Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors.

BACKGROUND: VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. METHODS: Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×1013 viral particles (vp)/patient (Part I), and 3.3×1012 vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×1013 vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×1013 vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×1013 vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. CONCLUSIONS: Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma. TRIAL REGISTRATION NUMBER: NCT02045602.

VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplastic stroma that limits the delivery of anticancer agents. VCN-01 is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB1 pathway and express hyaluronidase. Here, we evaluated the mechanism of action of VCN-01 in preclinical models and in patients with pancreatic cancer. METHODS: VCN-01 replication and antitumor efficacy were evaluated alone and in combination with standard chemotherapy in immunodeficient and immunocompetent preclinical models using intravenous or intratumoral administration. Hyaluronidase activity was evaluated by histochemical staining and by measuring drug delivery into tumors. In a proof-of-concept clinical trial, VCN-01 was administered intratumorally to patients with PDAC at doses up to 1×1011 viral particles in combination with chemotherapy. Hyaluronidase expression was measured in serum by an ELISA and its activity within tumors by endoscopic ultrasound elastography. RESULTS: VCN-01 replicated in PDAC models and exerted antitumor effects which were improved when combined with chemotherapy. Hyaluronidase expression by VCN-01 degraded tumor stroma and facilitated delivery of a variety of therapeutic agents such as chemotherapy and therapeutic antibodies. Clinically, treatment was generally well-tolerated and resulted in disease stabilization of injected lesions. VCN-01 was detected in blood as secondary peaks and in post-treatment tumor biopsies, indicating virus replication. Patients had increasing levels of hyaluronidase in sera over time and decreased tumor stiffness, suggesting stromal disruption. CONCLUSIONS: VCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005556-42 and NCT02045589.

Attention and response control in ADHD. Evaluation through integrated visual and auditory continuous performance test.

This study assesses attention and response control through visual and auditory stimuli in a primary care pediatric sample. The sample consisted of 191 participants aged between 7 and 13 years old. It was divided into 2 groups: (a) 90 children with ADHD, according to diagnostic (DSM-IV-TR) (APA, 2002) and clinical (ADHD Rating Scale-IV) (DuPaul, Power, Anastopoulos, & Reid, 1998) criteria, and (b) 101 children without a history of ADHD. The aims were: (a) to determine and compare the performance of both groups in attention and response control, (b) to identify attention and response control deficits in the ADHD group. Assessments were carried out using the Integrated Visual and Auditory Continuous Performance Test (IVA/CPT, Sandford & Turner, 2002). Results showed that the ADHD group had visual and auditory attention deficits, F(3, 170) = 14.38; p < .01, deficits in fine motor regulation (Welch´s t-test = 44.768; p < .001) and sensory/motor activity (Welch'st-test = 95.683, p < .001; Welch's t-test = 79.537, p < .001). Both groups exhibited a similar performance in response control, F(3, 170) = .93, p = .43.Children with ADHD showed inattention, mental processing speed deficits, and loss of concentration with visual stimuli. Both groups yielded a better performance in attention with auditory stimuli.

Attention and response control in ADHD. Evaluation through integrated visual and auditory continuous performance test

This study assesses attention and response control through visual and auditory stimuli in a primary care pediatric sample. The sample consisted of 191 participants aged between 7 and 13 years old. It was divided into 2 groups: (a) 90 children with ADHD, according to diagnostic (DSM-IV-TR) (APA, 2002) and clinical (ADHD Rating Scale-IV) (DuPaul, Power, Anastopoulos, & Reid, 1998) criteria, and (b) 101 children without a history of ADHD. The aims were: (a) to determine and compare the performance of both groups in attention and response control, (b) to identify attention and response control deficits in the ADHD group. Assessments were carried out using the Integrated Visual and Auditory Continuous Performance Test (IVA/CPT, Sandford & Turner, 2002). Results showed that the ADHD group had visual and auditory attention deficits, F(3, 170) = 14.38; p < .01, deficits in fine motor regulation (Welch´s t-test = 44.768; p < .001) and sensory/motor activity (Welch’st-test = 95.683, p < .001; Welch’s t-test = 79.537, p < .001). Both groups exhibited a similar performance in response control, F(3, 170) = .93, p = .43.Children with ADHD showed inattention, mental processing speed deficits, and loss of concentration with visual stimuli. Both groups yielded a better performance in attention with auditory stimuli

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Guía de vacunaciones en adultos, niños y adolescentes: consenso de expertos / Guide vaccinations in adults, children and adolescents: expert consensus

Este consenso ha sido actualizado por profesionales interesados y con experiencia en la vacunación, pertenecientes a la Sociedad Venezolana de Infectología y Sociedad Venezolana de Puericultura y Pediatría y Sociedad Venezolana de Salud Pública. El esquema de vacunas del adulto aplica a personas desde los 18 años de edad, mientras que el esquema de niños y adolescentes a personas hasta los 18 años de edad. Se considera esquema completo, cuando se han administrado todas las dosis y/o sus respectivos refuerzos, de acuerdo con su edad correspondiente y riesgos. Se presentan los esquemas en forma de calandelarios de manera que los profesionales del sector salud y afines, como la población en general puedan utilizarlos de manera práctica como esquema de bolsillo para su consulta rápida

Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C.

The pathogenic mechanisms of accelerated graft fibrosis in hepatitis C recurrence after liver transplantation (LT) are not well established. The aim of the study was to assess whether a greater activation of hepatic stellate cells (HSC), the major collagen-producing cells in the liver, can occur in these patients as compared to non-LT patients with chronic hepatitis C. We determined the amount of activated HSC by computer-based morphometric analysis of alpha-smooth muscle actin (alphaSMA)-positive cells and the hepatic TGFbeta(1) expression by immunohistochemistry in 46 LT patients with hepatitis C recurrence, 35 non-LT patients with chronic hepatitis C, and 16 controls. Hepatic alphaSMA and TGFbeta(1) expression was higher in LT patients with hepatitis C recurrence than in controls and was correlated with fibrosis stage and progression rate. No significant difference in alphaSMA and TGFbeta(1) expression was observed between LT and non-LT patients with hepatitis C, with the exception of a higher transforming growth factor beta-1 (TGFbeta(1)) expression in non-LT patients in the early stages of fibrosis. LT patients receiving cyclosporine (CsA) or tacrolimus (FK) had a similar fibrosis progression rate and alphaSMA and TGFbeta(1) expression. In conclusion, the accelerated fibrosis observed in LT patients with hepatitis C recurrence does not seem to be related to a greater amount of activated HSC and TGFbeta(1) expression in the grafts of these patients as compared to non-LT patients with chronic hepatitis C. In LT patients, the amount of activated HSC and TGFbeta(1) expression correlated with fibrosis stage and progression, without any apparent influence of the type of calcineurin inhibitor administered.

Results of a pilot trial of immunotherapy with dendritic cells pulsed with autologous tumor lysates in patients with advanced cancer.

AIMS AND BACKGROUND: The purpose of the study was to test the immunological and clinical effects of infusions of dendritic cells pulsed with autologous tumor lysate in patients with advanced cancer. PATIENTS AND METHODS: Peripheral blood mononuclear cells from 15 patients with metastatic cancer (melanoma in 10, lung cancer in 2, renal cell carcinoma in 1, sarcoma in 1, breast cancer in 1) were harvested by leukapheresis after mobilization with GM-CSF (5 microg/kg/day s.c. for 4 days). Mononuclear cells were separated and cultured in GM-CSF (1000 U/ml) and interleukin-4 (1000 U/ml) for 7 days. Phenotype was assessed by 2-color flow cytometry and immunocytochemistry. On day 6, dendritic cells were pulsed with 1 g of fresh autologous tumor lysate for 24 h and infused intravenously. Interleukin-2 (6 million IU), interferon a (4 million IU) and GM-CSF (400 microg) were injected s.c. daily for 10 days beginning on the day of dendritic cell infusion. Treatment was repeated every 21 days for 3 courses. RESULTS: The morphology, immunocytochemistry and phenotype of cultured cells was consistent with dendritic cells: intense positivity for HLA-DR and CD86, with negativity for markers of other lineages, including CD3, CD4, CD8 and CD14. More than 5 x 10(7) dendritic cells were injected in all patients. Nine patients developed >5 mm delayed type cutaneous hypersensitivity reactions to tumor lysate+/-GM-CSF after the first immunization (larger than GM-CSF in all cases). Median delayed type cutaneous hypersensitivity to lysate +/- GM-CSF was 3 cm after the third immunization. One melanoma patient with skin, liver, lung and bone metastases had a partial response lasting 8 months (followed by progression in the brain). Seven patients had stable disease for >3 months, and 7 had progression. CONCLUSIONS: Infusion of tumor lysate-pulsed dendritic cells induces a strong cell-mediated antitumor immune reaction in patients with advanced cancer and has some clinical activity.

[Interdisciplinary relationships and humanization in intensive care units]. / Relaciones interdisciplinarias y humanización en las unidades de cuidados intensivos.

OBJECTIVE: To analyze those aspects of the relationship between the health care team of an ICU that may be decisive in the construction of humanized care. DESIGN: phenomenology: descriptive and exploratory. ANALYSIS and observation unit: Polyvalent 23-bed adult ICU. DATA COLLECTION: nine extensive interviews. POPULATION: healthcare professionals in interaction in the ICU that is being studied. ANALYSIS: assigning of data to emergent categories. Contrasting with existing theories. RESULTS: Identification of guideline values circumspect to the humanistic paradigm. The value of professional role is accepted as emergency factor of certain attitudes. All the professional groups detect lack of independence situations, which are not always attributable to hierarchical reasons. Systematic interdisciplinary communication is evaluated positively. Humanization requires time, resources, and intergroup relationships and explicit commitment by the institution. CONCLUSIONS: Relief of great suffering situations is the main reason for interdisciplinary disagreement. Construction of a tolerant setting and institutional recognition as factors favoring humanized care. Lack of time and resources as obstacles to the humanization of care.

Relaciones interdisciplinarias y humanización en las unidades de cuidados intensivos / Interdisciplinary relationships and humanization in intensive care units

Objetivo. Analizar los aspectos de la relación entre el equipo asistencial de una unidad de cuidados intensivos (UCI) que puedan ser decisivos en la construcción de una atención humanizada. Método. Diseño: fenomenológico; descriptivo y exploratorio. Unidad de análisis y observación: UCI polivalente de adultos de 23 camas. Recogida de datos: 9 entrevistas a fondo. Población: profesionales sanitarios en interacción en la UCI objeto de estudio. Análisis: asignación de datos a categorías emergentes. Contrastación con teorías existentes. Resultados. Identificación de valores guía circunscritos al paradigma humanista. Valores asociados a características personales más que profesionales. Se acepta el valor del rol profesional como factor de emergencia de determinadas actitudes. Todos los grupos profesionales detectan situaciones de falta de autonomía, no siempre atribuibles a causa jerárquica. Se valora positivamente la comunicación interdisciplinaria sistemática. La humanización requiere tiempo, recursos, buena relación intergrupal y el compromiso explícito de la institución. Conclusiones. El alivio de situaciones de gran sufrimiento, principal motivo de desacuerdo interdisciplinario. La construcción de un entorno tolerante y el reconocimiento institucional como factores favorecedores de la atención humanizada. La falta de tiempo y recursos como obstáculos a la humanización de la atención

Objective. To analyze those aspects of the relationship between the health care team of an ICU that may be decisive in the construction of humanized care. Method. Design: phenomenology: descriptive and exploratory. Analysis and observation unit: Polyvalent 23-bed adult ICU. Data collection: nine extensive interviews. Population: healthcare professionals in interaction in the ICU that is being studied. Analysis: assigning of data to emergent categories. Contrasting with existing theories. Results. Identification of guideline values circumspect to the humanistic paradigm. The value of professional role is accepted as emergency factor of certain attitudes. All the professional groups detect lack of independence situations, which are not always attributable to hierarchical reasons. Systematic interdisciplinary communication is evaluated positively. Humanization requires time, resources, and intergroup relationships and explicit commitment by the institution. Conclusions. Relief of great suffering situations is the main reason for interdisciplinary disagreement. Construction of a tolerant setting and institutional recognition as factors favoring humanized care. Lack of time and resources as obstacles to the humanization of care

Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics.

BACKGROUND: Homocysteine (Hcy) is formed as an intermediary in methionine metabolism. Impairment of Hcy remethylation or transulfuration leads to hyperhomocysteinemia, which is considered as a risk factor for atherosclerotic vascular disease and stroke in chronic alcoholics. The aim of the study was to investigate the prevalence of hyperhomocysteinemia in chronic alcoholics and the influence of alcohol consumption, vitamin deficiencies and liver damage on the plasma levels of Hcy. METHODS: 228 chronic alcoholic patients consecutively admitted for detoxication, classified according to clinical and biochemical data in normal liver (n = 117), and in mild to moderate liver disease (n = 111), and 49 healthy controls were studied. Blood levels of Hcy, vitamin B6, vitamin B12 and folate were measured. RESULTS: Plasma Hcy was significantly higher in chronic alcoholics than in controls (9.66 +/- 8.1 vs. 6.93 +/- 2.33 mumol/liter, p < 0.025). Furthermore, plasma Hcy levels were significantly higher in chronic alcoholics with liver injury (12.17 +/- 10.14 mumol/liter) than in those with normal liver and in controls (p < 0.001). The prevalence of hyperhomocysteinemia was also significantly higher in alcoholics with liver damage than in those with normal liver and in controls (29.7%, 5.1%, and 2%, respectively, p < 0.001). Serum folate values were lower in chronic alcoholics than in controls (4.7 +/- 2.6 vs. 7.6 +/- 2.4 nmol/liter, p < 0.001). The lowest values of folate were found in alcoholics with liver disease, especially in those with hyperhomocysteinemia, with a negative correlation between the two parameters. CONCLUSIONS: Moderate hyperhomocysteinemia is common in chronic alcoholics, mainly in those with liver damage, suggesting that, although folate deficiencies may have a contributory role, liver impairment, through changes in methionine metabolism, is the most important mechanism for the elevated plasma Hcy found in these patients.

Critical role of mitochondrial glutathione in the survival of hepatocytes during hypoxia.

Hypoxia is known to stimulate reactive oxygen species (ROS) generation. Because reduced glutathione (GSH) is compartmentalized in cytosol and mitochondria, we examined the specific role of mitochondrial GSH (mGSH) in the survival of hepatocytes during hypoxia (5% O2). 5% O2 stimulated ROS in HepG2 cells and cultured rat hepatocytes. Mitochondrial complex I and II inhibitors prevented this effect, whereas inhibition of nitric oxide synthesis with Nomega-nitro-L-arginine methyl ester hydrochloride or the peroxynitrite scavenger uric acid did not. Depletion of GSH stores in both cytosol and mitochondria enhanced the susceptibility of HepG2 cells or primary rat hepatocytes to 5% O2 exposure. However, this sensitization was abrogated by preventing mitochondrial ROS generation by complex I and II inhibition. Moreover, selective mGSH depletion by (R,S)-3-hydroxy-4-pentenoate that spared cytosol GSH levels sensitized rat hepatocytes to hypoxia because of enhanced ROS generation. GSH restoration by GSH ethyl ester or by blocking mitochondrial electron flow at complex I and II rescued (R,S)-3-hydroxy-4-pentenoate-treated hepatocytes to hypoxia-induced cell death. Thus, mGSH controls the survival of hepatocytes during hypoxia through the regulation of mitochondrial generation of oxidative stress.

Efecto del ácido levofolínico sobre las concentraciones de homocisteína plasmática en la mujer joven y sana en la consulta preconcepcional / Effects of levofolinic acid on plasma homocysteine concentrations in healthy and young women in preconceptional care

FUNDAMENTO: El aumento de la homocisteína plasmática total (tHcy) es un factor de riesgo para los defectos del tubo neural. Se estudia el efecto de la suplementación con ácido levofolínico (l,5-formil-tetrahidrofólico) sobre los valores de la tHCy plasmática en la mujer en edad reproductiva. PACIENTES Y MÉTODO: Treinta mujeres sanas de 18 a 35 años recibieron 5 mg/día de ácido levofolínico por vía oral durante 30 días. La tHcy y los folatos intraeritrocitarios se determinaron antes de la suplementación (día 0), los días 2, 5, 10 y 30 durante el tratamiento, y 30 (día 60) y 60 días (día 90) después de finalizado. La tHcy plasmática se determinó por inmunoanálisis de polarización de fluorescencia (coeficiente de variación [CV] intraanálisis e interanálisis < 8 por ciento) y el ácido fólico intraeritrocitario, mediante inmunoanálisis quimioluminiscente (CV intraanálisis e interanálisis < 5 por ciento). RESULTADOS: La tHCy plasmática disminuye a partir del segundo día de tratamiento (día 0 frente a 2: media de la diferencia, -1,24 µmol/l; intervalo de confianza [IC] del 95 por ciento, -0,84 a -1,63; p < 0,001). El descenso máximo (32,3 por ciento) se observa a los 30 días (media de la diferencia, -2,72 µmol/l; IC del 95 por ciento, -2,20 a -3,24; p < 0,001). Tras finalizar el tratamiento el efecto hipohomocisteinémico persiste el día 60 (media de la diferencia, -2,67 µmol/l; IC del 95 por ciento, -2,07 a -3,26; p < 0,001) y 90 (media de la diferencia, -1,49 µmol/l; IC del 95 por ciento, -0,94 a -2,03; p < 0,001). La respuesta fue mayor cuando la tHcy plasmática fue de 9 µmol/l o más. CONCLUSIONES: El ácido levofolínico provoca un descenso temprano, intenso y persistente de las concentraciones de tHcy plasmática (AU)