Viral shedding and viraemia of Andes virus during acute hantavirus infection: a prospective study.

BACKGROUND: Andes virus (ANDV) is a zoonotic Orthohantavirus leading to hantavirus cardiopulmonary syndrome. Although most transmissions occur through environmental exposure to rodent faeces and urine, rare person-to-person transmission has been documented, mainly for close contacts. This study investigates the presence and infectivity of ANDV in body fluids from confirmed cases and the duration of viraemia. METHODS: In this prospective study, 131 participants with confirmed ANDV infection were enrolled in Chile in a prospective study between 2008 and 2022. Clinical samples (buffy coat, plasma, gingival crevicular fluid [GCF], saliva, nasopharyngeal swabs [NPS], and urine) were collected weekly for 3 weeks together with clinical and epidemiological data. Samples were categorised as acute or convalescent (up to and after 16 days following onset of symptoms). Infectivity of positive fluids was assessed after the culture of samples on Vero E6 cells and use of flow cytometry assays to determine the production of ANDV nucleoprotein. FINDINGS: ANDV RNA was detected in 100% of buffy coats during acute phase, declining to 95% by day 17, and to 93% between days 23-29. ANDV RNA in GCF and saliva decreased from 30% and 12%, respectively, during the acute phase, to 12% and 11% during the convalescent phase. Successful infectivity assays of RT-qPCR-positive fluids, including GCF, saliva, NPS, and urine, were observed in 18 (42%) of 43 samples obtained during the acute phase of infection. After re-culture, the capacity to infect Vero E6 cells was maintained in 16 (89%) of 18 samples. Severity was associated with the presence of ANDV RNA in one or more fluids besides blood (odds ratio 2·58 [95% CI 1·42-5·18]). INTERPRETATION: ANDV infection is a systemic and viraemic infection, that affects various organs. The presence of infectious particles in body fluids contributes to our understanding of potential mechanisms for person-to-person transmission, supporting the development of preventive strategies. Detection of ANDV RNA in additional fluids at hospital admission is a predictor of disease severity. FUNDING: National Institutes of Health and Agencia de Investigación y Desarrollo. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Esquizofrenia resistente al tratamiento: dos copos de nieve / Treatment-Resistant Schizophrenia: Two Snowflakes

Presentamos el caso de dos pacientes, con edades comprendidas entre 18 y 25 años, que han sido hospitalizados previamente en diversas instituciones debido a su resistencia a múltiples tratamientos y regímenes terapéuticos. A pesar de haber tenido intervenciones terapéuticas diversas, ninguna ha sido exitosa. Estos casos han suscitado múltiples interrogantes debido a las notables similitudes en sus presentaciones clínicas, a pesar de tener diferentes tiempos de evolución de la enfermedad. Ambos pacientes presentan delirios e ideaciones de perjuicio hacia sus perspectivas madres. SE intento, sin éxito, administrar antipsicóticos atípicos no incluidos en la lista nacional de medicamentos para ambos pacientes, sin obtener una respuesta clínica positiva. Es sorprendente que, además de compartir numerosas características clínicas, ambos pacientes son varones, fueron admitidos casi simultáneamente en nuestra institución y comparten el mismo nombre.

Star'd y mas allá: una mirada profunda a la eficacia de los antidepresivos / Star'd and Beyond: An In-Depth Look at the Efficacy of Antidepressants

El estudio STAR'D busco identificar las intervenciones terapéuticas más eficaces para pacientes con trastorno depresivo mayor no tratado previamente. Se trató de un ensayo clínica naturalista y a gran escala, diseñado para determinar las estrategias terapéuticas más eficiente en aquellos pacientes que no responden a un tratamiento inicial. Aunque algunos profesionales consideraron el estudio alentador al proporcionar una ruta secuencias de alternativas farmacológicas, muchos lo vieron como un recordatorio revelador de las limitaciones inherentes de los antidepresivos: estos medicamentos no son la solución definitiva para la depresión. Este artículo tiene como propósito brindar un panorama conciso del estudio STAR'D, seguido de una reflexión crítica sobre sus hallazgos e implicaciones en el ámbito clínico.

Early Interventional Treatments for Patients with Cancer Pain: A Narrative Review.

Between 10% and 20% of patients with cancer-related pain cannot achieve adequate control following the three-step ladder guidelines by the World Health Organization. Therefore, a "fourth step", including interventional approaches, has been suggested for those cases. Systematic reviews support the early use of interventional procedures to treat refractory cancer pain, control symptoms and prevent opioid dose escalation. There is strong evidence of the efficacy of celiac plexus or splanchnic neurolysis, vertebroplasty, kyphoplasty and intrathecal drug delivery. Those procedures have been found to be associated with a decrease in the symptom burden and opioid consumption, improved quality of life, and suggested as having a potentially positive impact on survival. Several studies have recommended using specific interventional techniques at earlier stages, possibly even when opioid treatment is first being considered. Conversely, leaving these options as a last analgesic resource might not be advisable since the burden these procedures might impose on too ill patients is significant. The objective of this review was to collect the available evidence published on the use of interventional treatments for refractory cancer pain with a particular interest in comparing early versus late indications. The results of the search demonstrated a very low number and quality of articles particularly addressing this question. This scarce number of evidence precluded performing a systematic analysis. A detailed and narrative description of the potential benefits of integrating interventional techniques into clinical guidelines at the early stages of the disease is provided.

Penicillium digitatum, First Clinical Report in Chile: Fungal Co-Infection in COVID-19 Patient.

Penicillium digitatum is one of the most important phytopathogens. It causes deterioration and rotting of citrus fruits, generating significant economic losses worldwide. As a human pathogen, it is extremely rare. We present a case of pulmonary co-infection in a patient diagnosed with pneumonia due to SARS-CoV-2. A 20-year-old female patient, primigravid, 36 weeks of gestation, without comorbidities, and diagnosed with severe pneumonia due to the SARS-CoV-2, showed rapid lung deterioration for which their pregnancy was interrupted by surgery. The patient was hospitalized in the Intensive Care Unit (ICU), connected to mechanical ventilation and receiving corticosteroids and antibiotics. The diagnosis of pulmonary fungal infection was made through bronchoalveolar lavage (BAL) culture, and the species identification was performed by sequencing of ß-tubulin. Phylogenetic analysis with related species was performed for the confirmation of species identification. Antifungal susceptibility tests were performed for itraconazole (4 µg/mL), voriconazole (2 µg/mL), and amphotericin B (2 µg/mL). The patient was successfully treated with itraconazole. This is the second worldwide report of pulmonary infection by P. digitatum and the first in Chile. Although it is a fungus that rarely infects humans, it could represent an emerging opportunistic fungal pathogen, with associated risk factors that should be considered in the differential diagnosis of Penicillium species isolated from infections in humans.

Endothelial NCK2 promotes atherosclerosis progression in male but not female Nck1-null atheroprone mice.

A better understanding of endothelial dysfunction holds promise for more effective interventions for atherosclerosis prevention and treatment. Endothelial signaling by the non-catalytic region of the tyrosine kinase (NCK) family of adaptors, consisting of NCK1 and NCK2, has been implicated in cardiovascular development and postnatal angiogenesis but its role in vascular disease remains incompletely understood. Here, we report stage- and sex-dependent effects of endothelial NCK2 signaling on arterial wall inflammation and atherosclerosis development. Male and female Nck1-null atheroprone mice enabling inducible, endothelial-specific Nck2 inactivation were fed a high fat diet (HFD) for 8 or 16 weeks to model atherosclerosis initiation and progression, respectively. Analysis of aorta preparations en face during disease progression, but not initiation, showed a significant reduction in plaque burden in males, but not females, lacking endothelial NCK2 relative to controls. Markers of vascular inflammation were reduced by endothelial NCK2 deficiency in both males and females during atherosclerosis progression but not initiation. At advanced stages of disease, plaque size and severity of atherosclerotic lesions were reduced by abrogation of endothelial NCK2 signaling only in males. Collectively, our results demonstrate stage- and sex-dependent modulation of atherosclerosis development by endothelial NCK2 signaling.

¿Quién gobierna? Gobernamentalidad en la intervención de adolescentes infractores en el sur de Chile / Who governs? Governamentality in adolescent offenders intervention in the south of Chile

En Chile diversas investigaciones coinciden en afirmar que la implementación de la Ley de Responsabilidad Penal Adolescente no ha logrado proteger los derechos de los jóvenes sancionados. Desde la perspectiva teórica de la gobernamentalidad, este estudio tiene como objetivo comprender la articulación entre las tecnologías de gobierno y las prácticas de subjetivación de adolescentes con infracción de ley en un programa de Libertad Asistida en el sur de Chile. Utilizamos una metodología cualitativa de estudio de caso de un programa que consideró entrevistas a interventores, observación de talleres, análisis de documentos y de perfiles Facebook. Como principales resultados afirmamos que en el programa se produce una articulación entre las tecnologías que pretenden gobernar comportamientos de los adolescentes y las prácticas o tecnologías del yo de los adolescentes que permite, al mismo tiempo, la mantención del programa, así como de contra conductas de los adolescentes que entra en conflicto con la ley. Se discute el rol del sistema de licitación de estos programas y su relación con la lógica penal de cuantificación de las sanciones en la producción de sujetos.(AU)

In Chile, several investigations coincide in affirming that the implementation of the Adolescent Penal Responsibility Law has failed to protect the rights of penalized youth. From the theoretical perspective of governmentality, this study aims to understand the articulation between government technologies and the subjectivization practices of adolescents with a law violation in an Assisted Freedom program in southern Chile. We used a qualitative methodology of case study of the program that consisted of interviews with staff, observation of workshops, analysis of documents and Facebook profiles of adolescents. As main results we affirm that in the program there is an articulation between the technologies that seek to govern adolescent behaviors and the practices or technologies of the self of adolescent that allows both, the maintenance of the program, and counter-behaviors of the teenagers who conflict with the law. The role of the bidding system for these programs and its relationship with the penal logic of quantifying sanctions in the production of subjects are discussed.(AU)

Nck adaptors at a glance.

The non-catalytic region of tyrosine kinase (Nck) family of adaptors, consisting of Nck1 and Nck2, contributes to selectivity and specificity in the flow of cellular information by recruiting components of signaling networks. Known to play key roles in cytoskeletal remodeling, Nck adaptors modulate host cell-pathogen interactions, immune cell receptor activation, cell adhesion and motility, and intercellular junctions in kidney podocytes. Genetic inactivation of both members of the Nck family results in embryonic lethality; however, viability of mice lacking either one of these adaptors suggests partial functional redundancy. In this Cell Science at a Glance and the accompanying poster, we highlight the molecular organization and functions of the Nck family, focusing on key interactions and pathways, regulation of cellular processes, development, homeostasis and pathogenesis, as well as emerging and non-redundant functions of Nck1 compared to those of Nck2. This article thus aims to provide a timely perspective on the biology of Nck adaptors and their potential as therapeutic targets.

Use of bisphosphonates in a retrospective case series of children and adolescents with complex regional pain syndrome.

BACKGROUND: There is increasing evidence for the use of bisphosphonates to treat Complex Regional Pain Syndrome in adults. However, there are scarce data for their use in children with Complex Regional Pain Syndrome. AIM: This retrospective case series aimed to analyze the effects of intravenous bisphosphonate use in children and adolescents with Complex Regional Pain Syndrome enrolled in a multidimensional pain treatment program. METHODS: We analyzed the data of 16 patients (15 females and 1 male, mean age 14 ± 3 years) who received infusions of zoledronic acid (0.015 ± 0.0044mg/kg), pamidronate (0.72 ± 0.17mg/kg), or both depending on their initial response between October 2014 and December 2019. The primary endpoint of the study was the patient's global impression of change. Secondary outcomes included pain intensity, physical function, role function (school attendance), need for pain medications, and adverse effects. RESULTS: Nine of 16 patients reported meaningful improvements (global impressions of change of 84% or higher) at a median follow-up time of 16 (8-21) months after their last infusion of bisphosphonates. There were also meaningful reductions in pain intensity and the need for pain medications. There was an increase in the proportion of patients with minimal or without physical disability, and almost all patients normalized their school activities. Thirteen patients (81%) reported adverse effects, mostly flu-like symptoms, for a few days after the infusion. CONCLUSION: The use of bisphosphonate infusions may represent an effective treatment option for children with Complex Regional Pain Syndrome, not responding to multidisciplinary pain treatment programs.

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder.

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

Monogenic variants in dystonia: an exome-wide sequencing study.

BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. FUNDING: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

An immunotherapy effect analysis in Rasmussen encephalitis.

BACKGROUND: Immune-mediated mechanisms substantially contribute to the Rasmussen encephalitis (RE) pathology, but for unknown reasons, immunotherapy is generally ineffective in patients who have already developed intractable epilepsy; overall laboratory data regarding the effect of immunotherapy on patients with RE are limited. We analyzed multiple samples from seven differently treated children with RE and evaluated the effects of immunotherapies on neuroinflammation. Immunotherapy was introduced to all patients at the time of intractable epilepsy and they all had to undergo hemispherothomy. METHODS: Immunohistochemistry, flow cytometry, Luminex multiplex bead and enzyme-linked immunosorbent assay techniques were combined to determine: 1) inflammatory changes and lymphocyte subpopulations in 45 brain tissues; 2) lymphocyte subpopulations and the levels of 12 chemokines/cytokines in 24 cerebrospinal fluid (CSF) samples and 30 blood samples; and 3) the dynamics of these parameters in four RE patients from whom multiple samples were collected. RESULTS: Sustained T cell-targeted therapy with cyclophosphamide, natalizumab, alemtuzumab, and intrathecal methotrexate (ITMTX), but not with azathioprine, substantially reduced inflammation in brain tissues. Despite the therapy, the distributions of CD8+ T cells and the levels of C-X-C motif ligand (CXCL) 10, CXCL13, and B cell activating factor (BAFF) in patients' CSF remained increased compared to controls. A therapeutic approach combining alemtuzumab and ITMTX was the most effective in producing simultaneous reductions in histopathological inflammatory findings and in the numbers of activated CD8+ T cells in the brain tissue, as well as in the overall CD8+ T cell population and chemokine/cytokine production in the CSF. CONCLUSIONS: We provide evidence that various T cell-targeted immunotherapies reduced inflammation in the brains of RE patients. The observation that intractable epilepsy persisted in all of the patients suggests a relative independence of seizure activity on the presence of T cells in the brain later in the disease course. Thus, new therapeutic targets must be identified. CXCL10, CXCL13 and BAFF levels were substantially increased in CSF from all patients and their significance in RE pathology remains to be addressed.

Nck adapter proteins promote podosome biogenesis facilitating extracellular matrix degradation and cancer invasion.

BACKGROUND: Podosomes are membrane-bound adhesive structures formed by actin remodeling. They are capable of extracellular matrix (ECM) degradation, which is a prerequisite for cancer cell invasion and metastasis. The signaling mechanism of podosome formation is still unknown in cancer. We previously reported that Nck adaptors regulate directional cell migration and endothelial lumen formation by actin remodeling, while deficiency of Nck reduces cancer metastasis. This study evaluated the role of Nck adaptors in podosome biogenesis and cancer invasion. METHODS: This study was conducted in vitro using both healthy cells (Human Umbilical Vein Endothelial Cell, 3T3 fibroblasts) and cancer cells (prostate cancer cell line; PC3, breast cancer cell line; MDA-MB-231). Confocal and TIRF imaging of cells expressing Green Fluorescence Protein (GFP)  mutant under altered levels of Nck or downstream of kinase 1 (Dok1) was used to evaluate the podosome formation and fluorescent gelatin matrix degradation. Levels of Nck in human breast carcinoma tissue sections were detected by immune histochemistry using Nck polyclonal antibody. Biochemical interaction of Nck/Dok1 was detected in podosome forming cells using immune precipitation and far-western blotting. RESULTS: This study demonstrates that ectopic expression of Nck1 and Nck2 can induce the endothelial podosome formation in vitro. Nck silencing by short-hairpin RNA blocked podosome biogenesis and ECM degradation in cSrc-Y530F transformed endothelial cells in this study. Immunohistochemical analysis revealed the Nck overexpression in human breast carcinoma tissue sections. Immunoprecipitation and far-western blotting revealed the biochemical interaction of Nck/p62Dok in podosome forming cells. CONCLUSIONS: Nck adaptors in interaction with Dok1 induce podosome biogenesis and ECM degradation facilitating cancer cell invasion, and therefore a bona fide target of cancer therapy.

Interventional procedures in children and adolescents with chronic non-cancer pain as part of a multidisciplinary pain treatment program.

BACKGROUND: Interventional procedures are part of multidisciplinary pain treatment programs to treat chronic non-cancer pain conditions in children and adolescents. However, the real benefit of these interventions remains unclear. AIMS: The aim of this study was to analyze the potential benefits of the interventional procedures in children and adolescents with chronic non-cancer pain in the setting of a multidisciplinary pain treatment program. METHODS: We retrospectively reviewed the charts of 98 children and adolescents receiving 314 diagnostic or therapeutic interventional procedures. We applied the following definitions of efficacy Short-term positive therapeutic effect: block that produced a minimum of 50% reduction in pain intensity for at least 4 weeks. Long-term positive therapeutic effect: a patient with a minimum of 50% reduction in pain intensity for at least 6 months Full recovery: a patient free of pain, not taking analgesics with normal physical and role functioning 6 months after the last procedure. RESULTS: Seventy-six of 112 diagnostic blocks (68%) were associated with a 50% reduction in pain intensity for at least 4 weeks after the procedure. One hundred and sixty-six of 202 therapeutics blocks (82%) were associated with a short-term benefit. Seventy-two of 98 patients (73%) referred a 50% reduction in their pain intensity (17%) or had full recovery 6 months after the procedures (56%) and a MPTP. Psychiatric comorbidity and more advanced age were factors associated with failure to respond to interventional procedures. CONCLUSION: The use of interventional procedures may represent a valid therapeutic option, associated with positive clinical outcomes within a multidisciplinary program.

Nck deficiency is associated with delayed breast carcinoma progression and reduced metastasis.

Although it is known that noncatalytic region of tyrosine kinase (Nck) regulates cell adhesion and migration by bridging tyrosine phosphorylation with cytoskeletal remodeling, the role of Nck in tumorigenesis and metastasis has remained undetermined. Here we report that Nck is required for the growth and vascularization of primary tumors and lung metastases in a breast cancer xenograft model as well as extravasation following injection of carcinoma cells into the tail vein. We provide evidence that Nck directs the polarization of cell-matrix interactions for efficient migration in three-dimensional microenvironments. We show that Nck advances breast carcinoma cell invasion by regulating actin dynamics at invadopodia and enhancing focalized extracellular matrix proteolysis by directing the delivery and accumulation of MMP14 at the cell surface. We find that Nck-dependent cytoskeletal changes are mechanistically linked to enhanced RhoA but restricted spatiotemporal activation of Cdc42. Using a combination of protein silencing and forced expression of wild-type/constitutively active variants, we provide evidence that Nck is an upstream regulator of RhoA-dependent, MMP14-mediated breast carcinoma cell invasion. By identifying Nck as an important driver of breast carcinoma progression and metastasis, these results lay the groundwork for future studies assessing the therapeutic potential of targeting Nck in aggressive cancers.

Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection.

Cryptococcus neoformans (Cn) is a deadly fungal pathogen whose intracellular lifestyle is important for virulence. Host mechanisms controlling fungal phagocytosis and replication remain obscure. Here, we perform a global phosphoproteomic analysis of the host response to Cryptococcus infection. Our analysis reveals numerous and diverse host proteins that are differentially phosphorylated following fungal ingestion by macrophages, thereby indicating global reprogramming of host kinase signaling. Notably, phagocytosis of the pathogen activates the host autophagy initiation complex (AIC) and the upstream regulatory components LKB1 and AMPKα, which regulate autophagy induction through their kinase activities. Deletion of Prkaa1, the gene encoding AMPKα1, in monocytes results in resistance to fungal colonization of mice. Finally, the recruitment of AIC components to nascent Cryptococcus-containing vacuoles (CnCVs) regulates the intracellular trafficking and replication of the pathogen. These findings demonstrate that host AIC regulatory networks confer susceptibility to infection and establish a proteomic resource for elucidating host mechanisms that regulate fungal intracellular parasitism.

Nitrous oxide for procedural analgesia at home in a child with epidermolysis bullosa.

Epidermolysis bullosa comprises a range of conditions characterized by fragile skin with painful blistering induced by minor trauma and friction. The Dowling-Meara variant is a severe form characterized by disseminated painful blistering requiring lifelong skin and wound care. The natural history of the disease is characterized by a chronic course that tends to improve with advancing age. Various multimodal analgesic strategies have been proposed for painful procedures in children with epidermolysis bullosa. In this case report, we describe the use of nitrous oxide for pain control at home of blister treatments in a 4-year-old child with the Dowling-Meara variant.

Identidad étnica y conductas sociales en adolescentes indígenas mapuche sancionados por la Ley de Responsabilidad Penal Adolescente en regiones del sur de Chile / Ethnic Identity and Social Behaviors in Indigenous Juvenile Offenders Sentenced by the Law in the South of Chile

RESUMEN Se analiza la relación entre identidad étnica y conductas sociales en 60 adolescentes indígenas infractores de ley autoidentificados como mapuche. La identidad étnica se obtiene con la Escala IEM; conductas sociales, con CACSA; delitos autorreportados, con EDA y judicializados, con Ficha FER-R. El objetivo fue evaluar la asociación entre grado de desarrollo de identidad étnica con presencia de conductas antisociales y prosociales. Los resultados indican que a mayor desarrollo de identidad étnica menor presencia de conductas antisociales, no observándose relación entre identidad étnica y conductas prosociales. Se discute la relevancia de la identidad étnica como factor protector específico en adolescentes infractores mapuche y en adolescentes de otros pueblos indígenas en general, convirtiéndose en posible foco de intervención para desestimar estas conductas.

ABSTRACT We examined the relationship between ethnic identity and social behaviors in 60 indigenous juvenile offenders self-identified as mapuche. Ethnic identity is obtained with IEM scale, social behaviors with CACSA, self-reported and sentenced offenses with EDA and FER-R. The objective was to evaluate the association between the degree of ethnic identity development with presence of antisocial and prosocial behavior. The results indicate that ethnic identity development was related to lesser presence of antisocial behaviors, though no relationship between ethnic identity and prosocial behaviors. The possible relevance of ethnic identity as a protective factor in mapuche youth offenders in specific and in general to adolescents of other indigenous people, becoming a possible focus of intervention to dismiss these behaviors is discussed.

Respuesta virológica e inmunológica a la terapia anti-retroviral en pacientes portadores de infección por VIH atendidos en una red de salud académica de Chile / Virological and immunological outcomes to antiretroviral therapy in HIV-infected patients of an academic medical center in Chile

Introduction: Red Salud UC is an Academic health network where HIV-infected patients from the public and private health system are followed by a multidisplinary team. Aim: To determine virologic and immunologic response after 144 weeks of starting first antiretroviral therapy in these patients. Methods: A retrospective analysis of adult HIV patients attended between 1992 and 2011 was performed. Demographic and clinical characteristics, antiretroviral therapies data and immunologic and virologic outcomes were collected. CD4 count and HIV viral load changes up to 144 weeks after initiation of antiretroviral therapy were analyzed. Results: 860 patients were included in the analyses. Median age was 42 years, 93% were men. Median CD4+ count at baseline was 202 cells/mm³. The most used ART regimen was zidovudine/lamivudine plus efavirenz. First line anti-retroviral therapy was changed in 42% patients, being the most common cause, drug toxicity. At week 144, median CD4+ lymphocyte cell count was 449 cells/mm³. Ninety percent and 96% had undetectable viral load measured as < 50 copies/mL or < 400 copies/mL respectively. Discussion: First report of a university cohort, with CD4 and viral load follow up for 144 weeks, including Chilean patients from public and private system. After initiation of ART, an excellent immunologic and virologic response was observed in this cohort.

Introducción: La Red de Salud UC es una red académica de atención, donde pacientes portadores del VIH del área pública y privada de salud son atendidos por un equipo profesional multidisciplinario. Objetivo: Determinar las respuestas virológicas e inmunológicas a 144 semanas de iniciada la primera terapia antiretroviral en dichos pacientes. Métodos: Análisis retrospectivo de registros de pacientes adultos portadores de VIH atendidos entre 1992 y 2011. Se recolectaron datos demográficos, clínicos, terapia anti-retroviral, resultados inmunológicos y virológicos. Se analizaron los resultados de linfocitos T CD4+ y carga viral de VIH a las 144 semanas de iniciada la primera terapia anti-retroviral. Resultados: Fueron incluidos en el análisis 860 pacientes. El promedio de edad fue 42 años, 93% hombres. La mediana basal de LT CD4+ fue 202 céls/mm³. La terapia más utilizada fue zidovudina/lamivudina/efavirenz. En 42% de los pacientes se cambió la terapia de primera línea; la causa más común fue toxicidad a los anti-retrovirales. A la semana 144 de iniciada la terapia, la mediana de LT CD4+ fue de 449 céls/mm³. Alcanzaron cargas virales indetectables 90 y 96% con < 50 copias ARN/mL o < 400 copias ARN/mL respectivamente. Discusión: Primer reporte de pacientes tratados en un centro universitario, con seguimiento inmuno-virológico a 144 semanas, que incluye pacientes del área pública y privada de salud chilena. Después del inicio de la terapia, se observó una excelente respuesta inmuno-virológica.

The Cytoskeletal Adapter Protein Spinophilin Regulates Invadopodia Dynamics and Tumor Cell Invasion in Glioblastoma.

Glioblastoma is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive glioblastoma cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin αvß8 and its intracellular binding partner, Spinophilin (Spn), which regulates glioblastoma cell invasion in the brain microenvironment. We show for the first time that Spn binds directly to the cytoplasmic domain of ß8 integrin in glioblastoma cells. Genetically targeting Spn leads to enhanced invasive cell growth in preclinical models of glioblastoma. Spn regulates glioblastoma cell invasion by modulating the formation and dissolution of invadopodia. Spn-regulated invadopodia dynamics are dependent, in part, on proper spatiotemporal activation of the Rac1 GTPase. Glioblastoma cells that lack Spn showed diminished Rac1 activities, increased numbers of invadopodia, and enhanced extracellular matrix degradation. Collectively, these data identify Spn as a critical adhesion and signaling protein that is essential for modulating glioblastoma cell invasion in the brain microenvironment. IMPLICATIONS: Tumor cell invasion is a major clinical obstacle in glioblastoma and this study identifies a new signaling pathway regulated by Spinophilin in invasive glioblastoma. Mol Cancer Res; 14(12); 1277-87. ©2016 AACR.