Barriers of Access to Opioid Medicines within the Context of Palliative Care in Latin America: The Perception of Health Professionals.

Background: Different sets of barriers have been identified to explain the difficulties in the access and availability of opioid analgesics in palliative care, particularly in low- and middle-income countries, including Latin America. Objective: To validate a structured questionnaire for the access to opioid medicines and to investigate the perception of health professionals regarding access barriers to opioid analgesics in 17 countries of the Latin American Region. Design: Survey to identify the domains and barriers of access to opioid medicines according to health professionals, including physicians, nurses, and pharmacists affiliated to institutions that provide palliative care in Latin America between August 2019 and October 2020. Results: We analyzed responses from 426 health professionals. The median age was 44 years old (ranging from 23 to 73 years) with an average experience in palliative care of 10 years (range: 1-35), 71.8% were women, and 49.8% were affiliated to specialized health care facilities of urban areas (94.6%). The main barriers perceived to be extremely relevant by the respondents were "belief that patients can develop addiction" and "financial limitations of patients" for the patient's domain and the "appropriate education, instruction, and training of professionals" for health professional's domain. Conclusions: It is necessary to develop strategies to strengthen less-developed health systems of the region to review legal frameworks, ensure integrated palliative care systems, and deploy multidisciplinary strategies for sensitizing, training, and raising the awareness of patients, caregivers and, particularly, health professionals regarding appropriate prescription and rational use of opioid analgesics.

[Adverse reactions to drugs used for COVID-19 in five Latin American countriesReações adversas a medicamentos utilizados para a COVID-19 em cinco países da América Latina]. / Reacciones adversas a medicamentos utilizados para la COVID-19 en cinco países de América Latina.

Objective: Characterize and describe reports of suspected adverse reactions to a group of drugs used in Colombia, Costa Rica, Cuba, Chile, El Salvador, Mexico, and Peru to treat or prevent coronavirus disease (COVID-19) between 1 March and 31 August 2020. Methods: A list of the 13 drugs used to treat or prevent COVID-19 was prepared, based on official and unofficial sources. Drawing on the databases of the national pharmacovigilance programs of the participating countries, reports of suspected adverse reactions to these drugs were collected for the period from 1 March and 31 August 2020. Results: A total of 3 490 reports of suspected adverse reactions were received from the pharmacovigilance programs of Peru (n = 3 037), Cuba (n = 270), Colombia (n = 108), Chile (n = 72), and El Salvador (n = 3). The drugs with the highest number of reported adverse reactions were azithromycin, ivermectin, and hydroxychloroquine. Diarrhea was the most frequent event (15.0%). Of the total suspected adverse reactions, 11.9% were reported as serious. The most frequent was QT prolongation following use of hydroxychloroquine. Of these suspected serious adverse reactions, 54.5% occurred in people over 65 years of age. Conclusions: While it is not possible to establish a causal relationship from the evaluation of spontaneous reports, the present study confirms the presence of adverse reactions-some of them serious-involving drugs used to treat or prevent COVID-19.

Objetivo: Caracterizar e descrever as notificações de suspeitas de reações adversas a um grupo de medicamentos utilizados na Colômbia, Costa Rica, Cuba, Chile, El Salvador, México e Peru, para tratar ou prevenir a doença do coronavírus (COVID-19), entre 1º de março e 31 de agosto de 2020. Métodos: Foi elaborada uma lista dos 13 medicamentos usados para tratar ou prevenir a COVID-19, segundo fontes oficiais e não oficiais. A partir das bases de dados dos programas nacionais de farmacovigilância dos países participantes, foram coletadas notificações de suspeitas de reações adversas a esses medicamentos, recebidas no período entre 1º de março e 31 de agosto de 2020. Resultados: Foram recebidas 3.490 notificações de suspeitas de reações adversas dos programas de farmacovigilância do Peru (n = 3.037), Cuba (n = 270), Colômbia (n = 108), Chile (n = 72) e El Salvador (n = 3). Os medicamentos com maior número de notificações de reações adversas foram azitromicina, ivermectina e hidroxicloroquina. A diarreia foi o evento mais frequente (15,0%). Do total de suspeitas de reações adversas, 11,9% foram notificadas como graves. A mais frequente foi o prolongamento do intervalo QT após o uso de hidroxicloroquina. Dessas suspeitas de reações adversas graves, 54,5% ocorreram em pessoas com mais de 65 anos. Conclusão: Embora não seja possível estabelecer uma relação causal com base na avaliação de relatos espontâneos, o presente estudo confirma a presença de reações adversas ­ algumas graves ­ a medicamentos que foram usados para tratar ou prevenir a COVID-19.

Strengthening therapeutic adherence and pharmacovigilance to antimalarial treatment in Manaus, Brazil: a multicomponent strategy using mHealth.

BACKGROUND: Public health initiatives for improving adherence to primaquine based regimens and enhancing effective pharmacovigilance are needed to support the efforts for malaria elimination in real world conditions. METHODS: A multicomponent patient-oriented strategy using a Smart Safety Surveillance (3S) approach including: (1) educational materials for treatment counselling and identification of warning symptoms of haemolytic anaemia; (2) an mHealth component using Short Message Service (SMS) treatment reminders and (3) development and implementation of follow-up phone surveys three days after treatment completion, using a web-based platform linked to the local information system of malaria. Adherence was measured using the Morisky Medication Adherence Scale. Self-reported events were registered using a structured questionnaire and communicated to the Brazilian Health Regulatory Agency. RESULTS: Educational materials were disseminated to 5594 patients, of whom 1512 voluntarily entered the mHealth component through the local information system; 7323 SMS were sent, and 1062 participants completed a follow-up survey after treatment. The mean age of patients was 37.36 years (SD 13.65), 61.24% were male, 98.54% were infected with. Plasmodium vivax and 95.90% received a short regimen of chloroquine plus primaquine (CQ + PQ 7 days), as per malaria case management guidelines in Brazil. From the 1062 surveyed participants 93.31% were considered adherent to the treatment. Most of the patients (95.20%) reported at least one adverse event. Headache, lack of appetite and nausea/vomiting were the most frequently reported adverse events by 77.31%, 70.90% and 56.78% of the patients respectively. A quarter of the patients reported anxiety or depression symptoms; 57 (5.37%) patients reported 5 to 6 warning symptoms of haemolytic anaemia including jaundice and dark urine in 44 (4.14%). Overall, three patients presenting symptoms of haemolytic anaemia attended a hospital and were diagnosed with G6PD deficiency, and one had haemolysis. All of them recovered. CONCLUSIONS: Under real world conditions, a multicomponent patient-oriented strategy using information and communication technologies allowed health care providers to reinforce treatment adherence and enhance safety surveillance of adverse events associated with regimens using primaquine. Active monitoring through phone surveys also reduced under-reporting of ADRs. This approach is low-cost, scalable and able to support prioritized activities of the national malaria programme.

Point prevalence survey of antibiotic use in hospitals in Latin American countries.

BACKGROUND: Point prevalence surveys (PPSs) on antibiotic use are useful for understanding different aspects related to prescription patterns in hospitals. METHODS: An adaptation of the WHO methodology for a PPS on antibiotic use was applied. Hospital wards were divided into medical (MED), surgical (SUR), ICUs, gynaecology and obstetrics (GO), high-risk (HR) and mixed wards (MIX). A web application (RedCap©) through a mobile device was used for data collection. RESULTS: Between December 2018 and August 2019, 5444 patients in 33 hospitals in five countries were included (10 hospitals in Cuba, 7 in Paraguay, 6 in El Salvador, 5 in Mexico and 5 in Peru). Of these patients, 54.6% received at least one antibiotic, with variations between and within hospitals and countries. Antibiotics were more frequently used in ICUs (67.2%), SUR (64.5%) and MED wards (54.2%), with 51.2% of antibiotics prescribed for community-acquired infections (CAIs), 22.9% for healthcare-associated infections (HAIs), 11.1% for surgical prophylaxis and 6.1% for unknown reasons. Adherence to guidelines was observed in 68.6% of cases (72.8% for CAIs, 72.4% for HAIs and 44.3% for prophylaxis). Third-generation cephalosporins were the class of antibiotics most frequently used (26.8%), followed by carbapenems (10.3%) and fluoroquinolones (8%). Targeted treatments were achieved in 17.3% of cases. CONCLUSIONS: Antibiotic use was generally higher than that published in other studies. There is an urgent need to promote and strengthen the antimicrobial stewardship programmes in Latin America.

Reacciones adversas a medicamentos utilizados para la COVID-19 en cinco países de América Latina / Adverse reactions to drugs used for COVID-19 in five Latin American countries / Reações adversas a medicamentos utilizados para a COVID-19 em cinco países da América Latina

RESUMEN Objetivo. Caracterizar y describir las notificaciones de sospechas de reacciones adversas de un grupo de medicamentos que se utilizaron en Colombia, Costa Rica, Cuba, Chile, El Salvador, México y Perú para tratar o prevenir la enfermedad por el coronavirus (COVID-19, por su sigla en inglés) entre el 1 de marzo y el 31 de agosto del 2020. Métodos. Se elaboró una lista de los 13 medicamentos utilizados para tratar o prevenir la COVID-19, según fuentes oficiales y no oficiales. Desde las bases de datos de los programas nacionales de farmacovigilancia de los países participantes, se recopilaron las notificaciones de sospechas de reacciones adversas a estos medicamentos recibidas en el período comprendido entre el 1 de marzo y 31 de agosto de año 2020. Resultados. Se recibieron 3 490 notificaciones de sospechas de reacciones adversas desde los programas de farmacovigilancia de Perú (n = 3 037), Cuba (n = 270), Colombia (n = 108), Chile (n = 72) y El Salvador (n = 3). Los medicamentos con mayor número de notificaciones de reacciones adversas fueron la azitromicina, la ivermectina y la hidroxicloroquina. La diarrea fue el evento más frecuente (15,0%). Del total de las sospechas de reacciones adversas, 11,9% fueron notificadas como graves. La más frecuente fue la prolongación del intervalo QT posterior al uso de hidroxicloroquina. De estas sospechas de reacciones adversas graves, 54,5% ocurrieron en personas mayores de 65 años. Conclusión. Si bien no es posible establecer una relación causal a partir de la evaluación de informes espontáneos, el presente estudio confirma la presencia de reacciones adversas, algunas graves, con medicamentos que se utilizaron para tratar o prevenir la COVID-19.

ABSTRACT Objective. Characterize and describe reports of suspected adverse reactions to a group of drugs used in Colombia, Costa Rica, Cuba, Chile, El Salvador, Mexico, and Peru to treat or prevent coronavirus disease (COVID-19) between 1 March and 31 August 2020. Methods. A list of the 13 drugs used to treat or prevent COVID-19 was prepared, based on official and unofficial sources. Drawing on the databases of the national pharmacovigilance programs of the participating countries, reports of suspected adverse reactions to these drugs were collected for the period from 1 March and 31 August 2020. Results. A total of 3 490 reports of suspected adverse reactions were received from the pharmacovigilance programs of Peru (n = 3 037), Cuba (n = 270), Colombia (n = 108), Chile (n = 72), and El Salvador (n = 3). The drugs with the highest number of reported adverse reactions were azithromycin, ivermectin, and hydroxychloroquine. Diarrhea was the most frequent event (15.0%). Of the total suspected adverse reactions, 11.9% were reported as serious. The most frequent was QT prolongation following use of hydroxychloroquine. Of these suspected serious adverse reactions, 54.5% occurred in people over 65 years of age. Conclusions. While it is not possible to establish a causal relationship from the evaluation of spontaneous reports, the present study confirms the presence of adverse reactions—some of them serious—involving drugs used to treat or prevent COVID-19.

RESUMO Objetivo. Caracterizar e descrever as notificações de suspeitas de reações adversas a um grupo de medicamentos utilizados na Colômbia, Costa Rica, Cuba, Chile, El Salvador, México e Peru, para tratar ou prevenir a doença do coronavírus (COVID-19), entre 1º de março e 31 de agosto de 2020. Métodos. Foi elaborada uma lista dos 13 medicamentos usados para tratar ou prevenir a COVID-19, segundo fontes oficiais e não oficiais. A partir das bases de dados dos programas nacionais de farmacovigilância dos países participantes, foram coletadas notificações de suspeitas de reações adversas a esses medicamentos, recebidas no período entre 1º de março e 31 de agosto de 2020. Resultados. Foram recebidas 3.490 notificações de suspeitas de reações adversas dos programas de farmacovigilância do Peru (n = 3.037), Cuba (n = 270), Colômbia (n = 108), Chile (n = 72) e El Salvador (n = 3). Os medicamentos com maior número de notificações de reações adversas foram azitromicina, ivermectina e hidroxicloroquina. A diarreia foi o evento mais frequente (15,0%). Do total de suspeitas de reações adversas, 11,9% foram notificadas como graves. A mais frequente foi o prolongamento do intervalo QT após o uso de hidroxicloroquina. Dessas suspeitas de reações adversas graves, 54,5% ocorreram em pessoas com mais de 65 anos. Conclusão. Embora não seja possível estabelecer uma relação causal com base na avaliação de relatos espontâneos, o presente estudo confirma a presença de reações adversas - algumas graves - a medicamentos que foram usados para tratar ou prevenir a COVID-19.

[Indicators of rational prescription of medicines: feasibility of application in institutions in the AmericasIndicadores de prescrição racional de medicamentos: viabilidade de aplicação em instituições das Américas]. / Indicadores de prescripción racional de medicamentos: factibilidad de aplicación en instituciones de las Américas.

OBJECTIVE: Evaluate the feasibility of monitoring the quality of use of medicines in health institutions in countries of the Region of the Americas by means of rational prescription indicators. METHODOLOGY: A quantitative study of the use of medicines was conducted during the period 2016-2018. Rational prescription indicators were developed and selected in accordance with international reference values and the best available evidence for: 1) anti-inflammatory drugs: prescription of ibuprofen and/or naproxen as a percentage of all prescribed non-steroidal anti-inflammatory drugs; 2) oral antidiabetics: metformin as a percentage of all prescribed antidiabetics, and metformin and/or sulfonylureas as a percentage of all prescribed antidiabetics; 3) insulins: crystalline insulin and NPH as a percentage of total prescribed insulins; and 4) antihypertensive drugs: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs-II), and thiazide diuretics as a percentage of all prescribed antihypertensives. The defined daily dose (DDD) per 1 000 inhabitants was used as a measure of consumption per institution. RESULTS: Prescription of metformin as a percentage of all antidiabetics was lower than the value of the reference indicator (27.9%-67.6% vs. 88%), while the prescription of metformin and/or a sulfonylurea was comparable with that value (80.9%-97.5% vs. 88%). The values of NPH, crystalline, and NPH/crystalline insulin in relation to all prescribed insulins were variable with respect to the reference indicator (37.1%-100% vs. 75%). Prescription of ibuprofen and naproxen was below the value of the indicator (20%-50% vs. 80%). The percentage of ACE inhibitors, ARBs, and thiazides with respect to all antihypertensives ranged from 65.2%-77.2% to 65%, consistent with the value of the proposed indicator. CONCLUSIONS: The feasibility of applying the selected and constructed indicators of rational prescription was demonstrated. These indicators provide useful information for analyzing the quality of prescription in health institutions in countries in the Region and are a useful tool for periodically monitoring it.

OBJETIVO: Avaliar a viabilidade de monitorar a qualidade do uso de medicamentos em instituições de saúde em países da Região das Américas por meio de indicadores de prescrição racional. MÉTODOS: Foi realizado um estudo quantitativo do uso de medicamentos durante o período 2016-2018. Indicadores de prescrição racional foram desenvolvidos e selecionados de acordo com referências internacionais e as melhores evidências disponíveis para: 1) anti-inflamatórios: prescrições de ibuprofeno e/ou naproxeno como porcentagem da prescrição total de anti-inflamatórios não esteroidais; 2) antidiabéticos orais: prescrições de metformina como porcentagem de todos os antidiabéticos prescritos, metformina e/ou sulfonilureias como porcentagem de todos os antidiabéticos prescritos; 3) insulinas: insulina cristalina e NPH como porcentagem do total de insulinas prescritas; e 4) anti-hipertensivos: porcentagem de inibidores da enzima de conversão da angiotensina (IECA), antagonistas do receptor da angiotensina II (BRA) e diuréticos tiazídicos sobre o total de anti-hipertensivos prescritos. A dose diária definida (DDD) por 1 000 habitantes por dia (DHD) foi usada como medida de consumo por instituição. RESULTADOS: A prescrição de metformina em relação a todos os antidiabéticos foi inferior ao valor do indicador de referência (27,9%-67,6% x 88%), enquanto a prescrição de metformina e/ou uma sulfonilureia foi comparável ao valor de referência (80,9%-97,5% x 88%). As porcentagens de prescrição de insulina NPH, cristalina e NPH/cristalina em relação a todas as insulinas prescritas foram variáveis em relação ao valor de referência (37,1%-100% x 75%). A prescrição de ibuprofeno e naproxeno foi inferior ao valor de referência (20%-50% x 80%). A porcentagem de IECA, BRA e tiazídicos em relação a todos os anti-hipertensivos variou entre 65,2% e 77,2%, compatível com o valor do indicador proposto (65%). CONCLUSÕES: Demonstrou-se a viabilidade de aplicação dos indicadores de prescrição racional aqui selecionados e construídos, os quais fornecem informações úteis para analisar a qualidade da prescrição nas instituições de saúde dos países da Região e representam uma ferramenta útil para seu monitoramento periódico.

Scientific considerations for global drug development.

Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.

Addressing the challenges of regulatory systems strengthening in small states.

Countries should ensure equitable access to quality medicines. Regulatory systems for medicines and other health technologies are an essential part of well-functioning health systems and are a requisite for achieving Universal Health and the Sustainable Development Goals. The Pan American Health Organization, the World health Organization (WHO) regional office for the Americas, has assessed national regulatory capacities using a precursor of WHO Global Benchmarking Tool, and conducted an analysis of the data which suggests an association of regulatory capacity with population and the size of the economy. Regulatory capacity tends to decrease as population and gross domestic product decreases. This predominantly impacts the Caribbean sub-region in the Americas, which includes many states with small populations and economies. This paper will use the World Bank's term 'small states' to refer to countries with 1.5 million people or less and other larger countries that face similar challenges. The regulatory challenges of small states include small markets and limited human and financial resources. However, small states can build regulatory systems with a narrower scope that are less resource intensive and still ensure appropriate regulation and oversight. The approach should be tailored to accomplish a subset of WHO recommended essential functions, including marketing authorisation, licensing of establishments and postmarket surveillance/pharmacovigilance, depending on the need to oversee local manufacturing, which requires a comprehensive system. The approach should also include adoption of efficiencies, such as regionalisation and reliance. This model is currently being put in practice in the small states of the Caribbean Community and Pacific Islands and can inform other small states around the world.

Regionalization as an approach to regulatory systems strengthening: a case study in CARICOM member states.

Improving basic capacities for regulation of medicines and health technologies through regulatory systems strengthening is particularly challenging in resource-constrained settings. "Regionalization"-an approach in which countries with common histories, cultural values, languages, and economic conditions work together to establish more efficient systems-may be one answer. This report describes the Caribbean Regulatory System (CRS), a regionalization initiative being implemented in the mostly small countries of the Caribbean Community and Common Market (CARICOM). This initiative is an innovative effort to strengthen regulatory systems in the Caribbean, where capacity is limited compared to other subregions of the Americas. The initiative's concept and design includes a number of features and steps intended to enhance sustainability in resource-constrained contexts. The latter include 1) leveraging existing platforms for centralized cooperation, governance, and infrastructure; 2) strengthening regulatory capacities with the largest potential public health impact; 3) incorporating policies that promote reliance on reference authorities; 4) changing the system to encourage industry to market their products in CARICOM (e.g., using a centralized portal of entry to reduce regulatory burdens); and 5) building human resource capacity. If implemented properly, the CRS will be self-sustaining through user fees. The experience and lessons learned thus far in implementing this initiative, described in this report, can serve as a case study for the development of similar regulatory strengthening initiatives in resource-constrained environments.

Regulatory convergence and harmonization: barriers to effective use and adoption of common standards.

Objective To evaluate 1) the level of use and adoption of eight Technical Documents (TDs) published by the Pan American Network for Drug Regulatory Harmonization (PANDRH) member states and 2) identify the hurdles that can prevent countries from successfully adopting a common standard. Methods An in-depth analysis of the incorporation of PANDRH Technical Document No. 1 ("TDNo1") recommendations in member states' national requirements was carried out. Results The results illustrate the role of PANDRH in promoting convergence/harmonization among its members. Conclusions The study results show that the rate of use of TDs varied greatly by product/area and country. Timing, TD content, and product/area, and, more importantly, national capacities, are critical determinants of the level of TD guideline adoption. While PANDRH TDs have proven instrumental for the harmonization/convergence of member states' national requirements, as shown by the level of convergence across a majority of the national requirements issued for vaccine licensing, several countries had yet to incorporate common standards due, in large part, to weak national regulatory capacities. Therefore, harmonization/convergence initiatives should include the strengthening of national regulatory capacities as part of their core strategy, which will, in turn, allow for the incorporation and deployment of common standards in all participating countries.

Regulatory convergence and harmonization: barriers to effective use and adoption of common standards / La convergencia y la armonización regulatorias: barreras en el uso y la adopción eficaces de normas comunes

ABSTRACT Objective To evaluate 1) the level of use and adoption of eight Technical Documents (TDs) published by the Pan American Network for Drug Regulatory Harmonization (PANDRH) member states and 2) identify the hurdles that can prevent countries from successfully adopting a common standard. Methods An in-depth analysis of the incorporation of PANDRH Technical Document No. 1 (“TDNo1”) recommendations in member states’ national requirements was carried out. Results The results illustrate the role of PANDRH in promoting convergence/harmonization among its members. Conclusions The study results show that the rate of use of TDs varied greatly by product/area and country. Timing, TD content, and product/area, and, more importantly, national capacities, are critical determinants of the level of TD guideline adoption. While PANDRH TDs have proven instrumental for the harmonization/convergence of member states’ national requirements, as shown by the level of convergence across a majority of the national requirements issued for vaccine licensing, several countries had yet to incorporate common standards due, in large part, to weak national regulatory capacities. Therefore, harmonization/convergence initiatives should include the strengthening of national regulatory capacities as part of their core strategy, which will, in turn, allow for the incorporation and deployment of common standards in all participating countries.

RESUMEN Objetivo Evaluar (1) la medida en que se usan y se han adoptado ocho documentos técnicos (DT) publicados por los estados miembros de la Red Panamericana para la Armonización de la Reglamentación Farmacéutica (Red PARF) y (2) definir los obstáculos que pueden impedir que los países adopten una norma común. Métodos Se realizó un análisis minucioso de la incorporación de las recomendaciones contenidas en el Documento Técnico No. 1 (“DTNo1”) de la Red Panamericana para la Armonización de la Reglamentación Farmacéutica en los requisitos nacionales de los estados miembros. Resultados Los resultados ilustran el papel que desempeña la Red Panamericana para la Armonización de la Reglamentación Farmacéutica en la promoción de la convergencia y armonización entre sus miembros. Conclusiones Los resultados del estudio indican que el uso de los DT varía enormemente según el producto o el área y el país. El momento, el contenido del DT, el producto o área y, lo que es más importante, la capacidad nacional son factores determinantes del grado de adopción de las directrices contenidas en los DT. Si bien los DT de la Red Panamericana para la Armonización de la Reglamentación Farmacéutica han sido decisivos en la armonización y convergencia de los requisitos nacionales de los estados miembros, como demuestra el grado de convergencia de la mayor parte de los requisitos nacionales emitidos para la concesión de licencias para vacunas, varios países no habían incorporado normas comunes todavía debido, en gran parte, a una capacidad de reglamentación nacional deficiente. Por lo tanto, las iniciativas en pro de la armonización y convergencia deben comprender el fortalecimiento de la capacidad de reglamentación nacional como parte de su estrategia central, lo cual permitirá, a su vez, que se incorporen y desplieguen normas comunes en todos los países participantes.

Developmental and epigenetic regulation of the human TLR3 gene.

The receptor encoded by the human TLR3 gene recognizes double-strand RNAs (dsRNAs) associated with viral infection. TLR3 expression is strongly activated upon differentiation of monocytes to dendritic cells, and can be further stimulated by the dsRNA analog polyinosine:polycytosine (PI:C). We report evidence for developmental regulation of the TLR3 gene. In dendritic cells derived from cord blood, both differentiation- and PI:C-associated TLR3 transcriptional activation are impaired as compared to cells from adults. Consistent with relative expression patterns, chromatin states and remodeling differ between newborn and adult samples. TLR3 expression in newborn dendritic cells exhibits heterocellularity and allelic imbalance (skewing), features characteristic of cis-acting epigenetic control. These findings reveal a new source for variability in innate immune system function and provide a model for further study of perinatal epigenetic transitions during development.

Microtubule-dependent intracellular transport of murine polyomavirus.

The mechanisms used by murine polyomavirus for intracellular migration are yet to be clarified. In this work we selectively depolymerized microtubules or actin fibers and then studied the progression of polyomavirus infection in cultured cells. Our results demonstrate that microtubule depolymerization prevents polyomavirus migration toward the nucleus and from the nucleus to the cell surface, being also involved in viral release, while disruption of the actin microfilaments appears to have no detrimental effect on the virus ability to reach the nucleus. The ultrastructural observation of polyomavirus nonenveloped particles interacting with the free end and the lateral sides of microtubules together with the coimmunoprecipitation of tubulin and viral VP-1 further supports the idea that polyomavirus intracellular migration seems to be mediated by the interaction of polyomavirus major capsid protein VP-1 with tubulin.