Graft versus host disease-related eosinophilic fasciitis: cohort description and literature review.

BACKGROUND: Chronic graft versus host disease (cGVHD) simulating eosinophilic fasciitis (EF) is an underdiagnosed and challenging complication due to the lack of knowledge about its pathogenesis, refractoriness to traditional immunosuppressive agents and their negative impact on the physical function and quality of life. The aim of this study is to describe the clinical-biological characteristics and response to treatment of a case series and to provide a comprehensive literature review on cGVHD related EF involvement. METHODS: Prospective observational study to describe the clinical and diagnostic evaluation characteristics of patients with EF-like follow-up as part of our multidisciplinary cGVHD consultations. In addition, the literature on joint and/or fascial musculoskeletal manifestations due to cGVHD was comprehensively reviewed. RESULTS: 118 patients were evaluated in multidisciplinary cGVHD consultations, 39 of whom (33%) developed fasciitis. Notably, 11 patients had isolated joint contractures without sclerotic skin. After a median of three lines of treatment, the vast majority of patients achieved some degree of response. 94 potentially eligible articles were identified by the search strategy, with 17 of them, the majority isolated case reports, making the final selection. The validated staging scales used for the assessment were the Joint and Fascial Score and the Photographic Range of Motion. CONCLUSION: Fascial/articular involvement needs to be recognized and evaluated early. To our knowledge, our cohort is the second largest series to have been reported. Literature addressing fascial/joints complications related to cGVHD is scarce. The search for new biomarkers, the use of advanced imaging techniques and multidisciplinary approach may help improve the prognosis of patients with cGVHD.

COVID-19 infection characteristics and outcomes in a predominantly Latino community hospital.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has rapidly spread worldwide and claimed millions of lives. Several studies have attempted to understand the relationship between COVID-19 infection and health disparities. The aim of the current work was to evaluate the pre-admission health characteristics, symptomatology, diagnostic abnormalities, treatment measures and clinical outcomes of the community served by our institution, with a sub-analysis of our Hispanic community. Methods: This is a single-center, cross-sectional cohort study of patients with COVID-19 admitted from 15 March 2020 to 30 April 2020 to MacNeal Hospital. A retrospective chart review was performed including patients >18 years and a positive nasopharyngeal SARS-CoV-2 PCR. Demographical data, comorbidities, clinical data, treatment regimen, and patient outcomes were collected. Results: A total of 257 patients were included in the study of which 60.4% were identified as Hispanic. The median age at admission of Hispanic patients was significantly lower compared to non-Hispanic patients (56.6 vs. 65.7 years, p<0.01). Non-Hispanic patients had lower prevalence of hypertension, coronary artery disease, and chronic lung disease. Most common at presentation were shortness of breath (69.6%), cough (69.2%), and fever (64%). Hypertension was the most common comorbidity (53.6%). Approximately 89% of the patients received antibiotics, 40.4% hydroxy-chloroquine, 13.2% steroids, and 6% tocilizumab. Twenty six percent required mechanical ventilation (MV), and over half of them (56.7%) were Hispanic. The strongest factors associated with MV were smoking (OR 2.97, 95%CI 1.01-8.69), CRP >10 mg/dL (OR 4.53, 95%CI 1.49-13.38) and D-dimer >1.5 mcg/mL (OR 3.63, 95%CI 1.31-10.05). An oxygen saturation of >90% on room air on presentation was a protective factor when predicting intubation (OR 0.11, 95%CI 0.03-0.33). The overall 30-day mortality rate was 17.1% (n=44); 11.9% in the Hispanic group vs 26.3% in the non-Hispanic group (p<0.003). Conclusions: Our review of consecutive patients admitted with COVID-19 demonstrated that over half of patients were of Hispanic descent. Interestingly enough, despite being significantly younger and healthier, the need for mechanical ventilation in the Hispanic group was not significantly different compared to the non-Hispanic group. However, the Hispanic group had a lower mortality rate.

Graft versus host disease-related eosinophilic fasciitis: cohort description and literature review

Abstract Background: Chronic graft versus host disease (cGVHD) simulating eosinophilic fasciitis (EF) is an underdiagnosed and challenging complication due to the lack of knowledge about its pathogenesis, refractoriness to traditional immunosuppressive agents and their negative impact on the physical function and quality of life. The aim of this study is to describe the clinical-biological characteristics and response to treatment of a case series and to provide a comprehensive literature review on cGVHD related EF involvement. Methods: Prospective observational study to describe the clinical and diagnostic evaluation characteristics of patients with EF-like follow-up as part of our multidisciplinary cGVHD consultations. In addition, the literature on joint and/or fascial musculoskeletal manifestations due to cGVHD was comprehensively reviewed. Results: 118 patients were evaluated in multidisciplinary cGVHD consultations, 39 of whom (33%) developed fasciitis. Notably, 11 patients had isolated joint contractures without sclerotic skin. After a median of three lines of treatment, the vast majority of patients achieved some degree of response. 94 potentially eligible articles were identified by the search strategy, with 17 of them, the majority isolated case reports, making the final selection. The validated staging scales used for the assessment were the Joint and Fascial Score and the Photographic Range of Motion. Conclusion: Fascial/articular involvement needs to be recognized and evaluated early. To our knowledge, our cohort is the second largest series to have been reported. Literature addressing fascial/joints complications related to cGVHD is scarce. The search for new biomarkers, the use of advanced imaging techniques and multidisciplinary approach may help improve the prognosis of patients with cGVHD.

Pegasus, a small extracellular peptide enhancing short-range diffusion of Wingless.

Small Open Reading Frames (smORFs) coding for peptides of less than 100 amino-acids are an enigmatic and pervasive gene class, found in the tens of thousands in metazoan genomes. Here we reveal a short 80 amino-acid peptide (Pegasus) which enhances Wingless/Wnt1 protein short-range diffusion and signalling. During Drosophila wing development, Wingless has sequential functions, including late induction of proneural gene expression and wing margin development. Pegasus mutants produce wing margin defects and proneural expression loss similar to those of Wingless. Pegasus is secreted, and co-localizes and co-immunoprecipitates with Wingless, suggesting their physical interaction. Finally, measurements of fixed and in-vivo Wingless gradients support that Pegasus increases Wingless diffusion in order to enhance its signalling. Our results unveil a new element in Wingless signalling and clarify the patterning role of Wingless diffusion, while corroborating the link between small open reading frame peptides, and regulation of known proteins with membrane-related functions.

Gastroenteritis and Miliary Lung Opacities: An Interesting Combination of Findings.

A 19-year-old man with a one-year history of vaping with multiple emergency room visits for acute gastroenteritis like symptoms was noted to have asymptomatic hypoxia with a PaO2 of 65 mmHg. Computed tomography revealed bilateral nodular lung infiltrates. History was negative for travel, allergies, or animal exposure. An infectious work-up was negative for bacterial, viral, or fungal infections, including bronchoalveolar lavage sample cultures. He did not show improvement upon initial empiric antibacterial and antifungal treatment. His hypoxia improved with systemic steroids. E-cigarette-associated lung injury (EVALI) is a diagnosis of exclusion, and unfortunately, may produce prolonged gastrointestinal symptoms with clinically silent but severe lung injury.

Dynamics of the 4D genome during in vivo lineage specification and differentiation.

Mammalian gene expression patterns are controlled by regulatory elements, which interact within topologically associating domains (TADs). The relationship between activation of regulatory elements, formation of structural chromatin interactions and gene expression during development is unclear. Here, we present Tiled-C, a low-input chromosome conformation capture (3C) technique. We use this approach to study chromatin architecture at high spatial and temporal resolution through in vivo mouse erythroid differentiation. Integrated analysis of chromatin accessibility and single-cell expression data shows that regulatory elements gradually become accessible within pre-existing TADs during early differentiation. This is followed by structural re-organization within the TAD and formation of specific contacts between enhancers and promoters. Our high-resolution data show that these enhancer-promoter interactions are not established prior to gene expression, but formed gradually during differentiation, concomitant with progressive upregulation of gene activity. Together, these results provide new insight into the close, interdependent relationship between chromatin architecture and gene regulation during development.

Valor diagnóstico de la razón neutrófilos-linfocitos identificar apendicitis aguda complicada / Diagnostic value of the reason neutrofilos-lymphocytes identify complicated acute appendicitis

Objetivo: Determinar el valor diagnóstico de la Razón Neutrófilos Linfocitos (RNL) para apendicitis complicada en pacientes del Hospital Nacional Almanzor Aguinaga Asenjo. Material y método: Estudio cuantitativo, no experimental, descriptivo en 220 historias clínicas de pacientes con diagnóstico de Apendicitis Aguda que cumplieron con los criterios de selección para el estudio. Resultados: Se encontró 121 varones (55%). La media para edad fue 25,4 años, para tiempo de enfermedad de 36,96 horas, para tiempo hasta la cirugía de 15,84 horas, para tiempo de hospitalización de 5,44 días y para RNL de 8,84. Se encontró 105 apendicitis complicadas (47,7%), 4 apéndices normales (1,8%). La curva ROC para RNL dio un AUC=0,84 (p<0,05, IC al 95% = 0,786 a 0,894). Se observó una sensibilidad de 78,1% (IC al 95% = 69,3% - 84,9%), una especificidad de 84,3% (IC al 95% = 76,6% - 89,9%), VPP de 82,0% (IC al 95% = 73,3% - 88,3%), VPN 80,8% (IC al 95% = 72,9% - 86,9%), exactitud de 81,4% (IC al 95% = 75,7% - 86,0%), Odd Radio Diagnóstica de 19,21 (IC al 95% = 9,70 - 38,05), CPP de 4,99 (IC al 95% = 3,23 - 7,72), CPN de 0,26 (CI al 95% = 0,18 - 0,38) y un Índice J de Youden de 0,6244; para un valor RNL ≥ 6,0. Conclusiones: El RNL ≥ 6,0 se asocia con apendicitis complicada y parece ser una buena herramienta diagnostica subordinada al examen clínico.

Objetive: Determine the diagnostic value of the Ratio Neutrophils Lymphocytes ( RNL) incomplicated appendicitis for patients Almanzor Aguinaga Asenjo National Hospital . Material and Methods: Quantitative, non-experimental, descriptive study of 220 medical records of patients diagnosed with acute appendicitis coincided with the study inclusion criteria. Results: 121 men (55%) was found. The median for age was 25.4 years, 36.96 hour to time disease, 15.84 hours to time to surgery, 5.44 days to time of stay in hospital and 8.84 to RNL. 105 complicated appendicitis (47.7%), 4 normal appendices (1.8%) was found. The ROC curve for RNL gave an AUC = 0.84 (p <0.05, 95% CI = 0.786 to 0.894). A specificity of 84.3% (95% CI = 76.6% - 89.9%) - a sensitivity of 78.1% (84.9% CI 95% = 69.3%) was observed, PPV of 82.0% (95% CI = 73.3% - 88.3%), VPN 80.8% (95% CI = 72.9% - 86.9%), accuracy of 81.4% (95% CI = 75.7% - 86.0%), Odd Radio Diagnostic 19.21 (95% CI = 9.70 to 38.05), CPP 4.99 (95% CI = 3.23 to 7.72), CPN 0.26 (95% CI = 0.18 to 0.38) and J Youden index of 0.6244; for RNL ≥ 6.0 value. Conclusions: The RNL ≥ 6.0 is associated with complicated appendicitis and seems to be a good diagnostic tool subordinated to the clinical examination.

Population snapshots predict early haematopoietic and erythroid hierarchies.

The formation of red blood cells begins with the differentiation of multipotent haematopoietic progenitors. Reconstructing the steps of this differentiation represents a general challenge in stem-cell biology. Here we used single-cell transcriptomics, fate assays and a theory that allows the prediction of cell fates from population snapshots to demonstrate that mouse haematopoietic progenitors differentiate through a continuous, hierarchical structure into seven blood lineages. We uncovered coupling between the erythroid and the basophil or mast cell fates, a global haematopoietic response to erythroid stress and novel growth factor receptors that regulate erythropoiesis. We defined a flow cytometry sorting strategy to purify early stages of erythroid differentiation, completely isolating classically defined burst-forming and colony-forming progenitors. We also found that the cell cycle is progressively remodelled during erythroid development and during a sharp transcriptional switch that ends the colony-forming progenitor stage and activates terminal differentiation. Our work showcases the utility of linking transcriptomic data to predictive fate models, and provides insights into lineage development in vivo.

Stat5 signaling specifies basal versus stress erythropoietic responses through distinct binary and graded dynamic modalities.

Erythropoietin (Epo)-induced Stat5 phosphorylation (p-Stat5) is essential for both basal erythropoiesis and for its acceleration during hypoxic stress. A key challenge lies in understanding how Stat5 signaling elicits distinct functions during basal and stress erythropoiesis. Here we asked whether these distinct functions might be specified by the dynamic behavior of the Stat5 signal. We used flow cytometry to analyze Stat5 phosphorylation dynamics in primary erythropoietic tissue in vivo and in vitro, identifying two signaling modalities. In later (basophilic) erythroblasts, Epo stimulation triggers a low intensity but decisive, binary (digital) p-Stat5 signal. In early erythroblasts the binary signal is superseded by a high-intensity graded (analog) p-Stat5 response. We elucidated the biological functions of binary and graded Stat5 signaling using the EpoR-HM mice, which express a "knocked-in" EpoR mutant lacking cytoplasmic phosphotyrosines. Strikingly, EpoR-HM mice are restricted to the binary signaling mode, which rescues these mice from fatal perinatal anemia by promoting binary survival decisions in erythroblasts. However, the absence of the graded p-Stat5 response in the EpoR-HM mice prevents them from accelerating red cell production in response to stress, including a failure to upregulate the transferrin receptor, which we show is a novel stress target. We found that Stat5 protein levels decline with erythroblast differentiation, governing the transition from high-intensity graded signaling in early erythroblasts to low-intensity binary signaling in later erythroblasts. Thus, using exogenous Stat5, we converted later erythroblasts into high-intensity graded signal transducers capable of eliciting a downstream stress response. Unlike the Stat5 protein, EpoR expression in erythroblasts does not limit the Stat5 signaling response, a non-Michaelian paradigm with therapeutic implications in myeloproliferative disease. Our findings show how the binary and graded modalities combine to generate high-fidelity Stat5 signaling over the entire basal and stress Epo range. They suggest that dynamic behavior may encode information during STAT signal transduction.

Contrasting dynamic responses in vivo of the Bcl-xL and Bim erythropoietic survival pathways.

Survival signaling by the erythropoietin (Epo) receptor (EpoR) is essential for erythropoiesis and for its acceleration in hypoxic stress. Several apparently redundant EpoR survival pathways were identified in vitro, raising the possibility of their functional specialization in vivo. Here we used mouse models of acute and chronic stress, including a hypoxic environment and ß-thalassemia, to identify two markedly different response dynamics for two erythroblast survival pathways in vivo. Induction of the antiapoptotic protein Bcl-x(L) is rapid but transient, while suppression of the proapoptotic protein Bim is slower but persistent. Similar to sensory adaptation, however, the Bcl-x(L) pathway "resets," allowing it to respond afresh to acute stress superimposed on a chronic stress stimulus. Using "knock-in" mouse models expressing mutant EpoRs, we found that adaptation in the Bcl-x(L) response occurs because of adaptation of its upstream regulator Stat5, both requiring the EpoR distal cytoplasmic domain. We conclude that survival pathways show previously unsuspected functional specialization for the acute and chronic phases of the stress response. Bcl-x(L) induction provides a "stop-gap" in acute stress, until slower but permanent pathways are activated. Furthermore, pathologic elevation of Bcl-x(L) may be the result of impaired adaptation, with implications for myeloproliferative disease mechanisms.

Identification and analysis of mouse erythroid progenitors using the CD71/TER119 flow-cytometric assay.

The study of erythropoiesis aims to understand how red cells are formed from earlier hematopoietic and erythroid progenitors. Specifically, the rate of red cell formation is regulated by the hormone erythropoietin (Epo), whose synthesis is triggered by tissue hypoxia. A threat to adequate tissue oxygenation results in a rapid increase in Epo, driving an increase in erythropoietic rate, a process known as the erythropoietic stress response. The resulting increase in the number of circulating red cells improves tissue oxygen delivery. An efficient erythropoietic stress response is therefore critical to the survival and recovery from physiological and pathological conditions such as high altitude, anemia, hemorrhage, chemotherapy or stem cell transplantation. The mouse is a key model for the study of erythropoiesis and its stress response. Mouse definitive (adult-type) erythropoiesis takes place in the fetal liver between embryonic days 12.5 and 15.5, in the neonatal spleen, and in adult spleen and bone marrow. Classical methods of identifying erythroid progenitors in tissue rely on the ability of these cells to give rise to red cell colonies when plated in Epo-containing semi-solid media. Their erythroid precursor progeny are identified based on morphological criteria. Neither of these classical methods allow access to large numbers of differentiation-stage-specific erythroid cells for molecular study. Here we present a flow-cytometric method of identifying and studying differentiation-stage-specific erythroid progenitors and precursors, directly in the context of freshly isolated mouse tissue. The assay relies on the cell-surface markers CD71, Ter119, and on the flow-cytometric 'forward-scatter' parameter, which is a function of cell size. The CD71/Ter119 assay can be used to study erythroid progenitors during their response to erythropoietic stress in vivo, for example, in anemic mice or mice housed in low oxygen conditions. It may also be used to study erythroid progenitors directly in the tissues of genetically modified adult mice or embryos, in order to assess the specific role of the modified molecular pathway in erythropoiesis.