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BACKGROUND: It remains unknown whether the presence of coronary microcirculatory dysfunction (CMD) correlates with its equivalent condition in the brain, cerebral small vessel disease (CSVD). The cerebral-coronary connection (C3), a prospective blinded study, investigated the prevalence of CMD in patients with coronary artery disease (CAD) and its association with CSVD and cognitive function. METHODS AND RESULTS: Patients with documented CAD fulfilling inclusion criteria underwent physiological assessment of epicardial vessels and the microcirculation using intracoronary pressure and Doppler. Coronary microcirculation-related indices included coronary flow reserve (CFR) and hyperaemic microvascular resistance. Brain magnetic resonance imaging, transcranial Doppler (TCD), and neurocognitive examination were performed. Overall, 67 patients were included in the study (mean age 66 years, 73% female). Patients with abnormal CFR (<2.0) (55.2%) showed higher burden of white-matter hyperintensities: 43.2 vs. 20.0% (P = 0.044). After statistical adjustment, low CFR was associated with lower grey matter volume (P = 0.024) and with parameters of white-matter microstructural damage in diffusion-tensor imaging (lower fractional anisotropy and higher mean diffusivity, P = 0.029 and P = 0.032, respectively). Low CFR was associated with higher resistive (P = 0.027) and pulsatility (P = 0.043) values on TCD, and worse neurocognitive test scores (lower mini mental state examination, P = 0.025, and slower Trail Making Test A, P = 0.034). CONCLUSIONS: Coronary microcirculatory dysfunction is frequent in patients with CAD and correlates with CSVD, abnormal cerebral flow haemodynamics, and significant cognitive impairment. These findings support the hypothesis that microvascular dysfunction in the heart and the brain are part of a single pathological process affecting microcirculation in patients with CAD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04131075.
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Doença da Artéria Coronariana , Reserva Fracionada de Fluxo Miocárdico , Cardiopatias , Isquemia Miocárdica , Idoso , Feminino , Humanos , Masculino , Cognição , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários , Microcirculação/fisiologia , Estudos Prospectivos , Resistência VascularRESUMO
The expression of the human ß-like globin genes follows a well-orchestrated developmental pattern, undergoing two essential switches, the first one during the first weeks of gestation (ε to γ), and the second one during the perinatal period (γ to ß). The γ- to ß-globin gene switching mechanism includes suppression of fetal (γ-globin, HbF) and activation of adult (ß-globin, HbA) globin gene transcription. In hereditary persistence of fetal hemoglobin (HPFH), the γ-globin suppression mechanism is impaired leaving these individuals with unusual elevated levels of fetal hemoglobin (HbF) in adulthood. Recently, the transcription factors KLF1 and BCL11A have been established as master regulators of the γ- to ß-globin switch. Previously, a genomic variant in the KLF1 gene, identified by linkage analysis performed on twenty-seven members of a Maltese family, was found to be associated with HPFH. However, variation in the levels of HbF among family members, and those from other reported families carrying genetic variants in KLF1, suggests additional contributors to globin switching. ASF1B was downregulated in the family members with HPFH. Here, we investigate the role of ASF1B in γ- to ß-globin switching and erythropoiesis in vivo. Mouse-human interspecies ASF1B protein identity is 91.6%. By means of knockdown functional assays in human primary erythroid cultures and analysis of the erythroid lineage in Asf1b knockout mice, we provide evidence that ASF1B is a novel contributor to steady-state erythroid differentiation, and while its loss affects the balance of globin expression, it has no major role in hemoglobin switching.
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Proteínas de Ciclo Celular/genética , Eritropoese/genética , Chaperonas de Histonas/genética , Globinas beta/genética , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Células HEK293 , Chaperonas de Histonas/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Interferência de RNA , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , gama-Globinas/genéticaRESUMO
NEW FINDINGS: What is the central question of this study? What is the impact of obesity-independent hyperlipidaemia on skeletal muscle stem cell function of ApoE-deficient (ApoE-/- ) mice? What is the main finding and its importance? Compromised muscle stem cell function accounts for the impaired muscle regeneration in hyperlipidaemic ApoE-/- mice. Importantly, impaired muscle regeneration is normalised by administration of platelet releasate. ABSTRACT: Muscle satellite cells are important stem cells for skeletal muscle regeneration and repair after injury. ApoE-deficient mice, an established mouse model of hyperlipidaemia and atherosclerosis, show evidence of oxidative stress-induced lesions and fat infiltration in skeletal muscle followed by impaired repair after injury. However, the mechanisms underpinning attenuated muscle regeneration remain to be fully defined. Key to addressing the latter is to understand the properties of muscle stem cells from ApoE-deficient mice and their myogenic potential. Muscle stem cells from ApoE-deficient mice were cultured both ex vivo (on single fibres) and in vitro (primary myoblasts) and their myogenic capacity was determined. Skeletal muscle regeneration was studied on days 5 and 10 after cardiotoxin injury. ApoE-deficient muscle stem cells showed delayed activation and differentiation on single muscle fibres ex vivo. Impaired proliferation and differentiation profiles were also evident on isolated primary muscle stem cells in culture. ApoE-deficient mice displayed impaired skeletal muscle regeneration after acute injury in vivo. Administration of platelet releasate in ApoE-deficient mice reversed the deficits of muscle regeneration after acute injury to wild-type levels. These findings indicate that muscle stem cell myogenic potential is perturbed in skeletal muscle of a mouse model of hyperlipidaemia. We propose that platelet releasate could be a therapeutic intervention for conditions with associated myopathy such as peripheral arterial disease.
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Hiperlipidemias , Células Satélites de Músculo Esquelético , Animais , Diferenciação Celular , Proliferação de Células/fisiologia , Camundongos , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/fisiologia , Mioblastos , Regeneração/fisiologiaRESUMO
The initiation of gene transcription by RNA polymerase II is regulated by a plethora of proteins in human cells. The first general transcription factor to bind gene promoters is transcription factor IID (TFIID). TFIID triggers pre-initiation complex formation, functions as a coactivator by interacting with transcriptional activators and reads epigenetic marks. TFIID is a megadalton-sized multiprotein complex composed of TATA-box-binding protein (TBP) and 13 TBP-associated factors (TAFs). Despite its crucial role, the detailed architecture and assembly mechanism of TFIID remain elusive. Histone fold domains are prevalent in TAFs, and histone-like tetramer and octamer structures have been proposed in TFIID. A functional core-TFIID subcomplex was revealed in Drosophila nuclei, consisting of a subset of TAFs (TAF4, TAF5, TAF6, TAF9 and TAF12). These core subunits are thought to be present in two copies in holo-TFIID, in contrast to TBP and other TAFs that are present in a single copy, conveying a transition from symmetry to asymmetry in the TFIID assembly pathway. Here we present the structure of human core-TFIID determined by cryo-electron microscopy at 11.6 Å resolution. Our structure reveals a two-fold symmetric, interlaced architecture, with pronounced protrusions, that accommodates all conserved structural features of the TAFs including the histone folds. We further demonstrate that binding of one TAF8-TAF10 complex breaks the original symmetry of core-TFIID. We propose that the resulting asymmetric structure serves as a functional scaffold to nucleate holo-TFIID assembly, by accreting one copy each of the remaining TAFs and TBP.
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Modelos Moleculares , Fator de Transcrição TFIID/química , Células Cultivadas , Microscopia Crioeletrônica , Células HeLa , Humanos , Ligação Proteica , Estrutura Terciária de Proteína , Fator de Transcrição TFIID/genética , Fator de Transcrição TFIID/metabolismoRESUMO
Platelet concentrates (PCs) represent a blood transfusion product with a major concern for safety as their storage temperature (20-24°C) allows bacterial growth, and their maximum storage time period (less than a week) precludes complete microbiological testing. Pathogen inactivation technologies (PITs) provide an additional layer of safety to the blood transfusion products from known and unknown pathogens such as bacteria, viruses, and parasites. In this context, PITs, such as Mirasol Pathogen Reduction Technology (PRT), have been developed and are implemented in many countries. However, several studies have shown in vitro that Mirasol PRT induces a certain level of platelet shape change, hyperactivation, basal degranulation, and increased oxidative damage during storage. It has been suggested that Mirasol PRT might accelerate what has been described as the platelet storage lesion (PSL), but supportive molecular signatures have not been obtained. We aimed at dissecting the influence of both variables, that is, Mirasol PRT and storage time, at the proteome level. We present comprehensive proteomics data analysis of Control PCs and PCs treated with Mirasol PRT at storage days 1, 2, 6, and 8. Our workflow was set to perform proteomics analysis using a gel-free and label-free quantification (LFQ) approach. Semi-quantification was based on LFQ signal intensities of identified proteins using MaxQuant/Perseus software platform. Data are available via ProteomeXchange with identifier PXD008119. We identified marginal differences between Mirasol PRT and Control PCs during storage. However, those significant changes at the proteome level were specifically related to the functional aspects previously described to affect platelets upon Mirasol PRT. In addition, the effect of Mirasol PRT on the platelet proteome appeared not to be exclusively due to an accelerated or enhanced PSL. In summary, semi-quantitative proteomics allows to discern between proteome changes due to Mirasol PRT or PSL, and proves to be a methodology suitable to phenotype platelets in an unbiased manner, in various physiological contexts.
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Plaquetas/metabolismo , Testes de Função Plaquetária/métodos , Proteoma/metabolismo , Proteômica/métodos , HumanosRESUMO
Hemato-oncologic patients with chemotherapy-induced thrombocytopenia are one of the populations receiving platelet transfusions. The general practice with these patients is to give prophylactic platelet transfusions when platelet counts fall below 10×109PLT/L. However, in more than 40% of these patients, platelet transfusion does not prevent bleeding. The reason of the low efficacy of platelet transfusion in the context of chemotherapy patients is not entirely understood. We therefore aimed at immunophenotyping the expression of platelet surface and activation markers and thrombopoietin levels from hemato-oncologic patients before and after transfusion. A more detailed follow-up was performed in three patients that underwent autologous bone marrow transplantation. As previously reported, basal platelet activation was observed in hemato-oncologic patients. Based on flow cytometry parameters, i.e. the percentage of positivity and mean fluorescence intensity (MFI) distribution, our data provide an additional interpretation of platelet acquired qualitative changes in the hemato-oncologic patient. From our results we propose: first, the underlying activation of platelets in the hemato-oncologic patient is accompanied by loss of expression of the platelet receptors that are susceptible to protease-mediated shedding; second, soon after transfusion, the newly circulating donor platelets show additional activation, which may result in subsequent platelet receptor recycling and potential accelerated clearance of these activated platelets. In conclusion, the immunophenotype of circulating platelets changes after prophylactic platelet transfusion. Next to platelet count increment, exploration of this immunophenotype might help to explain transfusion refractory bleeding in hemato-oncologic patients. Eventually this may lead to personalization and improvement of the present platelet transfusion support regime.
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Transplante de Medula Óssea/métodos , Doenças Hematológicas/terapia , Transfusão de Plaquetas/métodos , Trombopoetina/sangue , Feminino , Citometria de Fluxo , HumanosRESUMO
FINDbase (http://www.findbase.org) aims to document frequencies of clinically relevant genomic variations, namely causative mutations and pharmacogenomic markers, worldwide. Each database record includes the population, ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related databases and the genetic variation together with its frequency in that population. Here, we report, in addition to the regular data content updates, significant developments in FINDbase, related to data visualization and querying, data submission, interrelation with other resources and a new module for genetic disease summaries. In particular, (i) we have developed new data visualization tools that facilitate data querying and comparison among different populations, (ii) we have generated a new FINDbase module, built around Microsoft's PivotViewer (http://www.getpivot.com) software, based on Microsoft Silverlight technology (http://www.silverlight.net), that includes 259 genetic disease summaries from five populations, systematically collected from the literature representing the documented genetic makeup of these populations and (iii) the implementation of a generic data submission tool for every module currently available in FINDbase.
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Bases de Dados de Ácidos Nucleicos , Frequência do Gene , Doenças Genéticas Inatas/genética , Mutação , Marcadores Genéticos , Genoma Humano , Humanos , Internet , FarmacogenéticaRESUMO
The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival.
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Calreticulina/genética , Janus Quinase 2/genética , Leucemia Mieloide Aguda/genética , Mutação , Mielofibrose Primária/genética , Trombocitemia Essencial/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Contagem de Plaquetas , Mielofibrose Primária/etiologia , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Receptores de Trombopoetina/genética , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Trombocitemia Essencial/complicações , Trombocitemia Essencial/mortalidade , Trombocitemia Essencial/patologiaRESUMO
BACKGROUND: Optimal rehabilitation programs for orthopedic joint replacement patients ensure faster return to function, earlier discharge from hospital, and improved patient satisfaction. Digital health interventions show promise as a supporting tool for re-enablement. OBJECTIVE: The main goal of this mixed methods study was to examine the usability of the AIMS platform from the perspectives of both patients and clinicians. The aim of this study was to evaluate a re-enablement platform that we have developed that uses a holistic systems approach to address the de-enablement that occurs in hospitalized inpatients, with the older adult population most at risk. The Active and Independent Management System (AIMS) platform is anticipated to deliver improved patient participation in recovery and self-management through education and the ability to track rehabilitation progression in hospital and after patient discharge. METHODS: Two well-known instruments were used to measure usability: the System Usability Scale (SUS) with 10 items and, for finer granularity, the User Experience Questionnaire (UEQ) with 26 items. In all, 26 physiotherapists and health care professionals evaluated the AIMS clinical portal; and 44 patients in hospital for total knee replacement, total hip replacement, or dynamic hip screw implant evaluated the AIMS app. RESULTS: For the AIMS clinical portal, the mean SUS score obtained was 82.88 (SD 13.07, median 86.25), which would be considered good/excellent according to a validated adjective rating scale. For the UEQ, the means of the normalized scores (range -3 to +3) were as follows: attractiveness=2.683 (SD 0.100), perspicuity=2.775 (SD 0.150), efficiency=2.775 (SD 0.130), dependability=2.300 (SD 0.080), stimulation=1.950 (SD 0.120), and novelty=1.625 (SD 0.090). All dimensions were thus classed as excellent against the benchmarks, confirming the results from the SUS questionnaire. For the AIMS app, the mean SUS score obtained was 74.41 (SD 10.26), with a median of 77.50, which would be considered good according to the aforementioned adjective rating scale. For the UEQ, the means of the normalized scores were as follows: attractiveness=2.733 (SD 0.070), perspicuity=2.900 (SD 0.060), efficiency=2.800 (SD 0.090), dependability=2.425 (SD 0.060), stimulation=2.200 (SD 0.010), and novelty=1.450 (0.260). All dimensions were thus classed as excellent against the benchmarks (with the exception of novelty, which was classed as good), providing slightly better results than the SUS questionnaire. CONCLUSIONS: The study has shown that both the AIMS clinical portal and the AIMS app have good to excellent usability scores, and the platform provides a solid foundation for the next phase of research, which will involve evaluating the effectiveness of the platform in improving patient outcomes after total knee replacement, total hip replacement, or dynamic hip screw.
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Satisfação do Paciente , Humanos , Masculino , Feminino , Inquéritos e Questionários , Idoso , Pessoa de Meia-Idade , Artroplastia de Substituição/reabilitação , Artroplastia do Joelho/reabilitação , Adulto , Aplicativos Móveis , Artroplastia de Quadril/reabilitação , Saúde DigitalRESUMO
BACKGROUND: Current studies on counterattacks are limited despite the fact that it is one of the most effective ways to score in soccer. The aim of the study was to investigate the characteristics of counterattacks in the Spanish league (La Liga) for the year 2021-2022. METHODS: The sample used in the study were 2631 counterattacks collected from a total of 380 games. The variables used were: 1) the space which the counterattack had started; 2) the number of players who participated; 3) the number of defending players; 4) the duration of the counterattack; 5) the touches to complete the counterattack; 6) the formation of both teams; 7) the way that counterattack was completed (final action); 8) the minute that the counterattack took place; and 9) which team had a home advantage. The results were analyzed using the Chi-square test. The level of significance was defined at P<0.05. RESULTS: Firstly, it appeared that most counterattacks began from the axis of the defensive zone lasting 6-15 seconds. There were 3-4 attackers participating against 4-6 defenders, using 5-9 touches. In addition, most of them took place in the 46-60 minute of the game and were completed in a shot. CONCLUSIONS: The study can help coaches and analysts to understand the characteristics of the counterattacks and adapt their training in a way to make their teams more effective, both in the attacking and defending phase.
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Desempenho Atlético , Futebol , Humanos , Distribuição de Qui-QuadradoRESUMO
Stevens-Johnson Syndrome (SJS) constitutes a rather uncommon, and rarely fatal hypersensitivity reaction that primarily impacts the skin and mucous membranes and in certain cases may be attributed to drug administration. The aim of this article is to present a case of etoricoxib-induced SJS in a 46-year-old, female patient. The patient presented herself, as a medical emergency, to the Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece, reporting pain, especially acute pain while eating certain foods, discomfort, dysphagia, and a wound in the left half of the hard palate. The clinical examination revealed a broad ulcer, in the left half of the hard palate as well as multiple ulcerations and erosions in the upper and lower lip. Her medical history was clear; however, the patient mentioned to have received etoricoxib, due to severe back pain, one day prior to our clinical examination. The patient received methylprednisolone 16 mg, twice per day, for two days, followed by methylprednisolone 8 mg, twice per day, for two more days. Her symptoms resigned and since the connection between etoricoxib and SJS was established, the patient was advised to avoid etoricoxib and be wary of adverse effects, when taking drugs especially non-steroidal anti-inflammatory medication. This is one of the first case reports in the literature, linking etoricoxib administration with the emergence of SJS, highlighting the importance of pharmacovigilance. The up-to-date registration of drug-induced adverse effects is of immense importance to protect future patients. SJS does not have a defined treatment strategy. Therefore, most patients are given supportive care and symptomatic treatment, which most commonly involves corticosteroids and antivirals such as acyclovir.
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Introduction Potentially malignant disorders, like oral lichen planus (OLP) and oral leukoplakia (OL) of several degrees of dysplasia, manifest a significant potential of malignant transformation being a precursor of oral squamous cell carcinoma (OSCC). The role of microvascularization in carcinogenesis is critical; therefore, microvascularization constitutes a major therapeutic target. DAPK-1 constitutes a possible cancer marker, with proven implications in other human cancers, and there isn't any study on its vascular endothelial expression in the oral cavity, particularly in oral cancer and oral potentially malignant diseases. The present study aims to investigate the vascular endothelial expression of the DAPK-1 in paraffin-embedded tissue samples of oral leukoplakia, oral squamous cell carcinoma, and oral lichen planus. Materials and methods The study focuses on the immunohistochemical, vascular-endothelial, expression pattern of biomarker DAPK-1 (NBP2-38468, Novus Biologicals, Centennial, CO, US). Tissue samples were obtained from six cases of oral lichen planus (OLP) (3 of reticular and 3 of erosive form), 30 cases of oral leukoplakia (OL) (10 with no dysplasia, 10 with mild dysplasia, and 10 with moderate/severe dysplasia), 22 cases of OSCC (2 well-differentiated, 17 moderately differentiated, and 3 poorly differentiated), as well as 5 cases of normal oral epithelium. The tissue samples were retrieved from the archives of the Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, as well as from St Lukas Hospital of Thessaloniki, Greece, from 2004-2019. In accordance with the Research and Ethics Committee guidelines of the Aristotle University, School of Dentistry, and the Helsinki II declaration, the study was conducted. The primary inclusion criteria for the study focused on the presence of sufficient precancerous or cancerous tissue. Conversely, inadequate tissue served as the exclusion criteria. The staining was evaluated exclusively in a quantitative manner. The vascular endothelial staining was evaluated as either positive or negative. If at least one endothelial cell exhibited positive staining, the section was classified as positive. Statistical analysis was carried out using SPSS Statistics v25.0 (IBM Corp., Armonk, NY, US) utilizing Pearson's chi-square or Fisher's exact test, depending on the sample size, to compare OLP to OL, OLP to OSCC, OLP to normal, OL to OSCC, OL to normal, and OSCC to normal. The significance level was established at 0.05 (p=0.05). Results A prevalence of positive OL cases may be noticed. The comparison between OLP and OL yielded Fisher's exact test of p>0.999, OLP and OSCC p=0.389, OLP and normal oral epithelium p>0.999, OL and OSCC p=0.226, OL and normal oral epithelium p>0.999, as well as OSCC and normal oral epithelium p=0.342. Conclusions The role of DAPK in tumorigenesis is already supported by limited literature. However, its implication in the development of OSCC and oral potentially malignant disorders (OPMDs) has yet to be elucidated. Its elevated expression in OL suggests a role in affecting the microenvironment, the vessels, in particular, surrounding oral potentially malignant lesions, possibly assisting their transition into cancer. The evaluation of the vascular-endothelial immunohistochemical profile of DAPK-1 in OL, OLP, and OSCC requires further studies in more tissue samples to illustrate its possible implications.
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Pigmented lesions in the oral cavity can arise from the accumulation of external substances or internal pigments, resulting in black or brown discoloration. The etiology can be categorized as physiologic, reactive, neoplastic, idiopathic, or indicative of systemic illness. Several systemic drugs have been linked to the development of oral and/or cutaneous pigmentation, either by stimulating the production of melanin or by the accumulation of the drug or its byproducts. The medications most commonly associated with this condition include antimalarials, hormones, oral contraceptives, phenothiazines, chemotherapeutics, amiodarone, minocycline, zidovudine, clofazimine, and ketoconazole. The aim of this case report is to illustrate the drug-induced appearance of multiple melanotic macules in an 89-year-old female patient. The patient was referred to the Department of Oral Medicine and Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece, complaining of the recent and constant appearance of black spots in her oral cavity. Her medical history revealed a multitude of prescribed drugs, with citalopram being the most recently prescribed one, approximately one year prior to the examination. The clinical examination revealed multiple melanotic macules, on the upper and lower lip as well as on the hard and soft palate. Based on these findings, a biopsy of a melanotic macule of the lip was carried out. The histopathological examination showed that the basal layer of the stratified squamous epithelium exhibited hyperpigmentation (melanin-pigmented basal cells). In addition, scattered melaninophages were noted in lamina propria. Psychotropic drugs associated with cutaneous hyperpigmentation include citalopram. Therefore, our case constitutes an exception since citalopram induced intraoral and perioral, instead of cutaneous, hyperpigmentation.
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Anemia of chronic disease is a complication accompanying many inflammatory diseases. The proinflammatory cytokine IFN-γ has been implicated in this form of anemia, but the underlying mechanism remains unclear. Here we describe a novel mouse model for anemia of chronic disease, in which enhanced CD27-mediated costimulation strongly increases the formation of IFN-γ-producing effector T cells, leading to a progressive anemia. We demonstrate that the anemia in these mice is fully dependent on IFN-γ and that this cytokine reduces both the life span and the formation of red blood cells. Molecular analysis revealed that IFN-γ induces expression of the transcription factors of interferon regulatory factor-1 (IRF-1) and PU.1 in both murine and human erythroid precursors. We found that, on IFN-γ stimulation, IRF-1 binds to the promoter of SPI.1 (PU.1) and induces PU.1 expression, leading to inhibition of erythropoiesis. Notably, down-regulation of either IRF-1 or PU.1 expression is sufficient to overcome IFN-γ-induced inhibition of erythropoiesis. These findings reveal a molecular mechanism by which chronic exposure to IFN-γ induces anemia.
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Anemia/etiologia , Modelos Animais de Doenças , Envelhecimento Eritrocítico/efeitos dos fármacos , Células Precursoras Eritroides/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Fator Regulador 1 de Interferon/fisiologia , Interferon gama/farmacologia , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Animais , Ligante CD27/genética , Ligante CD27/fisiologia , Doença Crônica , Ensaio de Unidades Formadoras de Colônias , Células Precursoras Eritroides/citologia , Fator Regulador 1 de Interferon/antagonistas & inibidores , Fator Regulador 1 de Interferon/biossíntese , Fator Regulador 1 de Interferon/sangue , Fator Regulador 1 de Interferon/genética , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/farmacologia , Proteínas Recombinantes de Fusão/fisiologia , Organismos Livres de Patógenos Específicos , Transativadores/antagonistas & inibidores , Transativadores/biossíntese , Transativadores/sangue , Transativadores/genéticaRESUMO
A pandemic, like other disasters, changes how systems work. In order to support research on how the COVID-19 pandemic impacted the dynamics of a single metropolitan area and the communities therein, we developed and made publicly available a "data-support system" for the city of Boston. We actively gathered data from multiple administrative (e.g., 911 and 311 dispatches, building permits) and internet sources (e.g., Yelp, Craigslist), capturing aspects of housing and land use, crime and disorder, and commercial activity and institutions. All the data were linked spatially through BARI's Geographical Infrastructure, enabling conjoint analysis. We curated the base records and aggregated them to construct ecometric measures (i.e., descriptors of a place) at various geographic scales, all of which were also published as part of the database. The datasets were published in an open repository, each accompanied by a detailed documentation of methods and variables. We anticipate updating the database annually to maintain the tracking of the records and associated measures.
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COVID-19 , Bases de Dados Factuais , Boston/epidemiologia , COVID-19/epidemiologia , Gerenciamento de Dados , Humanos , PandemiasRESUMO
In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p < 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (-23.3%, p < 0.0001) than in PV (-16.4%, p = 0.1730) and was associated with higher mortality rate (p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs.
Assuntos
Neoplasias da Medula Óssea/epidemiologia , COVID-19/epidemiologia , Transtornos Mieloproliferativos/epidemiologia , Trombocitemia Essencial/epidemiologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Medula Óssea/complicações , COVID-19/complicações , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/complicações , Pandemias , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2/fisiologia , Trombocitemia Essencial/complicaçõesRESUMO
We report the clinical presentation and risk factors for survival in 175 patients with myeloproliferative neoplasms (MPN) and COVID-19, diagnosed between February and June 2020. After a median follow-up of 50 days, mortality was higher than in the general population and reached 48% in myelofibrosis (MF). Univariate analysis, showed a significant relationship between death and age, male gender, decreased lymphocyte counts, need for respiratory support, comorbidities and diagnosis of MF, while no association with essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic-PMF (pre-PMF) was found. Regarding MPN-directed therapy ongoing at the time of COVID-19 diagnosis, Ruxolitinib (Ruxo) was significantly more frequent in patients who died in comparison with survivors (p = 0.006). Conversely, multivariable analysis found no effect of Ruxo alone on mortality, but highlighted an increased risk of death in the 11 out of 45 patients who discontinued treatment. These findings were also confirmed in a propensity score matching analysis. In conclusion, we found a high risk of mortality during COVID-19 infection among MPN patients, especially in MF patients and/or discontinuing Ruxo at COVID-19 diagnosis. These findings call for deeper investigation on the role of Ruxo treatment and its interruption, in affecting mortality in MPN patients with COVID-19.
Assuntos
COVID-19/mortalidade , Transtornos Mieloproliferativos/mortalidade , Pirazóis/administração & dosagem , SARS-CoV-2/isolamento & purificação , Suspensão de Tratamento/estatística & dados numéricos , Idoso , COVID-19/complicações , COVID-19/transmissão , COVID-19/virologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/virologia , Nitrilas , Prognóstico , Pirimidinas , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
AIM: The use of platelets as biomaterials has gained intense research interest. However, the mechanisms regarding platelet-mediated skeletal myogenesis remain to be established. The aim of this study was to determine the role of platelet releasate in skeletal myogenesis and muscle stem cell fate in vitro and ex vivo respectively. METHODS: We analysed the effect of platelet releasate on proliferation and differentiation of C2C12 myoblasts by means of cell proliferation assays, immunohistochemistry, gene expression and cell bioenergetics. We expanded in vitro findings on single muscle fibres by determining the effect of platelet releasate on murine skeletal muscle stem cells using protein expression profiles for key myogenic regulatory factors. RESULTS: TRAP6 and collagen used for releasate preparation had a more pronounced effect on myoblast proliferation vs thrombin and sonicated platelets (P < 0.05). In addition, platelet concentration positively correlated with myoblast proliferation. Platelet releasate increased myoblast and muscle stem cell proliferation in a dose-dependent manner, which was mitigated by VEGFR and PDGFR inhibition. Inhibition of VEGFR and PDGFR ablated MyoD expression on proliferating muscle stem cells, compromising their commitment to differentiation in muscle fibres (P < 0.001). Platelet releasate was detrimental to myoblast fusion and affected differentiation of myoblasts in a temporal manner. Most importantly, we show that platelet releasate promotes skeletal myogenesis through the PDGF/VEGF-Cyclin D1-MyoD-Scrib-Myogenin axis and accelerates skeletal muscle regeneration after acute injury. CONCLUSION: This study provides novel mechanistic insights on the role of platelet releasate in skeletal myogenesis and set the physiological basis for exploiting platelets as biomaterials in regenerative medicine.