Recommendations for modernizing infant vaccination schedules with combination vaccines in Colombia and Peru / Recomendaciones para modernizar los calendarios de vacunación infantil con vacunas combinadas en Colombia y Perú / Recomendações para modernizar os esquemas de vacinação infantil com vacinas combinadas na Colômbia e no Peru

ABSTRACT The objective of this article was to consider the vaccination challenges in Colombia and Peru and the role of pediatric combination vaccines in overcoming these challenges. Barriers to including new vaccines with more antigens remain apparent in parts of these countries, where vaccine-preventable diseases in infants continue to be a major problem. The challenges include the heterogeneity of vaccine coverage within each country and in neighboring countries, which can contribute to poor rates of vaccination coverage; the adverse impact of the inward migration of unvaccinated individuals, which has favored the re-emergence of vaccine-preventable diseases; vaccine shortages; and the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the associated shifts in health care resources. To improve the coverage of pediatric vaccines in Colombia and Peru, it will be necessary to ensure the widespread integration into vaccine schedules of combination vaccines containing diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b and hepatitis B antigens with a three-dose primary series delivered at 2, 4 and 6 months of age followed by a booster at 18 months of age. Such vaccines play important roles in preventing diphtheria, tetanus and pertussis; eradicating polio; and providing boosting against H. influenzae type b.

RESUMEN El objetivo de este artículo es considerar los desafíos que se enfrentan en Colombia y Perú con respecto a la vacunación y el papel de las vacunas combinadas pediátricas para superar estos desafíos. Los obstáculos para incluir vacunas nuevas con más antígenos siguen siendo evidentes en algunos lugares de estos países, donde las enfermedades prevenibles por vacunación en menores de 1 año continúan siendo un grave problema. Entre los desafíos se incluye la heterogeneidad de la cobertura de vacunación en cada país y en los países vecinos, lo que puede contribuir con que se registren tasas bajas de cobertura de vacunación; el impacto adverso de la migración interna de personas no vacunadas, lo que ha favorecido la reaparición de enfermedades prevenibles por vacunación; la escasez de vacunas, y el impacto de la pandemia del coronavirus de tipo 2 causante del síndrome respiratorio agudo grave (SARS-CoV-2) y los consiguientes cambios en los recursos de atención médica. Para mejorar la cobertura de las vacunas pediátricas en Colombia y Perú será necesario integrar de manera generalizada en los calendarios de vacunación vacunas combinadas con antígenos de difteria, tétanos, tos ferina acelular, poliovirus inactivados, Haemophilus influenzae tipo b y hepatitis B con una serie primaria de tres dosis administradas a los 2, 4 y 6 meses de edad, seguida de un refuerzo a los 18 meses de edad. Esas vacunas desempeñan un papel esencial en la prevención de la difteria, el tétanos y la tos ferina; la erradicación de la polio; y el refuerzo contra H. influenzae tipo b.

RESUMO O objetivo deste artigo foi avaliar os desafios da vacinação na Colômbia e no Peru e o papel das vacinas pediátricas combinadas na superação de tais desafios. Os obstáculos para incluir novas vacinas com mais antígenos permanecem visíveis em partes desses países, onde doenças imunopreveníveis em lactentes continuam a ser um grande problema. Os desafios incluem a heterogeneidade da cobertura vacinal dentro de cada país e nos países vizinhos, o que pode contribuir para baixas taxas de cobertura vacinal; o impacto adverso da migração interna de pessoas não vacinadas, o que favoreceu o ressurgimento de doenças imunopreveníveis; a escassez de vacinas; e o impacto da pandemia de síndrome respiratória aguda grave do coronavírus 2 (SARS-CoV-2) e mudanças relacionadas nos recursos de atenção à saúde. Para melhorar a cobertura das vacinas pediátricas na Colômbia e no Peru, será necessário assegurar sua integração generalizada em esquemas de vacinas combinadas contendo antígenos de difteria, tétano, pertussis acelular, poliovírus inativado, Haemophilus influenzae tipo B e hepatite B, com uma série primária de três doses aplicadas aos 2, 4 e 6 meses de idade seguidas de um reforço aos 18 meses de idade. Tais vacinas desempenham papéis importantes na prevenção da difteria, tétano e coqueluche; na erradicação da poliomielite; e no reforço contra H. influenzae tipo b.

Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration.

Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system, a hallmark in Parkinson's disease. The human cerebral dopamine neurotrophic factor (hCDNF) has recently emerged as a strong candidate for Parkinson's disease therapy. This study shows that hCDNF expression in dopamine neurons using the neurotensin-polyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological, biochemical, and behavioral alterations. Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the hCDNF gene, ranging in size from 20 to 150 nm, enabled the expression of a secretable hCDNF in vitro. Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable hCDNF in dopamine neurons, whose levels remained constant throughout the study in the substantia nigra compacta and striatum. Compared with the lesioned group, tyrosine hydroxylase-positive (TH+) nigral cell population and TH+ fiber density rose in the substantia nigra compacta and striatum after hCDNF transfection. An increase in ßIII-tubulin and growth-associated protein 43 phospho-S41 (GAP43p) followed TH+ cell recovery, as well as dopamine and its catabolite levels. Partial reversal (80%) of drug-activated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved. Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects. These findings support the potential of nanoparticle-mediated hCDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease. The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use (authorization No. 162-15) on June 9, 2019.

Radiogenomics: Hunting Down Liver Metastasis in Colorectal Cancer Patients.

Radiomics is a developing new discipline that analyzes conventional medical images to extract quantifiable data that can be mined for new biomarkers that show the biology of pathological processes at microscopic levels. These data can be converted into image-based signatures to improve diagnostic, prognostic and predictive accuracy in cancer patients. The combination of radiomics and molecular data, called radiogenomics, has clear implications for cancer patients' management. Though some studies have focused on radiogenomics signatures in hepatocellular carcinoma patients, only a few have examined colorectal cancer metastatic lesions in the liver. Moreover, the need to differentiate between liver lesions is fundamental for accurate diagnosis and treatment. In this review, we summarize the knowledge gained from radiomics and radiogenomics studies in hepatic metastatic colorectal cancer patients and their use in early diagnosis, response assessment and treatment decisions. We also investigate their value as possible prognostic biomarkers. In addition, the great potential of image mining to provide a comprehensive view of liver niche formation is examined thoroughly. Finally, new challenges and current limitations for the early detection of the liver premetastatic niche, based on radiomics and radiogenomics, are also discussed.

Correction: Earl et al. Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival. Cancers 2021, 13, 1612.

The authors wish to make the following corrections to this paper [...].

Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival.

Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10-15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.

Synthetic Monopartite Peptide That Enables the Nuclear Import of Genes Delivered by the Neurotensin-Polyplex Vector.

Neurotensin (NTS)-polyplex is a multicomponent nonviral vector that enables gene delivery via internalization of the neurotensin type 1 receptor (NTSR1) to dopaminergic neurons and cancer cells. An approach to improving its therapeutic safety is replacing the viral karyophilic component (peptide KPSV40; MAPTKRKGSCPGAAPNKPK), which performs the nuclear import activity, by a shorter synthetic peptide (KPRa; KMAPKKRK). We explored this issue and the mechanism of plasmid DNA translocation through the expression of the green fluorescent protein or red fluorescent protein fused with KPRa and internalization assays and whole-cell patch-clamp configuration experiments in a single cell together with importin α/ß pathway blockers. We showed that KPRa electrostatically bound to plasmid DNA increased the transgene expression compared with KPSV40 and enabled nuclear translocation of KPRa-fused red fluorescent proteins and plasmid DNA. Such translocation was blocked with ivermectin or mifepristone, suggesting importin α/ß pathway mediation. KPRa also enabled NTS-polyplex-mediated expression of reporter or physiological genes such as human mesencephalic-derived neurotrophic factor (hMANF) in dopaminergic neurons in vivo. KPRa is a synthetic monopartite peptide that showed nuclear import activity in NTS-polyplex vector-mediated gene delivery. KPRa could also improve the transfection of other nonviral vectors used in gene therapy.

A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants.

BACKGROUND: The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes. METHODS: Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. FINDINGS: Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC. INTERPRETATION: The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. FUNDING: This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016).

Resistencia antibiótica y distribución de serotipos en cepas neumocócicas invasivas en adultos hospitalizados en Lima, Perú / Antibiotic resistance and distribution of serotypes of invasive pneumococcal strains isolated from hospitalized adults in Lima, Peru

RESUMEN Objetivos. Describir las características clínicas, resistencia antibiótica y distribución de serotipos de cepas causantes de enfermedad neumocócica invasiva (ENI) en adultos. Materiales y métodos. Estudio tipo serie de casos. Se recolectaron cepas de neumococo de pacientes adultos hospitalizados con ENI en cinco hospitales nacionales y dos laboratorios de Lima durante los años 2009-2011. Resultados. Se estudiaron datos de 43 pacientes con ENI, el 58,2% fueron mayores de 60 años. Los diagnósticos fueron neumonía 39,5%, meningitis 30,2%, bacteriemia 13,9%, peritonitis 11,6%, artritis séptica 4,8%. El porcentaje de fallecidos fue 28,9%, de los cuales el 72,7% fueron mayores de 60 años. Las cepas de neumococo presentaron la siguiente resistencia: penicilina 0% en cepas no meningitis y 30,8% en cepas meningitis; ceftriaxona 4,5% y 16,7% de resistencia intermedia en cepas no meningitis y cepas meningitis respectivamente; 69% a trimetoprim/sulfametoxazol y 35,7% a eritromicina. Los serotipos más comunes fueron 19F, 23F, 6B, 14 y 6C. El porcentaje de cepas vacunales fue 44,2% para la vacuna conjugada siete-valente (PCV7) y para la PCV10, 51,2% para PCV13 y 60,4% para la vacuna polisacárida veintitrés-valente (PPV23). Conclusiones. El neumococo es un patógeno relevante en adultos, en especial en los adultos mayores, debido a su elevada mortalidad.

ABSTRACT Objectives. To describe the clinical characteristics, antibiotic resistance, and distribution of serotypes of bacterial strains that cause invasive pneumococcal disease (IPD) in adults. Materials and methods. Case series. Pneumococcal strains were isolated from 2009 to 2011 from hospitalized adult patients with IPD in five hospitals and two laboratories located in Lima. Results. The analysis of data from 43 patients with IPD indicated that 58.2% were older than 60 years. The most common complications were pneumonia (39.5%), meningitis (30.2%), bacteremia (13.9%), peritonitis (11.6%), and septic arthritis (4.8%). The mortality rate was 28.9%, and 72.7% of cases involved patients older than 60 years. The pneumococcal strains were resistant to the following antibiotics: penicillin, 0% and 30.8% in non-meningitis and meningitis strains, respectively; ceftriaxone, 4.5% and 16.7% in non-meningitis and meningitis strains, respectively; trimethoprim/sulfamethoxazole, 69.0%; and erythromycin, 35.7%. The most common serotypes were 19F, 23F, 6B, 14, and 6C. The percentage of vaccine strains was 44.2% for the 7-valent conjugate pneumococcal vaccine (PCV7) and PCV10, 51.2% for PCV13, and 60.4% for the 23-valent polysaccharide vaccine (PPV23). Conclusions. Pneumococcus is an important pathogen in adults, particularly in older adults, owing to its high mortality rate.

Características epidemiológicas, clínicas y bacteriológicas de meningitis neumocócica en pacientes pediátricos de Lima, Perú / Epidemiologic, clinical and bacteriologic characteristics of pneumococcal meningitis in pediatric patients from Lima, Peru

RESUMEN Objetivos. Describir las características clínicas, letalidad, susceptibilidad antibiótica y distribución de serotipos de meningitis neumocócica en pacientes pediátricos de Lima, Perú. Materiales y Métodos. Serie de casos de meningitis neumocócica en niños menores de 16 años. Los datos fueron obtenidos de dos estudios multicéntricos prospectivos, de vigilancia pasiva de enfermedad neumocócica invasiva realizados en Lima-Perú desde los años 2006 al 2008, y del 2009 al 2011. Resultados. Reportamos 44 episodios de meningitis neumocócica; 68,2% fueron en niños menores de 2 años. La tasa de letalidad fue 32,6; y 92,9% de los casos letales ocurrieron en niños menores de dos años (p<0,05). La desnutrición estuvo asociada a los casos letales (p<0,05). El 64,3% de los casos fatales murieron dentro de los 2 primeros días. El 41,9% de los cultivos con neumococo fueron resistentes a la penicilina, 23,3% mostró resistencia intermedia a ceftriaxona (ninguno mostró resistencia completa) y 9,3% mostró resistencia a cloranfenicol. Los serotipos más frecuentes fueron 6B, 14, 19F y 23F, los cuales constituyeron el 68,3% de todas las cepas; 84,1% de las cepas encontradas están incluidas en los serotipos de la vacuna 13 valente. Conclusiones. La meningitis neumocócica continúa siendo una enfermedad letal, especialmente en niños menores de 2 años. Dado que aproximadamente dos tercios de los casos letales fallecen en las primeras 48 h, es crítico un diagnóstico y tratamiento oportuno, así como asegurar el cumplimiento de la inmunización con la vacuna neumocócica.

ABSTRACT Objectives. To describe the clinical characteristics, lethality, antibiotic susceptibility, and serotype distribution of pneumococcal meningitis in pediatric patients in Lima, Peru. Materials and Methods. A case series of pneumococcal meningitis in children less than 16 years of age from two prospective, multicenter, passive surveillance studies of invasive pneumococcal diseases held in Lima-Peru from 2006 to 2008 and 2009 to 2011. Results. We report 44 pneumococcal meningitis episodes; 68.2% of them were in children less than 2 years old. The overall case fatality rate was 32.6%; 92.9% of fatal cases were in children less than 2 years of age (p<0.05). Malnutrition was associated with fatal cases (p<0.05). 64.3% of fatal cases died within the first two days. 41.9% of pneumococcal isolates were resistant to penicillin, 23.3% were intermediate resistant to ceftriaxone (none were highly resistant) and 9.3% were resistant to chloramphenicol. The most common serotypes were 6B, 14, 19F and 23F, which accounted for 68.3% of all strains; 84.1% of strains were PCV13 serotypes. Conclusions. Pneumococcal meningitis continues to be a lethal disease, especially in children less than 2 years of age. Since almost two third of lethal cases lead to death within the first 48 hours, prompt diagnosis and management is critical, as well as assurance of immunization with pneumococcal vaccine.

Oxacillin disk diffusion testing for the prediction of penicillin resistance in Streptococcus pneumoniae / Prueba de difusión con discos de oxacilina para predecir la resistencia a la penicilina de Streptococcus pneumoniae

ABSTRACT Objective To 1) describe the correlation between the zones of inhibition in 1-µg oxacillin disk diffusion (ODD) tests and penicillin and ceftriaxone minimum inhibitory concentrations (MICs) of meningeal and non-meningeal strains of Streptococcus pneumoniae and 2) evaluate the usefulness of the ODD test as a predictor of susceptibility to penicillin in S. pneumoniae and as a quick and cost-effective method easily implemented in a routine clinical laboratory setting. Methods S. pneumoniae isolates from healthy nasopharyngeal carriers less than 2 years old, obtained in a multicentric cross-sectional study conducted in various Peruvian hospitals and health centers from 2007 to 2009, were analyzed. Using Clinical and Laboratory Standards Institute (CLSI) breakpoints, the correlation between the zones of inhibition of the ODD test and the MICs of penicillin and ceftriaxone was determined. Results Of the 571 S. pneumoniae isolates, 314 (55%) showed resistance to penicillin (MIC ≥ 0.12 µg/mL) and 124 (21.7%) showed resistance to ceftriaxone (MIC ≥ 1 µg/mL). Comparison of the ODD test zones of inhibition and the penicillin MICs, using the CLSI meningeal breakpoints, showed good correlation (Cohen’s kappa coefficient = 0.8239). Conclusions There was good correlation between ODD zones of inhibition and penicillin meningeal breakpoints but weak correlation between the ODD results and non-meningeal breakpoints for both penicillin and ceftriaxone. Therefore, the ODD test appears to be a useful tool for predicting penicillin resistance in cases of meningeal strains of S. pneumoniae, particularly in low- and middle- income countries, where MIC determination is not routinely available.

RESUMEN Objetivo 1) Describir la correlación entre las zonas de inhibición observadas en la prueba de difusión con discos de oxacilina de 1 µg y la concentración inhibitoria mínima (CIM) de penicilina y ceftriaxona frente a cepas meníngeas y no meníngeas de Streptococcus pneumoniae y 2) evaluar si la prueba de difusión con discos de oxacilina permite predecir la sensibilidad de S. pneumoniae a la penicilina y sirve como método rápido y eficaz en función de los costos, y resulta fácil de aplicar en los laboratorios clínicos ordinarios. Métodos Se analizaron colonias de S. pneumoniae aisladas de la nasofaringe de portadores sanos menores de 2 años obtenidas en un estudio transversal multicéntrico realizado en diversos hospitales y centros de salud del Perú entre los años 2007 y 2009. Se determinó la correlación entre las zonas de inhibición observadas en la prueba de difusión con discos y la CIM de la penicilina y la ceftriaxona utilizando los valores críticos definidos por el Instituto de Estándares Clínicos y de Laboratorio. Resultados De las 571 colonias aisladas de S. pneumoniae, 314 (55 %) presentaron resistencia a la penicilina (CIM ≥ 0,12 µg/ml) y 124 (21,7%), resistencia a la ceftriaxona (CIM ≥ 1 µg/ml). Se observó una buena correlación (coeficiente κ de Cohen = 0,8239) entre las zonas de inhibición de la prueba de difusión con discos y la CIM de la penicilina utilizando los valores críticos del Instituto respecto de las cepas meníngeas. Conclusiones Se encontró una buena correlación entre las zonas de inhibición de la prueba de difusión con discos y los valores críticos de CIM de la penicilina respecto de las cepas meníngeas, pero una correlación débil entre los resultados de la prueba de difusión y los valores críticos tanto de la penicilina como de la ceftriaxona respecto de las cepas no meníngeas. Por consiguiente, la prueba de difusión con discos es un método de utilidad para predecir la resistencia a la penicilina de las cepas meníngeas de S. pneumoniae, en particular en los países de ingresos bajos y medianos, donde no suele ser posible determinar la CIM.

Resistencia antibiótica de streptococcus pneumoniae en portadores nasofaríngeos sanos de siete regiones del Perú / Antibiotic resistance of streptococcus pneumoniae among healthy nasopharyngeal carriers in seven regions of Peru

Objetivos. Determinar el patrón de susceptibilidad antibiótica de cepas de Streptococcus pneumoniae aisladas de portadores nasofaríngeos sanos menores de 2 años de siete regiones del Perú. Materiales y métodos. Entre el 2007 y 2009 se tomaron muestras de hisopado nasofaríngeo a 2123 niños sanos entre 2 y 24 meses de edad en los consultorios de crecimiento y desarrollo (CRED) y vacunación de hospitales y centros de salud de Lima, Piura, Cusco, Abancay, Arequipa, Huancayo, e Iquitos. Se determinó la resistencia a diez antibióticos mediante la prueba de disco-difusión de las cepas de neumococo aisladas. Resultados. Se aislaron 572 cepas. Se encontró altas tasas de resistencia a cotrimoxazol (58%); penicilina (52,2% no-sensibles); tetraciclina (29,1%); azitromicina (28,9%), y eritromicina (26,3%). La resistencia a cloranfenicol fue baja (8,8%). Se encontró 29,5% de multirresistencia. La resistencia a la azitromicina y a la penicilina fue diferente en las siete regiones (p<0,05), hallándose el mayor porcentaje de cepas no-sensibles a penicilina en Arequipa (63,6%), mientras que el menor fue en Cusco (23,4%). Conclusiones. Los elevados niveles de resistencia encontrados para penicilina, cotrimoxazol y macrólidos en cepas de neumococo aisladas de portadores sanos en todas las regiones estudiadas, y su asociación con uso previo de antibióticos, representan un importante problema de salud pública en nuestro país. Esto resalta la necesidad de implementar, a nivel nacional, estrategias para disminuir el uso irracional de antibióticos, sobre todo en la población pediátrica. Es necesario complementar los datos de resistencia a penicilina con la determinación de la concentración mínima inhibitoria para hacer las recomendaciones terapéuticas respectivas.

Objectives. To determine the pattern of antibiotic susceptibility of isolated Streptococcus pneumoniae strains of healthy nasopharyngeal carriers younger than 2 years in seven regions of Peru. Materials and methods. Between 2007 and 2009, nasopharyngeal swab samples were collected among 2123 healthy children aged 2-24 months in growth and development medical practices (CRED) and vaccination offices of hospitals and health centers in Lima, Piura, Cusco, Abancay, Arequipa, Huancayo, and Iquitos. The resistance to ten antibiotics through disk diffusion sensitivity testing of isolated pneumococcus strains was determined. Results. 572 strains were isolated. High rates of resistance to co-trimoxazole (58%), penicillin (52.2% non-sensitive); tetracycline (29,1%); azithromycin (28,9%), and erythromycin (26,3%). Resistance to chloramphenicol was low (8.8%). Multiresistance was found at 29.5%. Resistance to azithromycin and penicillin was different in all seven regions (p<0,05), the highest percentage of non-sensitive strains being found in Arequipa (63,6%), whereas the lowest percentage was found in Cusco (23.4%). Conclusions. High levels of resistance found to penicillin, co-trimoxasole and macrolides in isolated pneumococcus strains of healthy carriers in all studied regions, and their association to a previous use of antibiotics, represent a significant public health problem in our country. This emphasizes the need to implement nationwide strategies to reduce the irrational use of antibiotics, especially among children. It is necessary to complement data of resistance to penicillin with the determination of minimal inhibitory concentration to make proper therapeutic recommendations.

EBV-positive diffuse large B-cell lymphoma of the elderly is an aggressive post-germinal center B-cell neoplasm characterized by prominent nuclear factor-kB activation.

Here, we report a retrospective series of 47 EBV-positive diffuse large B-cell lymphoma associated with advanced age. Histopathology allowed to the identification of different histological patterns: cases with polymorphic diffuse large B-cell lymphoma (29 cases), Hodgkin-like (8 cases) and polymorphic lymphoproliferative disorder-like (9 cases) patterns. One case was purely monomorphic diffuse large B-cell lymphoma. We show that this lymphoma type is a neoplasm with prominent classical and alternative nuclear factor-kB pathway activation in neoplastic cells (79% of the cases showed nuclear staining for p105/p50, 74% for p100/p52 and 63% for both proteins), with higher frequency than that observed in a control series of EBV-negative diffuse large B-cell lymphoma (χ(2) <0.001). Most cases showed an activated phenotype (95% non-germinal center (Hans algorithm); 78% activated B cell (Choi algorithm)). Clonality testing demonstrated IgH and/or K/Kde/L monoclonal rearrangements in 64% of cases and clonal T-cell populations in 24% of cases. C-MYC (1 case), BCL6 (2 cases) or IgH (3 cases) translocations were detected by FISH in 18% cases. These tumors had a poor overall survival and progression-free survival (the estimated 2-year overall survival was 40 ± 10% and the estimated 2-year progression-free survival was 36 ± 9%). Thus, alternative therapies, based on the tumor biology, need to be tested in patients with EBV-positive diffuse large B-cell lymphoma of the elderly.

Serotipos de neumococo en niños portadores antes de la vacunación antineumocócica en el Perú / Pneumococcal serotypes in carrier children prior to the introduction of anti-pneumococcal vaccines in Peru

Objetivos. Determinar la frecuencia y distribución de serotipos de S. pneumoniae en portadores nasofaríngeos sanos menores de dos años previa al uso universal de la vacuna conjugada antineumocócica en el Perú. Materiales y métodos. Entre los años 2007 y 2009 se tomaron muestras de hisopado nasofaríngeo a 2123 niños sanos entre 2 y 24 meses de edad en los consultorios de crecimiento y desarrollo o vacunación de hospitales y centros de salud de siete ciudades del Perú: costa (Lima, Piura); sierra (Cusco, Abancay, Arequipa y Huancayo) y selva (Iquitos). Las cepas de neumococo fueron aisladas e identificadas en el laboratorio central del proyecto en Lima y serotipificadas por reacción de Quellung en el Laboratorio de Referencia de Neumococo del Centro de Control y Prevención de Enfermedades. Resultados. Se encontró 27,0% (573/2123) de portadores nasofaríngeos sanos de neumococo. En las 526 cepas analizadas se encontraron 42 serotipos; los más frecuentes fueron: 19F (18,1%), 6B (14,3%); 23F (8,9%) y 14 (6,5%). Conclusiones. La distribución de serotipos vacunales en las cepas analizadas fue de 50,0% para los serotipos presentes en la vacuna conjugada heptavalente; 50,2% para los serotipos presentes en la vacuna decavalente y 57,2% para la vacuna 13-valente.

Objectives. To determine the carriage rate and serotype distribution of Streptococcus pneumoniae in the nasopharynx of healthy children younger than 2 years prior to the universal use of the pneumococcal conjugate vaccines in Peru. Materials and methods. Between 2007 and 2009 we collected nasopharyngeal swab samples from 2,123 healthy children aged 2 to 24 months in the vaccination and healthy children consultation offices of pediatric hospitals and health centers in 7 cities in Peru: on the coast (Lima, Piura), highlands (Cusco, Abancay, Arequipa and Huancayo) and amazon basin (Iquitos). The pneumococcal strains were isolated and identified at the central laboratory of the project in Lima, and serotyped by Quellung reaction in the pneumococcal reference laboratory at the Center for Diseases Control and Prevention (CDC). Results. We found 27% (573/2123) of pneumococcal nasopharyngeal healthy carrier children. Among the 526 analyzed strains, we found 42 serotypes; the most common were: 19F (18.1%), 6B (14.3%); 23F (8.9%) and 14 (6.5%). Conclusions. The distribution of vaccine serotypes in the analyzed strains was of 50% for the serotypes present in the seven-valent vaccine, 50.2% for the serotypes present in the ten-valent vaccine and 57.2% for those present in the thirteen-valent vaccine.

Invasive pneumococcal diseases among hospitalized children in Lima, Peru / Enfermedades neumocócicas invasoras en niños hospitalizados en Lima, Perú

OBJECTIVE: To determine the epidemiology of invasive pneumococcal disease (IPD) and the antibiotic susceptibility and serotype distribution of S. pneumoniae in pediatric patients in Lima, Peru. METHODS: A 2-year, multicenter, passive surveillance study conducted from May 2006- April 2008 in 11 public hospitals and five private laboratories in Lima, Peru, in patients less than 16 years of age with sterile site cultures yielding S. pneumoniae. Antibiotic susceptibility was performed by Etest® (AB Biodisk, Solna, Switzerland). Strains were serotyped by the Quellung reaction. RESULTS: In all, 101 IPD episodes were studied, 68.3 percent of which were among children less than 24 months of age. Diagnoses were: pneumonia (47.5 percent), meningitis (38.6 percent), and sepsis (7.9 percent). The overall case fatality rate was 22.0 percent; case fatality rate in meningitis was 32.4 percent. While 80.0 percent of fatal cases were in those less than 24 months of age, only 50.7 percent of non-fatal cases (P < 0.05) were in this age group. Resistance rates were high for trimethoprim/ sulfamethoxazole (76.2 percent), erythromycin (24.8 percent), and penicillin (22.8 percent). The most common serotypes were 14, 6B, 19F, 23F, and 5, which accounted for 69.7 percent of all strains and 87.0 percent of penicillin non-susceptible strains. CONCLUSIONS: IPD in hospitalized children in Lima is associated with high antimicrobial resistance levels and elevated case fatality rate, especially in young children. This baseline data will be useful for evaluating the effects of vaccine introduction.

OBJETIVO: Determinar la epidemiología de la enfermedad neumocócica invasora y la sensibilidad a los antibióticos y la distribución de los serotipos de S. pneumoniae en pacientes pediátricos en Lima, Perú. MÉTODOS: Estudio multicéntrico de vigilancia pasiva durante dos años, entre mayo del 2006 y abril del 2008, en 11 hospitales públicos y 5 consultorios privados de Lima, en pacientes menores de 16 años con cultivos de sitios estériles positivos para S. pneumoniae. Se determinó la sensibilidad a los antibióticos mediante Etest® (AB Biodisk, Solna, Suiza). Se serotipificaron las cepas mediante la reacción de Quellung. RESULTADOS: En total, se estudiaron 101 episodios de enfermedad neumocócica invasora, 68,3 por ciento de ellos en niños menores de 24 meses, con los siguientes diagnósticos: neumonía (47,5 por ciento), meningitis (38,6 por ciento) y septicemia (7,9 por ciento). La tasa de letalidad general fue de 22,0 por ciento y la tasa de letalidad por meningitis de 32,4 por ciento. Si bien 80,0 por ciento de los casos mortales ocurrió en menores de 24 meses, solo 50,7 por ciento de los casos no mortales (P < 0,05) ocurrió en este grupo de edad. Las tasas de resistencia fueron elevadas para trimetoprima-sulfametoxazol (76,2 por ciento), eritromicina (24,8 por ciento) y penicilina (22,8 por ciento). Los serotipos más comunes, 14, 6B, 19F, 23F y 5, representaron 69,7 por ciento de todas las cepas, y 87,0 por ciento de las cepas no sensibles a la penicilina. CONCLUSIONES: La enfermedad neumocócica invasora en niños hospitalizados en Lima se asocia con altos niveles de resistencia a los antimicrobianos y una tasa de letalidad elevada, especialmente en niños pequeños. Estos datos iniciales serán útiles para evaluar los efectos de la introducción de las vacunas.

Diarrheagenic Escherichia coli in human immunodeficiency virus (HIV) pediatric patients in Lima, Peru.

We conducted a prospective study in three hospitals in Lima in human immunodeficiency virus (HIV) children to determine the frequency of diarrheagenic Escherichia coli. Five E. coli colonies/patients were studied by a multiplex real-time polymerase chain reaction to identify the six currently recognized groups of diarrhea-associated E. coli. We have analyzed 70 HIV-associated diarrheal and 70 control samples from HIV-infected children without diarrhea. Among the diarrheal episodes 19% were persistent, 3% dysenteric, and 33% were associated with moderate or severe dehydration. The diarrheagenic E. coli were the most commonly isolated pathogens in diarrhea (19%) and control samples (26%) (P = 0.42), including enteroaggregative (6% versus 10%), enteropathogenic (6% versus 10%), and enterotoxigenic E. coli (4% versus 3%), respectively. The HIV-infected children with diarrhea had the worse age-related immunosuppression, higher viral loads, and were on highly active antiretroviral treatment (HAART) less often than HIV-infected children without diarrhea. Diarrheagenic E. coli were highly resistant to ampicillin (74%) and cotrimoxazole (70%).

Oclusión y estrés en el síndrome dolor-disfunción temporomandibular: presentación de un paciente / Occlusion and stress in the temporomandibular pain-dysfunction syndrome: a case report

Se reporta una fémina de 20 años, estudiante de tercer año de Medicina con síndrome dolor disfunción temporo-mandibular, cuyo motivo de consulta fue el dolor, relacionado con el lado no habitual de masticación y de dormir. Los datos fueron tomados de su historia clínica donde fue inicialmente tratada. Nos basamos en la exploración clínica de músculos, articulaciones temporo-mandibulares y oclusión, para detectar como posibles causas: el estrés y una interferencia oclusal grosera. Se realizó un tratamiento multicausal: acupuntura, exodoncia, relajación progresiva de Jackonson, charlas educativas, plegable informativo control de placa dentobacteriana e higiene bucal y remisión al psicólogo. Pudimos constatar que una lesión funcional puede causar síntomas tan variados como el daño articular. El diagnóstico es fundamentalmente clínico y por su sencillez debería incorporarse al protocolo de exploración habitual. Consideramos el estrés un factor predisponerte principal y a la vez desencadenante. El estomatólogo del futuro guiará al paciente hacia una vida plena, libre de preocupaciones que alteren su salud mental. Siempre será necesario incorporar al Psicólogo en el equipo multidisciplinario que tratará la afección.

A 20 year-old female, a third year student of Medicine with temporomandibular pain-dysfunction syndrome is reported whose consultation reason was pain, related with the non habitual mastication and sleeping side. Data were taken of her clinical history where it was initially treated. We base ourselves on the clinical exploration of muscles, temporomandibular articulations and occlusion, to detect as possible causes: stress and a coarse occlusal interference. A multicausal treatment was carried out: acupuncture, exodontia, Jackonson´s progressive relaxation, educational talk, informative folding, control of dentobacterial plaque, oral hygiene and remission to the psychologist. We could verify that a functional lesion can cause such varied symptoms as the articular damage. Diagnosis is clinical fundamentally and for its simplicity should incorporate to the habitual exploration protocol. We consider stress a principal predisposing and at the same time triggering factor. The future stomatologist will guide the patient towards a full life, free of preoccupations that alter their mental health. It will always be necessary to incorporate the Psychologist in the multidisciplinary team that will treat the affection.

TCL1A expression delineates biological and clinical variability in B-cell lymphoma.

The assembly of a collection of gene-expression signatures of the major types of B-cell non-Hodgkin's lymphoma has identified increased T-cell leukemia/lymphoma 1A (TCL1) expression in multiple lymphoma types and cases, and has enabled the investigation of the functional and clinical importance of TCL1 expression. Specifically, Burkitt's lymphoma cases show a homogeneously strong expression of TCL1, whereas diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, nodal marginal zone lymphoma, and splenic marginal zone lymphoma display a striking variability in the intensity of TCL1 staining. This was validated in two independent series. A Gene-Set Enrichment Analysis of the genes correlated with TCL1A expression found that variation in the level of expression of TCL1A was significantly associated with some of the most important gene signatures recognizing B-cell lymphoma pathogenesis and heterogeneity, such as germinal center, B-cell receptor, NF-kappaB (and its target genes), death, MAP kinases, TNFR1, TOLL, and IL1R. Additionally, TCL1 expression was correlated with shorter time to treatment in chronic lymphocytic leukemia cases and shorter lymphoma-specific survival in mantle cell lymphoma series, thus indicating the clinical and biological significance of TCL1 expression, and suggesting TCL1A as a potential therapeutic target.

Effect of chemical composition on the induction of DNA damage by urban airborne particulate matter.

Airborne particulate matter (PM) contains a large number of genotoxic substances capable of endangering human health. In the present study, we have investigated the ability of chemically characterized water-soluble and organic-soluble fractions of two particle sizes (PM2.5 and PM10) from different regions of Mexico City to induce DNA damage in a human lung epithelial cell line. We also evaluated associations between the physicochemical parameters of the PM and its genotoxicity. The airborne particulate samples were collected from four regions of the city; a HiVol air sampler was used to collect PM10 on glass fiber filters and a tapered element oscillating system coupled to an automatic cartridge collection unit was used to collect PM2.5 on teflon filters. PM mass was determined by gravimetric analysis of the filters. Filters containing PM2.5 and one section of each PM10 filter were agitated either with deionized water to extract water-soluble compound, or with dichloromethane to prepare organic-soluble compounds. The chemical composition of the extracts was determined by ion and gas chromatography and atomic adsorption spectroscopy. A549 human type II alveolar epithelial cells were exposed to different concentrations of the PM2.5 and PM10 extracts, and alkaline single cell gel electrophoresis or the Comet assay was performed to measure DNA damage and repair. These analyses indicated that soluble transition metals and the organic-soluble PM fractions are crucial factors in the DNA damage induced by PM. PM composition was more important than PM mass for producing genotoxicity. The results of this study showed that the constituents of the water-soluble PM extract are more likely to induce DNA damage than the organic compounds.

Nitric oxide in pulmonary arteriovenous malformations and Fontan procedure.

Pulmonary arteriovenous malformations are a well documented complication of superior cavopulmonary (Glenn) connections. We report the successful management of a case of severe hypoxemia in the early postoperative period of a patient who underwent the Fontan operation. The patient had previously been diagnosed with pulmonary arteriovenous malformations; the use of inhaled nitric oxide was followed up with reversal of life-threatening hypoxemia. At 6-month postoperative follow-up, the patient was asymptomatic with near normal aortic saturation.