Lung cancer in Argentina: a modelling study of disease and economic burden.

OBJECTIVES: Lung cancer remains a significant global public health challenge and is still one of the leading causes of cancer-related death in Argentina. This study aims to assess the disease and economic burden of lung cancer in the country. STUDY DESIGN: Burden of disease study. METHODS: A mathematical model was developed to estimate the disease burden and direct medical cost attributable to lung cancer. Epidemiological parameters were obtained from local statistics, the Global Cancer Observatory, the Global Burden of Disease databases, and a literature review. Direct medical costs were estimated through micro-costing. Costs were expressed in US dollars (US$), April 2023 (1 US$ = 216.38 Argentine pesos). A second-order Monte Carlo simulation was performed to estimate the uncertainty. RESULTS: Considering approximately 10,000 deaths, 12,000 incident cases, and 14,000 5-year prevalent cases, the economic burden of lung cancer in Argentina in 2023 was estimated to be US$ 556.20 million (396.96-718.20), approximately 1.4% of the total healthcare expenditure for the country. The cost increased with a higher stage of the disease, and the main driver was drug acquisition (80%). A total of 179,046 disability-adjusted life years could be attributable to lung cancer, representing 10% of the total cancer. CONCLUSION: The disease and economic burden of lung cancer in Argentina implies a high cost for the health system and would represent 19% of the previously estimated economic burden for 29 cancers in Argentina.

Liver Transplant From a Donor With Situs Inversus Totalis Using Orthotopic and Retroversus Technique: A Case Report.

Situs inversus totalis is an infrequent genetic malformation affecting 0.01% of the population and consists of the total rotation of the organs 180 degrees, generating the so-called mirror-image reversal. For many years donors with this pathology were discouraged from organ donation. We present a case of hepatic and renal transplantation using the 2 techniques described, orthotopic and retroversus. The recipient was a 69-year-old man with end-stage liver and kidney disease due to alcoholism and diabetes, respectively, and a Model for End-Stage Liver Disease score of 32. There was no mismatch between recipient and donor. The implant started with the piggy-back technique using the retroversus technique, generating a tense portal vein anastomosis due to the superior situation of the elements of the hepatic hilum, so it was decided to undo suprahepatic anastomosis with the orthotopic technique, rotating the liver on its axis, without complications. Roux-en-Y hepaticojejunoanastomosis was carried out. The patient was discharged 15 days after surgery with normalization of renal function. Although both techniques must be taken into account, the one that fits best for a particular recipient should be used, given the particularities of size and shape of the liver graft. This can take some art and creativity from the surgical team.

Vacuna tetravalente CYD-TDV contra el Dengue / Quadrivalent vaccine CYD-TDV against Dengue

CONTEXTO CLÍNICO: El dengue es una enfermedad viral transmitida por la picadura del mosquito Aedes aegypti, vector de la enfermedad. El virus pertenece a la familia Flaviviridae, y existen cuatro variantes: los serotipos DEN1, DEN2, DEN3 y DEN4. El número de casos de dengue notificados anualmente a la Organización Mundial de la Salud há aumentado de 0,4 a 1,3 millones entre 1996-2005, llegando a 2,2 millones en el 2010 y 3,2 millones en el 2015. La Organización Mundial de la Salud (OMS) estima que alrededor de 50 a 100 millones de casos sintomáticos en los últimos años, predominantemente en Asia, seguida por América Latina y África. Los casos de infección que presentan síntomas probablemente representen alrededor del 25% de todas las infecciones por el virus. La incidencia reportada promedio entre 1995 y 2009 en Argentina fue de 1,6 casos por cada 100.000 habitantes, mientras que en países como Brasil, Paraguay y Bolivia es de 196, 107, y 108 casos cada 100.000 habitantes, respectivamente. TECNOLOGÍA: La vacuna CYD-TDV (Dengvaxia®) es una vacuna recombinante a virus atenuado de los cuatro serotipos virales (DEN1, DEN2, DEN3, DEN4) insertados en el esqueleto de la vacuna de la fiebre amarilla. Es um producto liofilizado para ser reconstituido antes de la inyección y aplicado en una dosis de 0,5 ml em por vía subcutánea. Se indica a pacientes de 9 a 60 años y debe administrarse en tres dosis a los 0, 6 y 12 meses. La vacuna está contraindicada en individuos con un historial de reacción alérgica a cualquier componente de la vacuna de dengue; individuos con inmunodeficiencia celular congénita o adquirida; personas con infección por VIH sintomática o con infección asintomática por VIH cuando se acompanha de evidencia de deterioro de la función inmune; mujeres embarazadas o mujeres en lactancia; además la aplicación debería ser pospuesta en personas con síndrome febril. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de la vacuna tetravalente CYD-TDV contra el dengue. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron dos RS, una GPC, una evaluación económica, y cuatro informes de políticas de cobertura. CONCLUSIONES: Evidencia de alta calidad demuestra que la vacuna tetravalente contra el dengue (CYD-TDV) es efectiva para prevenir la enfermedad sintomática, al comparar la incidencia de la misma en indivíduos vacunados versus no vacunados. El análisis de efectividad por subgrupos, demuestra que la misma es mayor en aquellos pacientes que han sido previamente sensibilizados de manera natural. Una guía de la Organización Mundial de la Salud (OMS) recomienda su aplicación en poblaciones que presentan una seroprevalencia mayor al 70%. En aquellas poblaciones con una seroprevalencia entre el 50 y 70%, refiere que su uso también sería aceptable, pero el impacto del programa sería menor. No recomienda su aplicación en poblaciones con una seroprevalencia menor al 50%. No se cuenta con información acerca de la seroprevalencia en Argentina, pero se estima que sería muy baja, en base a estudios de incidencia.

Aflibercept en retinopatía diabética / Aflibercept in diabetic retinopathy

CONTEXTO CLÍNICO: La retinopatía diabética (RD) es una de las principales causas de pérdida de visión principalmente entre pacientes entre 25 y 74 años.1 El 10% de los pacientes con diabetes tienen una limitación visual severa y 2% de ellos llega a la ceguera. La prevalencia de la RD aumenta con el tiempo de duración de la diabetes. Se calcula que en Argentina hay 2.600.000 personas diabéticas, de las cuales 700.000 tienen algún grado de retinopatía y 135.000 presentan RD proliferativa o edema macular (EM). La ceguera por RD es prevenible en un 80% de los casos con una detección y tratamiento temprano asociado a un manejo general. 3 Se han desarrollado y evaluado muchas intervenciones preventivas y terapéuticas con el objetivo de minimizar la morbilidad asociada a la RD. Preventivamente se sugiere un control estricto de la glucemia de forma precoz, mientras que para el tratamiento la cirugía láser de fotocoagulación es la principal recomendación.1 Se considera un cambio clínicamente significativo en el tratamiento de la RD, a la mejora de 2 escalones en la Escala de Gravedad de Retinopatía Diabético (DRSS, su sigla del inglés Diabetic Retinopathy Severity Scale) y una media de diferencia de 4 letras en agudeza visual. Adicionalmente, existen alternativas farmacológicas para el tratamiento del edema macular diabético (EMD) incluyen las drogas antiangiogénicas(Anti-VEGF) intravítreas y los corticoesteroides intravítreos. Los agentes Anti-VGEF (inhibidores del factor de crecimiento vascular endotelial) (bevacizumab, ranibizumab y aflibercept) han demostrado ser eficaces en el tratamiento de los pacientes con edema macular diabético. Se postula al aflibercept como una droga superior a los otros Anti-VGEF y a los corticoides en cuanto a la mejoría de la agudeza visual sin aumento importante de los efectos adversos. TECNOLOGÍA: El aflibercept es una proteína de fusión recombinante humana de los dominios de los receptores de VEGF humano 1 y 2 y la región Fc de las IgG humana de unión de todas las isoformas de VEGF A. Es um bloqueante potente y específico de VEGF subtipo A y del factor de crecimiento placentario relacionado (PIGF, su sigla del inglés Placental Growth Factor), factores angiogénicos. El tratamiento anti-VEGF previene el crecimiento inapropiado de vasos nuevos en la retina y disminuir la permeabilidad vascular reduciendo el edema macular. Las drogas Anti-VGEF bloquean a las citosinas, como el factor de crecimiento vascular endotelial (VEGF), los cuales son los responsables de la angiogénesis y del aumento de la permeabilidade vascular, presentes en la RD y en el EMD, siendo estos los principales responsables de la disminución en la agudeza visual. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de aflibercept para retinopatía diabética. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron cuatro ECAs, cuatro RS, dos series de casos, cuatro GPC, una evaluación económica, dos evaluaciones de tecnología sanitaria e ocho informes de políticas de cobertura aflibercept en retinopatia diabética. CONCLUSIONES: Existe evidencia de alta calidad para considerar que el aflibercept en pacientes con retinopatia diabética con compromiso severo de la agudeza visual y con un espesor central de la retina mayor a 400 micrones produce mejoras en la agudeza visual de forma clínica y estadísticamente significativas en comparación a otras drogas inhibidoras del crecimiento vascular (Anti-VGEF) durante el primer año de seguimiento,si bien dicha diferencia disminuye durante el segundo año de seguimiento. Existe evidencia de moderada calidad que no establece diferencias entre el aflibercept y los otros anti-VGEF en el desarrollo de efectos adversos sistémicos. Asimismo, evidencia de alta calidad permite considerar que el aflibercept, en la misma patología, produce mejoras considerables en la agudeza visual de forma clínica y estadísticamente significativas en comparación a la terapia de fotocoagulación con láser durante el primer año de seguimiento, al igual que otras drogas Anti-VGEF, aunque dicha diferencia disminuye en el seguimiento a dos años. Sin embargo, de acuerdo a evidencia de moderada calidad en relación a la terapia prolongada con aflibercept en pacientes con edema macular diabético existe incertidumbre en cuanto a la incidencia algunos eventos adversos sistémicos serios, y sobre la mortalidad por todas las causas en comparación a la terapia láser. Informes de Evaluaciones de Tecnología Sanitaria realizados en Canadá y Reino Unido consideran que la terapia con aflibercept podría ser costo-ahorrativa en comparación a la terapia con ranibizumab em pacientes con edema macular diabético (EMD). En cuanto al perfil de seguridad, las mismas informan que no hubo mayores problemas asociados con aflibercept y que basándose en la práctica clínica y los resultados de los ensayos, el mismo es bien tolerado. Las evaluaciones económicas analizadas en países de altos ingresos no consideran al aflibercept uma droga costo-efectiva. No existen evaluaciones económicas que estudien el impacto de esta droga em Argentina. Existe consenso en las guías de práctica clínica consultadas para recomendar al aflibercept como una alternativa terapéutica en pacientes con retinopatía diabética. Las políticas de cobertura consultadas provenientes de financiadores públicos y privados de Europa y Estados Unidos brindan cobertura. En cuanto a América Latina, los financiadores públicos consultados, no brindan cobertura.

Agentes biológicos en pacientes con espondiloartritis / Biological agents in patients with spondyloarthritis

CONTEXTO CLÍNICO: Las espondiloartritis (EspA) son un grupo de enfermedades reumáticas que comparten características genéticas y clínicas como dolor lumbar inflamatorio debido a sacroileitis y espondilitis (compromisso axial) y manifestaciones como entesitis, artritis, dactilitis, uveítis, o compromiso de otros órganos. Las principales EspA son la espondiloartritis axial (EspAax) y la artritis psoriásica (APs). Asimismo, dentro de la EspAax, se engloban la espondilitis anquilosante (EA) y la EspAax no radiográfica (EspAax-no rx). En la EA, hay un cierto grado de daño estructural visible en la radiografía simple, el cual no se observa en la EspAax-no rx. La EspAax-no rx puede evolucionar a EA. En general, las cifras de prevalencia de las EspA se sitúan entre el 0,1% y 2,5% de la población y se estima una incidencia que va desde 0,84 a 77 casos cada 100.000 habitantes/año. Por su parte, la psoriasis afecta aproximadamente al 3,2% de la población general y cerca de un tercio de los pacientes con psoriasis tiene artritis. Por lo tanto la prevalencia de la APs puede variar entre el 0,3% y el 1,0%. En pacientes con compromiso axial y falla o intolerancia al tratamiento con antiinflamatorios no esteroideos (AINES) se utilizan diferentes agentes biológicos. En pacientes con compromiso periférico y respuesta inadecuada o intolerancia a drogas convencionales (como metotrexate, sulfasalazina y leflunomida), también están indicados estos fármacos. TECNOLOGÍA: El adalimumab, etanercept, infliximab, certolizumab pegol y golimumab son terapias biológicas que inhiben al factor de necrosis tumoral alfa (anti-TNF), un mediador pro inflamatorio. El infliximab se administra en forma endovenosa, en semana cero, dos, seis y luego cada ocho semanas; en dosis de 5 mg/kg. Los otros cuatro anti TNF se administran en forma subcutánea: adalimumab 40 mg cada dos semanas; etanercept 50 mg por semana; certolizumab pegol 400 mg semana cero, semana dos y cuatro y luego 200 mg cada 15 días o 400 mg por mes; golimumab 50 mg por mes. El secukinumab es un anticuerpo monoclonal inhibidor de la interleuquina 17A, que se administra em dosis de 150 mg por inyección subcutánea, inicialmente en la semana cero, uno, dos y tres y, luego durante la fase de mantenimiento, mensualmente comenzando en la semana cuatro. Para pacientes que padecen psoriasis en placas de moderada a grave de forma concomitante o que son respondedores inadecuados a anti-TNF, la dosis recomendada es de 300 mg (administrada con igual frecuencia que la dosis de 150 mg). OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de agentes biológicos en espondiloartritis. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron tres ECAs, seis RS, siete GPC, una ETS con evaluación económica, y 37 informes de políticas de cobertura de agentes biológicos versus terapia habitual en pacientes espondiloartritis. En general, los desenlaces utilizados son el ASAS (su sigla en inglés Assessments in Ankylosing Spondylitis International Society) 20 o 40 en EA y EspAax-no rx y ACR (su sigla en inglés American College of Rheumatology) 20 en la artritis periférica en APs. CONCLUSIONES: Evidencia de moderada calidad muestra que adalimumab, etanercept, infliximab, certolizumab, golimumab (agentes anti factor de necrosis tumoral alfa -anti-TNF-) y secukinumab son efectivos en controlar la espondilitis anquilosante activa en adultos con respuesta inadecuada o intolerancia a antiinflamatorios no esteroideos (AINES). Evidencia de moderada calidad muestra la efectividad de adalimumab, etanercept, certolizumab y golimumab en pacientes con espondiloartritis axial no radiológica y respuesta inadecuada o intolerancia a AINES. Es importante señalar que el infliximab no cuenta con la aprobación de las principales agencias regulatorias de medicamentos para esta indicación, y los otros cuatro anti-TNF no cuentan con la aprobación por la Administración de Drogas y Medicamentos de EE.UU. (FDA), pero sí por la Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) y la Agencia Europea de Medicamentos (EMA). Evidencia de moderada calidad muestra que adalimumab, etanercept, infliximab, certolizumab, golimumab, ustekinumab y secukinumab son efectivos en controlar la artritis periférica activa a pesar del tratamiento con drogas convencionales en pacientes con artritis psoriásica, mientras que evidencia de baja calidad sugiere la utilidad de algunas de estos medicamentos en pacientes con artritis psoriásica y entesitis o dactilitis. Las guías de práctica clínica consultadas recomiendan el uso de la mayoría de estas drogas en las patologías y situaciones mencionadas; así como en los pacientes con compromiso axial por artritis psoriásica, extrapolando la evidencia disponible en pacientes con espondiloartritis axial. Los financiadores de salud tanto públicos como privados de todo el mundo que han sido relevados prestan cobertura a la mayoría de estas terapias en estos grupos de pacientes. Dado que no parece haber diferencias significativas en los efectos de estas drogas, muchas organizaciones deciden cuál o cuáles cubren o reembolsan en función de los costos. No se encontraron estudios locales de costo-efectividad, impacto financiero y organizacional, por lo que el impacto es incierto en esta dimensión.

Diálisis peritoneal versus hemodiálisis en enfermedad renal crónica estadio 5 / Peritoneal dialysis versus hemodialysis in chronic kidney disease stage 5

CONTEXTO CLÍNICO: La enfermedad renal crónica (ERC) es un problema mundial de salud pública. Se estima que la prevalencia mundial es del 17% en los mayores de 20 años.1 Se define por la presencia de marcadores de daño renal (albuminuria, marcadores histopatológicos o en imágenes, entre otros) o filtrado glomerular (FG) menor a 60 ml/min/1,73m2 por tres meses o más, siendo la única enfermedad en la que es posible la sustitución parcial de la función de un órgano vital para conservar la vida. En tal dirección, la Terapia Sustitutiva Renal (TSR) puede realizarse mediante três modalidades fundamentales: hemodiálisis, diálisis peritoneal y trasplante renal. El trasplante renal es la terapia de elección, pero en aquellos pacientes en los que esto está contraindicado o deben esperar para obtener un órgano, se debe proceder a otras terapias de sustitución renal. TECNOLOGÍA: La diálisis peritoneal (DP) es un procedimiento que permite depurar líquidos, sustancias orgánicas y productos de metabolismo cuando no hay funcionamiento renal adecuado. Este se realiza a través de una membrana natural (peritoneo). La estructura anatomo-funcional de esta membrana, las características físico-químicas de la solución de diálisis y el catéter, constituyen los tres elementos básicos de ésta diálisis. Existen tres métodos para la implantación de los catéteres: quirúrgico, percutáneo a ciegas (con trocar o guía metálica) y por vía laparoscópica. Asimismo, existen dos modalidades de DP: la diálisis peritoneal continua ambulatoria (DPCA) cuyo intercambio se realiza tres a cuatro veces por día; y la diálisis peritoneal automatizada (DPA) a través de una máquina denominada cicladora que permite realizar los intercambios automáticamente mientras el paciente duerme. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de diálisis peritoneal versus hemodiálisis em pacientes con enfermedad renal crónica - estadio 5. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron dos RS, un MA, dos análisis de propensión, un estudio observacional, seis GPC, uma ETS, dos evaluaciones económicas, y 15 informes de políticas de cobertura de diálisis peritoneal em pacientes con enfermedad renal crónica - estadio 5. CONCLUSIONS: Moderate quality evidence suggests that peritoneal dialysis, in patients with end stage renal disease not eligible for hemodialysis, offers clinical benefits comparable to those of hemodialysis. Moderate quality evidence suggests that in patients with end stage renal disease, peritoneal dialysis is at least as effective as hemodialysis in reducing mortality for any cause and cardiovascular mortality and it also reduces the risk of developing congestive heart failure when compared with hemodialysis. The assessment of other parameters such as ferritin, transferrin saturation index, parathyroid hormone and quality of life did not show significant differences between both types of dialysis. The clinical practice guidelines consider both types of dialysis as treatment alternatives in patients with end stage renal disease taking into account that both have advantages and disadvantages. The public and private health sponsors consulted cover both alternatives.

Nasal biopsies of children exposed to air pollutants.

Southwest Metropolitan Mexico City (SWMMC) atmosphere is a complex mixture of air pollutants, including ozone, particulate matter, and aldehydes. Children in SWMMC are exposed chronically and sequentially to numerous toxicants, and they exhibit significant nasal damage. The objective of this study was to assess p53 accumulation by immunohistochemistry in nasal biopsies of SWMMC children. We evaluated 111 biopsies from 107 children (83 exposed SWMMC children and 24 control children residents in a pollutant-compliant Caribbean island). Complete clinical histories and physical examinations, including an ear-nose-throat (ENT) exam were done. There was a significant statistical difference in the upper and lower respiratory symptomatology and ENT findings between control and exposed children (p < 0.001). Control children gave no respiratory symptomatology in the 3 months prior to the study; their biopsies exhibited normal ciliated respiratory epithelium and were p53-negative. SWMMC children complained of epistaxis, nasal obstruction. and crusting. Irregular areas of whitish-gray recessed mucosa over the inferior and middle turbinates were seen in 25% of SWMMC children, and their nasal biopsies displayed basal cell hyperplasia, decreased numbers of ciliated and goblet cells, neutrophilic epithelial infiltrates, squamous metaplasia. and mild dysplasia. Four of 21 SWMMC children with grossly abnormal mucosal changes exhibited strong transmural nuclear p53 staining in their nasal biopsies (p 0.005, odds ratio 26). In the context of lifetime exposures to toxic and potentially carcinogenic air pollutants, p53 nasal induction in children could potentially represent. a) a checkpoint response to toxic exposures, setting up a selective condition for p53 mutation, or b) a p53 mutation has already occurred as a result of such selection. Because the biological significance of p53 nuclear accumulation in the nasal biopsies of these children is not clear at this point, we strongly suggest that children with macroscopic nasal mucosal abnormalities should be closely monitored by the ENT physician. Parents should be advised to decrease the children's number of outdoor exposure hours and encourage a balanced diet with an important component of fresh fruits and vegetables.

Ultrastructural nasal pathology in children chronically and sequentially exposed to air pollutants.

Southwest Metropolitan Mexico City (SWMMC) children are repeatedly exposed to a complex mixture of air pollutants, including ozone, particulate matter, and aldehydes. Nasal biopsies taken from these children exhibit a wide range of histopathologic alterations: marked changes in ciliated and goblet cell populations, basal cell hyperplasia, squamous metaplasia, and mild dysplasias. We studied the ultrastructural features of 15 nasal biopsies obtained from clinically healthy children 4 to 15 yr of age, growing up in SWMMC. The results were compared with nasal biopsies from 11 children growing up in Veracruz and exposed to low pollutant levels. Ultrathin sections of nasal biopsies revealed an unremarkable mucociliary epithelium in control children, whereas SWMMC children showed an epithelium comprised of variable numbers of basal, ciliated, goblet, and squamous metaplastic as well as intermediate cells. Nascent ciliated cells, as evidenced by the presence of migratory kinetosomes, were common, as were ciliary abnormalities, including absent central microtubules, supernumerary central and peripheral tubules, ciliary microtubular discontinuities, and compound cilia. Dyskinesia associated with these abnormal cilia was suggested by the altered orientation of the central microtubules in closely adjacent cilia. A transudate was evident between epithelial cells, suggesting potential deficiencies in epithelial junction integrity. Particulate matter was present in heterolysosomal bodies in epithelial cells and it was also deposited in intercellular spaces. The severe structural alteration of the nasal epithelium together with the prominent acquired ciliary defects are likely the result of chronic airway injury in which ozone, particulate matter, and aldehydes are thought to play a crucial role. The nasal epithelium in SWMMC children is fundamentally disordered, and their mucociliary defense mechanisms are no longer intact. A compromised nasal epithelium has less ability to protect the lower respiratory tract and may potentially leave the distal acinar airways more vulnerable to reactive gases. Impairment of mucociliary clearance has the potential to increase the contact time between deposited mutagenic particulate matter and the epithelial surface, thus increasing the risk for nasal carcinogenesis. Chronic exposures to air pollutants affect the whole respiratory tract; the nasal epithelium is an accessible and valuable sentinel to monitor exposures to toxic or carcinogenic substances.

8-hydroxy-2'-deoxyguanosine, a major mutagenic oxidative DNA lesion, and DNA strand breaks in nasal respiratory epithelium of children exposed to urban pollution.

Southwest metropolitan Mexico City children are repeatedly exposed to high levels of a complex mixture of air pollutants, including ozone, particulate matter, aldehydes, metals, and nitrogen oxides. We explored nasal cell 8-hydroxy-2'-deoxyguanosine (8-OHdG), a major mutagenic lesion producing G-->T transversion mutations, using an immunohistochemical method, and DNA single strand breaks (ssb) using the single cell gel electrophoresis assay as biomarkers of oxidant exposure. Nasal biopsies from the posterior inferior turbinate were examined in children in grades one through five, including 12 controls from a low-polluted coastal town and 87 Mexico City children. Each biopsy was divided for the 8-OHdG and DNA ssb assays. There was an age-dependent increase in the percentage of nasal cells with DNA tails > 10 microm in Mexico City children: 19 +/- 9% for control cells, and 43 +/- 4, 50 +/- 16, 56 +/- 17, 60 +/- 17 and 73 +/- 14%, respectively, for first through fifth graders (p < 0.05). Nasal ssb were significantly higher in fifth graders than in first graders (p < 0.05). Higher levels (2.3- to 3-fold) of specific nuclear staining for 8-OHdG were observed in exposed children as compared to controls (p < 0.05). These results suggest that DNA damage is present in nasal epithelial cells in Mexico City children. Persistent oxidative DNA damage may ultimately result in a selective growth of pr eneoplastic nasal initiated cells in this population and the potential for nasal neoplasms may increase with age. The combination of 8-OHdG and DNA ssb should be useful for monitoring oxidative damage in people exposed to polluted atmospheres.

Cell proliferation in nasal respiratory epithelium of people exposed to urban pollution.

The nasal passages are a common portal of entry and are a prime site for toxicant-induced pathology. Sustained increases in regenerative cell proliferation can be a significant driving force in chemical carcinogenesis. The atmosphere in Mexico City contains a complex mixture of air pollutants and its residents are exposed chronically and sequentially to numerous toxicants and potential carcinogens. We were concerned that exposure to Mexico City's atmosphere might induce cytotoxicity and increase nasal respiratory epithelial cell proliferation. Nasal biopsies were obtained for DNA cell cycle analysis from 195 volunteers. The control population consisted of 16 adults and 27 children that were residents in a Caribbean island with low pollution. The exposed Mexico City population consisted of 109 adults and 43 children. Sixty-one of the adult subjects were newly arrived in Mexico City and were followed for 25 days from their arrival. Control children, control adult and exposed Mexico City children all had similar percentages of cells in the replicative DNA synthesis phase (S phase) of the cell cycle (%S). A significant increase in %S in nasal epithelial cells was seen in exposed adult residents in Mexico City biopsied at three different dates compared with control adults. Newly arrived adults exhibited a control level of cell turnover at day 2 after coming to the city. However, at days 7, 14 and 25 they exhibited significant increases in %S. These data demonstrate an increased and sustained nasal cell turnover rate in the adult population observable in as little as 1 week of residence in Mexico City. This increase in cell proliferation is in agreement with other reports of induced pathological changes in the nasal passages of Mexico City dwellers. These observations suggest an increased potential risk factor of developing nasal neoplasms for residents of large cities with heavy pollution.

Nasal epithelium as a sentinel for airborne environmental pollution.

A wide range of chemicals, particulate matter, and gaseous air pollutants are present in urban atmospheres and may pose a significant health risk for human populations. Nasal passages are the first site of contact of the respiratory tract with the environment and offer significant protection to the lower respiratory tract by conditioning the inspired air. This activity, which includes removal of certain pollutants, places the nose at risk of pathological changes, including cancer. Mexico City residents are exposed to a complex mixture of air pollutants. Based on predicted nasal air flow characteristics, four nasal biopsy sites were selected for study in adult male volunteers from a control low polluted town (n = 12) and southwest metropolitan Mexico City permanent residents (n = 54). Clinical data with emphasis on nasal symptoms and histopathological changes including basal and goblet cell hyperplasia, squamous metaplasia, epithelial dysplasia, and neovascularization were evaluated. Immunohistochemical staining was used to assess accumulation of p53 protein. Control individuals had no respiratory symptoms and their biopsies were unremarkable. Mexico City residents complained of epistaxis, rhinorrea, nasal crusting, dryness, and nasal obstruction. Their biopsies showed patchy shortening of cilia, deciliated areas, basal cell hyperplasia, and squamous metaplasia. Dysplastic lesions were predominantly located on antral squamous epithelium and in squamous metaplastic epithelium of the posterior inferior turbinates and they exhibited p53 nuclear accumulation. Individuals with > 10 h of daily outdoor exposure for 5 years or more had the highest rate of dysplasia. Subjects with epistaxis were more likely to have dysplasias and neovascularization. Results of this study suggest: (a) Nasal lesions in Mexico City residents are likely the result of many potentially toxic and/or carcinogenic pollutants, including ozone, aldehydes, particulate matter, and unmeasured pollutants; (b) the alteration of the nasal mucociliary defense mechanisms and the effects of reactive and/or water-soluble materials and particulates could be playing a major role in the nasal pathology; (c) the accumulation of p53 protein in dysplastic nasal lesions in the context of prolonged exposure to air pollutants raises the possibility that p53 mutations are already present and are providing the squamous cells with a selective advantage for clonal expansion; and (d) the nasal passages provide a valuable sentinel tissue for the detection of toxic air pollutants.

DNA damage in nasal respiratory epithelium from children exposed to urban pollution.

The nasal cavity is the most common portal of entry to the human body and a well-known target site for a wide range of air pollutants and chemically induced toxicity and carcinogenicity. DNA single-strand breaks (SSB) can be used as a biomarker of oxidant exposure and as an indicator of the carcinogenicity and mutagenicity of a substance. We examined the utility of using the alkaline single cell gel electrophoresis assay (SCGE) for measuring DNA damage in children's nasal epithelium exposed to air pollutants. We studied 148 children, ages 6-12, including 19 control children from a low polluted Pacific port and 129 children from Southwest Metropolitan Mexico City, an urban polluted area with high ozone concentrations year-round. Three sets of two nasal biopsies were taken in a 3-month period. All exposed children had upper respiratory symptoms and DNA damage in their nasal cells. Eleven- and twelve-year-olds had the most DNA damage, and more than 30% of children aged 9-12 exhibited patchy areas of squamous metaplasia over high-flow nasal regions. These areas had the greatest numbers of damaged DNA cells (P < or = 0.001) and a large number of DNA tails > 80 microns (P < 0.001) when compared to the contralateral macroscopically normal site in the same child. The youngest children with significantly less outdoor exposure displayed patchy areas of goblet cell hyperplasia and had the least DNA damage. These findings suggest that SCGE can be used to monitor DNA damage in children's nasal epithelium and, further, the identification of DNA damage in nasal proliferative epithelium could be regarded as a sentinel lesion, most likely due to severe and sustained cell injury.

Nasal inflammatory responses in children exposed to a polluted urban atmosphere.

Southwest Metropolitan Mexico City (SWMMC) preadolescent children have been exposed to a highly polluted urban atmosphere most of their lives. The main objective of this study was to determine by nasal lavage (NAL) the acute inflammatory nasal influx elicited in these children upon exposure to three different polluted days. Ozone, the main criteria pollutant for SWMMC, varied both in the number of hours above the National Ambient Air Quality Standard (NAAQS), which is 0.12 ppm as a 1-h maximum concentration not to be exceeded more than once per year, and in the maximal concentrations in the preceding three NAL sampling dates. Nasal neutrophilic influx, the surface expression of the B2 integrin CD11b on the nasal polymorphonuclear leukocytes (PMNs), rhinoscopic findings, respiratory symptoms, and nasal cytologies were evaluated in the 38 exposed children and in the 28 control children living in a nonpolluted Pacific coast port. SWMMC children had an average daily outdoor exposure of 7.7 h and complained of nasal mucus secretion, epistaxis, intermittent nasal obstruction, diurnal cough episodes, and chest discomfort. Nasal mucosal atrophy by rhinoscopy was present in 37/38, and all children had an abnormal nasal cytology. Exposed children had significantly higher nasal PMNs and nasal PMN-CD11b expression than controls. PMN median values in exposed children were higher than controls on all sampling dates (November 12, p < .001; November 17, p < .001; and November 24, p < .00001). Interestingly, a lower nasal neutrophilic response (p < .0004) was recorded in the SWMMC children 18 h after exposure to the highest O3 concentrations (up to 0.307 ppm) and the largest number of hours with O3 > 0.12 ppm (7 h). The question of a competing inflammatory response at the bronchioalveolar level with structural damage is raised. These NAL findings underscore the need to restrict outdoor activity in SWMMC children during the months of greater potential exposure to ozone.

Human nasal mucosal changes after exposure to urban pollution.

Millions of people worldwide are living in areas where ozone (O3) concentrations exceed health standards (an hourly average of 235 micrograms/m3/0.12 ppm, not to be exceeded more than once per year). Ozone induces acute nasal inflammatory responses and significant epithelial lesions in experimental animals and humans. To determine the nasal effects of a 15-day exposure to an urban polluted atmosphere with O3 as the main pollutant, we studied a population of healthy, young males newly arrived to southwest metropolitan Mexico City (SWMMC). The study included 49 non-smoking residents in an unpolluted port, Veracruz City; 14 subjects stayed in the port and served as controls, while 35 subjects traveled to SWMMC and had serial nasal lavages at different times after arriving in SWMMC. Subjects had exposures to ambient O3 an average of 10.2 hr/day, with a total cumulative O3 exposure of 10.644 ppm.hr. Nasal inflammatory responses, polymorphonuclear leukocyte PMN-CD11b surface expression, rhinoscopic changes, and respiratory symptoms were evaluated. Exposed subjects had massive nasal epithelial shedding and significant responses in PMN nasal influx (p < 0.00001) and in PMN-CD11b expression (p < 0.05). Cumulative O3 exposure correlated with respiratory symptoms, PMNs (rs = 0.2374, p < 0.01), and CD11b (rs = 0.3094, p < 0.01); 94% of exposed subjects experienced respiratory symptoms, and 97% left the city with an abnormal nasal mucosa by rhinoscopy. Nasal epithelial changes persisted 2 weeks after the exposed subjects returned to their nonpolluted environment. Exposure to an urban polluted atmosphere induces significant and persistent nasal epithelial alterations in healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

On the phasic reflex bronchodilation in the cat.

In records of tracheal pressure or flow taken from anesthetized cats appear large pressure-negative, or air inflow excursions, in response to single pulses applied to the central end of the vagus nerve. These responses have been attributed to phasic bronchodilation and not only due to the brief contractions of inspiratory muscles that occur as part of the total responses. Phasic bronchodilation responses appear mainly during inspiration but they may also occur in the expiratory phase through facilitation, during post-hyperventilatory apnea or that induced by constant current (d.c.) vagal stimulation. They are significantly reduced after lung sympathectomy. These bronchomotor responses showed long term depression (LTD) after spontaneous or reflexly evoked hiccups, and long term potentiation (LTP) after repetitive, or d.c. vagal stimulation. They are also potentiated on the experimental conditions that include exaggerated sympathetic activity. These and some other characteristics described indicate that bronchomotor responses are legitimate and can be used to follow the changes in excitability of the central generator of breathing.

On the phasic reflex bronchodilation in the cat.

In records of tracheal pressure or flow taken from anesthetized cats appear large pressure-negative, or air inflow excursions, in response to single pulses applied to the central end of the vagus nerve. These responses have been attributed to phasic bronchodilation and not only due to the brief contractions of inspiratory muscles that occur as part of the total responses. Phasic bronchodilation responses appear mainly during inspiration but they may also occur in the expiratory phase through facilitation, during post-hyperventilatory apnea or that induced by constant current (d.c.) vagal stimulation. They are significantly reduced after lung sympathectomy. These bronchomotor responses showed long term depression (LTD) after spontaneous or reflexly evoked hiccups, and long term potentiation (LTP) after repetitive, or d.c. vagal stimulation. They are also potentiated on the experimental conditions that include exaggerated sympathetic activity. These and some other characteristics described indicate that bronchomotor responses are legitimate and can be used to follow the changes in excitability of the central generator of breathing.