IGF-1 Regulates the extracellular level of active MMP-2 and promotes Müller glial cell motility

In ischemic proliferative retinopathies, Müller glial cells (MGCs) acquire migratory abilities. However, the mechanisms that regulate this migration remain poorly understood. In addition, proliferative disorders associated with enhanced activities of matrix metalloproteinases (MMPs) also involve insulin-like growth factor (IGF)-1 participation. Therefore, the main interest of this work was to investigate the IGF-1 effect on the extracellular proteolytic activity in MGCs.Methods: Cell culture supernatants and cell lysates of the human MGC line MIO-M1 stimulated with IGF-1 were analyzed for MMP-2 by zymographic and Western blot analysis. The MGCs´ motility was evaluated by scratch wound assay. The MMP-2, β1-integrin, and focal adhesions were detected by confocal microscopy. The localization of active MMPs and actin cytoskeleton were evaluated by in situ zymography.Results: The IGF-1 induced the activation of canonical signaling pathways through the IGF-1R phosphorylation. Culture supernatants showed a relative decrease in the active form of MMP-2, correlating with an increased accumulation of MMP-2 protein in the MGCs´ lysate. The IGF-1 effect on MMP-2 was abolished by an IGF-1R blocking antibody, αIR3, as well as by the PI3-kinase inhibitor, LY294002. The IGF-1 increased the migratory capacity of MGCs, which was blocked by the GM6001 MMP inhibitor, LY294002 and αIR3. Finally, IGF-1 induced the intracellular distribution of MMP-2 toward cellular protrusions and the partial colocalization with β1-integrin and phospo-focal adhesion kinase signals. Gelatinase activity was concentrated along F-actin filaments.Conclusions: Taken together, these data indicate that IGF-1, through its receptor activation, regulates MGCs´ motility by a mechanism that involves the MMP-2 and PI3K signaling pathway.Fil: Lorenc, Valeria Erika. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Jaldín Fincati, Javier Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Luna Pinto, Jose Domingo. Departamento de Vítreo-retina, Centro Privado de Ojos R; ArgentinaFil: Chiabrando, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Sanchez, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Development of Algorithm for Clinical Management of Sickle Cell Bone Disease: Evidence for a Role of Vertebral Fractures in Patient Follow-up

Sickle-cell disease (SCD) is a worldwide distributed hemoglobinopathy, characterized by hemolytic anemia associated with vaso-occlusive events. These result in acute and chronic multiorgan damage. Bone is early involved, leading to long-term disability, chronic pain and fractures. Here, we carried out a retrospective study to evaluate sickle bone disease (SBD) in a cohort of adults with SCD. We assessed bone density, metabolism and turnover. We also evaluated the presence of fractures and the correlation between SCD severity and skeletal manifestations. A total of 71 patients with SCD were analyzed. The mean age of population was 39 \ub1 10 years, 56% of which were females. We found osteoporosis in a range between 7% and 18% with a high incidence of vertebral fractures. LDH and AST were predictive for the severity of vertebral fractures, while bone density was not. Noteworthy, we identified -1.4 Standard Deviations T-score as the cutoff for detecting the presence of fractures in patients with SCD. Collectively our data allowed us to develop an algorithm for the management of SBD, which may be useful in daily clinical practice to early intersect and treat SBD

Clinical characteristics and outcomes among Brazilian patients with severe acute respiratory syndrome coronavirus 2 infection : An observational retrospective study

Funding: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) - grant numbers 115293/2019-1 and 162996/2019-5; Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) - grant number APQ-00208-20; and Liver Center at Universidade Federal de Minas Gerais.BACKGROUND: Since February 2020, data on the clinical features of patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their clinical evolution have been gathered and intensively discussed, especially in countries with dramatic dissemination of this disease. OBJECTIVE: To assess the clinical features of Brazilian patients with SARS-CoV-2 and analyze its local epidemiological features. DESIGN AND SETTING: Observational retrospective study conducted using data from an official electronic platform for recording confirmed SARS-CoV-2 cases. METHODS: We extracted data from patients based in the state of Pernambuco who were registered on the platform of the Center for Strategic Health Surveillance Information, between February 26 and May 25, 2020. Clinical signs/symptoms, case evolution over time, distribution of confirmed, recovered and fatal cases and relationship between age group and gender were assessed. RESULTS: We included 28,854 patients who were positive for SARS-CoV-2 (56.13% females), of median age 44.18 years. SARS-CoV-2 infection was most frequent among adults aged 30-39 years. Among cases that progressed to death, the most frequent age range was 70-79 years. Overall, the mortality rate in the cohort was 8.06%; recovery rate, 30.7%; and hospital admission rate (up to the end of follow-up), 17.3%. The average length of time between symptom onset and death was 10.3 days. The most commonly reported symptoms were coughing (42.39%), fever (38.03%) and dyspnea/respiratory distress with oxygen saturation < 95% (30.98%). CONCLUSION: Coughing, fever and dyspnea/respiratory distress with oxygen saturation < 95% were the commonest symptoms. The case-fatality rate was 8.06% and the hospitalization rate, 17.3%

Psychological Health Status of Psychiatric Patients Living in Treatment Communities before and during the COVID-19 Lockdown: A Brief Report

Many studies investigated the psychological impact of lockdown measures on the general population, while few studies focused on the psychiatric population. This study aimed to investigate the role of therapeutic communities in the management and containment of symptoms of patients with psychosis living in psychiatric residential facilities. Data were collected at two different points: November 2019 (Coronavirus disease 19 had not yet spread) and April 2020 (during the lockdown in Italy). Twenty-two study participants were recruited from three residential accredited psychiatric facilities. During lockdown, the patients showed a small increase in symptomatology in terms of emotional isolation. In addition, it was been observed significant differences in certain functional areas of the behavior, measured as lower inclination towards violent behaviors during lockdown, and higher scores in substance abuse and medical impairment. The lockdown condition could represent a form of containment; daily routines, along with adequate social support, are important aspects of the stability and the level of behavioral functioning of psychiatric patients. Social support and continuity of care offered by psychiatric communities can be an effective safeguard against the psychological impact of the COVID-19 epidemic

Epidemiology, management, and outcome of carbapenem-resistant Klebsiella pneumoniae bloodstream infections in hospitals within the same endemic metropolitan area

In the last decade, carbapenem-resistant Klebsiella pneumoniae (CR-Kp) has become endemic in several countries, including Italy. In the present study, we assessed the differences in epidemiology, management, and mortality of CR-Kp bloodstream infection (BSI) in the three main adult acute-care hospitals of the metropolitan area of Genoa, Italy.From January 2013 to December 2014, all patients with CR-Kp BSI were identified through the computerized microbiology laboratory databases of the three hospitals. The primary endpoints of the study were incidence and characteristics of CR-Kp BSI in hospitals within the same endemic metropolitan area. Secondary endpoints were characteristics of CR-Kp BSI in hospitals with and without internal infectious diseases consultants (IDCs) and 15-day mortality.During the study period, the incidence of healthcare-associated CR-Kp BSI in the entire study population was 1.35 episodes per 10,000 patient-days, with substantial differences between the three hospitals. Patients admitted to the two hospital with internal IDCs were more likely to receive post-susceptibility test combined therapy including carbapenems (77% vs. 26%, p &lt;. 0.001), adequate post-susceptibility test therapies (86% vs. 52%, p &lt;. 0.001), and post-susceptibility therapies prescribed by an infectious diseases specialist (84% vs. 14%, p &lt;. 0.001). Overall, the crude 15-days mortality was 26%. In the final multivariable model, only septic shock at BSI presentation was unfavorably and independently associated with 15-days mortality (odds ratio [OR] 6.7, 95% confidence intervals [CI] 2.6-17.6, p &lt;. 0.001), while a protective effect was observed for post-susceptibility test combined therapies including a carbapenem (OR 0.11, 95% CI 0.03-0.43, p = 0.002).Mortality of CR-Kp remains high. Differences in the incidence of CR-Kp BSI were detected between acute-care centers within the same endemic metropolitan area. Efforts should be made to improve the collaboration and coordination between centers, to prevent further diffusion of CR-Kp

Referencial fenomenológico nas pesquisas brasileiras de enfermagem a nível stricto sensu: panorama brasileiro

Objetivo: Caracterizar a produção científica stricto sensu da enfermagem brasileira que utilizou referencial fenomenológico.Método: Estudo descritivo-exploratório de caráter documental realizado a partir do Catálogo de Teses e Dissertações da CAPES no período de janeiro a abril de 2022.Resultados: A amostra foi constituída por 600 dissertações e teses, com predomínio do referencial heideggeriano, seguido de Schütz e Merleau-ponty. As temáticas se concentraram no cuidado de enfermagem na saúde da mulher, na saúde mental, na enfermagem pediátrica e do adolescente, na enfermagem oncológica, na enfermagem obstétrica, na Atenção Primária à Saúde, na família e na educação em enfermagem.Conclusão: A fenomenologia se apresenta como um referencial potente para o desvelamento dos fenômenos de interesse da enfermagem, contribuindo para a construção do conhecimento sobre o ser que cuida, o ser que é cuidado e o próprio cuidado em si. Palavras-chave: Pesquisa em enfermagem. Filosofia em enfermagem. Educação de pósgraduação em enfermagem

Safety and efficacy of ketorolac continuous infusion for multimodal analgesia of vaso-occlusive crisis in patients with sickle cell disease

Pain is an hallmark of sickle-cell-related acute clinical manifestations as part of acute vaso-occlusive crisis (VOC). In SCD pain has different origins such as vascular or neuropathic pain, which requires multimodal analgesia. This is based on the administration of drugs with different pharmacological mechanisms of action, maximizing analgesia and minimizing their adverse events and the risk of drug-addition in patients experiencing acute-recurrent pain events as in SCD. Ketorolac is a potent non-narcotic analgesic, being relatively safe and effective during pain-management in children and adults. Up to now, there is a lack of safety information on continuous infusion ketorolac as used to control acute pain in patients with SCD, and the benefits/risks ratio needs to be investigated. Here, we report for the first time the safety profile of ketorolac in the special population of patients with SCD. We confirmed that ketorolac in combination with tramadol, an opioid like molecule, is effective in pain control of adult patients with SCD experiencing acute severe VOCs defined by pain visual analog scale. Our study shows that short term (72&nbsp;h) continuous infusion of ketorolac plus tramadol is not associated with adverse events such as liver or kidney acute disfunction or abnormalities in coagulation parameters during patients' hospitalization and within 30 days after patients discharge. This is extremely important for patients with SCD, who should have access to multimodal therapy to control recurrent acute pain crisis in order to limit central sensitization a fearsome issue of undertreated recurrent acute pain and of chronic pain

SARS-CoV-2 infection in beta thalassemia: Preliminary data from the Italian experience

Patients with pre\u2010existent chronic morbidities are likely to be more severely affected by SARS\u2010Cov2 infection, but no data are available regarding Thalassemic Syndromes (TS). Note, TS and hemoglobin variants represent, according to WHO, one of the most frequent causes of anemia, affecting more than 7% of the world population.1 Thalassemic Syndromes are classified in either transfusion\u2010dependent thalassemia (TDT) or non\u2010transfusion\u2010dependent thalassemia (NTDT). Infectious complications, mainly from bacteria, constitute a common cause of mortality and morbidity in TS. Stress erythropoiesis, iron overload, splenectomy and adrenal insufficiency among others may contribute to increase susceptibility to infection.2 To verify the impact of SARS\u2010CoV\u20102 infection on TS, we set\u2010up a specific survey by electronic Case Report Form (eCRF).3 Inclusion criteria require at least 15\u2009days of follow\u2010up from either the onset of symptoms or SARS\u2010CoV2 positivity. The survey was approved by Ethics Committee and eCRF was shared with the Centers of Italian Hemoglobinopathies Network. The \u201cSociet\ue0 Italiana Talassemie ed Emoglobinopatie\u201d (SITE), has estimated the presence in Italy of approximately 5000 TDT and 1900 NTDT patients.3 As of 10 April 2020, 11 cases of TS and COVID\u201019 have been collected (see supplementary information). All the reported patients are in Northern Italy, where the rate of infection is higher, reflecting the national epidemiology. The mean age is 44\u2009\ub1\u200911\u2009years (range 31\u201061\u2009years) and 55% (6/11) are females. Ten patients are TDT, and one is NTDT. All the patients have thalassemia associated comorbidities, eight are splenectomized, and one patient (#9 in the supplementary table) has pulmonary hypertension treated with sildenafil. The likely source of infection has been detected in 55% (6/11) of cases: two had contacts with COVID\u201019 positive subjects, and four had occupational exposure (three are nurses working in hospital or assisted living facilities). Three patients were asymptomatic. One patient (#3 in supplementary information) was admitted for high fever and bone marrow hypoplasia, lymphopenia, and agranulocytosis (on treatment with deferiprone) and tested positive at the third swab. Six out of 11 were hospitalized, but no one required mechanical ventilation. The patient with more severe symptoms who required more intensive ventilation support with continuous positive airway pressure (CPAP) has a history of diffuse large B\u2010cell lymphoma, treated with chemotherapy in the previous year, currently in complete remission. Of the six people admitted to the hospital, only three received supposedly specific treatment for COVID\u201019: one hydroxychloroquine (HCQ), one HCQ plus ritonavir/darunavir, and one HCQ plus anakinra. Patient #3 did not receive HCQ due to concomitant therapy with amiodarone and an increased risk of life\u2010threatening arrhythmia. The clinical course ranged from 10 to 29\u2009days. Ten patients have clinically recovered and are on a daily remote phone call follow\u2010up. Splenectomy which was present in 8/11 patients did not seem to affect the clinical course. Of note, except for the patient with myelosuppression, no increase in blood requirement was observed. When luspatercept treatment was halted in the NTDT patient, hemoglobin fell from 110 to 82 g/L, a value similar to the pre\u2010luspatercept period. Neither death nor severe SARS or signs of cytokines storm were observed in these 11 subjects, which may be surprising, taking into account the mean age and the presence of severe comorbidities. Our data, although preliminary, do not indicate increased severity of COVID\u201019 in TS. A larger number of cases needs to be collected to define the impact of this new infection and its outcome in these fragile patients

Cobaltabis(dicarbollide) ([o-COSAN]&minus;) as Multifunctional Chemotherapeutics: A Prospective Application in Boron Neutron Capture Therapy (BNCT) for Glioblastoma

Purpose: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8&prime;-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. Methods: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. Results: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8&prime;-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. Conclusions: These small molecules, particularly [8,8&prime;-I2-o-COSAN]&minus;, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma

A novel allele specific polymerase chain reaction (As-pcr) assay to detect the v1016g knockdown resistance mutation confirms its widespread presence in aedes albopictus populations from Italy

Funding Information: Funding: The study received support from the project ”Sapienza 2017” and JP received support from FCT-Fundação para a Ciência e a Tecnologia, I.P., through national funds in the framework of the project PTDC/BIA-OUT/29477/2017. Funding Information: The study received support from the project ?Sapienza 2017? and JP received support from FCT-Funda??o para a Ci?ncia e a Tecnologia, I.P., through national funds in the framework of the project PTDC/BIA-OUT/29477/2017. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Polymerase chain reaction (PCR)-based genotyping of mutations in the voltage-sensitive sodium channel (vssc) associated with resistance to pyrethroid insecticides is widely used and represents a potential early warning and monitoring system for insecticide resistance arising in mosquito populations, which are vectors of different human pathogens. In the secondary vector Aedes albopictus—an Asian species that has invaded and colonized the whole world, including temperate regions—sequencing of domain II of the vssc gene is still needed to detect the V1016G mutation associated with pyrethroid resistance. In this study we developed and tested a novel allele-specific PCR (AS-PCR) assay to genotype the V1016G mutation in this species and applied it to the analysis of wild populations from Italy. The results confirm the high accuracy of the novel AS-PCR and highlight frequencies of the V1016G allele as >5% in most sampling sites, with peaks of 20–45% in coastal touristic sites where pyrethroid treatments are extensively implemented, mostly for mosquito nuisance reduction. The high frequency of this mutation observed in Italian Ae. albopictus populations should serve as a warning bell, advocating for increased monitoring and management of a phenomenon which risks neutralizing the only weapon today available to counteract (risks of) arbovirus outbreaks.publishersversionpublishe