Infantile-onset Pompe disease in seven Mexican children.

INTRODUCTION: Pompe disease (PD) is a rare form of metabolic myopathy; the classic infantile presentation is severe, with death occurring before reaching one year of life, and the non-classical form is of slower progression and survival can exceed one year. OBJECTIVE: To describe the genotype and characteristics of Mexican patients with infantile-onset PD. METHODS: Seven patients with PD confirmed by enzymatic activity determination and GAA gene molecular analysis were included. Mutations were reviewed in genomic databases. RESULTS: Median age at symptom onset was four months (1-12 months) and age at diagnosis was eight months (4-16 months). All patients had cardiomyopathy: four who died before one year of age had mutations that predicted severe disease (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) and were negative for cross-reactive immunologic material (CRIM). Three patients survived after one year of age with enzyme replacement therapy; one survived almost five years, another 18 months, and one girl was almost three years of age at the time of this report; their pathogenic variants predicted potentially less severe disease (c.1979G>A, c.655G>A, c.1447G>A) and they were positive for CRIM. CONCLUSION: There was a good correlation between genotype and phenotype in children with Pompe disease.

INTRODUCCIÓN: La enfermedad de Pompe (EP) es una forma rara de miopatía metabólica; la presentación infantil clásica es severa y el fallecimiento acontece antes del año de vida, y la forma no clásica es de progresión más lenta y la sobrevivencia puede superar el año. OBJETIVO: Describir genotipo y características de pacientes mexicanos con EP de inicio infantil. MÉTODOS: Se incluyeron siete pacientes con enfermedad confirmada mediante actividad enzimática y estudio molecular del gen GAA. Se revisaron las mutaciones en bases de datos genómicas. RESULTADOS: La mediana de la edad de inicio de los síntomas fue de cuatro meses (1-12 meses) y la edad de diagnóstico fue de ocho meses (4-16 meses). Todos los pacientes tenían cardiomiopatía: cuatro que fallecieron antes del año presentaron mutaciones que predicen enfermedad severa (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) y CRIM (cross-reactive immunologic material) negativo; tres sobrevivieron después del año de edad con terapia de reemplazo enzimático, uno casi cinco años, otro 18 meses y una niña tenía casi tres años al momento de este informe; sus variantes patogénicas predecían enfermedad potencialmente menos severa (c.1979G>A, c.655G>A, c.1447G>A) y CRIM positivo. CONCLUSIÓN: Existió buena correlación entre genotipo y fenotipo en niños con enfermedad de Pompe.

Enfermedad de Pompe de inicio infantil en siete niños mexicanos / Infantile-onset Pompe disease in seven Mexican children

Resumen Introducción: La enfermedad de Pompe (EP) es una forma rara de miopatía metabólica; la presentación infantil clásica es severa y el fallecimiento acontece antes del año de vida, y la forma no clásica es de progresión más lenta y la sobrevivencia puede superar el año. Objetivo: Describir genotipo y características de pacientes mexicanos con EP de inicio infantil. Métodos: Se incluyeron siete pacientes con enfermedad confirmada mediante actividad enzimática y estudio molecular del gen GAA. Se revisaron las mutaciones en bases de datos genómicas. Resultados: La mediana de la edad de inicio de los síntomas fue de cuatro meses (1-12 meses) y la edad de diagnóstico fue de ocho meses (4-16 meses). Todos los pacientes tenían cardiomiopatía: cuatro que fallecieron antes del año presentaron mutaciones que predicen enfermedad severa (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) y CRIM (cross-reactive immunologic material) negativo; tres sobrevivieron después del año de edad con terapia de reemplazo enzimático, uno casi cinco años, otro 18 meses y una niña tenía casi tres años al momento de este informe; sus variantes patogénicas predecían enfermedad potencialmente menos severa (c.1979G>A, c.655G>A, c.1447G>A) y CRIM positivo. Conclusión: Existió buena correlación entre genotipo y fenotipo en niños con enfermedad de Pompe.

Abstract Introduction: Pompe disease (PD) is a rare form of metabolic myopathy; the classic infantile presentation is severe, with death occurring before reaching one year of life, and the non-classical form is of slower progression and survival can exceed one year. Objective: To describe the genotype and characteristics of Mexican patients with infantile-onset PD. Methods: Seven patients with PD confirmed by enzymatic activity determination and GAA gene molecular analysis were included. Mutations were reviewed in genomic databases. Results: Median age at symptom onset was four months (1-12 months) and age at diagnosis was eight months (4-16 months). All patients had cardiomyopathy: four who died before one year of age had mutations that predicted severe disease (c.2431dup, c.2560C>T, c.655G>A, c.1987delC) and were negative for cross-reactive immunologic material (CRIM). Three patients survived after one year of age with enzyme replacement therapy; one survived almost five years, another 18 months, and one girl was almost three years of age at the time of this report; their pathogenic variants predicted potentially less severe disease (c.1979G>A, c.655G>A, c.1447G>A) and they were positive for CRIM. Conclusion: There was a good correlation between genotype and phenotype in children with Pompe disease.

Effectiveness of an Evidence-Based Amputee Rehabilitation Program: A Pilot Randomized Controlled Trial.

BACKGROUND: Despite the prevalence of lower limb amputation (LLA), only a small percentage of people with LLA actually receive physical therapy post amputation and are rehabilitated to their full potential level of function. There is a need for the development of a rehabilitation program that targets impairments and limitations specific to people with LLA. OBJECTIVE: The objective of this study was to determine whether the Evidence-Based Amputee Rehabilitation program would improve functional mobility of people with unilateral transtibial amputation (TTA) who have already completed physical therapy and prosthetic training. DESIGN: This study was a randomized, wait-list control, single-blinded pilot clinical trial. SETTING: This study researched participants who had received postamputation rehabilitation to varying degrees, either in an inpatient and/or outpatient settings. PARTICIPANTS: The participants in this study included veterans and nonveterans with unilateral TTA due to dysvascular disease and trauma. INTERVENTION: This study included a prescription-based rehabilitation program for people with amputations. MEASUREMENTS: Results were measured with The Amputee Mobility Predictor with (AMPPro) and without a prosthesis (AMPnoPro) and 6-Minute Walk Test (6MWT) at baseline and at the end of the 8-week intervention. RESULTS: The intervention group improved on the AMPPro scores (36.4 to 41.7), AMPnoro scores (23.2 to 27.1), and 6MWT distance (313.6 to 387.7 m). The effect size for the intervention was very large (1.32). In contrast, the wait-list control group demonstrated no change in AMPPro scores (35.3 to 35.6), AMPnoPro scores (24.7 to 25.0), and 6MWT distance (262.6 m to 268.8 m). LIMITATIONS: The sample size was small. A total 326 potential candidates were screened with 306 unable to meet inclusion criteria or unwilling to participate. CONCLUSION: People with unilateral TTA who received Evidence-Based Amputee Rehabilitation program demonstrated significant improvement in functional mobility, with most participants (66.7%) improved at least 1 K-level (58.3%) and greater than the minimal detectable change (66.7%).

Evaluation of antipyretic, sedative and hypnotic activities of methanol extract of Tabebuia hypoleuca (C. Wright ex Sauvalle) Urb. stems / [Evaluación de la actividad antipirética, sedante e hipnótica del extracto metanólico de los tallos de Tabebuia hypoleuca (C. Wright ex Sauvalle) Urb

Species of the genus Tabebuia are used in traditional medicine and are reported in the literature for their properties against various diseases. The objective of this study was to evaluate the antipyretic, sedative and hypnotic activities of methanol extract of Tabebuia hypoleuca stems (THME) using the Brewer's yeast induced pyrexia, Open field and Sodium thiopental-induced sleeping time tests, respectively. In the Brewer's yeast induced pyrexia test, THME at 500 mg/kg produced a significant (p<0.001) decrease of the fever as from the first hour after administration and was sustained for 4 h. In the Open-field test, THME did not cause any significant change in the number of crossings, rearing, preening and defecation, and either in the time of immobility. Moreover, THME did not produce changes in neither the sleeping latency nor the sleeping time induced by sodium thiopental. These results showed that THME administered orally at 500 mg/kg exerts antipyretic activity, probably mediated by the inhibition of the enzyme cyclooxygenase-2. This study also showed that THME does not exert sedative and hypnotic effects at the doses tested.

Especies del género Tabebuia se utilizan en la medicina tradicional y se reportan en la literatura por sus propiedades contra diversas enfermedades. El objetivo de este estudio fue evaluar la actividad antipirética, sedante e hipnótica del extracto metanólico de los tallos de Tabebuia hypoleuca (THME) utilizando las pruebas de pirexia inducida por levadura de cerveza, campo abierto y tiempo de sueño inducido por tiopental sódico respectivamente. En el ensayo de pirexia inducida por levadura de cerveza, THME a 500 mg/kg produjo una reducción significativa (p<0.001) de la fiebre a partir de la primera hora después de la administración y se mantuvo durante cuatro horas. En el ensayo de campo abierto, THME no causó ningún cambio significativo en el número de cruces, levantamientos, acicalamientos y defecación, ni en el tiempo de inmovilidad. Además, THME no produjo cambios ni en la latencia de sueño, ni en el tiempo de sueño inducido por tiopental sódico. Estos resultados mostraron que THME administrado oralmente en dosis de 500 mg/kg posee actividad antipirética, mediado probablemente a la inhibición de la enzima ciclooxigenasa-2. Este estudio también demostró que THME no posee actividad sedante e hipnótica en las dosis ensayadas.

Antinociceptive Activity of Methanol Extract of Tabebuia hypoleuca (C. Wright ex Sauvalle) Urb. Stems.

OBJECTIVE: The aim of this study was to evaluate the antinociceptive activity of the methanol extract of Tabebuia hypoleuca stems (THME). MATERIALS AND METHODS: The animals were divided into 5 groups of 8 mice for each test (negative controls, positive controls, and 3 groups treated with THME at doses of 150, 300, and 500 mg/kg, p.o.). The antinociceptive effect of THME was evaluated using the writhing, formalin, tail flick, and hot plate models in mice. RESULTS: In the writhing test, THME (150, 300, and 500 mg/kg) produced significantly (p < 0.001) fewer writhes induced by acetic acid than in the control group. In the formalin test, the licking time for THME at doses of 300 and 500 mg/kg was significantly shorter (p < 0.001) compared to the control group in the first phase of the formalin test, whereas in the second phase only the dose of 500 mg/kg showed an antinociceptive effect. In addition, THME at doses of 300 and 500 mg/kg significantly increased the latency time in the tail flick test (p < 0.05 and p < 0.001, respectively) and in the hot plate test (p < 0.01 and p < 0.001, respectively) compared to the control group. CONCLUSIONS: These results show that THME had antinociceptive activity using several models of nociception, and they suggest that the effect is mediated by the participation of both peripheral and central antinociceptive mechanisms.

Mutations Related to Antiretroviral Resistance Identified by Ultra-Deep Sequencing in HIV-1 Infected Children under Structured Interruptions of HAART.

Although Structured Treatment Interruptions (STI) are currently not considered an alternative strategy for antiretroviral treatment, their true benefits and limitations have not been fully established. Some studies suggest the possibility of improving the quality of life of patients with this strategy; however, the information that has been obtained corresponds mostly to studies conducted in adults, with a lack of knowledge about its impact on children. Furthermore, mutations associated with antiretroviral resistance could be selected due to sub-therapeutic levels of HAART at each interruption period. Genotyping methods to determine the resistance profiles of the infecting viruses have become increasingly important for the management of patients under STI, thus low-abundance antiretroviral drug-resistant mutations (DRM's) at levels under limit of detection of conventional genotyping (<20% of quasispecies) could increase the risk of virologic failure. In this work, we analyzed the protease and reverse transcriptase regions of the pol gene by ultra-deep sequencing in pediatric patients under STI with the aim of determining the presence of high- and low-abundance DRM's in the viral rebounds generated by the STI. High-abundance mutations in protease and high- and low-abundance mutations in reverse transcriptase were detected but no one of these are directly associated with resistance to antiretroviral drugs. The results could suggest that the evaluated STI program is virologically safe, but strict and carefully planned studies, with greater numbers of patients and interruption/restart cycles, are still needed to evaluate the selection of DRM's during STI.

Drug resistance mutations during structured interruptions of HAART in two HIV-1-infected children.

Information concerning structured treatment interruptions (STI) of the Highly Active Antiretroviral Therapy (HAART) and their risk for selecting antiretroviral drug resistance in children is scarce. In this study, we searched for antiretroviral drug resistance mutations at the end of five viral rebounds of two children with HIV and a chronically undetectable viral load (VL) who underwent an STI program. The HAART was interrupted for 4 weeks and then restarted and continued for 12 weeks for three cycles. VL, CD4+/CD8+ lymphocytes, and clinical status were evaluated at the end of each STI and at 6 and 12 weeks after HAART was resumed. Treatment of both the patients based on zidovudine+lamivudine+ritonavir remained identical during the study. The reverse transcriptase (RT)- and protease (PR)-coding regions were sequenced at the end of each viral rebound. One patient experienced progressively lower viral rebounds (269000-31300 at the first and third rebounds, respectively), while the other patient did not experience such a reduction, and the VL of both the patients fell to undetectable levels during therapy. In the five viral rebounds examined, no mutations for resistance to protease inhibitors (PIs) were found and the analysis indicated susceptibility to all PIs currently in clinical use. Although the mutation K103R associated with non-nucleoside reverse transcriptase inhibitor resistance was found in two viral rebounds of one patient, the analysis indicated the absence of resistance to RT inhibitors. As no mutation related to antiretroviral drug resistance was found, our results suggest that the STI program evaluated may have a low risk of selecting antiretroviral drug resistance. Nevertheless, further studies evaluating larger cohorts over longer periods are required before definitive conclusions about the safety of STI of HAART in children may be drawn.

Structured interruptions of highly active antiretroviral therapy in cycles of 4 weeks off/12 weeks on therapy in children having a chronically undetectable viral load cause progressively smaller viral rebounds.

OBJECTIVES: To evaluate the viral, immune and clinical impact of a structured treatment interruption (STI) program of highly active antiretroviral therapy (HAART) in three cycles of 4 weeks off/12 weeks on therapy in a cohort of children with HIV infection under chronic viral control. METHODS: Using a single-group time series experimentation design and following informed consent, the HAART of children with HIV and a chronically undetectable viral load (VL) was discontinued for 4 weeks and then restarted and continued for 12 weeks for a total of three cycles. The VL, CD4+/CD8+ lymphocytes, and clinical status were evaluated at the end of each STI and at 6 and 12 weeks after HAART was resumed. RESULTS: Four children with a median age of 10.3 years (range 6.5-11.2 years) were included in the study. Their clinical immune categories were: A1 (n=2), A2 (n=1), and B3 (n=1). Treatment of all four patients was with zidovudine (AZT)+lamivudine (3TC)+ritonavir (RTV). At the end of the first STI, VL was a median 214000 copies/ml (range 27400-616000), corresponding to 5.3 log(10) (range 4.4-5.8). At the end of the second STI, VL was a median 72400 copies/ml (range 17800-126000) or 4.7 log(10) (range 4.2-5.1), which corresponds to a rebound 0.6 log(10) lower than the first. At the end of the third STI, VL was a median 28200 copies/ml (range 5370-140000) or 4.45 log(10) (range 3.7-5.1), a rebound 0.85 log(10) lower than the first. All rebounds were followed by a decrease in the VL to undetectable levels during the treatment periods. CD8+ T lymphocyte counts increased during viral rebounds and an initial decrease in CD4+ T lymphocyte counts was followed by a tendency to increase even exceeding CD8+ T cell counts. Only one event of transitory severe immunosuppression occurred. There were no symptoms related to the HIV infection. CONCLUSIONS: The STI of HAART in cycles of 4 weeks off/12 weeks on therapy in children with chronically undetectable VL can cause progressively lower viral rebounds followed by a decrease to undetectable levels, with a low risk of severe immunosuppression and without the occurrence of symptoms related to HIV.