In silico bioavailability for BCS class II efavirenz tablets using biorelevant dissolution media for IVIVR and simulation of formulation changes.

OBJECTIVE: This work aims to evaluate the ability of biorelevant dissolution media to simulate the bioavailability of efavirenz tablets, establish an in vitro-in vivo relationship (IVIVR) based on in vivo data using GastroPlus® and simulate formulation changes using DDDPlus™. METHODS: Solubility and drug release profiles were conducted in SLS 0.5% and biorelevant media, such as FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2. The efavirenz physicochemical properties were used to simulate the plasma concentration profile and compare the simulated pharmacokinetic parameters in fasted and fed states. An IVIVR was developed using Loo-Riegelman as the deconvolution method to estimate drug bioavailability. DDDPlus™ was used to perform virtual trials of formulations to evaluate whether formulations changes and the efavirenz particle size could influence the bioavailability. RESULTS: The drug dissolution displayed higher levels in the biorelevant media that simulated gut-fed state (FeSSIF and FeSSIF-V2). The absorption model successfully predicted the efavirenz pharmacokinetics, and FeSSIF-V2 was chosen as the predictive dissolution media, while an IVIVR was established using the Loo-Riegelman deconvolution method. CONCLUSIONS: The present work provides valuable information about efavirenz solubility and kinetics in the gastrointestinal tract, allowing an IVIVR to support future formulation changes. This understanding is essential for rational science-driven formulation development. At least, this study also showed the validity and applicability of in vitro and in silico tools in the regulatory scenario helping on drug development.

Development and Characterization of PLGA Nanoparticles Containing 17-DMAG, an Hsp90 Inhibitor.

Leishmaniasis is a spectrum of neglected tropical diseases and its cutaneous form (CL) is characterized by papillary or ulcerated skin lesions that negatively impact patients' quality of life. Current CL treatments suffer limitations, such as severe side effects and high cost, making the search for new therapeutic alternatives an imperative. In this context, heat shock protein 90 (Hsp90) could present a novel therapeutic target, as evidence suggests that Hsp90 inhibitors, such as 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG), may represent promising chemotherapeutic agents against CL. As innovative input for formulation development of 17-DMAG, nano-based drug delivery systems could provide controlled release, targeting properties, and reduced drug toxicity. In this work, a double emulsion method was used to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles containing 17-DMAG. The nanoparticle was developed using two distinct protocols: Protocol 1 (P1) and Protocol 2 (P2), which differed concerning the organic solvent (acetone or dichloromethane, respectively) and procedure used to form double-emulsions (Ultra-Turrax® homogenization or sonication, respectively). The nanoparticles produced by P2 were comparatively smaller (305.5 vs. 489.0 nm) and more homogeneous polydispersion index (PdI) (0.129 vs. 0.33) than the ones made by P1. Afterward, the P2 was optimized and the best composition consisted of 2 mg of 17-DMAG, 100 mg of PLGA, 5% of polyethylene glycol (PEG 8000), 1.5 mL of the internal aqueous phase, 1% of polyvinyl alcohol (PVA), and 4 mL of the organic phase. Optimized P2 nanoparticles had a particle size of 297.2 nm (288.6-304.1) and encapsulation efficacy of 19.35% (15.42-42.18) by the supernatant method and 31.60% (19.9-48.79) by the filter/column method. Release kinetics performed at 37°C indicated that ~16% of the encapsulated 17-DMAG was released about to 72 h. In a separate set of experiments, a cell uptake assay employing confocal fluorescence microscopy revealed the internalization by macrophages of P2-optimized rhodamine B labeled nanoparticles at 30 min, 1, 2, 4, 6, 24, 48, and 72 h. Collectively, our results indicate the superior performance of P2 concerning the parameters used to assess nanoparticle development. Therefore, these findings warrant further research to evaluate optimized 17-DMAG-loaded nanoparticles (NP2-17-DMAG) for toxicity and antileishmanial effects in vitro and in vivo.

Control of an outbreak of post-transplant cutaneous mucormycosis by removing the vehicle: An intervention study of contiguous cohorts.

BACKGROUND: An outbreak of post-kidney transplant cutaneous mucormycosis (PK-CM), a severe and even fatal complication in immunocompromised patients, occurred in our institution. The objective of this study was to compare the usual fixation of sterile wound dressings with non-sterile elastic bandages and fixation with sterile bandages processed at our centralized sterile services department with regard to PK-CM prevention. METHODS: We conducted a before-and-after trial in a private tertiary care hospital. The pre-intervention cohort (n = 16) included all patients who had undergone kidney transplant (KT) during the outbreak (June 2010-April 2011), and the post-intervention cohort (n = 49) included all patients who had undergone KT between May 2011 and October 2013. From May 2011, only bandages sterilized by the centralized sterile services department were used to fix wound dressings of KT patients. RESULTS: Differences in age (50.2 years vs 51.3 years), sex (43.8% male vs 59.2% female), weight (63.3 kg vs 69.7 kg), hemodialysis vintage (55.6 months vs 47.8 months), and other risk factors were not observed between the pre- and post-intervention cohorts, respectively. PK-CM incidence dropped from 25% in the pre-intervention cohort (4/16) to 0% in the post-intervention cohort (0/49). Relative risk was 0 (P = .003). CONCLUSIONS: With regard to KT patients and sterile wound dressing fixation with non-sterile bandages versus the use of autoclaved bandages, fixation with autoclaved bandages proved to be effective for cutaneous mucormycosis outbreak control and prevention in our institution.

[Argentine consensus on late-onset Pompe's disease]. / Consenso argentino sobre enfermedad de Pompe de inicio tardío.

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Consenso argentino sobre enfermedad de Pompe de inicio tardío / Argentine consensus on late-onset Pompe's disease

La enfermedad de Pompe (EP) es un desorden metabólico autosómico recesivo infrecuente, producido por la ausencia o deficiencia de la enzima lisosomal alfa-glucosidasa ácida en los tejidos de los individuos afectados. Se considera enfermedad de Pompe de inicio tardío (EPIT) en aquellos individuos de más de un año de edad al comienzo de los síntomas. El objetivo del presente consenso es el de actualizar las pautas y recomendaciones para un correcto tratamiento de los pacientes con EPIT, tomando como referencia los lineamientos del Consenso Argentino para el diagnóstico, seguimiento y tratamiento de la enfermedad de Pompe publicado en el año 2013. Se organizó un consenso que reunió profesionales con experiencia en la EP en las áreas de clínica médica, diagnóstico de laboratorio, neuropatología, neumonología, nutrición, neurología, enfermedades metabólicas, enfermedades neuromusculares y rehabilitación. Se realizó una actualización de la bibliografía sobre EPIT, con especial atención en las publicaciones relevantes de los últimos cuatro años. Los términos finales del documento fueron consensuados por todo el grupo de trabajo. Cada participante proporcionó su declaración de conflicto de intereses. El resultado es una actualización del último Consenso Argentino para la EP, con particular enfoque en su forma de comienzo tardío. Tratándose de una afección infrecuente, en la que los datos disponibles son limitados, las presentes recomendaciones deben ser consideradas como opinión de expertos.

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

A contribuição da governança para aprimorar o uso dos recursos na Saúde Pública / Governance's contribution to improving the use of resources in Public Health

Este artigo apresenta a atuação do tribunal de Contas da União (TCU) na avaliação da governança na saúde pública sob diferentes perspectivas. Primeiramente, discute as implicações da execução da politica de saúde frente aos desafios da descentralização, situando o papel da governança e sus importância para as relações interfederativas, diante da necessária cooperação entre entes para assegurar a integralidade na oferta de serviços de saúde aos cidadãos . Destaca, também, a necessária harmonização dos recursos e esforços dentro de cada secretaria de saúde e de cada conselho de saúde, sob o ponto de vista da governança organizacional. O Conselho de Saúde representa o principal ator da governança, enquanto a Secretaria de Saúde o principal ator da gestão. Enquanto o primeiro dita os rumos e acompanha os resultados, o segundo mobiliza os recursos para o cumprimento dos objetivos. A governança organizacional orienta a organização para que organize os componentes de liderança, estratégia, processos de trabalho e controles, de modo a reduzir os riscos e aumentar o potencial de sucesso rumo aos objetivos. Cada organização operando de forma mais organizada significa também que estão potencialmente mais aptas às discussões e pactuações necessárias ao estabelecimento de acordos interfederativos, capazes de assegurar a prestação de serviços de saúde de forma otimizadas nas regiões de saúde. Por fim, são apresentados os resultados das avaliações realizadas pelo TCU e as principais recomendações

Usefulness of diffusion tensor imaging in amyotrophic lateral sclerosis: potential biomarker and association with the cognitive profile.

METHODS: This was a case-control study conducted from December 1, 2012 to December 1, 2014. Clinical and demographic data were recorded. A neuropsychological test battery adapted to ALS patients was used. An MRI with DTI was performed in all patients and fractional anisotropy (FA) was analyzed in the white matter using the tract based spatial statistics program. RESULTS: Twenty-four patients with ALS (15 females, mean age 66.9 + -2.3) and 13 healthy controls (four females, average age 66.9 + - 2) were included. The DTI showed white matter damage in ALS patients vs. healthy controls (p < 0.001). DISCUSSION: In our preliminary study the alterations of white matter in DTI were significantly associated with cognitive impairment in patients with ALS.

Incidence of Autoimmune Myasthenia Gravis in a Health Maintenance Organization in Buenos Aires, Argentina.

BACKGROUND: Different epidemiological studies, especially in Europe, have estimated the incidence density of myasthenia gravis (MG) to range between 1.7 and 21.3/1,000,000/person-year; however, data from regions such as Latin America are scarce. This study is aimed at estimating the incidence and prevalence of acquired MG in Buenos Aires, Argentina. METHODS: The study population comprised of affiliates of the Italian Hospital Medical Care Program, a prepaid health maintenance organization located in Buenos Aires. The evaluation method for case detection included a retrospective search from January 1, 2006, through December 31, 2012. RESULTS: Of the 60 cases identified, 36 (60%) were females. The median age at diagnosis was 69 years (IQR 51.5-79). The mean age at diagnosis was 63.3 years (SD ±20). A total of 28 patients (46.7%) had generalized MG and 32 had ocular MG (53.3%). Thirty five patients (58.3%) had acetylcholine receptor antibodies and 2 (3.3%) had muscle-specific receptor tyrosine kinase antibodies. The crude incidence density (ID) of MG was 61.33 per 1,000,000 person-years (95% CI 47.62-79.99). The adjusted ID for the Argentinean population was 38.8 per 1,000,000 person-years (95% CI 27.09-50.51) and for the Buenos Aires population was 47.49 (95% CI 34.73-60.25). CONCLUSIONS: The results obtained are similar to those published for other geographical areas.

Usefulness of diffusion tensor imaging in amyotrophic lateral sclerosis: potential biomarker and association with the cognitive profile / Utilidad del tensor de difusión en esclerosis lateral amiotrofica: potencial biomarcador y asociación con el perfil cognitivo

ABSTRACT The objective of this preliminary study was to correlate diffusion tensor imaging (DTI) alterations with the cognitive profile of patients with amyotrophic lateral sclerosis (ALS). Methods This was a case-control study conducted from December 1, 2012 to December 1, 2014. Clinical and demographic data were recorded. A neuropsychological test battery adapted to ALS patients was used. An MRI with DTI was performed in all patients and fractional anisotropy (FA) was analyzed in the white matter using the tract based spatial statistics program. Results Twenty-four patients with ALS (15 females, mean age 66.9 + -2.3) and 13 healthy controls (four females, average age 66.9 + - 2) were included. The DTI showed white matter damage in ALS patients vs. healthy controls (p < 0.001). Discussion In our preliminary study the alterations of white matter in DTI were significantly associated with cognitive impairment in patients with ALS.

RESUMEN El objetivo del presente estudio preliminar fue correlacionar alteraciones del Tensor de Difusión (TD) con el perfil cognitivo de pacientes con Esclerosis Lateral Amiotrofica (ELA). Metodos Se realizó estudio casos-controles entre el 1 de Diciembre del 2012 hasta el 1 de Diciembre del 2014. Se registraron datos clínicos y demográficos. Se utilizó batería de tests neuropsicológicos adaptada a ELA. Se realizó RMN de cerebro con TD en todos los pacientes, la Fracción de Anisotropía (FA) se analizó en sustancia blanca, utilizando el programa Tract Based Spatial Statistics. Resultados Se incluyeron 24 pacientes con ELA (15 mujeres, edad media 66.9 + -2.3) y 13 controles sanos (4 mujeres, edad media 66.9 +-2). El TD mostró daño en sustancia blanca en los pacientes con ELA vs controles (p < 0.001). Discusión En nuestro estudio preliminar las alteraciones de sustancia blanca en TD se asociaron significativamente con alteraciones cognitivas en pacientes con ELA.

Immune-mediated rippling muscle disease and myasthenia gravis.

Cases of acquired rippling muscle disease in association with myasthenia gravis have been reported. We present three patients with iRMD (immune-mediated rippling muscle disease) and AChR-antibody positive myasthenia gravis. None of them had thymus pathology. They presented exercise-induced muscle rippling combined with generalized myasthenia gravis. One of them had muscle biopsy showing a myopathic pattern and a patchy immunostaining with caveolin antibodies. They were successfully treated steroids and azathioprine. The immune nature of this association is supported by the response to immunotherapies and the positivity of AChR-antibodies.

Epidemiologia e Informação na Secretaria Municipal da Saúde de São Paulo no período de 1989 a 2001: elementos para escrita de uma história / Epidemiology and Information at the Municipal Health Department of São Paulo from 1989 to 2001: elements for writing a story

Esta obra faz parte do projeto de recuperação da memória histórica do Centro de Epidemiologia, Pesquisa e Informação (CEPI – 1989), do Programa de Aprimoramento das Informações de Mortalidade no Município São Paulo (PRO-AIM – 1989) e da Coordenação de Epidemiologia e Informação (CEInfo - 2001), estruturas da Secretaria Municipal da Saúde de São Paulo (SMS-SP). Trata-se de versão de uma história composta a partir, principalmente, de depoimentos e de informações extraídas de documentos recuperados de um acervo existente e disperso que se encontrava guardado pelos “personagens” dessa história.

Control of an outbreak of postoperative bone mucormycosis: An intervention study of contiguous cohorts.

An outbreak of postoperative bone mucormycosis following arthroscopic anterior cruciate ligament reconstruction in a tertiary referral center in Paraná, Argentina, could have been transmitted through an arthroscopic anterior cruciate ligament reconstruction-exclusive contaminated item. The outbreak was controlled after changing from a system of direct delivery of implants and instruments to the operating room without proper verification, to a controlled and centralized process; specifically, the institution's pharmacy verified the quality and traceability of implants, and instruments were processed only by the institution's central sterile services department.

Diagnósticos de enfermagem do domínio promoção da saúde em mulheres climatéricas com osteoporose / Nursing diagnoses of the domain health promotion in menopausal women with osteoporosis / Diagnóstico de enfermería del dominio promoción de la salud en mujeres climatéricas com osteoporosis

Objetivo: identificar os diagnósticos de enfermagem do domínio promoção da saúde em mulheres com osteoporose no climatério à luz do conceitual de Orem. Método: estudo descritivo, do tipo transversal, realizado com 35 mulheres com diagnóstico de osteoporose secundária à menopausa, na faixa etária de 45 aos 65 anos, atendidas em um centro de especialidades do município de Imperatriz (MA), Brasil. Resultados: os principais diagnósticos identificados foram: Disposição para autocontrole da saúde melhorado (94,2%) e Estilo de vida sedentário (83%). Conclusão:os achados demostraram que a identificação das necessidades de cuidados favorece a implantação de intervenções específicas, contribuindo para a qualidade da assistência de enfermagem às mulheres com osteoporose.(AU)

Objective: to identify the nursing diagnoses of the domain health promotion in women with osteoporosis during menopause in the light of Orem's concept. Method: descriptive, cross-sectional study conducted with 35 women diagnosed with osteoporosis secondary to menopause, aged from 45 to 65 years old, treated at a specialty center in the city of Imperatriz (MA), Brazil. Results: the main identified diagnoses were: Readiness for enhanced self-health management (94.2%) and Sedentary lifestyle (83%). Conclusion: the findings demonstrated that the identification of care needs favors the implementation of specific interventions, contributing to the quality of nursing care to women with osteoporosis.(AU)

Objetivo: identificar los diagnósticos de enfermería del dominio promoción de la salud en mujeres con osteoporosis en el climaterio con base en el concepto de Orem. Método: estudio descriptivo, del tipo transversal, realizado con 35 mujeres con diagnóstico de osteoporosis secundaria a la menopausia, en la edad de 45 a 65 años, atendidas en un centro de especialidades del municipio de Imperatriz (MA), Brasil. Resultados: los principales diagnósticos identificados fueron: Disposición para autocontrol de la salud mejorado (94,2%) y Estilo de vida sedentario (83%). Conclusión: los hallados demostraron que la identificación de las necesidades de cuidados favorece la implantación de intervenciones específicas, contribuyendo para la calidad de la asistencia de enfermería a las mujeres con osteoporosis.(AU)

[Presentations of transthyretin associated familial amyloid polyneuropathy in Argentina]. / Presentaciones de polineuropatía amiloidótica familiar asociada a transtiretina en la Argentina.

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is a hereditary disease with variable geographical distribution. The aim of this study was to present our experience with TTR-FAP patients. We retrospectively analyzed nine cases belonging to different families. Diagnostic criteria were based on the combination of compatible clinical picture, histopathological findings and genetic confirmation. Five cases showed the classic presentation and other 4 the late onset variant. The p.Val30Met mutation in the TTR gene was found in 6 cases and p.Ala36Pro, p.Thr60Ala and p.Tyr114Cys in the remaining 3, respectively. The median age of symptom onset was 35 years (26-60 range). Mean time to diagnosis was 4.2 ± 1.5 years. Our patient series showed the heterogeneity in clinical presentation of TTR-FAP in a non-endemic region of South America.

Presentaciones de polineuropatía amiloidótica familiar asociada a transtiretina en la Argentina / Presentations of transthyretin associated familial amyloid polyneuropathy in Argentina

La polineuropatía amiloidótica familiar asociada a transtiretina (PAF-TTR) es una enfermedad hereditaria con distribución geográfica variable. El objetivo de este trabajo fue presentar nuestra experiencia con pacientes con PAF-TTR. Se evaluaron retrospectivamente 9 casos pertenecientes a diferentes familias. Los criterios diagnósticos utilizados se basaron en la combinación de un cuadro clínico compatible, hallazgos histopatológicos y confirmación genética. Cinco casos mostraron la presentación clásica y 4 la variante de inicio tardío. La mutación p.Val30Met en el gen TTR fue hallada en 6 casos y p.Ala36Pro, p.Thr60Ala y p.Tyr114Cys en los 3 los restantes, respectivamente. La edad media de inicio fue 35 años (rango 26-60). El tiempo medio al diagnóstico fue de 4.2 ± 1.5 años. Siete pacientes recibieron diagnóstico erróneo inicial, 3 de la variante clásica y 4 de la tardía. Nuestra serie de pacientes mostró marcada heterogeneidad en la presentación clínica del grupo de PAF-TTR de inicio tardío, en una región no endémica de Sudamérica.

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is a hereditary disease with variable geographical distribution. The aim of this study was to present our experience with TTR-FAP patients. We retrospectively analyzed nine cases belonging to different families. Diagnostic criteria were based on the combination of compatible clinical picture, histopathological findings and genetic confirmation. Five cases showed the classic presentation and other 4 the late onset variant. The p.Val30Met mutation in the TTR gene was found in 6 cases and p.Ala36Pro, p.Thr60Ala and p.Tyr114Cys in the remaining 3, respectively. The median age of symptom onset was 35 years (26-60 range). Mean time to diagnosis was 4.2 ± 1.5 years. Our patient series showed the heterogeneity in clinical presentation of TTR-FAP in a non-endemic region of South America.

Cylindrical spirals associated with severe congenital muscle weakness and epileptic encephalopathy.

INTRODUCTION: Cylindrical spirals are characteristic muscular inclusions consisting of spiraling double-laminated membranes. They are found in heterogeneous clinical conditions. METHODS: We obtained muscle biopsies from 2 young sisters with severe congenital hypotonia, muscle weakness, and epileptic encephalopathy, and identified cylindrical spirals. RESULTS: We found an association between congenital encephalomyopathy and cylindrical spirals. CONCLUSIONS: In this morphological and ultrastructural study, we speculate on the origin of these peculiar structures.

[Treatment with vitamin D and slowing of progression to severe stage of Alzheimer's disease]. / Tratamiento con vitamina D y enlentecimiento de la progresión a estadio severo en enfermedad de Alzheimer.

The aim of the study was to analyze the impact of treatment with vitamin D in the progression of Alzheimer's disease. We performed a retrospective study including patients with mild stage of Alzheimer's disease with more than four years of follow-up. The presence of cardiovascular risk factors, osteoporosis, treatment with memantine, acetylcholinesterase inhibitors drugs and vitamin D were analyzed as independent variables. Time of progression to moderate and severe Alzheimer's disease was analyzed as dependent variable. The analysis was done using multivariate linear regression model, Kaplan Meier analysis, Chi-square and T test. Two hundred and two patients met the inclusion criteria. 11% of the patients (n = 23) remained in the mild stage of the disease, 54% (n = 110) developed the moderate form in a mean time of 3 ± 1.4 years while 35% (n = 69) developed the severe form in a mean time of 4.6 ± 1.4 years. Time of progression to severe stage of Alzheimer's disease was slower in patients under treatment with vitamin D compared with those without treatment (5.4 ± 0.4 years vs. 4.4 ± 0.16 years respectively, p=0.003). Treatment with vitamin D may be an independent protecting factor in the progression of Alzheimer's disease.