Case report: Sodium-glucose cotransporter 2 inhibitors induce left ventricular reverse remodeling in anthracycline-related cardiac dysfunction—a case series

PurposeTo describe the efficacy and safety of sodium-glucose cotransporter 2 inhibitors as a specific treatment for anthracycline-related cardiac dysfunction in a small real-world population.MethodsSeven patients with anthracycline-related cardiac dysfunction were clinically and echocardiographically evaluated before and after the introduction of sodium-glucose cotransporter 2 inhibitors.ResultsAfter a median period of 24 weeks with uninterrupted sodium-glucose cotransporter 2 inhibitors treatment, a significant clinical improvement was observed with at least one New York Heart Association Functional Class (NHYA FC) improvement in all patients (median NYHA FC: I vs. III, p < 0.010). A noteworthy left ventricular reserve remodeling (median left ventricular end diastolic volume indexed: 53 vs. 82.5 ml/m2, p = 0.018; median left ventricular ejection fraction: 50% vs. 40%, p = 0.17) was also observed. Sodium-glucose cotransporter 2 inhibitors therapy was well tolerated by every patients; no cases of discontinuation or relevant side effects were observed.ConclusionSodium-glucose cotransporter 2 inhibitors induce a significant clinical improvement and left ventricular reserve remodeling in patients affected by anthracycline-related cardiac dysfunction

Shorter Survival of SDF1-3′A/3′A Homozygotes Linked to CD4+ T Cell Decrease in Advanced Human Immunodeficiency Virus Type 1 Infection

The SDF-1 3′A allelic polymorphism has been reported to influence either positively or negatively the progression of human immunodeficiency virus type 1 (HIV-1) disease. Therefore, the SDF-1 genotype of 729 HIV-1-infected individuals pooled from 3 distinct cohorts was determined. A statistically nonsignificant association between the SDF1-3′A/3′A genotype and accelerated disease progression was evident among seroconverters (n = 319), but a striking correlation of decreased survival after either diagnosis of AIDS according to the 1993 definition or loss of CD4+ T cell counts <200 was observed. The relative hazards for SDF1-3′A/3′A homozygotes, compared with heterozygotes and wild-type homozygotes were 2.16 (P = .0047), for time from diagnosis according to the 1993 Centers for Disease Control and Prevention AIDS case definition (AIDS-'93) to death, and 3.43 (P = .0001), for time from CD4+ T cells <200 to death. Because no difference in survival was observed after diagnosis according to AIDS-'87, the association of the SDF1-3′A/3′A genotype with the accelerated progression of late-stage HIV-1 disease appears to be explained for the most part by the loss of CD4+ T lymphocyte

A Human Monoclonal Antibody with Neutralizing Activity against Highly Divergent Influenza Subtypes

The interest in broad-range anti-influenza A monoclonal antibodies (mAbs) has recently been strengthened by theidentification of anti-hemagglutinin (HA) mAbs endowed with heterosubtypic neutralizing activity to be used in the designof ‘‘universal’’ prophylactic or therapeutic tools. However, the majority of the single mAbs described to date do not bindand neutralize viral isolates belonging to highly divergent subtypes clustering into the two different HA-based influenzaphylogenetic groups: the group 1 including, among others, subtypes H1, H2, H5 and H9 and the group 2 including, amongothers, H3 subtype. Here, we describe a human mAb, named PN-SIA28, capable of binding and neutralizing all testedisolates belonging to phylogenetic group 1, including H1N1, H2N2, H5N1 and H9N2 subtypes and several isolates belongingto group 2, including H3N2 isolates from the first period of the 1968 pandemic. Therefore, PN-SIA28 is capable ofneutralizing isolates belonging to subtypes responsible of all the reported pandemics, as well as other subtypes withpandemic potential. The region recognized by PN-SIA28 has been identified on the stem region of HA and includes residueshighly conserved among the different influenza subtypes. A deep characterization of PN-SIA28 features may represent auseful help in the improvement of available anti-influenza therapeutic strategies and can provide new tools for thedevelopment of universal vaccinal strategies

Redução das internações por condições sensíveis à atenção primária no Brasil entre 1998-2009

OBJECTIVE: To describe the trends in hospitalizations for ambulatory care sensitive conditions between 1998 and 2009 in Brazil. METHODS: The ecological time series study used secondary data on hospitalizations for ACSC in the Sistema Único de Saúde (SUS, National Unified Health System). Data were obtained from the Hospital Information System. Hospital admission rates per 10,000 inhabitants were standardized by age range and gender, using the 2000 census male Brazilian population as standard. Trend analysis of the historic series was performed through generalized linear regression using the Prais-Winsten method. RESULTS: Between 1998 and 2009, there was an average annual reduction in admissions for ambulatory care sensitive conditions of 3.7% in men (95%CI -2.3;-5.1) and women (95%CI -2.5; -5.6). The trend varied in each state, although no increase in admissions was observed in any state. In both men and women, the highest reductions were observed in hospitalizations for gastrointestinal ulcers (-11.7% a year and -12.1%, respectively), avoidable conditions (-8.8% and -8.9%) and lower respiratory diseases (-8.0% and -8.1%). Hospitalization increased only for angina (men), kidney infections and urinary tract infections (men and women) and conditions related to prenatal care and delivery (women). The three groups of illness which led to the most admissions were infectious gastroenteritis and its complications, cardiac insufficiency and asthma. CONCLUSIONS: Between 1998 and 2009, there was a substantial reduction in admissions for ambulatory care sensitive conditions in Brazil, although some illnesses presented stability or even an increase, which calls for attention from the health sector.OBJETIVO: Describir la tendencia de hospitalizaciones por condiciones susceptibles a atención primaria entre 1998 y 2009 en Brasil. MÉTODOS: Estudio ecológico de series temporales con datos secundarios relacionados con las Internaciones Hospitalarias por condiciones susceptibles a atención primaria en el Sistema Único de Salud de Brasil. Los datos fueron obtenidos del Sistema de Informaciones Hospitalarias. Las tasas de internaciones por 10.000 habitantes fueron estandarizadas por grupo etario y sexo, considerando la población brasileña masculina recensada en 2000 como patrón. El análisis de tendencia de la serie histórica fue realizado por regresión linear generalizado por el método de Prais-Winsten. RESULTADOS: Hubo reducción en el promedio anual de internaciones por condiciones susceptibles a atención primaria de 3,7% entre hombres (IC95% -2,3;-5,1) y mujeres (IC95% -2,5;-5,6) entre 1998 y 2009. La tendencia varió en cada unidad federativa, sin embargo, en ninguna hubo aumento de las internaciones. En el sexo masculino y femenino las mayores reducciones fueron observadas en las internaciones por úlceras gastrointestinales (-11,7% al año y -12,1%, respectivamente), condiciones evitables (-8,8% y -8,9%) y enfermedades de las vías aéreas inferiores (-8,0% y -8,1%). Angina (hombres), infección en el riñón y tracto urinario (hombres y mujeres) y condiciones relacionados al prenatal y parto (mujeres) presentaron aumento en las internaciones. Los tres grupos de enfermedades que más ocasionaron internaciones fueron gastroenteritis infecciosas y complicaciones, internaciones por insuficiencia cardíaca y asma. CONCLUSIONES: Hubo reducción sustancial en las internaciones por condiciones susceptibles a atención primaria en Brasil entre 1998 y 2009, sin embargo, algunas enfermedades presentaron estabilidad o aumento, exigiendo atención del sector salud.OBJETIVO: Descrever a tendência de hospitalizações por condições sensíveis à atenção primária entre 1998 e 2009 no Brasil. MÉTODOS: Estudo ecológico de séries temporais com dados secundários referentes às internações hospitalares por condições sensíveis à atenção primária no Sistema Único de Saúde. Os dados foram obtidos do Sistema de Informações Hospitalares. As taxas de internações por 10.000 habitantes foram padronizadas por faixa etária e sexo, considerando a população brasileira masculina recenseada em 2000 como padrão. A análise de tendência da série histórica foi realizada por regressão linear generalizada pelo método de Prais-Winsten. RESULTADOS: Houve redução média anual de internações por condições sensíveis à atenção primária de 3,7% entre homens (IC95% -2,3;-5,1) e mulheres (IC95% -2,5;-5,6) entre 1998 e 2009. A tendência variou em cada unidade federativa, porém em nenhuma houve aumento das internações. No sexo masculino e feminino as maiores reduções foram observadas nas internações por úlceras gastrintestinais (-11,7% ao ano e -12,1%, respectivamente), condições evitáveis (-8,8% e -8,9%) e doenças das vias aéreas inferiores (-8,0% e -8,1%). Angina (homens), infecção no rim e trato urinário (homens e mulheres) e condições relacionadas ao pré-natal e parto (mulheres) apresentaram aumento nas internações. Os três grupos de doenças que mais ocasionaram internações foram gastrenterites infecciosas e complicações, internações por insuficiência cardíaca e asma. CONCLUSÕES: Houve redução substancial nas internações por condições sensíveis à atenção primária no Brasil entre 1998 e 2009, porém algumas doenças apresentaram estabilidade ou acréscimo, exigindo atenção do setor saúde

Activating Killer Immunoglobulin Receptors and HLA-C: A successful combination providing HIV-1 control

Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. KIRs are regulatory receptors expressed at the surface of NK and CD8+ T-cells that specifically bind HLA-A and -B alleles belonging to the Bw4 supratype and all the -C alleles expressing the C1 or C2 supratype. We here disclose a novel signature associated with the Elite Controller but not with the long-term nonprogressor status concerning 2DS activating KIRs and HLA-C2 alleles insensitive to miRNA148a regulation. Overall, our findings support a crucial role of NK cells in the control of HIV-1 viremia

Nef-specific CD45RA+ CD8+ T cells secreting MIP-1β but not IFN-γ are associated with nonprogressive HIV-1 infection

<p>Abstract</p> <p>Background</p> <p>Long-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease.</p> <p>Results</p> <p>We analyzed the functional and the differentiation phenotype of Nef- and Tat-specific CD8+ T cells in a cohort of HIV-1 infected NP in comparison to progressors, ART-treated seropositive individuals and individuals undergoing a single cycle of ART interruption. We observed that a distinctive feature of NP is the presence of Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma. This population was present in 7 out of 11 NP. CD45RA+ IFN-gamma^negMIP-1beta+ CD8+ T cells were not detected in HIV-1 infected individuals under ART or withdrawing from ART and experiencing a rebounding viral replication. In addition, we detected Nef-specific CD45RA+ IFN-gamma^negMIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease.</p> <p>Conclusion</p> <p>The novel antigen-specific CD45RA+ IFN-gamma^negMIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.</p

Cardiac magnetic resonance predictors of left ventricular remodelling following acute ST elevation myocardial infarction: The VavirimS study

Left ventricular (LV) remodelling (REM) ensuing after ST-elevation myocardial infarction (STEMI), has typically been studied by echocardiography, which has limitations, or cardiac magnetic resonance (CMR) in early phase that may overestimate infarct size (IS) due to tissue edema and stunning. This prospective, multicenter study investigated LV-REM performing CMR in the subacute phase, and 6&nbsp;months after STEMI

Heparin Protects Human Neural Progenitor Cells from Zika Virus-Induced Cell Death While Preserving Their Differentiation into Mature Neuroglial Cells

Zika virus (ZIKV) is an arbovirus member of the Flaviviridae family that causes severe congenital brain anomalies in infected fetuses. The key target cells of ZIKV infection, human neural progenitor cells (hNPCs), are highly permissive to infection that causes the inhibition of cell proliferation and induces cell death. We have previously shown that pharmaceutical-grade heparin inhibits virus-induced cell death with negligible effects on in vitro virus replication in ZIKV-infected hNPCs at the "high" multiplicity of infection (MOI) of 1. Here, we show that heparin inhibits formation of ZIKV-induced intracellular vacuoles, a signature of paraptosis, and inhibits necrosis and apoptosis of hNPCs grown as neurospheres (NS). To test whether heparin preserved the differentiation of ZIKV-infected hNPCs into neuroglial cells, hNPCs were infected at the MOI of 0.001. In this experimental condition, heparin inhibited ZIKV replication by ca. 2 log10, mostly interfering with virion attachment, while maintaining its protective effect against ZIKV-induced cytopathicity. Heparin preserved differentiation into neuroglial cells of hNPCs that were obtained from either human-induced pluripotent stem cells (hiPSC) or by fetal tissue. Quite surprisingly, multiple additions of heparin to hNPCs enabled prolonged virus replication while preventing virus-induced cytopathicity. Collectively, these results highlight the potential neuroprotective effect of heparin that could serve as a lead compound to develop novel agents for preventing the damage of ZIKV infection on the developing brain. IMPORTANCE ZIKV is a neurotropic virus that invades neural progenitor cells (NPCs), causing inhibition of their proliferation and maturation into neurons and glial cells. We have shown previously that heparin, an anticoagulant also used widely during pregnancy, prevents ZIKV-induced cell death with negligible inhibition of virus replication. Here, we demonstrate that heparin also exerts antiviral activity against ZIKV replication using a much lower infectious inoculum. Moreover, heparin interferes with different modalities of virus-induced cell death. Finally, heparin-induced prevention of virus-induced NPC death allows their differentiation into neuroglial cells despite the intracellular accumulation of virions. These results highlight the potential use of heparin, or pharmacological agents derived from it, in pregnant women to prevent the devastating effects of ZIKV infection on the developing brain of their fetuses

Pentosan Polysulfate Inhibits Attachment and Infection by SARS-CoV-2 In Vitro: Insights into Structural Requirements for Binding

Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS-CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side effect. One alternative, with structural similarities to heparin, is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated, and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective in inhibiting cell infection than low-molecular-weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection