Ikaros represses and activates PU.1 cell-type-specifically through the multifunctional Sfpi1 URE and a myeloid specific enhancer

Generation of myeloid and lymphoid cells from progenitors involves dynamic changes in transcription factor expression and use, and disruption of hematopoietic transcription factor function and expression can contribute to leukemic transformation. PU.1 and Ikaros are pivotal factors whose expression and utilization are dynamically altered during hematopoietic development. Here, we demonstrate that expression of PU.1, encoded by the Sfpi1 gene, is divergently regulated by Ikaros in distinct cell type-specific contexts. Chromatin immune precipitation analysis and functional perturbations revealed that Ikaros can directly repress or activate Sfpi1 transcription via different PU.1 cis-elements, with PU.1 and Ikaros collaborating at myeloid-specific elements but not at other elements. Our results thus shed light on how PU.1 and Ikaros can act as lineage competency factors to facilitate both myeloid and lymphoid developmental programs

Cell-Type-Specific Activation and Repression of PU.1 by a Complex of Discrete, Functionally Specialized cis-Regulatory Elements

The transcription factor PU.1 is critical for multiple hematopoietic lineages, but different leukocyte types require strictly distinct patterns of PU.1 regulation. PU.1 is required early for T-cell lineage development but then must be repressed by a stage-specific mechanism correlated with commitment. Other lineages require steady, low expression or upregulation. Until now, only the promoter plus a distal upstream regulatory element (URE) could be invoked to explain nearly all Sfpi1 (PU.1) activation and repression, including bifunctional effects of Runx1. However, the URE is dispensable for most Sfpi1 downregulation in early T cells, and we show that it retains enhancer activity in immature T-lineage cells even where endogenous Sfpi1 is repressed. We now present evidence for another complex of conserved noncoding elements that mediate discrete, cell-type-specific regulatory features of Sfpi1, including a myeloid cell-specific activating element and a separate, pro-T-cell-specific silencer element. These elements yield opposite, cell-type-specific responses to Runx1. T-cell-specific repression requires Runx1 acting through multiple nonconsensus sites in the silencer core. These newly characterized sites recruit Runx1 binding in early T cells in vivo and define a functionally specific scaffold for dose-dependent, Runx-mediated repression

A gene regulatory network armature for T lymphocyte specification

Choice of a T lymphoid fate by hematopoietic progenitor cells depends on sustained Notch–Delta signaling combined with tightly regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification, tests of the short-term Notch dependence of these gene expression changes, and analyses of the effects of overexpression of two essential transcription factors, namely PU.1 and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T cell precursors progress from primitive multipotency to T lineage commitment. Our analyses reveal separate contributions of Notch signaling, GATA-3 activity, and down-regulation of PU.1. Using BioTapestry (www.BioTapestry.org), the results have been assembled into a draft gene regulatory network for the specification of T cell precursors and the choice of T as opposed to myeloid/dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfi1 against Egr-2 and of TCF-1 against PU.1 as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose dependence of GATA-3 effects, the gene-specific modulation of PU.1 activity based on Notch activity, the lack of direct opposition between PU.1 and GATA-3, and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression

The effects of booster sessions on self-management interventions for chronic musculoskeletal pain: a systematic review and meta-analysis of randomised controlled trials

Our objective was to investigate the effectiveness of booster sessions after self-management interventions as a means of maintaining self-management behaviours in the treatment of chronic musculoskeletal pain. We searched MEDLINE, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials and PsycINFO. Two authors independently identified eligible trials and collected data. We calculated the odds ratio (OR) for the analyses of dichotomous data, and standardised mean differences (SMD) with 95% confidence interval (CI) for continuous variables. Our search identified 14 studies with a total of 1695 patients. All studies were at high risk of bias and provided very low quality evidence. For the primary outcomes, booster sessions had no evidence of an effect on improving patient-reported outcomes on physical function (SMD-0.13, 95%CI -0.32 to -0.06; P=0.18), pain-related disability (SMD-0.16, 95%CI -0.36 to 0.03; P=0.11) and pain self-efficacy (SMD 0.15, 95%CI -0.07 to 0.36; P=0.18). For the secondary outcomes, booster sessions caused a significant reduction in patient-reported pain catastrophising (SMD-0.42, 95%CI -0.64 to -0.19; P=0.0004), and no evidence of an effect on patient-reported pain intensity, depression, coping or treatment adherence. There is currently little evidence that booster sessions are an effective way to prolong positive treatment effects or improve symptoms of long-term musculoskeletal conditions following self-management interventions. However, the studies were few with high heterogeneity, high risk of bias and overall low quality of evidence. Our review argues against including booster sessions routinely to self-management interventions for the purpose of behaviour maintenance

Patient perspectives on the unwanted effects of multidisciplinary pain management programmes: A qualitative study.

OBJECTIVE: This study aimed to understand the impact of pain management programmes, focusing on the unwanted effects and their influence on patients' long-term use of self-management strategies. DESIGN: Qualitative study. SETTING: Specialist musculoskeletal hospital in North London, England. PARTICIPANTS: Patients with chronic musculoskeletal pain that have completed a pain management programme. INTERVENTION: Multidisciplinary pain management programmes. MAIN MEASURES: Data were collected regarding patients' experiences and unwanted effects from the pain management programme using semi-structured interviews. Data were analysed using thematic analysis. RESULTS: Fourteen participant interviews were included in the analysis (median age 54 years, 12 females). Four themes were generated from the data: Benefits and burdens, Pain management programme and real life, Social support and Healthcare interventions. Unwanted effects included heightened anxiety related to negative interactions with peers, being in a new environment, worries about ability to cope with the programme, social anxiety from being in a group, the strain on families due to participants being away from home and a sense of abandonment at end of the programme. Burdens associated with implementing pain management strategies were identified, including the emotional burden of imposing their self-management on close family and competing demands with time and energy spent on self-management at the expense of work or home commitments. CONCLUSIONS: Pain management programmes have an important role in helping patients to learn how to self-manage chronic pain. Their unwanted effects and the treatment burdens associated with long-term self-management may be an important consideration in improving the longevity of their beneficial effects

Patient perspectives on the unwanted effects of multidisciplinary pain management programmes: A qualitative study

Objective This study aimed to understand the impact of pain management programmes, focusing on the unwanted effects and their influence on patients’ long-term use of self-management strategies. Design Qualitative study. Setting Specialist musculoskeletal hospital in North London, England. Participants Patients with chronic musculoskeletal pain that have completed a pain management programme. Intervention Multidisciplinary pain management programmes. Main measures Data were collected regarding patients’ experiences and unwanted effects from the pain management programme using semi-structured interviews. Data were analysed using thematic analysis. Results Fourteen participant interviews were included in the analysis (median age 54 years, 12 females). Four themes were generated from the data: Benefits and burdens, Pain management programme and real life, Social support and Healthcare interventions. Unwanted effects included heightened anxiety related to negative interactions with peers, being in a new environment, worries about ability to cope with the programme, social anxiety from being in a group, the strain on families due to participants being away from home and a sense of abandonment at end of the programme. Burdens associated with implementing pain management strategies were identified, including the emotional burden of imposing their self-management on close family and competing demands with time and energy spent on self-management at the expense of work or home commitments. Conclusions Pain management programmes have an important role in helping patients to learn how to self-manage chronic pain. Their unwanted effects and the treatment burdens associated with long-term self-management may be an important consideration in improving the longevity of their beneficial effects

Comparison of partial least squares and artificial neural network chemometric techniques in determination of sulfamethoxazole and trimethoprim in pharmaceutical suspension by ATR-FTIR spectrometry

Abstract. Partial Least Square (PLS) and Artificial Neural Network (ANN) techniques were compared during development of an analytical method for quantitative determination of sulfamethoxazole (SMX) and trimethoprim (TMP) in Co-Trimoxazole ® suspension. The procedure was based on Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectrometry. The 800-2500 cm −1 spectral region was selected for quantitative analysis. R 2 and relative error of prediction (REP) in PLS technique were (0.989, 2.128) and (0.986, 1.381) for SMX and TMP, respectively. These statistical parameters were improved using the ANN models considering the complexity of the sample and the speediness and simplicity of the method. R 2 and RMSEC in modified method were (0.997, 1.064) and (0.997, 0.634) for SMX and TMP, respectively

Acute pulmonary edema secondary to upper airway obstruction by bilateral vocal cord paralysis after total thyroidectomy -A case report-

This paper reports the case of a 65-year-old woman with a history of mild arterial hypertension who presented with acute pulmonary edema immediately after a total thyroidectomy. The edema was found to have been caused by an acute upper airway obstruction secondary to bilateral vocal cord paralysis. Her pulmonary edema resolved with treatment including reintubation, mechanical ventilation with positive end-expiratory pressure, diuretics, morphine, and fluid restriction. This report discusses the possible pathogenesis of this rare clinical situation. This case highlights the possibility of an acute upper airway obstruction caused by bilateral vocal cord paralysis after a total thyroidectomy and the need for prompt treatment to prevent the development of pulmonary edema

The patient acceptability of a remotely delivered pain management programme for people with persistent musculoskeletal pain: A qualitative evaluation.

INTRODUCTION: Remotely delivered pain management programmes have been offered in place of in-person programmes by many chronic pain services since the onset of the COVID-19 pandemic. There is a lack of evidence regarding the acceptability of these programmes. In this evaluation, we have explored patients' acceptability of a remotely delivered pain management programme for patients with persistent musculoskeletal pain. METHODS: Qualitative data were collected using focus groups with participants who had previously attended the remote pain management programme. Data were analysed using abductive analysis. RESULTS: Three focus groups were conducted with a total of 13 participants. The programmme was either entirely acceptable, had some acceptable components or was not acceptable to patients. Factors leading to the programme being acceptable include learning to manage pain from home, receiving high quality care from home, enhancing the potential of rehabilitation using technology, enabling attendance on a pain management programme from home, overcoming social distancing requirements of COVID-19 using technology, and virtual peer support. Factors leading to the programme not being acceptable include having an inappropriate home environment for virtual therapy, communication challenges with virtual therapy, technological issues and concerns regarding the quality of care. CONCLUSIONS: There is a spectrum of acceptability with respect to the remote programme. The factors that influence this are dynamic, individual and situational. Hybrid programmes have the potential to enhance access to pain management programmes and improve patient experience and programme outcomes in the future