Archivo para la categoría EDUCACION PEDIATRICA CONTINUA

HEDERA HELIX

 

 

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24 AGO 09 | Hedera helix
Efecto secretolítico y bronquiolítico de la Alfa-Hederina
En este artículo, los autores analizaron los efectos de las principales saponinas del extracto de H. helix sobre la regulación del receptor beta2 adrenérgico.

Dres. Sieben A, Prenner L, Häberlein H y colaboradores
Biochemistry 48(15):3477-3482, Abr 2009
 

Introducción

En los pacientes con enfermedades respiratorias caracterizadas por la hipersecreción de moco viscoso y por tos, los estudios clínicos acerca del uso de extractos de las hojas de hiedra –Hedera helix– han mostrado una mejoría importante en estos individuos.

Asimismo, el producto induciría cambios espirométricos favorables y broncodilatación. Además, las saponinas del extracto ejercen un efecto antibacteriano. Estas son el principio activo y se las utiliza para la estandarización de este producto natural. Se estima que alrededor del 10% del extracto alcohólico de hiedra consiste en una mezcla compleja de saponinas; el hederacósido C sería la más importante.

Posiblemente la actividad expectorante de las saponinas está relacionada con la estimulación refleja de las glándulas bronquiales, desde la mucosa gástrica y a través de las vías parasimpáticas. Sin embargo, este mecanismo no explica el efecto broncodilatador que se comprueba en modelos experimentales de obstrucción bronquial inducida por el factor activador de plaquetas. Los resultados de los trabajos efectuados sugieren que el extracto de hojas de hiedra ejerce una actividad simpaticomimética que podría explicar el efecto secretolítico y bronquiolítico.

En este artículo, los autores analizaron los efectos de las principales saponinas del extracto de H. helix sobre la regulación del receptor beta2 adrenérgico. Mediante estudios de imágenes en células vivas y espectroscopia de correlación de fluorescencia (ECF), analizaron la dinámica de los receptores beta2 adrenérgicos; también, determinaron los niveles intracelulares de adenosinmonofosfato cíclico (AMPc), luego de la ocupación de los receptores.

Procedimientos experimentales

Los autores evaluaron la síntesis, la identidad y la unión del arterenol marcado con el colorante fluorescente Alexa 532 (Alexa-NA) sobre los receptores beta2 adrenérgicos (RbA). En los experimentos se utilizaron células de diversas líneas: línea A549 de células de cáncer humano, incubadas en medio RPMI 1640, evaluadas con ECF; líneas celulares de riñón humano HEK293 y células de músculo liso de la vía aérea humana (HASM).

Las células HEK293 fueron sometidas a transfección con un plásmido que codifica el RbA unido a una proteína fluorescente verde (RbA-PF). Se analizó la expresión del RbA en la superficie de células incubadas con Alexa-NA y en células tratadas previamente durante 24 horas con alfa-hederina, hederacósido C o hederagenina 1 µM.

Para el ensayo de la AMPc en células adherentes se utilizó un equipo comercial. Un día después de la siembra, las células se incubaron durante 24 horas con alfa-hederina, hederacósido C o hederagenina 1 µM. Para los experimentos de internalización, las células fueron incubadas durante 20 minutos con terbutalina 1 µM. Todas las mediciones se realizaron a 20° C.

Antes de la determinación de los niveles intracelulares de AMPc, las células se trataron con 10 µM de forscolina/terbutalina o con solución fosfato 10 µM a pH 7.4 durante 10 minutos a 37° C. La fluorescencia se midió con un lector de microplacas GENios luego de aplicar una longitud de onda de excitación de 530 nm y una longitud de onda de emisión de 610 nm.

El comportamiento de difusión tridimensional de los complejos RbA-PF en todos los experimentos de ECF (valores promedio y desviación estándar de 6 experimentos independientes) se conoció con una fórmula matemática. La significación estadística se comprobó con un modelo ANOVA (se consideraron significativos cuando el valor de p fue < 0.05). En los experimentos de unión al ligando, las células A549 fueron tratadas con Alexa532-NA 5 nM durante 15 minutos, antes de las determinaciones de ECF. En los experimentos de saturación se emplearon concentraciones de 2 a 200 nM.

Resultados

La influencia de la alfa-hederina, del hederacósido C y de la hederagenina sobre la regulación celular se conoció mediante estudios de internalización de los complejos RbA-PF en células HEK293 transfectadas. La estimulación con terbutalina 1 µM –un agonista beta2 adrenérgico específico– se asoció con una internalización endocítica importante de los receptores ocupados, a los 20 minutos. Respecto de las células control, las células estimuladas con terbutalina presentaron vesículas intracelulares amplias (endosomas precoces positivos para los complejos RbA-PF). La preincubación con alfa-hederina 1 µM durante 24 horas inhibió la internalización del receptor, incluso después del tratamiento de las células con terbutalina 1 µM durante 20 minutos. En comparación con el control positivo, en las células tratadas con alfa-hederina no se observaron vesículas intracelulares. Aunque las otras dos saponinas son similares estructuralmente a la alfa-hederina, ninguna de ellas influyó sobre la internalización de los receptores beta2 adrenérgicos ocupados.

El efecto inhibitorio de la alfa-hederina sobre la dinámica de los receptores se confirmó en experimentos en biomembranas de células A549, mediante ECF. Luego de la incubación de las células A549 con Alexa-NA 5 nM durante 15 minutos, el rayo láser se enfocó sobre la superficie superior de la membrana. Las fluctuaciones en la intensidad de la fluorescencia se midieron cada 60 segundos. El análisis de la curva de autocorrelación reveló una constante de tiempo de difusión rápida de 1.4 ms y una constante de tiempo de difusión lenta de 34.7 ms. Por el contrario, la constante de difusión libre del Alexa-NA fue de 0.060 ms. La unión total fue de 33%.

El pretratamiento de las células A549 con alfa-hederina 1 µM durante 24 horas comprometió significativamente el patrón de difusión del Alexa-NA. En los experimentos de ECF se constató un descenso en el nivel de complejos de receptor y ligando, dependiente de la dosis. El análisis de las curvas de autocorrelación mostró que la alfa-hederina en concentración de 0.01 µM no afectó sustancialmente la difusión, mientras que se comprobó una disminución del 25% y del 50% en los experimentos realizados con una concentración de alfa-hederina de 0.1 µM o de 1 µM, respectivamente. Las células A549 pretratadas con alfa-hederina 1 µM mostraron una mayor unión del Alexa-NA, respecto de las células control. Este incremento fue significativo cuando se utilizaron concentraciones de 2 a 50 nM.

En los experimentos de saturación, la preincubación con alfa-hederina se acompañó de una disminución de la constante de disociación. Los resultados en conjunto sugieren que la alfa-hederina no afecta el número de RbA en la membrana de las células A549. Por el contrario, el pretratamiento de las células con hederacósido C o con hederagenina no modificó la capacidad de unión del Alexa-NA, la concentración o la distribución relativa de los receptores en la superficie celular.

Los niveles intracelulares de AMPc en las células HASM se valoraron en condiciones de estimulación con forscolina y terbutalina con la finalidad de confirmar el incremento de la unión de los RbA después de la incubación con alfa-hederina, durante 24 horas. En comparación con las células control, en las células pretratadas con alfa-hederina se constató un aumento significativo del 13.5% en promedio en la concentración intracelular de AMPc. En cambio, el pretratamiento con hederacósido C o con hederagenina no afectó los niveles intracelulares del segundo mensajero.

Discusión

El extracto de hojas secas de hiedra se utiliza para el tratamiento de las enfermedades de las vías aéreas superiores. En este trabajo se utilizaron células alveolares tipo II (A549) y arterenol marcado con Alexa-532 para conocer la unión de los RbA, la dinámica y los procesos de señalización que tienen lugar después de la unión del receptor a su ligando.

En los experimentos de internalización se emplearon células HEK293 transfectadas con RbA-PF. Los estudios de imágenes en células vivas claramente confirmaron la internalización de los complejos de receptores y de proteína de fusión en las células HEK293 después del tratamiento con terbutalina 1 µM durante 20 minutos. Las células estimuladas mostraron vesículas grandes, coincidentemente con una disminución de la densidad de expresión de los receptores en la membrana celular, en presencia de una concentración elevada del agonista.

La fosforilación de los receptores ocupados por el agonista induce la unión de la beta-arrestina, de la c-Src y de la AP-2. La consecuencia final es la internalización del receptor mediante vesículas cubiertas con clatrina y la formación de los endosomas precoces. En las células HEK293, dicho proceso de internalización se inhibió en presencia de alfa-hederina en concentración 1 µM durante 24 horas. Estas células no presentaron vesículas en el citoplasma; después de la estimulación con terbutalina, la internalización fue insignificante. La preincubación con las otras dos saponinas no modificó el proceso de internalización, a juzgar por los estudios de imágenes en células vivas. Los mecanismos responsables de estas diferencias todavía no se conocen, añaden los autores. Tampoco se sabe, por el momento, el mecanismo mediante el cual la alfa-hederina inhibe la internalización de los receptores. Probablemente por ser más activa sobre la membrana celular, esta proteína modifica las interacciones entre las fosfoquinasas y otras proteínas (dinamina, beta-arrestina) y los RbA ocupados. El resultado final es la desensibilización y la redistribución de los complejos de receptores y ligandos y, en definitiva, una menor internalización.

En conjunto, los experimentos realizados demuestran claramente que la alfa-hederina afecta la actividad del RbA. Por este motivo, la dinámica de los complejos en la membrana de las células A549 se evaluó con ECF. Quince minutos después de la incubación de dichas células con Alexa-NA 5 nM se observaron diferencias en las constantes del tiempo de difusión, mientras que en las células pretratadas con alfa-hederina 1 µM se detectaron diferencias importantes en la unión total del Alexa-NA y en la distribución de los receptores. Los cambios fueron dependientes de la dosis –sólo se observaron con alfa-hederina en concentración de 1 µM–. La hederagenina y el hederacósido C, en concentraciones de hasta 1 µM, no modificaron la unión total de Alexa-NA ni la dinámica de distribución del receptor.

Después de la incubación con alfa-hederina se confirmó la mayor señalización a partir del RbA: la concentración intracelular del segundo mensajero, AMPc, se elevó significativamente. Este proceso podría ser responsable de la mayor producción de surfactante en las células alveolares tipo II, un hecho que explicaría la acción secretolítica del extracto de las hojas de hiedra. Un efecto similar en las células de músculo liso sería responsable de la acción broncodilatadora del extracto, concluyen los expertos.

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DERMATITIS INFECTIVA en niños

25 AGO 09 | Revisión Dermatitis infectiva

 

También conocida como dermatitis infantil crónica o dermatitis asociada al virus humano linfotrópico de células T-1 (HTLV-1).

Es una dermatitis exudativa severa que afecta cuero cabelludo, oido externo, áreas posteriores de pabellones auriculares, párpados, pliegues nasolabiales, nuca, axilas e ingle Dres. Beatriz Moritz Trope, María Elisa Ribeiro Lenzi. Clinics in Dermatology (2009) 27, 281-284

Desarrollo

 La dermatitis infectiva también conocida como dermatitis infantil crónica o dermatitis asociada al virus humano linfotrópico de células T-1 (HTLV-1). El virus humano de células T tipo 1 fue el primer retrovirus identificado como patógeno en humanos y el primer agente viral humano asociado a transformación maligna en células humanas. El virus fue identificado por primera vez de linfocitos de un hombre afroamericano con un tipo de linfoma con un acentuado compromiso cutáneo que hasta entonces se diagnosticaba como micosis fungoide. El HTLV-1 se trasmite horizontalmente por vía sexual y transfusiones de sangre.

La transmisión vertical de madre a hijo puede ocurrir en útero o por amamantamiento. El virus humano de células T linfotrópico -1 primariamente infecta a las células T CD4. La fusión del virus HTLV-1 con el receptor de células T conduce a la integración del genoma viral con el genoma de células CD4 infectadas. Estas células T CD4 infectadas son capaces de evadir los mecanismos de inmunovigilancia ocasionando a una infección latente que puede perdurar indefinidamente. A pesar de la infección persistente con HTLV-1, la mayoría de las personas con infección crónica por HTLV-1 permanecen asintomáticas; sin embargo, aproximadamente el 4% desarrolla complicaciones hematológicas, más comúnmente leucemia/linfoma de células T del adulto (ATLL), y el 1% al 2% desarrollan enfermedad neurológica, llamada mielopatía o paraparesis espástica tropical asociada a HTLV-1.

El compromiso dermatológico de ATLL varía considerablemente entre los pacientes pero está casi siempre presente. Una presentación cutánea inespecífica puede preceder al ATLL muchos años, y la infiltración temprana puede ser la precursora de la enfermedad. Las lesiones cutáneas son extremadamente heterogéneas y se pueden presentar como erupciones eritematosas papulosas, nódulos o eritrodermia. También se han descripto lesiones tumorales y ulceraciones. En relación a la mielopatía y paraparesis espástica tropical asociada a HTLV-1, se han descripto varias manifestaciones dermatológicas que incluyen xerosis, eritema malar y palmar, dermatitis seborreica, dermatofitosis, sarna costrosa y foliculitits decalvans. Manifestaciones clínicas La dermatitis infectiva fue descripta por primera vez como una presentación clínica distinta en un niño de Jamaica en 1966.

Las lesiones tenían una distribución cefálica con tendencia a recurrir. La enfermedad se caracteriza por presentarse como una dermatitis exudativa severa que afecta cuero cabelludo, oido externo, áreas posteriores de pabellones auriculares, párpados, pliegues nasolabiales, nuca, axilas e ingle (fig 1-5). Puede estar presente un rash generalizado papular fino. El prurito es común, y si es severo, puede originar dermatitis artefacta e infecciones secundarias. La rinitis es común, y aunque la distribución del rash es similar a la que se observa en eccemas atópicos y seborreicos, parece no haber historia personal ni familiar de atopía. Otros investigadores reexaminaron ésta misma población en 1990, y éstos mismos pacientes estaban infectados con HTLV-1, estableciendo una asociación.

Una cantidad significativa de niños del estudio original de 1966 posteriormente desarrollaron leucemia de células T/linfoma en la adultez (ATLL). Esto condujo a los investigadores a postular que las manifestaciones dermatológicas podrían ser consecuencia de HTLV-1 crónico que induce inmunosupresión de un sistema inmune inmaduro y puede representar un estadío “preleucémico” de ATLL. La epidemiología de la dermatitis infectiva está pobremente definida. Las manifestaciones clínicas son variables, por lo que muchos pacientes con formas leves de la enfermedad puede ser que nunca se reporten. La dermatosis infectiva tiene una edad promedio de inicio a los 2 años con una distribución igual por sexo.

DermatInfectiva03

Las manifestaciones cutáneas generalmente son menos severas con el paso de los años. La mayoría de los casos se presentan como lesiones símil impétigo alrededor de narinas y pabellones auriculares que se pueden extender al resto de la cara, cuero cabelludo y cuello (fig 1 y 2). Fig 1. Lesiones símil impétigo localizadas alrededor de pabellones auriculares que se extienden al resto de la cara. Fig 2. Lesiones símil impétigo localizadas alrededor de la boca y nariz. Eventualmente, pueden comprometerse los hombros y tronco. La evolución de la enfermedad causa exudación y prurito. Tienden a persistir pequeñas fisuras en los pabellones auriculares y nariz, que forman costras con el tiempo. Puede ocurrir blefaritis crónica (fig 3). Fig 3. Blefaritis. Histopatología. La patogénesis de dermatitis infectiva es desconocida. La microscopía revela un infiltrado inflamatorio crónico similar al que se observa en la dermatitis atópica y seborreica. No hay hallazgos patognomónicos ni específicos ya que no hay evidencia de linfocitos atípicos ni epidermotrofismo comúnmente visto en linfomas cutáneos.

 

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Diagnóstico de laboratorio

 No hay un test diagnóstico definitivo para dermatitis infectiva. El diagnóstico se basa en la correlación clínico y patológica y el hallazgo positivo de la serología para HTLV-1. Se han propuesto criterios diagnósticos de dermatitis infectiva que se resúmen en la tabla 1. Diagnóstico diferencial La dermatitis infectiva es altamente variable en lo que respecta a formas de presentación y la lista de diagnósticos diferenciales refleja el amplio espectro y heterogeneidad de la enfermedad. La edad de inicio, la distribución del rash, la seropositividad para HTLV-1 ayuda a limitar el rango de diagnósticos alternativos posibles.

Las condiciones comunes como impétigo, dermatitis seborreica, dermatitis atópica y de contacto encabezan la lista de diagnósticos diferenciales, y otras condiciones como candidiasis cutánea, micosis fungoide, y dermatosis por HIV que deben excluirse por biopsia, serología e inmunohistoquímica. Tratamiento La dermatosis infectiva debería responder a una terapia antibiótica apropiada. La enfermedad, desafortunadamente, muestra una fuerte tendencia a la recaída luego de suspender la terapia antibiótica. La terapia antibiótica profiláctica es rara vez práctica en regiones rurales donde los efectos adversos de la droga no pueden monitorearse y por lo tanto rara vez se recomienda en éstas situaciones.

Puede ser útil el uso de antibióticos tópicos (con o sin corticoides), antisépticos, y emolientes locales. En niños pequeños se debe prevenir el rascado. Los antihistamínicos pueden ayudar. No hay tratamiento probado para la infección por HTLV-1. Todavía no hay vacunas para el HTLV-1. Como con el HIV se han realizado muchos esfuerzos y progresos en éste campo. Tabla 1. Criterios diagnósticos para dermatitis infectiva Se requieren 4 criterios mayores para el diagnóstico. Criterios mayores 1. Dermatitis que afecta 2 o más sitios cuero cabelludo, axilas, ingle, oído externo y área posterior de pabellones auriculares, márgenes del párpado, piel paranasal, y/o cuello. 2. Descarga crónica de agua sin otros signos de rinitis y/o costras de las narinas anteriores. 3. Dermatitis crónica que recae con respuesta apropiada a los antibióticos. 4. Inicio en la infancia temprana. 5. Seropositividad para el virus humano de células T linfotrópico-1 Criterios menores 1. Cultivos positivos para Stafilococos aureus y / o Estreptococos B hemolíticos de la piel o narinas anteriores. 2. Rash papular fino generalizado. 3. Linfadenopatía generalizada. 4. Anemia. 5. Velocidad de sedimentación globular negativa. 6. Hipergamaglobulinemia (inmunoglobulina D o E, o ambas) 7. Elevación de CD4, CD8, y de la relación CD4/CD8.

¿Qué se sabe sobre el tema?

La dermatitis infectiva representa una forma severa de cambios cutáneos eccematosos recurrentes que se presenta en la niñez. Fue descripta por primera vez en 1966. Posteriormente, se reconoció su asociación con infección por HTLV-1. La dermatitis infectiva crónica se asocia con un incremento de riesgo de transformación maligna y puede ser un signo temprano de leucemia o linfoma de células T subyacente. El tratamiento es difícil y refractario en la mayoría de los casos. Fig 4. Lesiones exudativas símil eccema en la axila. Fig 5. Lesiones exudativas símil eccema en la ingle.

♦ Comentario y resúmen objetivo: Dra Geraldina Rodriguez Rivello

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HIV TRATAMIENTO EN NIÑOS Y ADOLESCENTES

The HIV Cycle and the Early Life Cycle: Treatment Effects and Side Effects in Children and Adolescents

Our recent understanding of the effects of highly active antiretroviral therapy (HAART) in children with HIV disease has matured rapidly, and the poster sessions at the 10th Conference on Retroviruses and Opportunistic Infections reflected this growing experience. The number of presentations reporting metabolic complications of antiretrovirals in HIV-infected children was also markedly higher than in past years. This, too, reflected the longer experience with HAART in children as well as greater exposure of children to treatment, albeit in developed countries.

Children and HAART

When antiretroviral use during pregnancy and the peripartum period fails to prevent HIV infection in infants, or in the absence of effective strategies such as vaccines to prevent breast-feeding transmission, the only alternative is to treat the infected infant. The ideal time to initiate treatment in children is currently a subject of debate. Simplified antiretroviral regimens with once-daily dosing undoubtedly facilitate adherence and are attractive alternatives for children, particularly adolescents.

Early Treatment

One ongoing phase 1/2 study evaluated emtricitabine (or FTC) in 82 HIV-infected children, age 4 months to 17 years, from Panama, South Africa, Mexico, and the United States.[1] A total of 51 antiretroviral-naive children received a regimen containing 6 mg/kg of FTC combined with stavudine and lopinavir/ritonavir. In addition, 31 children who had received a stable regimen containing 3TC (lamivudine) for ≥ 3 months with an undetectable virus load were also enrolled. Investigators followed the children for 48 weeks. At week 24, 92% of the previously untreated patients and 84% of the drug-experienced children developed or maintained an HIV virus load < 400 copies/mL. The incidence of serious adverse events was 14% in the naive group and 6% in the experienced patients. Serious adverse events included 1 case each of pancreatitis, vomiting, pleural effusion, leukopenia, and anemia. Pharmacokinetic analysis of a subset of 28 patients demonstrated that the 6-mg/kg/day dose produced similar exposure to that of adults receiving 200 mg daily.

Investigators from Pediatric AIDS Clinical Trials Group (PACTG) 1021,[2] an ongoing phase 1/2 trial of emtricitabine, didanosine, and efavirenz in a similar population of children (therapy-naive or minimally treated) ages 3-21 years, also presented preliminary results for week 16 of treatment. Overall efficacy was similar to those in the previously described trial, with a very small number of grade 3/4 laboratory abnormalities, including significant elevations in creatine phosphokinase (CPK) and gamma-glutamyl transferase (GGT) (1 patient each). Based on the preliminary findings of both trials, emtricitabine appears to be an encouraging agent for treating pediatric HIV.

Salvage Therapy

For salvage therapy, PACTG 1013[3] reported results using indinavir plus 2 doses of ritonavir in antiretroviral-experienced children. Study subjects were 2-18 years of age who had received at least 16 weeks of combination therapy and nonetheless had more than 10,000 copies of HIV RNA/mL of plasma and fewer than 3 primary protease gene mutations.

Patients received either intact or opened indinavir capsules at a dose of 350 mg/m2 twice daily, plus twice-daily ritonavir at 125 mg/m2 or 300 mg/m2 and at least 1 NRTI drug in combination. Pharmacokinetic analyses demonstrated that the ritonavir boost significantly increased indinavir levels, and that the higher-dose ritonavir increased pre-dose indinavir levels 4 times higher than lower-dose ritonavir. Combination therapy was associated with reductions in HIV RNA ≥ 0.75 log10 in 15 of 21 patients by week 16, which was sustained at 50 weeks of therapy. Although the regimens were generally well tolerated, drug discontinuation and virologic failures were essentially attributable to the poor palatability of the regimen and the high pill burden.

Structured Treatment Interruptions in Children

An alternative and unconventional approach to antiretroviral therapy delivery was reported by the PACTG 1015 team.[4] Their ongoing study proposes using progressively increasing structured treatment interruptions for patients with effective viral suppression in order to elicit improved HIV-specific CD4+ and CD8+ cell responses. Candidates for the study are 4-21 years of age and have reached total viral suppression on a HAART regimen that contains at least 1 protease inhibitor (PI), with a CD4% above 20, and without use of any nonnucleoside reverse transcriptase inhibitors (NNRTIs) or abacavir.

The patients receive sequential cycles of structured treatment interruptions, increased in increments of 2 days/cycle, followed by HAART: 3 days of interruption followed by 3 weeks of HAART, with subsequent 5-day interruption followed by 3 weeks of HAART, and so on. After the 5-day interruption, patients receive HAART until virus load levels reach < 50 HIV RNA copies/mL, and then a new cycle of interruption occurs. The protocol allows up to 7 weeks of treatment interruption.

The team presented results for 10 patients. For most of these, plasma viremia rebounded within 5-9 days off therapy. Viral suppression was regained in all of these individuals, with no appearance of new resistance mutations. Changes in CD4+ and CD8+ percentages were not noted; however, transient declines in lymphocytes were seen. Changes in viremia did produce increases in HIV-specific CD4+ and CD8+ cell responses as measured by interferon gamma ELISpot assays.[5]

The structured treatment interruption approach is certainly of scientific relevance; however, the clinical benefit of improved HIV-specific CD4+ and CD8+ cell responses in patients with previous total suppression of HIV RNA levels has yet to be determined. Certainly the theoretical benefits should be weighed against the potential risk of not achieving de novo viral suppression or of seeding cellular reservoirs during the periods of rebound viremia. The practicality of this regimen is also problematic, and it is doubtful that this procedure can be carried outside the realms of a clinical protocol.

Older children and adolescents often practice unstructured treatment interruptions with no evidence of clinical benefit. Furthermore, patients might develop significant adherence issues if placed on progressively interrupted treatment regimens. PACTG 1015 may help elucidate the clinical utility of such a cumbersome and potentially dangerous process.

Less Costly Surrogate Markers for Monitoring HAART

Delivering antiretroviral treatment to children bears a greater expense than the cost of drug. The cost and technology involved in laboratory monitoring of HAART treatment is a partial impediment to antiretroviral dispensation in resource-limited settings. A study by Mofenson and colleagues[6] from the National Institutes of Health in Bethesda, Maryland, evaluated the use of total lymphocyte count and immune complex dissociated (ICD) p24 antigen in lieu of CD4+ cell count and HIV RNA polymerase chain reaction (PCR) in predicting child mortality due to HIV disease. The patient population consisted of antiretroviral-naive HIV-infected children recruited for an intravenous immunoglobulin (IVIG) clinical trial 12-15 years ago. Serial HIV RNA levels, ICD p24 antigen levels, total lymphocyte counts, hematocrit, CD4+ cell counts, and albumin levels were measured in specimens collected every 3 months.

In the current study, investigators assessed the value of simple baseline measures such as ICD p24 antigen, lymphocyte counts, hematocrit, and albumin levels to predict long-term childhood mortality, and compared the predictive value of these measures with that of HIV RNA and CD4+ cell counts. They enrolled 376 children who had a 40% mortality rate during the follow-up period. Using univariate analyses, total lymphocyte counts, ICD p24 antigen, albumin levels, and hematocrit were all associated with mortality risk in children. Using standardized risk ratios, lymphocyte counts proved the best predictor of mortality, and with multivariate proportional hazards model, lymphocyte counts and albumin levels were independently associated with mortality risk. Except for ICD p24 antigen, the sensitivity of all assays in predicting child death was less than 50%, including CD4+ cell count and HIV RNA. The specificity of ICD p24 antigen was poor (32%) compared with all other assays, which were 83% specific or greater in predicting child survival. Given these findings, and the comparability of these assays, “low-tech” approaches could potentially be used in resource-limited settings as prognostic markers or initiation of antiretroviral therapy.

When Therapy Goes Bad: Complications of HAART in Children

A number of studies addressed the metabolic complications of antiretroviral regimens in children. Researchers from Spain determined lactate and alanine plasma levels in 102 HIV-exposed, uninfected infants who received zidovudine following birth at 6 weeks and 3, 6, and 12 months of age.[7] Increased levels of both products were detected in 64% of babies at any given time point, with higher numbers of patients showing abnormalities at 6 weeks of age (60%). The team reported that 3 of the patients experienced mild neurologic symptoms (axial hypotonia), which resolved by 6 months.

The lack of a control group muddies the interpretation of these results. Lactate levels are extremely difficult to interpret and ideally an equal number of non-HIV-exposed infants born to uninfected mothers with the same background risk factors for HIV infection should be screened in the same manner.

The same investigators reported a 22% fat redistribution rate among 80 older HIV-infected children (mean age 9 years) receiving HAART. Dyslipidemia was found in 60% of these patients. Duration of antiretroviral therapy was not statistically different between children with or without fat redistribution. These values are much higher than those previously described in children; however, we now have a population of children with longer exposure to HAART.

Body Composition and Biochemical Changes

Investigators from PACTG 1010[8] reported results of an interim analysis of 63 subjects in a carefully designed study of body composition and biochemical changes in children starting or switching antiretroviral therapy. Children underwent anthropometric measures, bioelectric impedance analysis, fasting lipid panel, indices of glucose homeostasis, growth factors, and virus load and CD4+ cell subsets at entry and at 4 subsequent study visits between weeks 12 and 48.

Over time, changes occurred in almost every marker, with positive associations with virus load. A modest correlation was found between a greater suppression of HIV RNA and loss of peripheral fat, increased central adiposity, and a greater anabolic response. Increased height-for-age Z-score was associated with a positive change in CD4+ cells rather than virus load, suggesting that such changes are consistent with immunologic host recovery rather than a virologic response. A significant increase in insulin levels and a modest increase in cholesterol levels and IGF-1 were noted with reductions in IGFBP-1.

Anabolic changes appeared to be mediated by reductions in proinflammatory cytokines. Investigators noted these changes at weeks 24 and 36, but no association between these changes and virus load was seen at week 48. Insulin resistance appeared to be a cause rather than a result of fat redistribution. Aside from weight and height, which were reported as Z-scores, age-adjusted comparisons to normal controls have not yet been made, and thus, it is unclear whether many of these changes could be attributable to normal growth.

An analysis of 1812 HIV-infected children compared with 187 uninfected subjects, ages 4-21 years, followed in PACTG 219[9] found a 13% prevalence of hypercholesterolemia, well in excess of the 5% expected. Hypercholesterolemia was associated with virologic suppression, increased in CD4+ cell subsets, good adherence by self-report, younger age, Hispanic ethnicity, and PI use, particularly dual or triple PIs.

Changes in Mitochondrial DNA

One small pilot study measured the mitochondrial DNA (mDNA) content of the placenta and cord blood of 8 women on NNRTIs and compared it with that of 5 uninfected women.[10] The mean mDNA copies per cells from placenta of HIV-infected women was significantly reduced compared with the other group (52 vs 880 copies). Cord blood mDNA levels were also reduced significantly when both groups were compared. At the tissue level, there was evidence of some degree of mitochondrial toxicity, but this did not attain any clinical significance.

Bone Mineral Density

A cross-sectional study from Houston, Texas, examined the effect of HAART on bone mineral density (BMD) in children.[11] Investigators performed lumbar spine and total-body dual-energy x-ray absorptiometry (DEXA) scans in 27 children aged 6-17 years. In all, 66% of children were taking PI-containing HAART. No children were hypocalcemic or vitamin D-deficient. On scanning, however, 52% of the children were osteopenic (Z-score between -1 and -2.5) and 23% had osteoporosis (Z-score under -2.5). There was no difference in mean BMD Z-scores between children taking PIs or not. However, the longer a patient received PIs, the greater the risk for osteopenia. The findings were more prevalent in males. It is extremely important to be aware of the baseline degree of BMD loss among HIV-infected children, since the findings can be attributable to HIV disease itself rather than to treatment. Larger prospective trials are warranted.

Examining Treatment Failure

A detailed study from investigators at the University of California San Diego provided an alternative explanation for treatment failure of pediatric patients receiving nelfinavir.[12] Transport and metabolism of many drugs depend on the multidrug-resistance transporter gene (MDR1), which encodes for P-glycoprotein, and also on genes that encode for the transport of isoenzymes of cytochrome P450 (CYP). Genetic polymorphisms on the MDR1 or CYP genes of patients could be responsible for varying concentrations of antiretroviral drugs in plasma and thus affect virologic and immunologic responses.

In this study, 71 pediatric patients receiving nelfinavir and efavirenz in PACTG 382 underwent DNA genotyping to determine allelic variants. Although no changes specific to efavirenz were noted, children with MDR-3435 C/C genotype experienced slower virologic responses to HAART and demonstrated lower plasma concentrations and higher clearance rates of nelfinavir. P-glycoprotein appears to play an important role in the pharmacokinetics and virologic response to nelfinavir.

References

  1. Saez-Llorens X, Violari A, Ndiweni D, et al. Once-daily emtricitabine in HIV-infected pediatric patients with other antiretroviral agents. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 872.
  2. McKinney R, Rathore M, Jankelovich S, et al. PACTG 1021: an ongoing phase I/II study of once-daily emtricitabine, didanosine, and efavirenz in therapy-naive or minimally treated pediatric patients. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 873.
  3. Chadwick EG, Rodman JH, Samson P, et al. Antiviral activity, tolerance and pharmacokinetics of indinavir with two doses of ritonavir as salvage therapy in children. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 875.
  4. Borkowsky W, Yogev R, Muresan P, et al. T-cell and virologic outcomes of a progressively increasing structured treatment interruption study in chronically-infected children and adolescents. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 885.
  5. McFarland E, Borokowsky W, Muresan P, et al. Increases in HIV-specific CD4+ and CD8+ T-cell mediated responses in children undergoing structured treatment interruption. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 884.
  6. Mofenson L, Harris DR, Bethel J, et al. Second tier surrogate markers for use in resource-limited settings: association of total lymphocyte count and immune-complex dissociated p24 antigen with mortality in HIV-infected children. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 879.
  7. Fortuny C, Noguera A, Vilaseca MA, et al. Hyperlactatemia in children exposed to antiretrovirals and its relation with lipodystrophy syndrome in HIV-infected HAART-treated pediatric patients. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 777.
  8. Chantry C, Cervia J, Hughes M, et al. Body composition and biochemical changes in children starting or switching combination antiretroviral chemotherapy. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 775.
  9. Farley J, Gona P, Crain M, et al. Prevalence of hypercholesterolemia and associated risk factors among perinatally HIV-infected children (4 -19 years) in PACTG 219C. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 773.
  10. Shiramizu B, Shikuma K, Kamemoto L, et al. Placenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 771.
  11. Schwarzwald H, Ellis KJ, Evans DL, et al. Effect of HAART on bone density in HIV-infected children. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 778.
  12. Singh K, Saitoh A, Powell C, et al. Allelic variants of MDR1 alter pharmacokinetics of nelfinavir resulting in higher drug levels and more rapid decline in plasma HIV-1 RNA in children. Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Massachusetts. Abstract 100.

 COPIA CON FINES ACADEMICOS

 

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flu H1N1 news GUATEMALA

WASHINGTON (Reuters) Jul 15 – Many people are confused about just how many patients have been infected with the new H1N1 flu, which in turn makes it hard to tell how bad the pandemic is, British researchers have said.

But better methods of measuring the swine flu toll in real-time could help reduce some of that confusion, according to the team at Imperial College London.

And without this information, they said, governments are operating in the dark when assessing what their response should be.

“If you don’t test people, you don’t know how many people are out there who have it,” Dr. Tini Garske, an expert in disease modeling who led the study, said in a telephone interview. “The number of confirmed cases doesn’t tell you a lot.”

The World Health Organization has confirmed 94,512 cases globally and 429 deaths from the H1N1 flu, which was declared a pandemic last month.

The U.S. Centers for Disease Control and Prevention, however, says at least a million people have been infected and the virus is spreading out of control.

Most countries are now only testing a sample of patients, and many people who become infected do not become ill enough to seek medical attention, let alone get tested.

Diagnostic kits for H1N1 are expensive, and most governments save them for when they are really needed.

But if no one knows just how many people are infected overall, with serious disease and with mild disease, how can anyone say how severe the pandemic is?

In an article published online July 14 in the British Medical Journal, Dr. Garske and colleagues said current case fatality ratios are only around 0.5%. This rate is similar to that from seasonal influenza.

But Dr. Garske noted that this varies greatly from country to country. Unlike seasonal flu, H1N1 is causing severe illness in previously healthy young adults and children.

“Accurately predicting the severity of this swine flu pandemic is a very tricky business, and our research shows that this can only be achieved if data is collected according to well-designed study protocols and analyzed in a more sophisticated way than is frequently being performed at present,” Dr. Garske said.

“If we fail to get an accurate prediction of severity, we will not be providing healthcare planners, doctors and nurses, with the information that they need to ensure they are best prepared to fight the pandemic as we head into the flu season this autumn.”

Dr. Garske’s team outlined ways to improve estimates, including using individual towns as examples.

Watching families can also help give researchers an idea of how the flu spreads. If one sick family member infects one other family member, or two, or three, that number can be used to estimate the infection rate in places where cases are not being painstakingly diagnosed and recorded, she said.

“You don’t need to know about everybody, but you need some subpopulations,” she said.

Br Med J 2009.

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DERMATITIS ATOPICA Autoevaluación

 

Therapeutic options for treating atopic dermatitis (AD) in children, including the differences between topical corticosteroids and topical calcineurin inhibitors, are reviewed in an article in the October issue of Pediatrics. The review also highlights new treatment strategies being used by specialists in AD, including comprehensive “education-as-intervention” models, wet wraps, bleach baths, and systemic immunomodulatory therapies.

“Parents of patients with…AD turn to their primary caregivers for guidance regarding this physically demanding and psychologically stressful condition,” write Andrew C. Krakowski, MD, from the University of California, San Diego, and colleagues. “It is a chronic illness that requires a multifaceted treatment strategy in the setting of limited therapeutic options. Balancing safety concerns with efficacious treatment is of particular importance in the pediatric population.”

One of the most prevalent skin disorders in young children is AD, affecting 10% to 20% of children younger than 10 years and often adversely affecting the child’s overall health and development. Onset is usually by age 1 year in approximately 60% of affected infants and by age 5 years in approximately 85% of affected children.

The cornerstone for treatment of AD is still topical corticosteroids because of their broad-spectrum anti-inflammatory activity as well as their antiproliferative, immunosuppressive, and vasoconstrictive actions. One of the chief mechanisms of action is thought to be suppression of the release of inflammatory cytokines. Concerns about potential long-term risks for corticosteroid use, particularly in young children, have been to some extent alleviated by recent evidence.

Regimens of corticosteroid therapy may include starting treatment with a more potent preparation to induce remission, followed by a relatively quick tapering down of preparation potency as the AD improves, with a subsequent stepwise model allowing as-needed management on the basis of disease activity. Another strategy is to use short bursts of a potent preparation followed by a steroid-free “holiday period” of emollient use only until relapse occurs. Yet another strategy is use of more prolonged, continuous treatment with less potent preparations.

“Regarding dosage frequency, 1 large systematic review revealed that using twice-daily applications of topical corticosteroids was no more effective than once-daily application,” the study authors write. “Ultimately, providers should consider drug-specific FDA [US Food and Drug Administration] indications when educating and instructing patients on topical corticosteroid usage.”

For children with severe and/or refractory AD, wet wraps with once-daily application of topical corticosteroids appear to be effective and safe in the short-term, although temporary systemic bioactivity of the corticosteroids has been reported as a serious adverse effect. If overused or used incorrectly, wet wraps may also cause maceration of the skin and secondary infections, and they may promote skin dryness if sufficient emollients are not included in the regimen.

For selected patients, notably those who are prone to frequent flares and who need AD treatment in sensitive skin areas, such as around the eye, face, neck, and genital area, topical calcineurin inhibitors appear to be an effective therapeutic option that can offer targeted anti-inflammatory activity and can also reduce steroid use.

Some patients may require systemic anti-inflammatory activity offered by oral immunomodulating agents, such as azathioprine, cyclosporine, and mycophenolate. Phototherapy is also proposed to have anti-inflammatory activity.

Available treatments target various features of AD. Emollients, moisturizers, and barrier devices relieve xerosis by moisturizing dry skin and helping to repair the defective skin barrier. Topical or orally administered anti-infective agents are used to treat cutaneous bacterial, fungal, or viral infections. Another approach to reducing infections is use of bleach baths, which are proposed to decrease the microbial load on colonized and/or superinfected skin.

In selected patients, antihistamines may be useful as adjunctive therapy. Their sedating effect may help children sleep through the night, thereby indirectly decreasing night-time scratching resulting in skin excoriation.

Overall management depends not only on pharmacotherapy but also on a multiprong approach. Clinicians should educate caregivers about the chronic, unpredictable course of AD, typically marked by flares that can occur despite optimal management. Because of the compromised epidermal barrier in AD, it is essential to pay careful attention to proper skin care.

Realizing that AD is a multifactorial disease, with one of the proposed mechanisms being immune dysfunction, clinicians should counsel their patients to avoid potential triggers, which helps prevent known allergic reactions and inflammatory responses.

Potential triggers may be those associated with direct contact, such as toiletries containing alcohol, astringents, or fragrances; harsh detergents or soaps; or abrasive clothing made of wool or synthetics. Physiologic and emotional stressors precipitating AD flares may include psychological stress; infections with Staphylococcus aureus, viruses, or fungi; and overheating or sweating.

Dietary triggers include food allergens found in cow’s milk, eggs, peanuts, tree nuts such as walnuts or cashews, soy, wheat, fish, shellfish, or foods processed with any of the above.

To achieve long-term success for patients with AD, a team-oriented approach is needed, including primary care clinicians, specialists, nurses, psychologists, behavioral therapists, and other healthcare professionals.

“Successful management involves educating patients and their families about AD, reducing signs and symptoms of the condition, preventing and decreasing the degree and frequency of flares, modifying the overall disease course, and, possibly, slowing the atopic march,” the study authors conclude. “A comprehensive long-term strategy that encompasses education, trigger avoidance, excellent skin care, and treatment (pharmacologic and nonpharmacologic measures) is vital. Physicians should use their understanding of the variety of available treatment options to develop a personalized therapeutic strategy that is tailored to the individual child’s age and needs, extent and localization of AD at presentation, and overall disease course (including persistence, frequent flares, etc).”

Two of the study authors have disclosed serving as investigators and consultants for multiple pharmaceutical-sponsored studies on atopic dermatitis.

Pediatrics. 2008;122:812-824.

Clinical Context

AD affects 10% to 20% of children, according to Larsen and Hanifin in the February 2002 issue of Immunology and Allergy Clinics of North America. The primary factors in AD are epidermal barrier function defects and skin inflammation. The diagnosis of AD is based on combined essential, important, and associated nonspecific features. Essential features include pruritus, eczematous dermatitis, typical morphologic features with age-specific patterns, and chronic or relapsing nature.

This review of AD describes the management of AD, including topical corticosteroids, topical calcineurin inhibitors, and new treatments.

Study Highlights

  • Education is a crucial part of management:
    • A 6-week education program for parents resulted in improved quality of life and eczema severity for their children older than 12 months.
    • Comprehensive centers can provide care in dermatology, allergy, infectious disease, and behavioral psychology.
  • Trigger avoidance measures include mattress covers, low-pile carpet, pets that do not produce dander, and avoidance of known food allergens.
  • The American Academy of Pediatrics 2008 breast-feeding guidelines recommend exclusive breast-feeding for at least 4 months to decrease AD incidence in the first 2 years of life in children at high risk for AD.
  • There is no evidence that delaying solid food, including cow’s milk, fish, eggs, and peanut-containing foods, after ages 4 to 6 months protects against AD.
  • Studies on probiotic effects on risk for AD had conflicting results.
  • Skin care recommendations include dye-free, fragrance-free emollients and moisturizers applied at least twice a day, ointments, and ceramide-rich products.
  • “510(k) medical devices” are approved by the US Food and Drug Administration as new barrier products.
  • Bathing in lukewarm water with moisturizing cleanser for several minutes once or twice a day should be followed by use of a towel to pat dry and emollients.
  • Avoid fragrance soaps or bubble baths.
  • First-line treatment of AD flares is topical corticosteroids:
    • Class I are most potent and class VII, least potent.
    • Adverse effects are skin atrophy, striae, telangiectasias, hypopigmentation, rosacea, perioral dermatitis, acne, cataracts, glaucoma, hypothalamic-pituitary-adrenal axis suppression, growth retardation, and bone density reduction.
    • Twice-a-day use has the same effect as once-a-day use.
  • The topical calcineurin inhibitors tacrolimus and pimecrolimus are second-line treatment for short-term and noncontinuous long-term use in immunocompetent patients at least 2 years old with moderate to severe AD:
    • Long-term safety is not known, according to 2006 US Food and Drug Administration boxed warning.
    • Indications include AD persistence or frequent flares requiring almost continuous topical corticosteroids and involvement of sensitive skin areas.
  • Sedating antihistamines hydroxyzine and diphenhydramine might improve sleep but do not directly affect AD-related pruritus.
  • Possible complications include overgrowth of S aureus, Molluscum contagiosum, eczema herpeticum, eczema vaccinatum, and fungal infections.
  • If bacterial superinfection occurs, culture for methicillin-resistant S aureus should be considered.
  • Diluted bleach baths can decrease local skin infections and need for systemic antibiotics.
  • Wet wraps and once-daily topical corticosteroids are effective for severe or refractory AD, but close supervision is needed because of risk for skin maceration or secondary infection.
  • Systemic immunomodulatory therapies can be used for refractory AD:
    • Multiple phototherapy sessions
    • Short-term cyclosporine; long-term use can be linked with hypertension and renal toxicity
    • Azathioprine monotherapy; monitor blood cell counts and liver function tests
    • Mycophenolate mofetil appears safe; prospective controlled studies are needed.
  • Dermatology referral indications include moderate or severe AD, poor response to moderate-potency topical corticosteroids, persistent AD, frequent flares, AD-related hospitalization, and systemic therapy.
  • Other specialty referrals include allergy referral for suspected specific triggers and gastroenterology or immunology referral for possible eosinophilic gastroenteritis or esophagitis with failure to thrive or frequent systemic infections.

Pearls for Practice

  • In children with atopic dermatitis, the first-line treatment is topical corticosteroids, with potency ranging from the least potent class VII to the most potent class I. Second-line treatment of frequent flares or sensitive skin areas is a topical calcineurin inhibitor, for use in children 2 years or older.
  • New treatment modalities for children with atopic dermatitis include education models; bleach bath; wet wraps; and systemic immunomodulatory therapies, including phototherapy, cyclosporine, azathioprine, and mycophenolate mofetil
A 12-month-old child who was recently diagnosed with atopic dermatitis presents to your office for a flare-up of the condition. The physical examination is significant for erythematous, mildly excoriated areas in the antecubital fossa. There is no crusting or folliculitis. The parents are currently using a fragrance-free moisturizer twice a day. Which of the following is the most appropriate next step in management?
  a) Topical calcineurin inhibitor
  b) Topical steroid class I
  c) Topical steroid class VII
  d) Antibiotic treatment of methicillin-resistant S aureus
  e) All of the above

 

Which of the following statements about the treatment of atopic dermatitis in children is most accurate?
  a) Multiple phototherapy treatments are effective
  b) Incorrect use of wet wraps is linked with skin maceration
  c) Bleach baths can reduce the need for systemic antibiotics
  d) Liver function tests should be monitored if azathioprine is used
  e) All of the above

 

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Guidelines Address Physical Activity for Individuals 6 Years and Older

October 9, 2008 — The US Department of Health and Human Services (HHS) has issued guidelines regarding the types and amounts of physical activity that provide substantial health benefits for physical activity for individuals 6 years and older. These 2008 Physical Activity Guidelines for Americans are posted online at the HHS Web site. Although primarily targeting policymakers and health professionals, the information in these guidelines may also be useful to interested members of the lay public.

“Along with President Bush, I believe that physical activity should be an essential component of any comprehensive disease prevention and health promotion strategy for Americans,” HHS Secretary Michael O. Leavitt writes in a letter introducing the guidelines. “We know that sedentary behavior contributes to a host of chronic diseases, and regular physical activity is an important component of an overall healthy lifestyle. There is strong evidence that physically active people have better health-related physical fitness and are at lower risk of developing many disabling medical conditions than inactive people.”

Regular physical activity each week, sustained for months and years, can produce long-term health benefits. Strong evidence links regular physical activity with a lower risk for early death, heart disease, stroke, type 2 diabetes, hypertension, hyperlipidemia, metabolic syndrome, colon and breast cancers, and depression. Regular physical activity also promotes prevention of weight gain, weight loss when combined with diet, better cardiorespiratory and muscular fitness, fall prevention, and better cognitive function in older adults.

The 2008 Physical Activity Guidelines were designed to complement the Dietary Guidelines for Americans, which were developed by HHS and the US Department of Agriculture. When used together, these guidelines may help promote good health and reduce the risk for chronic diseases by emphasizing the importance of being physically active and eating a healthy diet.

When writing the guidelines, HHS primarily used a report from an appointed external scientific advisory committee (the Physical Activity Guidelines Advisory Committee) as well as comments from the public and government agencies.

Major research findings on the health benefits of physical activity, gathered by the Physical Activity Guidelines Advisory Committee after a review of the literature and other available evidence, are as follows:

  • Regular physical activity lowers the risk for many adverse health outcomes.
  • Although some physical activity is better than none, higher intensity, greater frequency, and/or longer duration of physical activity provide additional benefits for most health outcomes.
  • At least 150 minutes per week of moderate-intensity physical activity, such as brisk walking, is needed for most health benefits, but more physical activity provides additional benefits.
  • Aerobic (endurance) and muscle-strengthening (resistance) physical activity both promote better health.
  • In every studied racial and ethnic group, and in children and adolescents, young and middle-aged adults, and older adults, physical activity is linked to health benefits.
  • People with disabilities also receive health benefits from physical activity.
  • The benefits provided by physical activity far outweigh the risk for harms.

 

Key guidelines for physical activity for children and adolescents are as follows:

  • Children and adolescents should engage in at least 1 hour of physical activity daily, preferably in physical activities that are appropriate for their age, that are enjoyable, and that offer variety.
  • Most of this activity should be either moderate- or vigorous-intensity aerobic physical activity.
  • Vigorous-intensity physical activity, muscle-strengthening physical activity, and bone-strengthening physical activity should each be performed at least 3 days per week.

 

Key guidelines for physical activity for adults, including older adults, are as follows:

  • All adults should avoid inactivity. Participation in any amount of physical activity is associated with some health benefits relative to no physical activity.
  • At least 150 minutes per week of moderate-intensity, or 75 minutes a week of vigorous-intensity aerobic physical activity, or an equivalent combination of moderate- and vigorous-intensity aerobic activity offers substantial health benefits.
  • Aerobic activity should preferably be spread throughout the week and performed in episodes of at least 10 minutes.
  • Aerobic physical activity of 300 minutes per week of moderate intensity, or 150 minutes per week of vigorous intensity aerobic physical activity, or an equivalent combination of moderate- and vigorous-intensity activity, is associated with additional and more extensive health benefits.
  • Engaging in physical activity beyond this amount provides additional health benefits.
  • Muscle-strengthening activities that are moderate or high intensity and involve all major muscle groups should be performed on 2 or more days per week for additional health benefits.

 

Additional guidelines specific to older adults are as follows:

  • When chronic conditions prevent older adults from doing 150 minutes of moderate-intensity aerobic activity per week, they should be as physically active as their abilities and conditions allow. They should understand whether and how their conditions affect their ability to do regular physical activity safely.
  • Older adults at risk of falling should do exercises that maintain or improve balance.
  • Older adults should determine their level of effort for physical activity relative to their fitness level.

 

Adults, children, and adolescents with disabilities should follow the guidelines for their age group if possible, or if not, they should be as physically active as their abilities allow, with guidance from their healthcare provider. They should avoid inactivity.

Healthy pregnant and postpartum women who are not already engaged in vigorous-intensity physical activity should get at least 2 hours and 30 minutes of moderate-intensity aerobic activity per week, preferably spread throughout the week. Those who regularly engage in vigorous-intensity aerobic activity or in high amounts of activity can continue with this regimen, provided that their condition remains unchanged and that they consult with their healthcare provider regarding their activity level throughout their pregnancy.

US Dept of Health and Human Services. 2008 Physical Activity Guidelines for Americans.

Published online October 18, 2008.

Clinical Context

Regular physical activity each week, sustained for months and years, is linked to long-term health benefits, including reduced risks for early death, heart disease, stroke, type 2 diabetes, hypertension, hyperlipidemia, metabolic syndrome, colon and breast cancers, and depression. Evidence is also strong that regular physical activity is associated with prevention of weight gain, weight loss when combined with diet, better cardiorespiratory and muscular fitness, fall prevention, and better cognitive function in older adults.

The HHS designed these Physical Activity Guidelines for Americans to be used together with Dietary Guidelines for Americans, which were developed by HHS and the US Department of Agriculture. When used together, these recommendations may provide health benefits and lower the risk for chronic diseases by highlighting the importance of being physically active and eating a healthy diet.

Study Highlights

  • Health benefits of physical activity are as follows:
    • Regular physical activity reduces the risk for many adverse health outcomes.
    • Some physical activity is better than none. Greater intensity, higher frequency, and/or longer duration of physical activity offer additional benefits for most health outcomes.
    • Moderate-intensity physical activity, such as brisk walking, at least 150 minutes per week is needed for most health benefits. More physical activity offers additional benefits.
    • Aerobic (endurance) and muscle-strengthening (resistance) physical activity both promote better health.
    • Physical activity is linked to health benefits in every studied racial and ethnic group; in children and adolescents; in young, middle-aged, and older adults; and in people with disabilities.
    • The benefits provided by physical activity far outweigh the risk for harms.
  • Key guidelines for physical activity are as follows:
    • Children and adolescents should engage in 1 or more hours of physical activities daily, preferably those that are age appropriate, enjoyable, and that offer variety. Most of this activity should be moderate- or vigorous-intensity aerobic physical activity, with vigorous-intensity physical activity, muscle-strengthening physical activity, and bone-strengthening physical activity each to be performed 3 or more days per week.
    • All adults should avoid inactivity; some physical activity is better than none.
    • In adults, at least 150 minutes per week of moderate-intensity, 75 minutes per week of vigorous-intensity aerobic physical activity, or an equivalent combination of both, offers substantial health benefits.
    • Aerobic activity should preferably be spread throughout the week, in episodes of at least 10 minutes. Additional, more extensive health benefits are offered by 300 or more minutes per week of moderate intensity, 150 minutes per week of vigorous-intensity aerobic physical activity, or an equivalent combination of both. More of this activity is even better.
    • Moderate- or high-intensity muscle-strengthening activities that involve all major muscle groups should be performed on 2 or more days per week for additional health benefits.
    • Older adults should follow the adult guidelines whenever possible, or they should be as physically active as their abilities and conditions allow, while observing safety precautions.
    • Older adults at risk of falling should do exercises that maintain or improve balance.
    • Adults, children, and adolescents with disabilities should follow guidelines for their age group if possible. If not, they should be as physically active as their abilities allow, with guidance from their healthcare provider.
  • Healthy pregnant and postpartum women not already engaged in vigorous-intensity physical activity should get 2.5 or more hours of moderate-intensity aerobic activity per week, preferably spread throughout the week. Those already engaged in such activity can continue their usual activity levels, provided that their condition remains unchanged and that they consult with their healthcare provider.

Pearls for Practice

  • The HHS 2008 Physical Activity Guidelines for Americans describe the numerous health benefits of regular physical activity in reducing the risk for many adverse health outcomes in every age, racial, and ethnic group studied. Some physical activity is better than none, but greater intensity, higher frequency, and/or longer duration of physical activity offer additional benefits for most health outcomes.
  • Key guidelines for physical activity are that children and adolescents should engage in 1 or more hours of physical activities daily, mostly moderate- or vigorous-intensity aerobic physical activity, with vigorous-intensity physical activity, muscle-strengthening physical activity, and bone-strengthening physical activity each performed 3 or more days per week. In adults, at least 150 minutes per week of moderate-intensity, 75 minutes a week of vigorous-intensity aerobic physical activity, or an equivalent combination of both, offers substantial health benefits.
According to the HHS 2008 Physical Activity Guidelines for Americans, which of the following statements about the effects of physical activity on health benefits is correct?
  a) For those who do not follow guidelines for optimal activity, smaller amounts of activity provide no benefit
  b) The risks for physical activity often outweigh the benefits
  c) Physical activity in excess of recommended guidelines can be harmful
  d) Aerobic and muscle-strengthening physical activity both promote better health

 

According to the HHS 2008 Physical Activity Guidelines for Americans, which of the following statements about recommended physical activity levels is not correct?
  a) Children and adolescents should engage in 1 or more hours of physical activities daily
  b) Structured calisthenic programs are better for children than playground sports of comparable intensity
  c) Adults should engage in at least 150 minutes per week of moderate-intensity, 75 minutes per week of vigorous-intensity aerobic physical activity, or an equivalent combination of both
  d) Older adults at risk of falling should do exercises that maintain or improve balance

 

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