Adverse Health Effects of the Long-Term Simultaneous Exposure to Arsenic and Particulate Matter in a Murine Model.

PM2.5 and arsenic are two of the most hazardous substances for humans that coexist worldwide. Independently, they might cause multiple organ damage. However, the combined effect of PM2.5 and arsenic has not been studied. Here, we used an animal model of simultaneous exposure to arsenic and PM2.5. Adult Wistar rats were exposed to PM2.5, As, or PM2.5 + As and their corresponding control groups. After 7, 14, and 28 days of exposure, the animals were euthanized and serum, lungs, kidneys, and hearts were collected. Analysis performed showed high levels of lung inflammation in all experimental groups, with an additive effect in the coexposed group. Besides, we observed cartilaginous metaplasia in the hearts of all exposed animals. The levels of creatine kinase, CK-MB, and lactate dehydrogenase increased in experimental groups. Tissue alterations might be related to oxidative stress through increased GPx and NADPH oxidase activity. The findings of this study suggest that exposure to arsenic, PM2.5, or coexposure induces high levels of oxidative stress, which might be associated with lung inflammation and heart damage. These findings highlight the importance of reducing exposure to these pollutants to protect human health.

Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis-van Creveld Syndrome.

BACKGROUND: Ellis-van Creveld syndrome (EvCS) is an autosomal recessive ciliopathy with a disproportionate short stature, polydactyly, dystrophic nails, oral defects, and cardiac anomalies. It is caused by pathogenic variants in the EVC or EVC2 genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the EVC2 gene in two Mexican patients. METHODS: Two Mexican families were enrolled in this study. Exome sequencing was applied in the probands to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in the parents. Finally, a prediction of the three-dimensional structure of the mutant proteins was made. RESULTS: One patient has a compound heterozygous EVC2 mutation: a novel heterozygous variant c.519_519 + 1delinsT inherited from her mother, and a heterozygous variant c.2161delC (p.L721fs) inherited from her father. The second patient has a previously reported compound heterozygous EVC2 mutation: nonsense mutation c.645G > A (p.W215*) in exon 5 inherited from her mother, and c.273dup (p.K92fs) in exon 2 inherited from her father. In both cases, the diagnostic was Ellis-van Creveld syndrome. Three-dimensional modeling of the EVC2 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons. CONCLUSION: The identified novel heterozygous EVC2 variants, c.2161delC and c.519_519 + 1delinsT, were responsible for the Ellis-van Creveld syndrome in one of the Mexican patients. In the second Mexican patient, we identified a compound heterozygous variant, c.645G > A and c.273dup, responsible for EvCS. The findings in this study extend the EVC2 mutation spectrum and may provide new insights into the EVC2 causation and diagnosis with implications for genetic counseling and clinical management.

Predictores de potenciales reacciones adversas e interacciones medicamentosas en pacientes post accidente cerebrovascular en Perú

Objetivo Identificar los predictores clínicos y farmacoterapéuticos asociados a los niveles de severidad de las reacciones adversas (RAM) e interacciones medicamentosas (IM) en pacientes hospitalizados post accidente cerebrovascular. Métodos Estudio analítico, predictivo y transversal mediante el modelo de regresión lineal múltiple. Los niveles de severidad de las potenciales reacciones adversas e interacciones medicamentosas se evaluaron mediante Drugs.com. Resultados De la evaluación de 992 prescripciones médicas de 55 (56,7%) pacientes mujeres y 42 (43,3%) varones post accidente cerebrovascular isquémico 62 (63,9%) y hemorrágico 35 (36,1%), se identificó un total de 11 790±46,8 potenciales reacciones adversas y 1 034±9,8 interacciones medicamentosas. La hipertensión arterial se asoció a las reacciones adversas graves y moderadas, en tanto que la neumonía intrahospitalaria y alcalosis metabólica a reacciones adversas leves y moderadas. La alcalosis metabólica se asoció a las interacciones medicamentosas moderadas y leves. Los predictores farmacoterapéuticos como la prescripción en polifarmacia y el uso de antibióticos se relacionaron con reacciones adversas graves, moderadas y leves; los antidiabéticos se relacionaron con interacciones medicamentosas graves, moderadas y los fármacos para terapia cardiaca con interacciones medicamentosas leves. Conclusiones Las variables clínicas como factores de riesgo cardiovascular, presencia de comorbilidades que exacerban las enfermedades crónicas no trasmisibles, los signos y síntomas de alarma, el mayor tiempo de estancia hospitalaria y la prescripción en polifarmacia fueron predictores de mayor frecuencia de reacciones adversas e interacciones medicamentosas graves y moderadas que requieren especial vigilancia y estudio individualizado.

Objective To identify clinical and pharmacotherapeutic predictors associated with severity levels of adverse reactions and drug-drug interactions in post-stroke hospita-lized patients. Methods Analytic, predictive, cross-sectional study using multiple linear regression modeling. Severity levels of potential adverse reactions and drug-drug interactions were assessed using Drugs.com. Results From the evaluation of 992 medical prescriptions of 55 (56.7%) female and 42 (43.3%) male patients post ischemic stroke 62(63.9%) and hemorrhagic stroke 35 (36.1%); a total of 11 790±46.8 potential adverse reactions and 1 034±9.8 drug-drug interactions were identified; arterial hypertension was associated with severe and moderate adverse reactions; while in-hospital pneumonia and metabolic alkalosis with mild and moderate adverse reactions. While metabolic alkalosis was associated with moderate and mild drug-drug interactions. Pharmacotherapeutic predictors such as polypharmacy prescription and antibiotic use were related to moderate and mild severe adverse reactions; antidiabetic drugs were related to moderate and severe drug-drug interactions and cardiac therapy drugs were related to mild drug-drug interactions. Conclusions Clinical variables such as cardiovascular risk factors, presence of comorbidities that exacerbate chronic noncommunicable diseases, alarm signs and symptoms, longer hospital stay, as well as polypharmacy prescriptions, were predictors of a higher frequency of severe and moderate adverse reactions and drug-drug interactions, which require special vigilance and individualized study.

How Genetics Can Drive Initial Therapy Choices for Older Patients with Acute Myeloid Leukemia.

OPINION STATEMENT: Treatment of older adults with acute myeloid leukemia (AML) is challenging. Therapy decisions must be guided by multiple factors including aging-related conditions (e.g., comorbidities, functional impairment), therapy benefits and risks, patient preferences, and disease characteristics. Balancing these factors requires understanding the unique, and frequently higher-risk cytogenetic and molecular characteristics of AML in older adult populations, which should caution providers not to reduce therapy intensity on the basis of age alone. Instead, geriatric assessments should be employed to determine fitness for therapy. Treatment options in AML are increasingly targeted to specific mutations or recognized to have differential benefits on the basis of genomics, and representation of older adults and geriatric outcome reporting in clinical trials is improving. Additionally, newer studies have begun to explore personalized therapy strategies on the basis of initial genetic testing. Review and refinement of practice guidelines for older patients on the basis of these advances is needed and is anticipated to remain an important topic in ongoing hematology/oncology clinical education.

Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib.

Donor derived regulatory T lymphocytes and the JAK1/2 kinase inhibitor ruxolitinib are currently being evaluated as therapeutic options in the treatment of chronic graft versus host disease (cGvHD). In this work, we aimed to determine if the combined use of both agents can exert a synergistic effect in the treatment of GvHD. For this purpose, we studied the effect of this combination both in vitro and in a GvHD mouse model. Our results show that ruxolitinib favors the ratio of thymic regulatory T cells to conventional T cells in culture, without affecting the suppressive capacity of these Treg. The combination of ruxolitinib with Treg showed a higher efficacy as compared to each single treatment alone in our GvHD mouse model in terms of GvHD incidence, severity and survival without hampering graft versus leukemia effect. This beneficial effect correlated with the detection in the bone marrow of recipient mice of the infused donor allogeneic Treg after the adoptive transfer.

Antígeno prostático específico (PSA) relacionado al perfil antropométrico en pacientes del Hospital II Huamanga Carlos Tuppia García-Godos, EsSalud. Ayacucho

Objetivo: Determinar la asociación del nivel de antígeno prostático específico (PSA) plasmático y PSA masa según riesgo de padecer enfermedades prostáticas con el perfil antropométrico. Materiales y métodos: Estudio correlacional, de enfoque cuantitativo de dimensión transversal y retrospectiva. La muestra estuvo constituida por 156 historias clínicas de pacientes varones, con pruebas de PSA y datos antropométricos. Para el análisis de la relación de las variables se utilizó la prueba Rho de Spearman, con un nivel de confianza de 95 %. Resultados: La edad promedio de los pacientes fue 67,85±10,83 años y presentaron un valor medio de PSA de 3,57±7,30 ng/mL. El 9,60 % (15 pacientes) tuvo un riesgo bajo de padecer enfermedades prostáticas (PSA = 4,1-9,90 ng/mL); el 5,10 % (8 individuos) mostró riesgo intermedio (PSA= 10-19,90 ng/mL); y el 3, 80 %(6 pacientes) tuvo un riesgo alto (PSA ≥20 ng/mL). El promedio del índice de masa corporal (IMC) fue 26,37±3,81 kg/m2 : 85 pacientes (54,50 %) tenían sobrepeso; y 18 (11,50 %), obesidad. La media de PSA masa fue14,89±30,50 μg; la superficie corporal (SC) se calculó en 3,93± 2,72 m2; y el volumen plasmático fue 4,18± 0,21 L. Se evidenció una correlación positiva muy baja entre el PSA plasmático y la edad (rho = 0,184; p = 0,022), así como con entre la PSA masa y la edad (rho = 0,176; p = 0,028). Se obtuvo una asociación positiva moderada entre el PSA plasmático y la superficie corporal (SC) (rho = 0,456; p = 0,000); y entre el PSA masa y SC (rho = 0,463; p = 0,000). No se encontró relación entre el IMC y el PSA. Conclusiones: Se evidenció la asociación entre el valor de PSA plasmático y PSA masa con el perfil antropométrico, según el riesgo de padecer enfermedades prostáticas, que fue mayor con la superficie corporal y la edad.

Objective: To determine the association between plasma and mass prostate-specific antigen (PSA) levels and the anthropometric profile, taking into account the risk of prostate pathologies. Materials and methods: A correlational, quantitative, cross-sectional and retrospective study conducted with a sample of 156 medical records of male patients with PSA tests and anthropometric data. Spearman's Rho with a 95 % confidence level was used to analyze the relationship between the variables. Results: The average age of the patients was 67.85 ± 10.83 years and their mean PSA value was 3.57 ± 7.30 ng/mL. Fifteen (15) patients (9.60 %) had a low risk (PSA = 4.1 - 9.90 ng/mL), eight (5.10 %) a medium risk (PSA = 10 - 19.90 ng/mL) and six (3.80 %) a high risk (PSA ≥ 20 ng/mL) of developing prostate pathologies. The mean body mass index (BMI) was 26.37 ± 3.81 kg/m2: 85 patients (54.50 %) were overweight and 18 (11.50 %) were obese. The mean mass PSA was 14.89 ± 30.50 μg, the body surface area (BSA) was 3.93 ± 2.72 m2 and the plasma volume was 4.18 ± 0.21 L. A very low positive correlation was evidenced between plasma PSA and age (rho = 0.184; p = 0.022) and between mass PSA and age (rho = 0.176; p = 0.028). There was a moderate positive association between plasma PSA and BSA (rho = 0.456; p = 0.000) and between mass PSA and BSA (rho = 0.463; p = 0.000). No relationship was found between BMI and PSA. Conclusions: The association between plasma and mass PSA levels and the anthropometric profile was demonstrated, taking into account the risk of prostate pathologies, which increased with BSA and age.

ENTPDases from Pathogenic Trypanosomatids and Purinergic Signaling: Shedding Light towards Biotechnological Applications.

ENTPDases are enzymes known for hydrolyzing extracellular nucleotides and playing an essential role in controlling the nucleotide signaling via nucleotide/purinergic receptors P2. Moreover, ENTPDases, together with Ecto-5´-nucleotidase activity, affect the adenosine signaling via P1 receptors. These signals control many biological processes, including the immune system. In this context, ATP is considered as a trigger to inflammatory signaling, while adenosine (Ado) induces anti-inflammatory response. The trypanosomatids Leishmania and Trypanosoma cruzi, pathogenic agents of Leishmaniasis and Chagas Disease, respectively, have their own ENTPDases named "TpENTPDases," which can affect the nucleotide signaling, adhesion and infection, in order to favor the parasite. Besides, TpENTPDases are essential for the parasite nutrition, since the Purine De Novo synthesis pathway is absent in them, which makes these pathogens dependent on the intake of purines and nucleopurines for the Salvage Pathway, in which TpENTPDases also take place. Here, we review information regarding TpNTPDases, including their known biological roles and their effect on the purinergic signaling. We also highlight the roles of these enzymes in parasite infection and their biotechnological applications, while pointing to future developments.

Assessing the impact on intestinal microbiome and clinical outcomes of antibiotherapy optimisation strategies in haematopoietic stem cell transplant recipients: study protocol for the prospective multicentre OptimBioma study.

INTRODUCTION: Haematopoietic stem cell transplantation (HSCT) is a life-saving treatment for a number of haematological diseases. Graft versus host disease (GVHD) is its main complication and hampers survival. There is strong evidence that intestinal microbiota diversity of the recipient may increase the risk of GVHD worsening survival. Antibiotic regimens used during the early phase of the transplant may influence clinical outcomes by reducing intestinal microbiota diversity. Present guidelines of European Conference on Infections in Leukaemia exhort to optimising antibiotic use in haematological patients including HSCT recipients. The present study aims to investigate if, in HSCT recipients, the optimisation of antibacterial use may preserve intestinal microbiota composition reducing the incidence and severity of acute GVHD and improving relevant clinical outcomes. METHODS AND ANALYSIS: This is a prospective longitudinal observational study of two cohorts of HSCT recipients: (1) the intervention cohort includes patients treated in centres in which a predefined strategy of antibiotherapy optimisation is implemented, with the objective of optimising and reducing antibiotic administration according to clinical criteria and (2) the control cohort includes patients treated in centres in which a classic permissive strategy of antibiotic prophylaxis and treatment is used. Adult patient receiving a first HSCT as a treatment for any haematological condition are included. Clinical variables are prospectively recorded and up to five faecal samples are collected for microbiota characterisation at prestablished peritransplant time points. Patients are followed since the preconditioning phase throughout 1-year post-transplant and four follow-up visits are scheduled. Faecal microbiota composition and diversity will be compared between both cohorts along with acute GVHD incidence and severity, severe infections rate, mortality and overall and disease-free survival. ETHICS AND DISSEMINATION: The study was approved between 2017 and 2018 by the Ethical Committees of participant centres. Study results will be disseminated through peer-reviewed journals and national and international scientific conferences. TRIAL REGISTRATION NUMBER: NCT03727113.

Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study.

Graft-versus-host disease is the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. First-line treatment is based on the use of high doses of corticosteroids. Unfortunately, second-line treatment for both acute and chronic graft-versus-host disease, remains a challenge. Ruxolitinib has been shown as an effective and safe treatment option for these patients. Seventy-nine patients received ruxolitinib and were evaluated in this retrospective and multicenter study. Twenty-three patients received ruxolitinib for refractory acute graft-versus-host disease after a median of 3 (range 1-5) previous lines of therapy. Overall response rate was 69.5% (16/23) which was obtained after a median of 2 weeks of treatment, and 21.7% (5/23) reached complete remission. Fifty-six patients were evaluated for refractory chronic graft-versus-host disease. The median number of previous lines of therapy was 3 (range 1-10). Overall response rate was 57.1% (32/56) with 3.5% (2/56) obtaining complete remission after a median of 4 weeks. Tapering of corticosteroids was possible in both acute (17/23, 73%) and chronic graft-versus-host disease (32/56, 57.1%) groups. Overall survival was 47% (CI: 23-67%) at 6 months for patients with aGVHD (62 vs 28% in responders vs non-responders) and 81% (CI: 63-89%) at 1 year for patients with cGVHD (83 vs 76% in responders vs non-responders). Ruxolitinib in the real life setting is an effective and safe treatment option for GVHD, with an ORR of 69.5% and 57.1% for refractory acute and chronic graft-versus-host disease, respectively, in heavily pretreated patients.

Influencia de la lengua dispar (tutunakú y español) en los mensajes e instrucciones que emite el personal de salud y la de las receptoras de la información / Influence of disparate language (Tutunakú and Spanish) in messages and instructions issued by health personnel and those receiving the information

Resumen OBJETIVO: Identificar la influencia de la lengua dispar (tutunakú y español) entre los mensajes e instrucciones que emite el personal de salud y la de las receptoras de esa información, en particular la dirigida a la práctica de la autoexploración con fines de prevención del cáncer de mama. MATERIALES Y MÉTODOS: Estudio descriptivo, transversal, efectuado en mujeres indígenas, mayores de 20 años, a quienes se aplicó un instrumento semiestructurado para la identificación de factores de riesgo y protección de cáncer de mama. Para determinar la asociación de las variables de hablantes de totonakú con el nivel de conocimiento, prevención y riesgo de cáncer de mama se utilizó la prueba de χ2. RESULTADOS: Se estudiaron 187 mujeres; de las que 109 (58.5%) solo hablaban tutunakú y 78 (41.5%) eran bilingües (tutunakú y español). La edad promedio de las participantes fue de 43.4 años (DE ± 14.8), con límites de 20 y 80 años. En relación con la escolaridad: 93 de 109 (85.5%) de las monolingües eran analfabetas y solo 44 de las 78 (57.1%) mujeres bilingües habían concluido la educación básica. Por lo que se refiere al conocimiento del cáncer de mama, las mujeres monolingües tuvieron menor nivel de conocimiento y menor práctica de la autoexploración; solo 34 de las 78 bilingües practicaban la autoexploración. CONCLUSIÓN: Si bien el riesgo de cáncer de mama no muestra asociación con el hecho de hablar una lengua sí lo tiene, directamente, con la escolaridad, con la capacidad necesaria para comprender instrucciones que permitan la práctica de la autoexploración.

Abstract OBJECTIVE: To identify the influence of the disparate language (tutunaku and Spanish) between the messages and instructions issued by health personnel and those of the recipients of this information, in particular that directed at the practice of self-examination for the purpose of breast cancer prevention. MATERIALS AND METHODS: Descriptive, cross-sectional study, carried out on indigenous women over 20 years of age, to whom a semi-structured instrument was applied for the identification of risk factors and protection from breast cancer. To determine the association of Totonaku speakers' variables with the level of knowledge, prevention and risk of breast cancer, the test of 2 was used. RESULTS: A total of 187 women were studied; 109 (58.5%) spoke only tutunaku and 78 (41.5%) were bilingual (tutunaku and Spanish). The average age of participants was 43.4 years (SD 14.8), with limits of 20 and 80 years. With regard to schooling: 93 of 109 (85.5%) of the monolingual women were illiterate and only 44 of 78 (57.1%) of the bilingual women had completed basic education. With regard to knowledge of breast cancer, monolingual women had a lower level of knowledge and less practice of self-examination; only 34 of the 78 bilingual women practiced self-examination. CONCLUSION: Although the risk of breast cancer is not associated with speaking a language, it is directly associated with schooling, with the ability to understand instructions that allow the practice of self-examination.

Allocation to Matched Related or Unrelated Donor Results in Similar Clinical Outcomes without Increased Risk of Failure to Proceed to Transplant among Patients with Acute Myeloid Leukemia: A Retrospective Analysis from the Time of Transplant Approval.

Clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-SCT) from unrelated donors (URDs) approach those of matched related donor (MRD) transplants in patients with acute myeloid leukemia (AML). Yet, available data fail to account for differences in pretransplantation outcomes between these donor selection strategies. In this regard, URD allo-HSCT is associated with longer waiting times to transplantation, potentially resulting in higher probabilities of failure to reach transplant. We retrospectively analyzed 108 AML patients accepted for first allo-HSCT from the time of approval to proceed to transplant. Fifty-eight (54%) patients were initially allocated to MRD, while URD search was initiated in 50 (46%) patients. Time to transplant was longer in patients allocated to a URD when compared with patients assigned to an MRD (median 142 days versus 100 days; p < .001). Forty-three of 58 (74%) patients in the MRD group and 35 of 50 (70%) patients in the URD group underwent transplantation (odds ratio [OR], 1.22; p = .63). Advanced disease status at the time of allo-HSCT approval was the only predictor of failure to reach transplantation in the multivariate analysis (OR, 4.78; p = .001). Disease progression was the most common cause of failure to reach allo-HSCT (66.7%) in both the MRD and URD groups. With a median follow-up from transplantation of 14.5 (interquartile range, 5 to 29) months, the 2-year estimate of overall survival (OS) from allo-HSCT was 46% in the MRD group and 57% in the URD group (p = .54). There were no differences in OS according to donor type allocation in the multivariate analysis (hazard ratio, 1.01; p = .83). When including patients from the time of transplant approval, 2-year OS was 39% in the MRD group versus 42% in the URD group. Our study suggests that allocation of AML patients to URDs may result in comparable clinical outcomes to MRD assignment without a significant increase in the risk of failure to reach transplant.

Determinación de plomo en leche materna de madres lactantes en nueve distritos de laciudad de Lima, Perú / Determination of lead levels in breast milk of breastfeeding mothers in nine districts in Lima, Peru

Objetivo: Determinar los niveles de plomo en leche materna en puérperas primíparas provenientes de nueve distritos de la ciudad de Lima. Materiales y método: Se realizó un estudio transversal entre octubre de 2010 y agosto de 2012. Se incluyeron 100 muestras de leche materna, de mujeres que vivieron como mínimo cinco años en la misma zona de Lima. El método de análisis fue la espectrofotometría de absorción atómica. Resultados: El 37% de las muestras tuvieron un nivel detectable de plomo, seis de ellos entre 5,0 y 9,9 ng/g y cinco mayores de 10 ng/g. No se identificaron condiciones de riesgo asociados. Conclusión: Se concluye que un porcentaje importante de nuestras muestras de leche materna presentaron contaminación con plomo, particularmente en residentes de la zona norte de Lima

Objective: To determine lead levels in breast milk in primiparous women from nine districts in Lima. Materials and methods: We conducted a cross-sectional study between October 2010 and August 2012. One-hundred samples of breast milk were included, these were from women who lived for more than 5 years in the same area in Lima. We used the atomic absorption spectrophotometry method for the measurements. Result: Thirty-seven percent of the samples had detectable lead levels, six of them were between 5.0 and 9.9 ng/g and five were over 10 ng/g. We did not identify associated risk factors. Conclusion: An important percentage of samples of breast milk are contaminated with lead, particularly in persons living in northern Lima

XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer.

PURPOSE: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects. EXPERIMENTAL DESIGN: To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models. RESULTS: Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects. CONCLUSIONS: Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials.

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.

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.

Miocarditis fulminante y enfermedad diarreica aguda por Coxsackie virus B6 / Fulminant myocarditis and acute gastroenteritis due to Coxsackie virus B6

Presentamos el caso de una paciente joven que presentó choque cardiogénico por virus Coxsakie B6. La paciente acudió a una clínica particular con un cuadro clínico compatible con gastroenterocolitis aguda a la que después de una hora de estar recibiendo hidratación y manejo del cuadro diagnosticado, se agregó hipotensión que llegó al estado de choque, hipoxemia severa y compromiso pulmonar bilateral intersticial por lo que ingresó a Unidad de Cuidados Intensivos, donde recibió manejo de soporte. Debido al cuadro clínico y elevación de enzimas cardiacas se sospechó de compromiso cardiaco, la ecocardiografía evidenció cambios sugerentes de miocarditis. La evolución fue favorable y se le pudo dar de alta después de una semana. El diagnóstico etiológico del cuadro se hizo en el seguimiento, presentando serología con elevación de títulos para virus Coxsakie B6.

We present the case of a young woman who suffered cardiogenic due to by Coxsackie virus B6. The patient attended a private clinic with an acute gastroenteritis and after one hour of receiving hydratation,she developed hypotension and shock, severe hypoxemia and bilateral lung infiltrate. The patient entered the Intensive Care Unit, where she received hemodynamic support. Due to the clinical picture and cardiac enzymes increase, a cardiac failure was suspected and the echocardiographic findings suggested "myocarditis". The evolution was successful and Coxsackie B6 virus infection diagnosis was made during the follow up by increase of the levels of antibodies for virus Coxsackie B6.

Indazolylpyrazolopyrimidine as highly potent B-Raf inhibitors with in vivo activity.

Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.

Discovery of highly potent and selective type I B-Raf kinase inhibitors.

A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.

Novel pyrazolopyrimidines as highly potent B-Raf inhibitors.

A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.