Toll-Like Receptor 7 (TLR-7) and TLR-9 Agonists Improve Hepatitis C Virus Replication and Infectivity Inhibition by Plasmacytoid Dendritic Cells.

Plasmacytoid dendritic cells (pDCs) are innate immune cells with high antiviral activity triggered by Toll-like receptor 7 (TLR-7) and TLR-9 stimulation. Moreover, they are important mediators between innate and adaptive immunity. Although nowadays there is available an effective therapeutic arsenal against hepatitis C virus (HCV), a protective vaccine is not available. We have analyzed the pDCs' response to HCV infection in a hepatitis C virus (HCV)-Huh7.5 virus-cell system, which allows completion of the virus infectious cycle. pDCs were cocultured following human immunodeficiency virus (HIV) aldrithiol-2 (AT-2 [TLR-7 agonist]) inactivation and CpG (TLR-9 agonist) stimulation. We employed three virus derivatives-wild-type Jc1, interferon (IFN)-resistant virus IR, and high-replicative-fitness virus P100-in order to explore additional IFN-α-related virus inhibition mechanisms. pDCs inhibited HCV infectivity and replication and produced IFN-α. After TLR-7 and TLR-9 stimulation, inhibition of infectivity and IFN-α production by pDCs were enhanced. TLR-7 stimulation drove higher TNF-related apoptosis-inducing ligand (TRAIL) expression in pDCs. Additionally, TLR-7- and TLR-9-stimulated pDCs exhibited a mature phenotype, improving the antigen presentation and lymph node homing-related markers. In conclusion, pDCs could serve as a drug target against HCV in order to improve antiviral activity and as an enhancer of viral immunization.IMPORTANCE We implemented a coculture system of pDCs with HCV-infected hepatoma cell line, Huh7.5. We used three HCV derivatives in order to gain insight into pDCs' behavior against HCV and associated antiviral mechanisms. The results with this cell coculture system support the capacity of pDCs to inhibit HCV replication and infectivity mainly via IFN-α, but also through additional mechanisms associated with pDC maturation. We provided evidence that TLR agonists can enhance antiviral pDCs' function and can induce phenotypic changes that may facilitate the interplay with other immune cells. These findings suggest the possibility of including TLR agonists in the strategies of HCV vaccine development.

[Anti-smoking intervention in the acute phase of acute coronary syndrome: Is there additional benefit in patients included in a cardiac rehabilitation program?] / Intervención antitabaco en fase aguda del síndrome coronario agudo: ¿existe beneficio adicional en pacientes incluidos en un programa de rehabilitación cardiaca?

BACKGROUND: Smoking is a challenge in secondary prevention after acute coronary syndrome (ACS). The objective was to assess whether the early anti-smoking intervention (ASI), in the acute hospitalization phase, improves the abstinence rate obtained during a cardiac rehabilitation program (CRP). METHODS: Multicenter clinical trial in which smoker patients admitted for ACS were randomized 1:1 to receive or not ASI from the first day of admission. Upon discharge, both groups were referred to the CRP, performing abstinence controls using co-oximetry. Patients lost were considered smokers. RESULTS: 72 patients were included, 58 men (80.5%), mean age 53 ± 8.1 years. They were admitted for ST elevation myocardial infarction 42 (58%), non-ST elevation myocardial infarction 29 (40%) and unstable angina 1 (1.3%). They smoked an average of 22 ± 11.3 cigarettes/day (pack-year index 37 ± 20). They completed the Richmond test (8.8 ± 1.3) and Fagestrom (5.69 ± 2.1). 36 patients (50%) were randomized to ASI, with no differences in the baseline characteristics of both groups. The dropout rate at the time of inclusion in CRP was higher in the ASI group (69 vs. 44%; p 0.034; OR 2.84), without statistical significance at discharge from the CRP (58 vs. 50%; p 0.478; OR 1.4) or at 12 months (58 vs. 44%; p 0.24; OR 1.75). CONCLUSIONS: The ASI during admission significantly improves the smoking cessation rate at the time of inclusion in the CRP. Part of these beneficial effects are reduced in the follow-up losing statistical significance with respect to the control group.

Coxsackieviruses and quasispecies theory: evolution of enteroviruses.

Enterovirus populations display quasispecies dynamics, characterized by high rates of mutation and recombination, followed by competition, selection, and random drift acting on heterogeneous mutant spectra. Direct experimental evidence indicates that high mutation rates and complex mutant spectra can serve for the adaptation of enteroviruses to complex environments. Studies with the RNA-dependent RNA polymerase of picornaviruses suggest that multiple enzyme sites may influence the template-copying fidelity (incorporation of incorrect vs correct nucleotide) during RNA replication. Mutation and recombination are an unavoidable consequence of the molecular mechanisms inherent to the process of viral genome replication and underlie the diversification of enterovirus genomes as they multiply in human and animal hosts. The diversity of disease manifestations associated with closely related enteroviruses is probably attributable to profound biological effects of some mutations that, because of their limited number, do not necessarily affect the phylogenetic position of the virus. The combination of highly dynamic mutant spectra with unpredictable alterations of biological behavior by minimal genetic change defies classical classification schemes. The result is the need to update the grouping of enteroviruses quite frequently into genetic and serological types and subtypes. The tolerance of enterovirus genomes to remain replication-competent despite multiple mutation and recombination events encourages the engineering of live-attenuated vaccines. Also, the application of quasispecies theory to an understanding of the limits of viral genomes to accept mutations, together with an increasingly deeper understanding of the mechanisms of mutagenesis by nucleoside analogs, has paved the way for the application of lethal mutagenesis as a new antiviral strategy.

Viruses as quasispecies: biological implications.

During viral infections, the complex and dynamic distributions of variants, termed viral quasispecies, play a key role in the adaptability of viruses to changing environments and the fate of the population as a whole. Mutant spectra are continuously and avoidably generated during RNA genome replication, and they are not just a by-product of error-prone replication, devoid of biological relevance. On the contrary, current evidence indicates that mutant spectra contribute to viral pathogenesis, can modulate the expression of phenotypic traits by subpopulations of viruses, can include memory genomes that reflect the past evolutionary history of the viral lineage, and, furthermore, can participate in viral extinction through lethal mutagenesis. Also, mutant spectra are the target on which selection and random drift act to shape the long-term evolution of viruses. The biological relevance of mutant spectra is the central topic of this chapter.

High HCV subtype heterogeneity in a chronically infected general population revealed by high-resolution hepatitis C virus subtyping.

OBJECTIVES: This study aimed to characterize the chronically infected general hepatitis C virus (HCV) population in Barcelona using a highly sensitive subtyping method that can identify the 67 recognized HCV subtypes and diagnose mixed infection by various genotypes/subtypes in a single individual. The resulting information has implications for selecting optimal direct-acting antiviral (DAA) treatment for each patient and establishing public healthcare policies in our setting. METHODS: Consecutive HCV patients (treatment-naïve or interferon-based failures) attending Vall d'Hebron Hospital outpatient clinics from February 2015 to May 2016 (N=1473) were included in the study. Patient samples were characterized using HCV subtyping by next-generation ultra-deep pyrosequencing. RESULTS: The following genotypes (G) were found: G1 (1126/1473 (76.4%)), G4 (145/1473 (9.8%)), G3 (135/1473 (9.2%)), G2 (51/1473 (3.5%)), and G5 (1/1473 (0.1%)). Twenty-two subtypes were seen: 1b (790/1473 (53.6%)), 1a (332/1473 (22.5%)), 3a (133/1473 (9.0%)), 4d (105/1473 (7.1%)), 4a (29/1473 (2.0%)), and 2c (25/1473 (1.7%)), with 16 low-prevalence subtypes accounting for the remaining 3.0% (44/1473). There was a worrisome 1.0% (15/1473) of mixed infections. G2 (51/1473 (3.5%)) showed a high level of heterogeneity. Analyses by age groups showed a predominance of G1b over G1a (428/506 (84.6%) vs. 24/506 (4.7%)) in patients born before 1950 (N=506/1473), and similar percentages of these subtypes in those born between 1951 and 1975 (N=834/1473) (315/834, 37.8% vs. 266/834, 31.9%) and after 1976 (N=133/1473) (47/133, 35.3% vs. 42/133, 31.6%). CONCLUSIONS: Subtype distribution showed a higher level of heterogeneity than was expected, particularly for G2. Prevalence of mixed infections was around 1%. HCV subtype distribution related to patient age group suggested that patients born from 1936 to 1975 in our setting should undergo screening for the infection. Next-generation sequencing enabled better classification of candidates for DAA-based treatment.

Tumor Inflamatorio de Pott: reporte de un caso y revisión de la literatura / Pott's puffy tumor: a case report and review of the literature

INTRODUCCIÓN: El Tumor inflamatorio de Pott es una complicación rara de una patología frecuente, como son los cuadros infecciosos sinusales, cada vez más inusual por el uso extendido de antibióticos de amplio espectro, es más frecuente en la población adolescente por la neumatización similar al adulto. Se presenta como un aumento de volumen blando a nivel frontal con una osteomielitis del hueso frontal y un absceso subperióstico. MATERIALES Y MÉTODOS: En este trabajo, se presenta una revisión bibliográfica del tema y un caso de un paciente de 9 años, quien cursó con un cuadro infeccioso sinusal, que posterior desarrollo un aumento de volumen frontal, mostrando las imágenes perioperatorias e intraoperatorias. DISCUSIÓN Y CONCLUSIÓN: El absceso subperióstico secundario a la sinusitis, es una complicación rara. Sin embargo, se debe pensar en el diagnostico en pacientes de evolución tórpida y/o que presentan sintomatología neurológica, como convulsiones, se debe completar el estudio con neuroimagen contrastada.

INTRODUCTION: Pott's inflammatory tumor is a rare complication of a frequent pathology, such as sinus infections, increasingly unusual due to the use of broad-spectrum antibiotics, it is more frequent in the adolescent population due to pneumatization similar to that of adults. It presents as an increase in volume at a frontal level with osteomyelitis of the frontal bone and a subperiosteal abscess. ;MATERIAL AND METHODS: In this work, we present a bibliographic review and a case of a 9-year-old patient, who presented with an infectious sinus, which later developed an increase in frontal volume, the perioperative and intraoperative images are shown. DISCUSSION AND CONCLUSION: Subperiosteal abscess secondary to sinusitis is a rare complication. However, the diagnosis should be considered in patients with torpid evolution and / or who present neurological symptoms, such as seizures, the study must be completed with a contrast brain image.

Morbimortalidad Asociada A La Cirugia De Meningioma Del Foramen Magno. Revision De La Literatura: Reporte De Caso / Morbimortality Associated With The Foramen Magno Meningioma Surgery: A Case Report

Resumen Los meningiomas son tumores del sistema nervioso central que representan alrededor del 14,3% a 19%, de ellos solo un 1.8% a 3,2% surge en el foramen magno, por años el abordaje de esta clase de tumores conllevaba una gran morbimortalidad asociada debido a que el foramen magno contiene una serie de estructuras anatómicas y neurovasculares críticas, sin embargo con el progreso de las técnicas quirúrgicas, el manejo de la anestesia neurológica y la formación de neurocirujanos con experiencia en cirugías de base de cráneo, ha podido revertir estos resultados y hacer de la cirugía una alternativa segura con bajas tasas de complicaciones. El presente trabajo pretende revisar la literatura acerca de la morbimortalidad asociada a los meningiomas de foramen magno y presentar un caso abordado en nuestro centro.

The meningiomas are tumors of the central nervous system that represent around 14.3% to 19%, of them only 1.8% to 3.2% arise in the foramen magnum, for years the approach of this class of tumors entailed a great associated morbidity and mortality because the foramen magnum contains a series of critical anatomical and neurovascular structures, however with the progress of surgical techniques, the management of neurological anesthesia and the training of neurosurgeons with experience in skull base surgeries, it has been able to reverse these results and make surgery a safe alternative with low complication rates. The present work aims to review the literature about morbidity and mortality associated with meningiomas of foramen magnum and present a case addressed in our center.

Iron deficiency anemia: adverse effects on infant psychomotor development.

In a double-blind, placebo-control prospective cohort study of 196 infants from birth to 15 months of age, assessment was made at 12 months of age of the relationship between iron status and psychomotor development, the effect of a short-term (10-day) trial of oral iron vs placebo, and the effect of long-term (3 months) oral iron therapy. Development was assessed with the mental and psychomotor indices and the infant behavior record of the Bayley Scales of Infant Development in 39 anemic, 30 control, and 127 nonanemic iron-deficient children. Anemic infants had significantly lower Mental and Psychomotor Developmental Index scores than control infants or nonanemic iron-deficient infants (one-way analysis of variance, P less than .0001). Control infants and nonanemic iron-deficient infants performed comparably. No difference was noted between the effect of oral administration of iron or placebo after 10 days or after 3 months of iron therapy. Among anemic infants a hemoglobin concentration less than 10.5 g/dL and duration of anemia of greater than 3 months were correlated with significantly lower motor and mental scores (P less than .05). Anemic infants failed specifically in language capabilities and body balance-coordination skills when compared with controls. These results, in a design in which intervening variables were closely controlled, suggest that when iron deficiency progresses to anemia, but not before, adverse influences in the performance of developmental tests appear and persist for at least 3 months despite correction of anemia with iron therapy. If these impairments prove to be long standing, prevention of iron deficiency anemia in early infancy becomes the only way to avoid them.

Breakfast omission and cognitive performance of normal, wasted and stunted schoolchildren.

This study focuses on the effects of breakfast omission on cognitive performance. We studied 279 children from low socioeconomic level background ranging in age from 8 years 7 months to 10 years 11 months, categorized nutritionally as: normal, wasted or stunted. Evaluation comprised three cognitive tasks designed to be applied with a microcomputer. Assessment took place in their natural setting, after a mean of 14 h of overnight fasting, some having received a standard breakfast at random while the remaining children continued a fasting situation. We found no consistent association between study condition and performance in short-term visual memory, problem solving and attention tasks in any of the three nutritional groups. Stunted children showed significantly lower scores in the attention test irrespective of having received breakfast or not. These results suggest that given a motivating short-term task and maintaining routine conditions, missing breakfast does not affect the accuracy of the cognitive performance of children. Nutritionally affected children did not show a particular vulnerability to the fasting condition, but did show a specific cognitive deficit.

[Rhabdomyolysis and acute renal failure secondary to statins]. / Rabdomiolisis y fracaso renal agudo secundario a estatinas.

Statins are competitive inhibitors of hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase and are the most commonly used drugs to treat hyperlipidaemia. Muscle toxicity is an adverse effect reported with a low incidence and rarely associated with acute renal failure due to rhabdomyolysis. We describe two patients with chronic renal failure treated with pravastatin and simvastatin who suffered rhabdomyolysis and acute renal failure. One patient started pravastatin several days after cessation of bezafibrate and developed acute renal failure without needing dialysis. The other was treated with simvastatin three years ago and suffered rhabdomyolysis when renal function was impaired after indomethacin was prescribed for backache. He needed hemodialysis because of acute cardiac failure and died from a respiratory infection while on mechanical ventilation. Myopathy was reversible in both patients. We recommend starting statins with the lower doses in chronic renal failure and monitoring muscle enzymes when renal function changes or when new drugs with potential interactions are prescribed.

[Ileocecal tuberculosis during hemodialysis simulating carcinoma of the colon]. / Tuberculosis ileocecal en hemodiálisis simulando un carcinoma de colon.

Extrapulmonary tuberculosis is more frequent in hemodialysis patients than in the general population but intestinal localization is an unusual presentation of this infectious disease. We report a 60 year old patient on regular hemodialysis with intestinal tuberculosis masquerading as colon cancer. The patient presented with rectal bleeding, abdominal pain and fever and the radiological findings were compatible with ileocecal carcinoma. After surgery histological examination showed non-caseating granulomas but mycobacterial culture was not available. We performed a colonoscopy and obtained a biopsy of colonic mucosa for culture and other analyses. We identified acid-fast bacilli with Ziehl-Neelsen staining of formaldehyde preserved, paraffin-embedded tissue from the hemicolectomy and the colonic mucosal biopsy. Treatment with isoniazid, rifampicin and pyrazinamide for nine months was successful and well tolerated. Intestinal tuberculosis is a rare entity that we must keep in mind in a patient with abdominal pain, unexplained fever, digestive bleeding and particularly with a positive tuberculin reaction. When culture is not possible we can obtain intestinal samples by colonoscopy and use appropriate staining of paraffin-embedded tissues.

[Cognitive functions of school children with normal IQ and histories of severe and early malnutrition]. / Estudio de funciones cognitivas en escolares de nivel intelectual normal con antecedentes de desnutrición grave y precoz.

This is a cross section study designed to evaluate the long lasting consequences of early and severe undernutrition on the development of basic cognitive functions. Attention, memory and problem-solving capacity were assessed in a group of 16 school children, who were severely undernourished during the first two years of age. They were compared with a group of 16 children with a normal growth. All subjects, age 8 to 10, had a normal intellectual coefficient and they belonged to the me same socioeconomical level. Memory was measured with a modified version of subtest of digits from WISC; attention was evaluated with a modified version of the Continuous Performance Task and problem-solving was measured with the Anstey Domino Test. A personal computer was used to assess the cognitive functions. The children who were undernourished during infancy presented lower scores in memory (number of the digits) and in problems solving (number of correct answers). They also had a worse performance than the control group in the same response time, when attention was evaluated. These results suggest that early severe undernutrition had deletereous effects on basic cognitive functions.

Análisis epidemiológico y clínico del embarazo ectópico: Hospital Base de los Ángeles / Clinical and epidemiological analysis of ectopic pregnancy

Antecedentes: El embarazo ectópico (EE) se produce cuando el blastocisto se implanta en un sitio distinto al endometrio de la cavidad uterina, siendo el sitio más frecuente las trompas de Falopio. Objetivo: Conocer la incidencia y caracterizar el perfl de las pacientes con EE desde el punto de vista clínico, médico, quirúrgico y obstétrico. Método: Se realizó un estudio observacional analítico. La muestra fue obtenida a través de un muestreo no probabilístico consecutivo, obteniendo una muestra fnal de 70 pacientes. Resultados: El promedio de edad materna fue 30,6 años. El 78,6 por ciento eran multíparas y 90 por ciento no usaban ningún método anticonceptivo. El 85,7 por ciento no tenían antecedentes de cirugías previas y el 91,4 por ciento no presentó antecedentes mórbidos. El 5,7 por ciento tenía antecedentes de proceso infamatorio pélvico, 18,5 por ciento tabaquismo, 12,9 por ciento abortos previos, 14,3 por ciento embarazo ectópico anterior. El manejo fue quirúrgico en 95,7 por ciento. El 78,6 por ciento presentó alguna complicación asociada, siendo la más frecuente el hematosalpinx. Conclusión: Los antecedentes epidemiológicos y clínicos de nuestra experiencia fueron concordantes con los registrados en la literatura y avalan nuestra conducta quirúrgica.

Background: Ectopic pregnancy (EP) occurs when the developing blastocyst becomes implanted at a site other than the endometrium of the uterine cavity. The most common extra-uterine location is the fallopian tube. Objective: The aim of our study is to know the incidence and the clinical, medical, obstetric and surgical profle of patients with EP. Method: An observational analytic study was made with a fnal sample of 70 patients. Results: Mean age was 30.6 years old, 78.6 percent were multiparas and 90 percent didn't use any contraceptive method. 85 percent had no history of previous surgery and 91.4 percent had no morbid background. 7.5 percent had history of pelvic infammatory disease, 18.5 percent smoked, 12.9 percent had previous abortion and 14.3 percent previous EP. The management was surgical in 95 percent of patients; 78.6 percent presented an associated complication, being hema-tosalpinx the most often. Conclusion: The epidemiological and clinical background of our experience was consistent with those reported in the literature and guarantees our surgical treatment.

HIV-1 protease cleaves eukaryotic initiation factor 4G and inhibits cap-dependent translation.

Several animal viruses inhibit host protein synthesis, but only some members of the picornavirus group are known to do so by cleaving translation initiation factor eIF4G. Here we report that infection of human CD4(+) cells with HIV-1 also leads to proteolysis of eIF4G and profound inhibition of cellular translation. Purified HIV-1 protease directly cleaves eIF4GI at positions 678, 681, and 1086, separating the three domains of this initiation factor. Proteolysis of eIF4GI by HIV-1 protease, as with poliovirus 2A protease, inhibits protein synthesis directed by capped mRNAs but allows internal ribosome entry site-driven translation. These findings indicate that HIV-1, a member of retrovirus group, shares with picornaviruses the capacity to proteolyze eIF4G.