The adult heart requires baseline expression of the transcription factor Hand2 to withstand RV pressure overload

AIMS: Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV).Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a 'fetal gene program' contributing to pathological cardiac remodeling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodeling in response to pressure overload induced by pulmonary artery banding (PAB). METHODS AND RESULTS: In the present study, Hand2F/F and MCM- Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived hemodynamic parameters as well as molecular remodeling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV-pressure overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass and impaired cardiac function. RNA sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. CONCLUSIONS: Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressure overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodeling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure. TRANSLATIONAL PERSPECTIVE: RV failure associated with pulmonary hypertension reduces long-term survival rate to 55% within 3 years, suggesting that 3 years after diagnosis almost half of the patients will die. To revert these numbers an adequate RV-specific and, therefore, more efficient treatment is needed. Our work suggests that current therapies and potential mechanisms underlying LV failure may not be suitable for RV failure. While Hand2 deletion is favorable in LV response to stress, it is particularly detrimental in the RV under similar conditions, and thus, highlighting potential severe consequences of not differentiating therapeutic targets or treatment for RV or LV failure

The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells

In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34(+) samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34(+) samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients

Pediatric pain : prevalence, assessment, and management in a teaching hospital

The goal of this study was to examine the prevalence, assessment and management of pediatric pain in a public teaching hospital. The study sample consisted of 121 inpatients (70 infants, 36 children, and 15 adolescents), their families, 40 physicians, and 43 nurses. All participants were interviewed except infants and children who could not communicate due to their clinical status. The interview included open-ended questions concerning the inpatients’ pain symptoms during the 24 h preceding data collection, as well as pain assessment and pharmacological/non-pharmacological management of pain. The data were obtained from 100% of the eligible inpatients. Thirty-four children/adolescents (28%) answered the questionnaire and for the other 72% (unable to communicate), the family/health professional caregivers reported pain. Among these 34 persons, 20 children/adolescents reported pain, 68% of whom reported that they received pharmacological intervention for pain relief. Eighty-two family caregivers were available on the day of data collection. Of these, 40 family caregivers (49%) had observed their child’s pain response. In addition, 74% reported that the inpatients received pharmacological management. Physicians reported that only 38% of the inpatients exhibited pain signs, which were predominantly acute pain detected during clinical procedures. They reported that 66% of patients received pharmacological intervention. The nurses reported pain signs in 50% of the inpatients, which were detected during clinical procedures. The nurses reported that pain was managed in 78% of inpatients by using pharmacological and/or non-pharmacological interventions. The findings provide evidence of the high prevalence of pain in pediatric inpatients and the under-recognition of pain by health professionals

Efeito do uso de bioinsumos sobre populações de pragas e inimigos naturais na cultura da soja no Sudoeste de Goiás.

Os resultados deste estudo indicam benefícios na utilização de bioinsumos na agricultura, destacando positivamente sua influência direta ou indireta na biodiversidade de artrópodes, bem como na dinâmica populacional de pragas e inimigos naturais. A transição gradual do uso de inseticidas químicos para produtos biológicos pode ser uma estratégia eficaz para promover o controle biológico natural e preservar a diversidade de insetos benéficos. Essa abordagem de substituir o uso do inseticida químico de amplo espectro por bioinseticidas específicos para os insetos-alvo está alinhada com a crescente conscientização sobre a necessidade de práticas agrícolas mais sustentáveis para enfrentar os desafios ambientais e conservar a biodiversidade

Caracterização físico-química de citros para avaliação da qualidade do fruto.

O Brasil é líder mundial na produção de frutos e de suco concentrado de laranja. Entretanto, a opção pelo mercado de laranjas e tangerinas ? in natura? pode render maiores lucros aos produtores, como ocorre na Espanha e na Califórnia (EUA)

Tinnitus handicap inventory: cross-cultural adaptation to Brazilian Portuguese

BACKGROUND: tinnitus can cause damage to the life quality of patients. The assessment of to what extent a patient's quality of life has been affected by tinnitus can be useful to understand the limitations imposed by this symptom. Also it can be useful for therapeutic programming and for the verification of therapy effectiveness (pre and post treatment evaluation). AIM: to culturally adapt the Tinnitus Handicap Inventory (THI), to use it with the Brazilian population and to evaluate its reproducibility. METHOD: the cultural adaptation of the THI (Newman et al., 1996) followed the steps indicated by Guillemin et al., (1993), which include the translation from English to Portuguese, linguistic adaptation and revision of the grammatical and idiomatic equivalences. Assessment of inter and intra-researcher reproducibility of results was also made. Participants of this study were thirty patients (19 females, 63,3% and 11 males, 36,7%) with tinnitus from an otoneurology specialized ambulatory, with ages between 39 and 79 years. RESULTS: the THI was adapted in order to be used with the Brazilian population and was named Brazilian Tinnitus Handicap Inventory. There was no statistically significant difference regarding inter and intra-researcher reproducibility of the results when using the Brazilian version of the questionnaire. A decline in the quality of life regarding emotional, functional and/or catastrophic aspects was observed for all of the assessed patients. CONCLUSION: the THI was translated and culturally adapted in order to be used with the Brazilian population, demonstrating to be a reliable instrument to verify the damage caused by tinnitus in the quality of life of individuals.TEMA: o zumbido pode provocar muitos prejuízos na qualidade de vida dos pacientes. A avaliação de quanto a qualidade de vida é prejudicada pelo zumbido pode ser útil para o melhor conhecimento do paciente em relação às limitações impostas por este sintoma, a programação terapêutica e a verificação da eficácia terapêutica, quando aplicado antes e após o tratamento. OBJETIVO: adaptar culturalmente o Tinnitus Handicap Inventory (THI) para aplicação na população brasileira e avaliar a sua reprodutibilidade. MÉTODO: a adaptação cultural do THI (Newman et al., 1996) seguiu as etapas indicadas por Guillemin et al. (1993), que incluem a tradução do idioma Inglês para o Português, adaptação lingüística e revisão das equivalências gramatical e idiomática. Realizou-se, também, a avaliação das reprodutibilidades inter e intra-pesquisadores deste questionário. Participaram 30 pacientes com zumbido, dos sexos feminino 19 (63,3%) ou masculino 11 (36,7%), com idade entre 39 e 79 anos (média 56,8 anos), encaminhados a partir de ambulatório específico em otoneurologia. RESULTADOS: o THI foi adaptado para ser aplicado na população brasileira, denominado THI Brasileiro. Não houve diferença estatisticamente significante quanto à reprodutibilidade inter-pesquisadores nos resultados obtidos à aplicação da versão brasileira deste questionário, bem como da reprodutibilidade intra-pesquisadores. Verificou-se prejuízo da qualidade de vida em relação aos aspectos emocionais, funcionais e/ou catastróficos em todos os pacientes avaliados. CONCLUSÃO: o THI foi traduzido e adaptado culturalmente para ser aplicado na população brasileira, mostrando-se um instrumento confiável para verificação do prejuízo causado pelo zumbido na qualidade de vida.Irmandade de Misericórdia da Santa Casa de São PauloUniversidade Federal de São Paulo (UNIFESP) Setor de Reabilitação Vestibular da Disciplina de OtoneurologiaEscola Paulista de MedicinaUNIFESP Departamento de Otorrinolaringologia e Departamento de Cirurgia de Cabeça e PescoçoInstituto de Psicologia da USPUNIFESP Disciplina de Otoneurologia e Cirurgia de Cabeça e PescoçoUNIFESP, Setor de Reabilitação Vestibular da Disciplina de OtoneurologiaEscola Paulista de MedicinaUNIFESP, Depto. de Otorrinolaringologia e Depto. de Cirurgia de Cabeça e PescoçoUNIFESP, Disciplina de Otoneurologia e Cirurgia de Cabeça e PescoçoSciEL