rates, vaccination uptakes and COVID-19 infections. Various solutions were passionately presented to address these disparities including novel health technologies, community engagement and partnerships, improvement in health literacy and alternative therapeutics. There were no hitches despite the complex breakout sessions, and above all, attendees were satisfied and offered outstanding evaluation scores. This was definitely a summit that metamorphosed from pessimism to a triumphant success! Copyright © 2020 Salihu et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in this journal, is properly cited.

Fibrillin-rich microfibrils (FRMs) constitute integral components of the dermal elastic fibre network with a distinctive ultrastructural 'beads-on-a-string' appearance that can be visualised using atomic force microscopy and characterised by measurement of their length and inter-bead periodicity. Their deposition within the dermis in photoprotected skin appears to be contingent on skin ethnicity, and influences the ultrastructure of papillary - but not reticular - dermal FRMs. Truncation and depletion of FRMs at the dermal-epidermal junction of skin occurs early in photoageing in people with lightly pigmented skin; a process of accelerated skin ageing that arises due to chronic sun exposure. Accumulation of ultraviolet radiation (UVR)-induced damage, either by the action of enzymes, oxidation or direct photon absorption, results in FRM remodelling and changes to ultrastructure. In the current study, the direct effect of UVR exposure on FRM ultrastructure was assayed by isolating FRMs from the papillary and reticular dermis of photoprotected buttock skin of individuals of either black African or white Northern European ancestry and exposing them to solar-simulated radiation (SSR). Exposure to SSR resulted in significant reduction in inter-bead periodicity for reticular dermis-derived FRMs across both cohorts. In contrast, papillary dermal FRMs exhibited significantly increased inter-bead periodicity, with the magnitude of damage greater for African FRMs, as compared to Northern European FRMs. Our data suggest that FRMs of the dermis should be considered as two distinct populations that differentially accrue damage in response to SSR. Furthermore, papillary dermal FRMs derived from black African subjects show greater change following UVR challenge, when extracted from skin. Future studies should focus on understanding the consequences of UVR exposure in vivo, regardless of skin ethnicity, on the molecular composition of FRMs and how this UVR-induced remodelling may affect the role FRMs play in skin homeostasis.

The dermal elastic fibre network is the primary effector of skin elasticity, enabling it to extend and recoil many times over the lifetime of the individual. Fibrillin-rich microfibrils (FRMs) constitute integral components of the elastic fibre network, with their distribution showing differential deposition in the papillary dermis across individuals of diverse skin ethnicity. Despite these differential findings in histological presentation, it is not known if skin ethnicity influences FRM ultrastructure. FRMs are evolutionarily highly conserved from jellyfish to man and, regardless of tissue type or species, isolated FRMs have a characteristic 'beads-on-a-string' ultrastructural appearance, with an average inter-bead distance (or periodicity) of 56 nm. Here, skin biopsies were obtained from the photoprotected buttock of healthy volunteers (18-27 years; African: n = 5; European: n = 5), and FRMs were isolated from the superficial papillary dermis and deeper reticular dermis and imaged by atomic force microscopy. In the reticular dermis, there was no significant difference in FRM ultrastructure between European and African participants. In contrast, in the more superficial papillary dermis, inter-bead periodicity was significantly larger for FRMs extracted from European participants than from African participants by 2.20 nm (p < .001). We next assessed whether these differences in FRM ultrastructure were present during early postnatal development by characterizing FRMs from full-thickness neonatal foreskin. Analysis of FRM periodicity identified no significant difference between neonatal cohorts (p = .865). These data suggest that at birth, FRMs are developmentally invariant. However, in adults of diverse skin ethnicity, there is a deviation in ultrastructure for the papillary dermal FRMs that may be acquired during the passage of time from child to adulthood. Understanding the mechanism by which this difference in papillary dermal FRMs arises warrants further study.

Background Working in palliative medicine requires emotional resilience and is associated with compassion fatigue and burnout. However, research into support strategies for palliative care teams is lacking. Schwartz rounds improve caregiver psychological wellbeing but are limited by implementation costs. This project aimed to: ascertain staff satisfaction with their counselling service; measure wellbeing; and pilot an emotional support forum. Methods This study was conducted in a specialist palliative care unit with 20 inpatient beds and day therapy unit. Discussions were held with the counselling, medical and nursing staff to develop the support service. A survey was distributed to MDT members, giving 24 anonymous responses. Subsequently, a monthly emotional support forum was piloted, facilitated by a ward nurse and supported by the counsellors and ward manager. A follow-up survey was distributed 16 months later with 32 respondents. Results The initial survey identified staff may benefit from emotional support, with over 50% experiencing disturbed sleep, intrusive thoughts and feeling sad or depressed at some point over the past month. Preferred options were mindfulness sessions and an emotional support forum. Over 70% of respondents to the second survey attended the forum at some point. Of those, 85% felt it an inclusive and safe environment and 74% found it helpful. 48% could not attend as often as hoped, predominantly due to time constraints and staffing. There were no significant differences between measures of anxiety and depression before and after forum introduction. Conclusions Staff were more aware of the counselling service to support patients/relatives than themselves, but many engaged with the forum and found it helpful. Areas for improvement include increasing awareness and facilitating forum attendance. This study was not designed to detect objective changes in anxiety/depression, however, our qualitative findings support the forum as a low cost and convenient approach to improving staff wellbeing.

Langerhans cells (LCs) are sentinels of skin's immune system, their loss from epidermis contributing to UVR suppression of cell-mediated immunity (CMI). Omega-3 polyunsaturated fatty acids show potential to reduce UVR suppression of CMI in mice and humans, potentially through modulation of LC migration. Our objectives were to examine whether eicosapentaenoic acid (EPA) ingestion influences UV-mediated effects on epidermal LC numbers and levels of immunomodulatory mediators including prostaglandin (PG)D2 , which is expressed by LC. In a double-blind randomised controlled study, healthy individuals took 5-g EPA-rich (n=40) or control (n=33) lipid for 12 weeks; UVR-exposed and unexposed skin samples were taken pre- and postsupplementation. Epidermal LC numbers were assessed by immunofluorescence for CD1a, and skin blister fluid PG and cytokines were quantified by LC-MS/MS and Luminex assay, respectively. Presupplementation, UVR reduced mean (SEM) LC number/mm2 from 913 (28) to 322 (40) (P

This article defines amicable pairs in the complex numbers and finds that some amicable pairs in the natural numbers are also amicable in the complex numbers. Unlike the case in the natural numbers, it is proved that no $(2,1)$ pairs made up of natural numbers where the common factor is a power of $2$ exist as Gaussian amicable pairs. Many pairs are found with complex parts using the DivisorSigma function in Mathematica. The factorizations into primes is given so that the type of pair might be determined.

In mouse thymocyte development, signaling by the TCR through the ERK pathway is required for positive selection of conventional naive T cells. The Ets transcription factor ELK4 (SAP-1), an ERK-regulated cofactor of the SRF transcription factor, plays an important role in positive selection by activating immediate-early genes such as the Egr transcription factor family. The role of ELK4–SRF signaling in development of other T cell types dependent on ERK signaling has been unclear. In this article, we show that ELK4, and its close relative ELK1, act cell autonomously in the thymus to control the generation of innate-like αβ CD8+ T cells with memory-like characteristics. Mice lacking ELK4 and ELK1 develop increased numbers of innate-like αβ CD8+ T cells, which populate the periphery. These cells develop cell autonomously rather than through expansion of PLZF+ thymocytes and concomitantly increased IL-4 signaling. Their development is associated with reduced TCR-mediated activation of ELK4–SRF target genes and can be partially suppressed by overexpression of the ELK4–SRF target gene EGR2. Consistent with this, partial inhibition of ERK signaling in peripheral CD8+T cells promotes the generation of cells with innate-like characteristics. These data establish that low-level ERK signaling through ELK4 (and ELK1) promotes innate-like αβ CD8+ T cell differentiation, tuning conventional versus innate-like development.

Excessive ultraviolet radiation (UVR) exposure of the skin is associated with adverse clinical outcomes. Although both exogenous sunscreens and endogenous tissue components (including melanins and tryptophan-derived compounds) reduce UVR penetration, the role of endogenous proteins in absorbing environmental UV wavelengths is poorly defined. Having previously demonstrated that proteins which are rich in UVR-absorbing amino acid residues are readily degraded by broadband UVB-radiation (containing UVA, UVB and UVC wavelengths) here we hypothesised that UV chromophore (Cys, Trp and Tyr) content can predict the susceptibility of structural proteins in skin and the eye to damage by physiologically relevant doses (up to 15.4 J/cm2) of solar UVR (95% UVA, 5% UVB). We show that: i) purified suspensions of UV-chromophore-rich fibronectin dimers, fibrillin microfibrils and β- and γ-lens crystallins undergo solar simulated radiation (SSR)-induced aggregation and/or decomposition and ii) exposure to identical doses of SSR has minimal effect on the size or ultrastructure of UV chromophore-poor tropoelastin, collagen I, collagen VI microfibrils and α-crystallin. If UV chromophore content is a factor in determining protein stability in vivo, we would expect that the tissue distribution of Cys, Trp and Tyr-rich proteins would correlate with regional UVR exposure. From bioinformatic analysis of 244 key structural proteins we identified several biochemically distinct, yet UV chromophore-rich, protein families. The majority of these putative UV-absorbing proteins (including the late cornified envelope proteins, keratin associated proteins, elastic fibre-associated components and β- and γ-crystallins) are localised and/or particularly abundant in tissues that are exposed to the highest doses of environmental UVR, specifically the stratum corneum, hair, papillary dermis and lens. We therefore propose that UV chromophore-rich proteins are localised in regions of high UVR exposure as a consequence of an evolutionary pressure to express sacrificial protein sunscreens which reduce UVR penetration and hence mitigate tissue damage., Graphical abstract, Highlights Major structural proteins such as collagen I and tropoelastin are UVA-resistant. In contrast, proteins which are rich in Cys, Trp and Tyr residues are UV-susceptible. These proteins are concentrated in UV exposed tissues. UV-chromophore (Cys, Trp, Tyr)-rich proteins may act as endogenous sunscreens.

Serum response factor (SRF) recruits members of two families of signal-regulated coactivators, the extracellular signal-regulated kinase (ERK)-regulated ternary complex factors (TCFs) and the actin-regulated myocardin-related transcription factors (MRTFs), to its target genes through its DNA-binding domain. Whether coactivator association is required for SRF function in vivo and whether particular SRF functions reflect specific coupling to one or the other signal pathway have remained largely unexplored. We show that SRF is essential for thymocyte positive selection and thymic T(reg) and NK T-cell development but dispensable for early thymocyte development and negative selection. Expression of wild-type SRF, or mutants lacking the N-terminal phosphorylation sites or C-terminal transcriptional activation domain, restores positive selection in SRF null thymocytes. In contrast, SRF.V194E, which cannot recruit TCF or MRTF family members, is inactive, although it is recruited to target genes. Fusion of a TCF C-terminal activation domain to SRF.V194E effectively restores ERK-dependent single-positive (SP) thymocyte development. The resulting SP thymocytes exhibit normal surface marker expression and proliferation following T-cell receptor cross-linking. Thus, ERK signaling through the TCF pathway to SRF is necessary and sufficient for SRF function in thymocyte positive selection.

Regulatory T cells (Treg) play an important role in immune regulation. Their development in the thymus requires TCR activation and recognition of peptide-MHC, although the downstream signals controlling commitment to the lineage are unclear. To compare the requirements for positive selection and Treg development, we studied knockout and transgenic mice defective in Raf signaling and the ERK effector SRF accessory protein 1 (SAP-1), a member of the ternary complex factor family of Ets domain transcription factors. Although SAP-1 deficient mice display a severe defect in thymocyte positive selection, Treg development was unimpaired as assessed by expression of Foxp3 and the activation markers CD25, GITR, CTLA4, and CD103 in the CD4+ cell population. In contrast, inhibition of Raf signaling by the interfering dominant negative Raf derivative reduced both Foxp3+ and Foxp3− CD4+ populations. In SAP-1-deficient CD4+CD25+ Treg cells, TCR crosslinking efficiently induced ERK activation, but transcriptional induction of the immediate early gene Egr-1 was impaired. Nevertheless, neither deletion of SAP-1 nor expression of a dominant negative Raf derivative affected the ability of CD4+CD25+ Treg cells to suppress CD4+CD25− cell proliferation in vitro. Finally the suppressive activity of CD4+CD25+ Treg cells lacking SAP-1 in an in vivo colitis model was not significantly impaired. The signaling requirements for development of Treg cells in the thymus are thus distinct from those required for “conventional” T cell positive selection, and ERK signaling to SAP-1 is not required for the suppressive activity of Treg cells.

We find three new ways to construct Smith numbers from primes that contain small digits and a known digit sum. The resulting Smith numbers may have a fairly large number of digits.

International audience; Chemokine signaling is important for the seeding of different sites by hematopoietic stem cells (HSCs) during development. Serum response factor (SRF) controls multiple genes governing adhesion and migration, mainly by recruiting members of the myocardin-related transcription factor (MRTF) family of G-actin-regulated cofactors. We used vav-iCre to inactivate MRTF-SRF signaling early during hematopoietic development. In both Srf- and Mrtf-deleted animals, hematopoiesis in fetal liver and spleen is intact but does not become established in fetal bone marrow. Srf-null HSC progenitor cells (HSC/Ps) fail to effectively engraft in transplantation experiments, exhibiting normal proximal signaling responses to SDF-1, but reduced adhesiveness, F-actin assembly, and reduced motility. Srf-null HSC/Ps fail to polarize in response to SDF-1 and cannot migrate through restrictive membrane pores to SDF-1 or Scf in vitro. Mrtf-null HSC/Ps were also defective in chemotactic responses to SDF-1. Srf-null HSC/Ps exhibit substantial deficits in cytoskeletal gene expression. MRTF-SRF signaling is thus critical for expression of genes required for the response to chemokine signaling during hematopoietic development.

Adenovirus sensitivity, TCD50 value and mean time to cytopathic effect (CPE) were compared in Madin-Darby canine kidney (MDCK), rhesus monkey kidney (RhMK), human lung carcinoma (A549) and in newly identified continuous human lung (CHL) cell cultures. High-titer stock and positive original specimens were inoculated in culture. Patients specimens were also placed in shell-vial cultures. A549 and CHL cells demonstrated comparable sensitivity, however the former generally produced CPE earlier. Sensitivity was respectively reduced and poor in RhMK and MDCK cultures, as expected in cells of nonhuman origin. The performance of CHL for adenoviruses and other pathogens makes them a useful addition in diagnostic virology laboratories.

An outbreak of echovirus type 30, primarily affecting infant under 1 year old, was documented in Nassau County, N.Y., USA. Twenty-four of the 40 infected patients were definitively diagnosed with aseptic meningitis. A positive correlation was found between the proportion of polymorphonuclear leukocytes and the overall cerebrospinal fluid white cell count.

The ternary complex factors (TCFs; SAP-1, Elk-1, and Net) are serum response factor cofactors that share many functional properties and are coexpressed in many tissues. SAP-1, the predominant thymus TCF, is required for thymocyte positive selection. In this study, we assessed whether the different TCFs are functionally equivalent. Elk-1 deletion, but not the hypomorphic Netδ mutation, exacerbated the SAP-1 positive selection phenotype, but triply deficient thymocytes were no more defective than SAP-1−/− Elk-1−/− cells. Inactivation of the other TCFs did not affect SAP-1–independent processes, including β-selection, regulatory T cell selection, and negative selection, although reduced marginal zone B cells were observed in SAP-1−/− Elk-1−/− animals. Ectopic expression of Elk-1, but not Net, rescued positive selection of SAP-1−/− thymocytes; thus, SAP-1 and Elk-1 are functionally equivalent in this system, and the SAP-1 null selection phenotype reflects only its high expression in the thymus. Array analysis of TCR-stimulated double-positive cells identified SAP-1–dependent inducible genes whose transcription was further impaired in SAP-1−/− Elk-1−/− cells; thus, these genes, which include Egr-1 and Egr-2, represent candidate mediators of positive selection. Chromatin immunoprecipitation revealed subtly different promoter targeting between the different TCFs. Ectopic expression of Egr-1 restored positive selection in SAP-1 null thymocytes, establishing it (and possibly other Egr family members) as the major effector for ERK–SAP-1 signaling in thymocyte positive selection.

The aim of this study was to compare the effects of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta) on protease and catabolic cytokine and receptor gene expression in normal and degenerate human nucleus pulposus cells in alginate culture.Cells isolated from normal and degenerate nucleus pulposus regions of human intervertebral discs were cultured in alginate pellets and stimulated by the addition of 10 ng/mL TNF-alpha or IL-1beta for 48 hours prior to RNA extraction. Quantitative real-time polymerase chain reaction was used to assess the effect of TNF-alpha or IL-beta stimulation on the expression of matrix metalloproteinase (MMP)-3, -9 and -13, TNF-alpha, TNF receptor 1 (TNF-R1), TNF receptor 2 (TNF-R2), IL-1alpha, IL-1beta, IL-1 receptor 1 (IL-1R1) and IL-1 receptor antagonist (IL-1Ra).MMP-3 and MMP-9 gene expressions were upregulated to a greater level by IL-1beta than TNF-alpha. MMP-13 was upregulated by each cytokine to a similar extent. TNF-alpha and TNF-R2 expressions were upregulated by both TNF-alpha and IL-beta, whereas TNF-R1 expression was not significantly affected by either cytokine. IL-1beta and IL-1Ra expressions were significantly upregulated by TNF-alpha, whereas IL-1alpha and IL-1R1 were unchanged.TNF-alpha does not induce MMP expression to the same degree as stimulation by IL-1beta, but it does act to upregulate IL-1beta expression as well as TNF-alpha and TNF-R2. The net result of this would be an increased inflammatory environment and accelerated degradation of the matrix. These results support the hypothesis that, while TNF-alpha may be an important initiating factor in matrix degeneration, IL-1beta plays a greater role in established pathological degradation.