A TH17-intrinsic IL-1ß-STAT5 axis drives steroid resistance in autoimmune neuroinflammation.

Steroid resistance poses a major challenge for the management of autoimmune neuroinflammation. T helper 17 (TH17) cells are widely implicated in the pathology of steroid resistance; however, the underlying mechanisms are unknown. In this study, we identified that interleukin-1 receptor (IL-1R) blockade rendered experimental autoimmune encephalomyelitis (EAE) mice sensitive to dexamethasone (Dex) treatment. Interleukin-1ß (IL-1ß) induced a signal transducer and activator of transcription 5 (STAT5)-mediated steroid-resistant transcriptional program in TH17 cells, which promoted inflammatory cytokine production and suppressed Dex-induced anti-inflammatory genes. TH17-specific deletion of STAT5 ablated the IL-1ß-induced steroid-resistant transcriptional program and rendered EAE mice sensitive to Dex treatment. IL-1ß synergized with Dex to promote the STAT5-dependent expression of CD69 and the development of central nervous system (CNS)-resident CD69+ TH17 cells. Combined IL-1R blockade and Dex treatment ablated CNS-resident TH17 cells, reduced EAE severity, and prevented relapse. CD69+ tissue-resident TH17 cells were also detected in brain lesions of patients with multiple sclerosis. These findings (i) demonstrate that IL-1ß-STAT5 signaling in TH17 cells mediates steroid resistance and (ii) identify a therapeutic strategy for reversing steroid resistance in TH17-mediated CNS autoimmunity.

Proposal and Validation of a New Index to Assess the Difficulty of Lower Third Molar Extraction.

There is no current consensus on the parameters that determine the difficulty of mandibular third molar extraction in terms of the time required, which is essential to prevent complications and optimize the time of the intervention. This study aims to obtain, using the mathematical method of multiple linear regression, an equation that allows estimating the extraction time of a lower third molar according to its complexity, as well as to validate this equation in a sample of external wisdom teeth. METHODS: A prospective cohort study on a sample of patients of the Master of Oral Surgery of the University of Seville in which multiple linear regression coefficients were calculated with a subsequent validation study of the results in the sample of patients operated in the Hospital Palmaplanas of Mallorca. RESULTS: The regression line obtained after applying the statistical methodology to the cohort of patients from the University of Seville obtained significant dependent variables such as depth, roots, and odontosection. Once applied to the cohort of patients from the Palmaplanas Hospital in Mallorca, a regression coefficient was obtained between the data received and the estimated 0.770. CONCLUSIONS: The formula proposed in this article presents significant validity in the prediction of the surgical time of extraction of the lower third molars included.

Re-estratificação de risco de candidatos à terapia de ressincronização cardíaca guiada pela ecocardiografia com speckle tracking / Risk re-stratification of candidates for cardiac resynchronization therapy guided by speckle tracking echocardiography

INTRODUÇÃO: A fração de ejeção do ventrículo esquerdo (FEVE) é o parâmetro utilizado para a classificação dos diferentes fenótipos de insuficiência cardíaca (IC). Embora pacientes portadores de IC com FEVE reduzida (ICFER) e evidência de bloqueio de ramo esquerdo (BRE) possam ser considerados para a Terapia de Ressincronização Cardíaca (TRC), há uma taxa de aproximadamente 30% de não-respondedores. Nesse contexto, é fundamental a avaliação de novas técnicas capazes de identificar subgrupos com maior risco de desfechos e que devem ser priorizados para a TRC. OBJETIVO: Avaliar a FEVE com o Global Longitudinal Strain (GLS) na predição de eventos maiores em candidatos à TRC. MÉTODOS: Foram incluídos 99 pacientes candidatos à TRC (ICFER com FEVE≤35% e padrão de BRE no ECG), avaliados no período entre fevereiro de 2008 e outubro de 2012 com follow up de 8 anos. As análises foram segmentadas em grupos com eventos combinados: internação por IC, óbito e/ou transplante cardíaco. RESULTADOS: Pacientes com desfecho apresentaram uma FEVE=26,2(±0,05)% e GLS=-13,9(±12,3)%, enquanto pacientes sem desfecho apresentaram FEVE=27,6(±0,05)% e GLS=-16,2(±7,2)%. A diferença entre os grupos foi estatisticamente significante para o GLS (p=0,04), mas sem significância para FEVE (p=0,07) (Figura 1). À análise de Kaplan-Meier utilizando um valor de corte do módulo de GLS<-16%, observou-se uma diferença significante nas curvas de sobrevida com significância pelo teste de log-rank (p=0.005) (Figura 2). CONCLUSÃO: O GLS é uma ferramenta com potencial uso na re-estratificação de pacientes com ICFER candidatos à TRC. Esse recurso além de descrever uma piora da evolução, pode também ajudar na decisão dos grupos que se beneficiariam de uma intervenção mais precoce.

Alterações da repolarização ventricular estão associadas às anormalidades da função sistólica longitudinal em pacientes com ICFEP / Changes in ventricular repolarization are associated with abnormalities in longitudinal systolic function in patients with HFPEF

INTRODUÇÃO: A insuficiência cardíaca de fração de ejeção preservada (ICFEP) é uma síndrome clínica decorrente de uma diversa combinação de anormalidades fisiopatológicas que confluem na elevação das pressões de enchimento do coração. Dentre tais alterações, alguns fenótipos de pacientes podem apresentar anormalidades da função sistólica do ventrículo esquerdo, a despeito de valores da fração de ejeção dentro dos limites da normalidade. Atualmente, há uma escassez de estudos que avaliam qual o papel das alterações no eletrocardiograma (ECG) na ICFEP e como estas podem contribuir para melhor identificação dos mecanismos que levam à intolerância ao exercício. OBJETIVOS: Avaliar a associação entre alterações da repolarização ventricular com as anormalidades na função sistólica do ventrículo esquerdo em uma população com diagnóstico de ICFEP. MÉTODOS: Estudo observacional transversal de 50 pacientes com diagnóstico de ICFEP confirmado pelo escore europeu HFA-PEFF. A repolarização ventricular foi avaliada através da medida do ângulo espacial QRS-T pelo vetocardiograma (método de Kors) e pelo índice TpicoTfim no ECG. As alterações da função sistólica do ventrículo esquerdo foram avaliadas através da medida do Global Longitudinal Strain (GLS) na ecocardiografia com Speckle Tracking. RESULTADOS: Obteve-se uma amostra de 48 pacientes com idade média de 50 (±5) anos, sendo 67% (33) do sexo feminino. Houve correlação moderada e estatisticamente significante entre o GLS e os parâmetros de repolarização ventricular: TpicoTfim (r=0.42; p<0.001) e o ângulo QRS-T (r= 0.58; p-value<0.001). À análise de regressão linear, obteve-se um ß coeficiente de 0.040 do ângulo QRS-T, denotando que para cada aumento de 25º no ângulo QRS-T, há a uma queda de 1% na função sistólica longitudinal pelo GLS. CONCLUSÃO: Nossos dados sugerem que as alterações da repolarização ventricular identificam pacientes com ICFEP que possuem anormalidades da função sistólica do ventrículo esquerdo apesar de apresentarem valores da fração de ejeção dentro dos limites da normalidade. Particularmente, o ângulo espacial QRS-T se mostrou um parâmetro promissor, superior ao TpicoTfim, e com potencial para ser incluído no arsenal multiparamétrico da avaliação diagnóstica da ICFEP.

Cross-estimulação de apresentação tardia devido a implante de eletrodo atrial em anel tricuspídeo / Late-presenting cross-stimulation due to tricuspid ring atrial lead implantation

INTRODUÇÃO: A cross-estimulação é um evento raro que é definido pela ocorrência da estimulação de uma câmara cardíaca quando se espera que outra câmara seja estimulada. Familiarizar-se com a cross-estimulação é um passo fundamental para se evitar o diagnóstico incorreto e a abordagem inadequada. DESCRIÇÃO DO CASO: Paciente 66 anos, masculino, portador de marcapasso bicameral programado em DDD, com histórico de limiar de captura atrial elevado, comparece em consulta de rotina de telemetria assintomático, porém apresentando episódios de captura ventricular intermitente após estimulação pelo eletrodo atrial. Testes de sensibilidade evidenciaram ritmo atrial sinusal com bloqueio atrioventricular total sem escape ventricular. Durante teste de limiar de captura atrial em unipolar, foi observado que, para uma largura de pulso de 1,0ms, uma voltagem acima de 2,0mV apresentava captura ventricular com diferente morfologia do QRS estimulado pelo eletrodo ventricular e com uma voltagem abaixo de 1,5mV era incapaz de capturar o átrio. Análise em bipolar apresentou evento semelhante em diferentes limiares. Radiografia torácica mostrou implante de eletrodo atrial em anel tricuspídeo, sendo confirmada a ocorrência de cross-estimulação do ventrículo por eletrodo atrial. Visto que o paciente não apresentava necessidade de estimulação atrial, optou-se por reprogramar para VDD. CONCLUSÃO: A cross-estimulação ocasionada pela estimulação ventricular por um eletrodo atrial implantado no anel tricuspídeo, próximo ao miocárdio ventricular, pode se apresentar tardiamente em decorrência do aumento do limiar de captura atrial, o que deve nos motivar a buscar ativamente a ocorrência desse evento com a estimulação com alta energia durante o implante. Dependendo da necessidade de estimulação atrial e da presença de margem de segurança entre o limiar de captura atrial e ventricular pelo eletrodo atrial, a abordagem mais adequada pode ser a reprogramação, em vez de intervenção cirúrgica.

The Effect of Largemouth Bass Virus on Bass Populations in Kansas Impoundments.

Largemouth Bass virus (LMBV) first became a concern in Kansas when it was identified as a potential cause of decreased catch rates at Crawford State Fishing Lake in 2007. The discovery of LMBV in eight additional impoundments from 2008 to 2017 increased concern about the prevalence and effects of LMBV in Kansas. In response, the Kansas Department of Wildlife, Parks, and Tourism tested 25 Largemouth Bass Micropterus salmoides impoundments for the presence of LMBV. The objectives of this study were to quantify the incidence of LMBV and examine differences in population metrics (i.e., body condition, relative abundance, and growth). A total of 1,260 Largemouth Bass were collected by using standard spring electrofishing surveys, and sagittal otoliths were collected from all of the sampled fish to estimate growth rates. Of the 25 study impoundments, 14 tested positive for LMBV. There was no evidence of LMBV effects on body condition, relative abundance of quality-length fish, or growth rates. The initial dates of LMBV infection of Largemouth Bass in these impoundments are unknown. The LMBV-positive populations in Kansas may have been exposed to the virus many years ago, and the fish may be in the process of rebounding from any potential negative effects.

Zika Virus Causes Acute and Chronic Prostatitis in Mice and Macaques.

BACKGROUND: Sexual transmission and persistence of Zika virus (ZIKV) in the male reproductive tract has raised concerned for potential damaging effects on function. Animal studies have demonstrated that ZIKV virus can infect and damage the testis and epididymis, and these results has been correlated to lower sperm counts in ZIKV-infected humans. The prostate plays a vital role in the male reproductive tract, with acute and chronic prostatitis linked to male infertility. METHODS: In this study, we evaluated the effects of ZIKV virus on the prostate in mice and nonhuman primates. RESULTS: In mice, ZIKV infected the prostate and triggered inflammation that persisted even after virus clearance. Evidence of chronic prostatitis associated with ZIKV infection remained for several months. Similar histological findings were observed in the prostate of ZIKV-infected rhesus macaques. CONCLUSIONS: These studies establish that ZIKV replicates in the prostate and can cause acute and chronic inflammatory and proliferative changes in mouse and nonhuman primate models.

Zika Virus Causes Acute Infection and Inflammation in the Ovary of Mice Without Apparent Defects in Fertility.

BACKGROUND: Zika virus (ZIKV) has become a global concern because infection of pregnant mothers was linked to congenital birth defects. Zika virus is unique from other flaviviruses, because it is transmitted vertically and sexually in addition to by mosquito vectors. Prior studies in mice, nonhuman primates, and humans have shown that ZIKV targets the testis in males, resulting in persistent infection and oligospermia. However, its effects on the corresponding female gonads have not been evaluated. METHODS: In this study, we assessed the effects of ZIKV on the ovary in nonpregnant mice. RESULTS: During the acute phase, ZIKV productively infected the ovary causing accumulation of CD4+ and virus-specific CD8+ T cells. T cells protected against ZIKV infection in the ovary, as higher viral burden was measured in CD8-/- and TCRßδ-/- mice. Increased cell death and tissue inflammation in the ovary was observed during the acute phase of infection, but this normalized over time. CONCLUSIONS: In contrast to that observed with males, minimal persistence and no long-term consequences of ZIKV infection on ovarian follicular reserve or fertility were demonstrated in this model. Thus, although ZIKV replicates in cells of the ovary and causes acute oophoritis, there is rapid resolution and no long-term effects on fertility, at least in mice.

Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice.

Spondweni virus (SPOV) is the flavivirus that is most closely related to Zika virus (ZIKV). Although SPOV causes sporadic human infections in Africa, recently it was found in Culex mosquitoes in Haiti. To investigate the pathogenic spectrum of SPOV, we developed infection models in mice. Although two SPOV strains failed to cause disease in immunocompetent mice, each accumulated in the brain, spleen, eye, testis, and kidney when type I interferon signaling was blocked and unexpectedly caused infection, immune cell infiltration, and swelling in the ankle. In pregnant mice, SPOV replicated in the placenta and fetus but did not cause placental insufficiency or microcephaly. We identified human antibodies from ZIKV or DENV immune subjects that neutralized SPOV infection and protected against lethal challenge. Our experiments describe similarities and differences in clinical syndromes between SPOV and ZIKV and suggest that their serological relatedness has implications for antibody therapeutics and flavivirus vaccine development.

Complicações mecânicas raras no infarto agudo do miocárdio / Rare mechanical complications in acute myocardial infarction

JBOI, masculino, 80 anos, hipertenso, DPOC, ex-tabagista, renal crônico não dialítico, com cirurgia de revascularização miocárdica em 2000, apresentou infarto com supra de ST de parede inferior, com oclusão da ponte AO-CD, sendo reperfundido por angioplastia primária. Evolui após 01 semana com quadro de dispneia aos moderados esforços e ortopnéia. Feito diagnóstico de comunicação interventricular (CIV) e hematoma intrapericárdico com compressão de átrio direito. Paciente transferido para o Hospital Dante Pazzanese estável hemodinamicamente, sem droga vasoativa, em ar ambiente, para avaliação de complicação mecânica do infarto. Realizado ecocardiograma e ressonância nuclear magnética cardíaca que evidenciaram presença de CIV inferoseptal basal de 3mm e pseudoaneurisma com ruptura de parede livre de ventrículo esquerdo. Após 20 dias do evento, é realizada ventriculorrafia e drenagem de hematoma. Paciente evolui com instabilidade hemodinâmica refrataria no pós-operatório, falecendo 25 dias após a data do infarto. Algumas complicações mecânicas do IAM são ruptura de parede livre de ventrículo esquerdo, CIV e regurgitação mitral. A incidência de ruptura de parede livre é menor que 1% dos casos, podendo ocorrer em até 5 dias do IAM. A incidência de ruptura livre até 12 horas da reperfusão é de 0.7%, sendo mais comum em infarto de parede anterior. Os fatores de risco encontrado são idade acima de 70 anos, ausência de circulação colateral e sexo feminino. A ruptura do septo interventricular, causando a CIV, tem uma incidência de 0.2%, ocorrendo entre 3 a 5 dias pós IAM. Quando ocorre infarto inferior sua localização é na região da base do septo. A mortalidade cirúrgica é de 47% e no tratamento clinico de 94%. O caso acima mostra uma evolução raríssima de duas complicações mecânicas simultâneas com sobrevivência ao quadro inicial, no entanto com óbito após o procedimento cirúrgico, devido alta mortalidade e morbidade da complicação mecânica do IAM. (AU)

Three steps to maintain predictable interdental papilla and gingiva emergence profiles in immediate implant placement. A 3-year follow-up case report.

We present a case that describes a three-step clinical technique to provide guidelines to replace fractured teeth with immediate implant placement using the same dental structure as a temporary crown and a regenerative approach. This approach predictably maintains the interdental papilla and gingiva emergence profile to ensure a favorable cosmetic result. A 3-year follow-up has shown good clinical outcomes and stability in crestal bone levels. Consequently, this is an innovative way to do temporary crown and design restorations in everyday clinical practice. Key words:Interdental papilla, dental implant, inmmediate implant, gingival aesthetics, dental aesthetics.

Satisfaction in complete denture wearers with and without adhesives: A randomized, crossover, double-blind clinical trial.

BACKGROUND: The purpose of this study was to compare the satisfaction of patients regarding retention, stability and accumulation of particles with a randomized, double-blind crossed method in users with complete dentures with and without adhesive. MATERIAL AND METHODS: Seventeen edentulous individuals were randomized and received new upper and lower complete dentures. After a period of adaptation, they participated in some masticatory tests and clinical revisions, after use the protheses with and without the use of two denture adhesives: Adhesive A (Fittydent, Fittydent International GmbH) and adhesive B (Corega, GlaxoSmithKline) at 0, 7 and 14 days. Satisfaction was measured immediately after each test through a survey using a VAS scale (0-10) and data were analyzed with McNemar's test with Bonferroni correction. RESULTS: The results showed significant differences (p<.01) between the study groups with adhesive A - B and the group without adhesive, but no significant differences were found between the two stickers for any of the variables studied. CONCLUSIONS: Complete denture adhesives significantly improved the satisfaction of patients because a better retention, stability and less accumulation of particles of the food substitute between the denture and the mucosa is obtained compared with non-use of complete denture adhesives. Key words:Complete dentures, patient satisfaction, denture adhesives, clinical trials.

Transfer of Cell-Surface Antigens by Scavenger Receptor CD36 Promotes Thymic Regulatory T Cell Receptor Repertoire Development and Allo-tolerance.

The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α+ dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α+ DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens. The absence of CD8α+ DCs or CD36 altered thymic T cell selection, as evidenced by TCR repertoire analysis and the loss of allo-tolerance in murine allogeneic BM transplantation (allo-BMT) studies. Decreases in these DCs and CD36 expression in peripheral blood of human allo-BMT patients correlated with graft-versus-host disease. Our findings suggest that CD36 facilitates transfer of mTEC-derived cell-surface antigen on CD8α+ DCs to promote tolerance to host antigens during homeostasis and allo-BMT.

Modified mRNA Vaccines Protect against Zika Virus Infection.

The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (∼1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern.

The FDA-approved drug sofosbuvir inhibits Zika virus infection.

The rapidly expanding Zika virus (ZIKV) epidemic has affected thousands of individuals with severe cases causing Guillain-Barré syndrome, congenital malformations, and microcephaly. Currently, there is no available vaccine or therapy to prevent or treat ZIKV infection. We evaluated whether sofosbuvir, an FDA-approved nucleotide polymerase inhibitor for the distantly related hepatitis C virus, could have antiviral activity against ZIKV infection. Cell culture studies established that sofosbuvir efficiently inhibits replication and infection of several ZIKV strains in multiple human tumor cell lines and isolated human fetal-derived neuronal stem cells. Moreover, oral treatment with sofosbuvir protected against ZIKV-induced death in mice. These results suggest that sofosbuvir may be a candidate for further evaluation as a therapy against ZIKV infection in humans.

Comparison of masticatory efficacy among complete denture wearers with two adhesives and dentate individuals: A randomized, crossover, double-blind clinical trial.

STATEMENT OF PROBLEM: The masticatory efficacy between dentate and edentulous individuals with and without the use of dental adhesives has been little studied. A comparative study of the addition of various agents of synthetic adhesion (vinyl methyl ether versus polyvinyl acetate) to these adhesives is needed. PURPOSE: The purpose of this randomized, crossover, double-blind clinical trial was to compare the masticatory efficacy of wearers of complete dentures with and without dental adhesives of 2 different compositions and that of dentate controls. MATERIAL AND METHODS: Seventeen participants with edentulism (edentulous control and 2 experimental groups) received new maxillary and mandibular complete dentures. After an adjustment period, they participated in masticatory tests with and without the use of 2 denture adhesives (Fittydent; Fittydent International GmbH and Corega; GlaxoSmithKline). The participants with edentulism were compared with 17 dentate controls. Masticatory efficacy was evaluated while the participants were masticating a substitute for irreversible hydrocolloid (20 g) and performing a single test of mastication (with 20 masticatory strokes) at 0, 7, and 14 days. Masticatory efficiency was measured immediately after each test with the sieving method and was calculated according to the weight of the particles of the substitute in each of the sieve filters. Data were analyzed using 1-way ANOVA for simple pairs, and a multiple comparison was made using the Wilcoxon test with Bonferroni correction (α=.05). RESULTS: Significant differences were found between the 2 adhesives (P<.05) in the masticatory efficacy for filters 2 and 3, and nonsignificant differences occurred for filter 1. Compared with the edentulous control group, significant differences between the use or nonuse of adhesives were found in the edentulous group for the 3 filters (P<.05). Compared with the dentate control group, significant differences were found in masticatory efficiency between the dentate control group and the other groups for all comparisons (P<.05). CONCLUSIONS: Masticatory efficacy was higher with the use of Corega denture adhesive. The masticatory efficacy was significantly higher in dentate participants compared with participants with edentulism who had complete dentures, with or without denture adhesives. A significant increase of masticatory efficacy was observed among edentulous participants with denture adhesives in relation to those not using denture adhesives.

Novas perspectivas na abordagem da síncope neurocariogênica / New perspectives in the approach of neurocariogenic syncope

A síncope é definida como uma perda súbita da consciência associada a déficit de tônus postural, com recuperação espontânea e completa, causada por hipoperfusão cerebral transitória. É um sintoma frequente na população, e em algumas situações pode ser o único a preceder a morte súbita. Existem diversas formas de apresentação para a síncope: a cardiogênica, runológica, psiquiátrica e a neurocardiogênica...

Zika virus infection damages the testes in mice.

Infection of pregnant women with Zika virus (ZIKV) can cause congenital malformations including microcephaly, which has focused global attention on this emerging pathogen. In addition to transmission by mosquitoes, ZIKV can be detected in the seminal fluid of affected males for extended periods of time and transmitted sexually. Here, using a mouse-adapted African ZIKV strain (Dakar 41519), we evaluated the consequences of infection in the male reproductive tract of mice. We observed persistence of ZIKV, but not the closely related dengue virus (DENV), in the testis and epididymis of male mice, and this was associated with tissue injury that caused diminished testosterone and inhibin B levels and oligospermia. ZIKV preferentially infected spermatogonia, primary spermatocytes and Sertoli cells in the testis, resulting in cell death and destruction of the seminiferous tubules. Less damage was caused by a contemporary Asian ZIKV strain (H/PF/2013), in part because this virus replicates less efficiently in mice. The extent to which these observations in mice translate to humans remains unclear, but longitudinal studies of sperm function and viability in ZIKV-infected humans seem warranted.