Prevalence of p.G87V and p.Gln298=Variations in LIPA Gene Within Middle Eastern Population Living Around Los Angeles.

Background: The LIPA gene encodes for lysosomal acid lipase (LAL), which catalyzes the hydrolysis of cholesterol esters and triglycerides. Variations in the LIPA gene impair LAL activity, predisposing patients to a rare metabolic disorder called LAL deficiency (LAL-D). The lack of functioning LAL promotes lipid accumulation and subsequent dyslipidemia, which can increase the likelihood of complications in both infants and adults. Although the worldwide prevalence is 1:500,000 births, the frequency in Mizrahi Jewish populations is projected to be as high as 1 in every 4200 births (Valles-Ayoub et al.) based on the LIPA p.G87V variant frequency among 162 individuals. Materials and Methods: This study was conducted to validate the previously reported prevalence of LAL-D in the Mizrahi Jewish population based on the pathogenic LIPA missense variants in exon 4 (c.260G>T; p.G87V) and exon 8 (c.894G>A; p.Gln298=) using a larger cohort of those with Middle Eastern ancestry living around Los Angeles. Among the 1184 individual samples sequenced, 660 self-reported as Mizrahi Jewish, while the remaining 524 came from other Middle Eastern groups labeled as "non-Jewish." Results: Of the 1184 samples, 22 alleles of the exon 4 variant were identified (1.85%), and 2 alleles of the exon 8 variant were identified (0.16%). For the exon 4 variant, 20 of 22 (90.9%) heterozygotes were Mizrahi Jewish, while 2 of 22 (9.09%) heterozygotes were "non-Jewish." For the exon 8 variant, 2 of 2 (100%) heterozygotes were Mizrahi Jewish. This suggests that the prevalence of LAL-D in this population is 1 in 900, which suggests that LAL-D may be 4.6% higher in the Mizrahi Jewish population in previous reports. Conclusion: These findings show increased prevalence of LIPA gene exon 4 variation p.G87V in the Middle East population when compared to the general population, indicating the need for prenatal screening in those of Mizrahi Jewish ancestry.

Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.

The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.

Physicochemical Composition and Apparent Degree of Polymerization of Fructans in Five Wild Agave Varieties: Potential Industrial Use.

In this study, we characterize fructan extracts from five wild agave varieties at three ages to identify their potential use in the food industry. Physicochemical parameters (solids soluble total and pH), sugar content and fructan distribution profiles by high-performance anion-exchange chromatography (HPAEC) were evaluated. We found that the ages and variety influenced the carbohydrate content and also fructan dispersion. Two- to four-year-old plants exhibited the highest concentrations of free sugars and fructans, with a low apparent degree of polymerization (DPa) of ≤9 monomers, which highlights their potential use as prebiotics. Conversely, 10- to 12-year-old plants presented a low concentration of free sugars and fructans with a maximum DPa of 70 monomers, which can be used to obtain fractions with high, intermediate and low DPa. These fractions have a potential use in the food industry as prebiotic, soluble fibers, stabilizers and sweeteners, among others. The agave varieties Agave spp., Agave salmiana, and Agave atrovirens showed mainly fructooligosaccharides (FOSs). Due to the presence of these low molecular carbohydrates, prebiotics, fermented products and/or syrups could be obtained. A. salmiana spp. crassipina and Agave tequilana variety cenizo presented DPa ≤50 and DPa ≤70, respectively, which could be useful in the production of fructan fractions of different DPa. These fractions might be used as functional ingredients in the manufacture of a wide range of food products.

Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness.

Most genetically distinct inherited retinal degenerations are primary photoreceptor degenerations. We selected a severe early onset form of Leber congenital amaurosis (LCA), caused by mutations in the gene LCA5, in order to test the efficacy of gene augmentation therapy for a ciliopathy. The LCA5-encoded protein, Lebercilin, is essential for the trafficking of proteins and vesicles to the photoreceptor outer segment. Using the AAV serotype AAV7m8 to deliver a human LCA5 cDNA into an Lca5 null mouse model of LCA5, we show partial rescue of retinal structure and visual function. Specifically, we observed restoration of rod-and-cone-driven electroretinograms in about 25% of injected eyes, restoration of pupillary light responses in the majority of treated eyes, an ∼20-fold decrease in target luminance necessary for visually guided behavior, and improved retinal architecture following gene transfer. Using LCA5 patient-derived iPSC-RPEs, we show that delivery of the LCA5 cDNA restores lebercilin protein and rescues cilia quantity. The results presented in this study support a path forward aiming to develop safety and efficacy trials for gene augmentation therapy in human subjects with LCA5 mutations. They also provide the framework for measuring the effects of intervention in ciliopathies and other severe, early-onset blinding conditions.

Use of induced pluripotent stem cell models to probe the pathogenesis of Choroideremia and to develop a potential treatment.

Choroideremia (CHM) is a rare monogenic, X-linked recessive inherited retinal degeneration resulting from mutations in the Rab Escort Protein-1 (REP1) encoding CHM gene. The primary retinal cell type leading to CHM is unknown. In this study, we explored the utility of induced pluripotent stem cell-derived models of retinal pigmented epithelium (iPSC-RPE) to study disease pathogenesis and a potential gene-based intervention in four different genetically distinct forms of CHM. A number of abnormal cell biologic, biochemical, and physiologic functions were identified in the CHM mutant cells. We then identified a recombinant adeno-associated virus (AAV) serotype, AAV7m8, that is optimal for both delivering transgenes to iPSC-RPEs as well as to appropriate target cells (RPE cells and rod photoreceptors) in the primate retina. To establish the proof of concept of AAV7m8 mediated CHM gene therapy, we developed AAV7m8.hCHM, which delivers the human CHM cDNA under control of CMV-enhanced chicken ß-actin promoter (CßA). Delivery of AAV7m8.hCHM to CHM iPSC-RPEs restored protein prenylation, trafficking and phagocytosis. The results confirm that AAV-mediated delivery of the REP1-encoding gene can rescue defects in CHM iPSC-RPE regardless of the type of disease-causing mutation. The results also extend our understanding of mechanisms involved in the pathophysiology of choroideremia.

NIPBL+/- haploinsufficiency reveals a constellation of transcriptome disruptions in the pluripotent and cardiac states.

Cornelia de Lange syndrome (CdLS) is a complex disorder with multiple structural and developmental defects caused by mutations in structural and regulatory proteins involved in the cohesin complex. NIPBL, a cohesin regulatory protein, has been identified as a critical protein responsible for the orchestration of transcriptomic regulatory networks necessary for embryonic development. Mutations in NIPBL are responsible for the majority of cases of CdLS. Through RNA-sequencing of human induced pluripotent stem cells and in vitro-derived cardiomyocytes, we identified hundreds of mRNAs, pseudogenes, and non-coding RNAs with altered expression in NIPBL+/- patient-derived cells. We demonstrate that NIPBL haploinsufficiency leads to upregulation of gene sets identified in functions related to nucleosome, chromatin assembly, RNA modification and downregulation of Wnt signaling, cholesterol biosynthesis and vesicular transport in iPSC and cardiomyocytes. Mutations in NIPBL result in the dysregulation of many genes responsible for normal heart development likely resulting in the variety of structural cardiac defects observed in the CdLS population.

Cornelia de Lange syndrome and molecular implications of the cohesin complex: Abstracts from the 7th biennial scientific and educational symposium 2016.

Cornelia de Lange Syndrome (CdLS) is due to mutations in the genes for the structural and regulatory proteins that make up the cohesin complex, and is considered a cohesinopathy disorder or, more recently, a transcriptomopathy. New phenotypes have been recognized in this expanding field. There are multiple clinical issues facing individuals with all forms of CdLS, particularly in the neurodevelopmental system, but also gastrointestinal, cardiac, and musculoskeletal. Aspects of developmental and cell biology have found common endpoints in the biology of the cohesin complex, with improved understanding of the mechanisms, easier diagnostic tests, and the possibility of potential therapeutics, all major clinical implications for the individual with CdLS. The following abstracts are the presentations from the 7th Cornelia de Lange Syndrome Scientific and Educational Symposium, June 22-23, 2016, in Orlando, FL, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting. In addition to the scientific and clinical discussions, there were talks related to practical aspects of behavior including autism, transitions, communication, access to medical care, and databases. At the end of the symposium, a panel was held, which included several parents, affected individuals and genetic counselors, and discussed the greatest challenges in life and how this information can assist in guiding future research. The Research Committee of the CdLS Foundation organizes this meeting, reviews, and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board and publications. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD.

[Not Available]. / Efectos de la suplementación de omega-3 y entrenamiento de intervalos de alta intensidad en el rendimiento físico, presión arterial y composición corporal en individuos sedentarios con sobrepeso.

Introducción: el entrenamiento de intervalos de alta intensidad (HIIT) y el consumo de ácidos grasos omega-3 (O3) ha demostrado cada uno por separado aumentar la capacidad aeróbica, metabolismo oxidativo y función cardiovascular.Objetivo: examinar el efecto combinado de HIIT más suplementación de O3 en el rendimiento físico, presión arterial y composición corporal en jóvenes sedentarios.Método: 28 jóvenes sedentarios con sobrepeso (Edad=22 ± 4 años; IMC=25.8 ± 2.4 kg·m-2) fueron distribuidos aleatoriamente en cuatro grupos: grupo O3/HIIT (n=7) realizó un protocolo de HIIT, tres veces por semana durante seis semanas y consumió 2 g·día-1 de O3; grupo HIIT (n=7) realizó solo el HIIT; grupo O3 (n=7) solo consumió O3; y grupo CONTROL (n=7) que no realizó ninguna intervención. Consumo de oxígeno peak (VO2peak), velocidad máxima (Vmax), presión arterial sistólica y diastólica (PAS y PAD), y porcentaje de grasa fueron medidos antes y después de la intervención.Resultados: el consumo de oxígeno peak aumentó más en el grupo O3/HIIT (+10.9%) en comparación con HIIT, O3 y CONTROL. Velocidad máxima aumentó en O3/HIIT (+7.1%) y HIIT (+11.9%). La presión arterial sistólica disminuyó más en O3 (-6.8%) en comparación con O3/HIIT, HIIT y CONTROL. Por último, O3/HIIT (-19.2%), HIIT (-20.2%), y O3 (-15.2%) presentaron mayores disminuciones del porcentaje de masa grasa en relación al CONTROL.Conclusión: nuestros resultados sugieren un efecto potenciador de la capacidad aeróbica máxima producto de la combinación de HIIT y suplementación de O3. Además, se observó una disminución de masa grasa en todos los grupos intervenidos.

Efectos de la suplementación de omega-3 y entrenamiento de intervalos de alta intensidad en el rendimiento físico, presión arterial y composición corporal en individuos sedentarios con sobrepeso / Effects of omega-3 supplementation and high intensity interval training in physical performance, blood pressure and body composition in overweight individuals

Introducción: el entrenamiento de intervalos de alta intensidad (HIIT) y el consumo de ácidos grasos omega-3 (O3) ha demostrado cada uno por separado aumentar la capacidad aeróbica, el metabolismo oxidativo y la función cardiovascular. Objetivo: examinar el efecto combinado de HIIT más suplementación de O3 en el rendimiento físico, presión arterial y composición corporal en jóvenes sedentarios. Métodos: 28 jóvenes sedentarios con sobrepeso (edad = 22 ± 4 años; IMC = 25,8 ± 2,4 kg·m -2 ) fueron distribuidos aleatoriamente en cuatro grupos: grupo O3/HIIT (n = 7) realizó un protocolo de HIIT, tres veces por semana durante seis semanas y consumió 2 g·día -1 de O3; grupo HIIT (n = 7) realizó solo el HIIT; grupo O3 (n = 7) solo consumió O3; y grupo control (n = 7) que no realizó ninguna intervención. Consumo de oxígeno peak (VO 2 peak ), velocidad máxima (Vmax ), presión arterial sistólica y diastólica (PAS y PAD), y porcentaje de grasa fueron medidos antes y después de la intervención. Resultados: el consumo de oxígeno peak aumentó más en el grupo O3/HIIT (+10,9%) en comparación con HIIT, O3 y control. Velocidad máxima aumentó en O3/HIIT (+7,1%) y HIIT (+11,9%). La presión arterial sistólica disminuyó más en O3 (-6,8%) en comparación con O3/HIIT, HIIT y control. Por último, O3/HIIT (-19,2%), HIIT (-20,2%), y O3 (-15,2%) presentaron mayores disminuciones del porcentaje de masa grasa en relación al control. Conclusión: nuestros resultados sugieren un efecto potenciador de la capacidad aeróbica máxima producto de la combinación de HIIT y suplementación de O3. Además, se observó una disminución de masa grasa en todos los grupos intervenidos (AU)

Background: High Intensity Interval Training (HIIT) has shown to increase oxidative capacity and maximum oxygen consumption (VO2max ) in different populations. On the other side, the consumption of Omega-3 fatty acids (O3) has positive effects on oxidative metabolism. Objective: To observe the effects of a combination of HIIT and O3 supplementation on parameters of physical performance, blood pressure, and body composition in overweight adults. Methods: 28 young, non-active, overweight individuals (22 ± 4 years; BMI = 25.8 ± 2.4 kg/m2 ) participated in the study. They were randomly assigned to four groups: an O3/HIIT (n = 7) which performed HIIT, 3 times per week, during six weeks and took 2 g of O3 supplement daily; a HIIT group (n = 7) whom performed HIIT protocol; an O3 group (n = 7) consumed 2 g of O3 supplement daily; and a control group (n = 7). VO2max , maximum race speed, blood pressure, body fat percentage, and the sum of six skinfolds were measured at baseline and after the 6 week intervention. Results: Peak oxygen consumption increased more in the O3/HIIT group (+10.9%) when compared to the HIIT group, O3 group, and control group. Maximum race speed increased only the O3/HIIT group (+7.1%) and HIIT group (+11.9%). Systolic blood pressure decreased the most in the O3 group (-6.8%), compared to O3/HIIT, HIIT, and control. Lastly, fat percentage decreased in every group (-19.2% in O3/HIIT group, -20.2% in HIIT group, and -15.2% in O3 group), when compared to the control group. Conclusion: The results observed in VO 2peak in the O3/HIIT group, suggest an augmented effect when HIIT and O3 supplementation are combined during six weeks. Furthermore, fat percentage improved in all intervened groups when compared to control group (AU)

Generation of poikiloderma with neutropenia (PN) induced pluripotent stem cells (iPSCs).

Poikiloderma with neutropenia (PN, Clericuzio-type poikiloderma with neutropenia) is a rare autosomal recessive disorder caused by biallelic mutations in the USB1 gene (Alias C16orf57 and MPN1). To date, there have been only 37 reported cases worldwide of this disorder that presents with neutropenia, early onset poikiloderma, respiratory infections, palmo-plantar hyperkeratosis, and skeletal defects. Here we described the generation of human induced pluripotent stem cell lines (PN1 and PN2) from the peripheral blood of a 1-year-old patient using the dox-inducible STEMCCA vector. This patient presented with bacteremia, pneumonia, and neutropenia. Analysis of bone marrow demonstrated normal cellularity with trilineage hematopoiesis and neutropenia.

A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of enalapril for children with hypertension.

Despite widespread use to treat childhood hypertension, enalapril has never been studied systematically to determine effectiveness, dose response, and safety in a pediatric population. This study was conducted prospectively in 110 hypertensive children ages 6 to 16 years in two sequential phases. The primary outcome variable for both phases of the study was trough (24-h postdose) sitting diastolic blood pressure. The primary objective of the first phase of the study was to determine whether enalapril lowered blood pressure in children in a dose-dependent manner. During a 2-week, double-blind, randomized, dose-response period, patients were stratified by weight (< 50 kg or > or = 50 kg), then assigned to one of three dosing groups: low(0.625 or 1.25 mg), middle (2.5 or 5 mg), or high dose (20 or 40 mg). Reduction in blood pressure was examined as a function of dose ratio (1:4:32) and on a weight-adjusted basis. On completion of the dose-response phase of the study, patients entered a 2-week, double-blind, randomized withdrawal to either enalapril or placebo. Antihypertensive effectiveness, defined as the difference in sitting diastolic blood pressure between the placebo and enalapril groups, was determined. Adverse events were carefully recorded throughout the study. The dose-response relationship for enalapril had a negative slope and was linear over the chosen dosing range, suggesting that larger doses of enalapril were associated with a greater reduction in blood pressure. Randomized withdrawal to active drug orplacebo confirmed the antihypertensive effectiveness of enalapril in the middle- and high-dose groups. The antihypertensive effect of enalapril was maintained across age, gender, race, and Tanner stage. Enalapril appears to be an effective and generally well-tolerated antihypertensive agent in children ages 6 to 16 years. An initial dose of 2.5 mg in children weighing < 50 kg and 5 mg in children weighing > 50 kg (mean = 0.08 mg/kg) administered once daily effectively lowered blood pressure within 2 weeks in most patients. Blood pressure was reduced in a dose-dependent fashion, with larger doses resulting in a greater reduction.

Evaluación de un modelo de intervención para fomentar estilos de vida saludables en preescolares / Evaluation of an intervention model to stimulate healthy life habits in preeschool children

El propósito del estudio fué probar un modelo de intervención orientado a fomentar estilos de vida saludables en preescolares con énfasis en hábitos alimentarios y actividad física. La muestra estuvo constituida por 100 preescolares (50 intervenidos y 50 controles) de 4 centros INTEGRA de la Región Metropolitana. El modelo consideró educación alimentaria y fomento de la actividad física, desarrollada por el personal institucional previamente capacitado y en una modificación de la alimentación institucional. Para validar la metodología de evaluación de impacto se determinó estado nutricional, ingesta alimentaria, desarrollo motor, conocimientos alimentarios maternos y hábitos alimentarios del niño en el hogar. Para la evaluación del proceso se realizaron visitas de observación y entrevistas. El 35 por ciento de los niños estudiados presentaba exceso de peso. Se observó un bajo consumo de verduras, frutas, pescados, calcio y fibra y alto consumo de golosinas. Las madres mostraron un buen nivel de información. Las modificaciones a la alimentación no produjeron problemas ni de aceptación ni adminstrativos. La promoción de alimentación y actividad física saludable se incorporó a la rutina diaria. Se demostró la necesidad de capacitación y asesoría en terreno. Se concluye que el modelo es factible de aplicar con los esquemas de funcionamiento y recursos institucionales y solo se deben modificar algunos instrumentos de evaluación por su baja sensibilidad para medir impacto

Carcinoma epidermoide de cavidad bucal; revision de 3622 casos entre 1985-1990 / Epidermoid carcinoma of buccal cavity

El proposito de este trabajo es demostrar la prevalencia del cancer de boca en nuestro medio. Para lo cual se tomaron en cuenta los siguientes parametros: edad, sexo, ubicacion de la lesion, diagnostico histopatologico, grado de diferenciacion, formas macroscopicas, estadio clinico, factores de riesgo, estatus socioeconomico y cuadro clinico. Se revisaron retrospectivamente 3266 informes histopatologicos del departamento de patologia del Hospital Clinico "Viedma" y las historias clinicas de la Fac. de odontologia de la UMSS de Cochabamba, en el periodo comprendido entre enero de 1985 a diciembre de 1990. Se informa de 20 casos (6.5

de los 20 casos de cancer de boca corresponden a carcinoma epidermoide. Presentandose el tipo histopatologico mas frecuente como carcinoma epidermoide moderadamente diferenciado, la mayoria de las lesiones provienen de mucosa bucal, el grupo etareo mas afectado corresponde entre la cuarta a septima decada de la vida. El carcinoma epidermoide bucal afecto con mayor frecuencia al sexo femenino 2:1. Los pacientes acudieron a la consulta por la presencia de ulceras y tumor vegetante. Siendo en este estudio el carcinoma epidermoide el mas frecuente en nuestra casuistica, como en la literatura nacional e internacional.

) de cancer bucal de 310 casos que corresponden a 9.5

de la totalidad de casos revisados. El 60