IL-17A and Streptococcus pneumoniae respiratory infection: Prospects for the development of new immunotherapies

Nasopharyngeal colonization by Streptococcus pneumoniae constitutes a pre-requisite for development of pneumonia and invasive pneumococcal diseases. Colonization is typically asymptomatic and is resolved due to a dynamic and complex interplay between microbiota, host immune system and environmental factors. Working with a murine model of pneumococcal nasopharyngeal colonization, we have shown that IL-17A is a key cytokine in this process, since Il17a-/- mice were persistently colonized for up to 6 months whereas wild type mice cleared colonization in 10 days. We are currently trying to elucidate the downstream mechanisms that may account for the phenotype showed in Il17a-/- mice, including the production of specific antibodies, as well as the recruitment of innate cells and the expression of immune mediators in WT and Il17a-/- mice. On the other hand, we have studied the role of IL-17A in the development of protective immunity against acute pneumococcal pneumonia. Previously, we showed that prior sublethal infection resulted in solid protection against invasive pneumonia which is associated with over expression of IL-17A together with the presence of Th17 cells in the lungs. However, Il17a-/- mice showed same level of protection than WT, demonstrating that IL-17A by itself is not essential for protective immunity. Interestingly Il17a-/- mice showed overexpression of other IL-17 related genes suggesting a complex network where compensatory effects may be occurring. Finally, we have developed and tested alternative immunotherapies against pneumococcal pneumonia, and have evaluated the role of IL17A in the protection afforded. Overall, we believe that deciphering the molecular basis of protective immunity will result in the development of new cost-effective immunotherapies against pneumococcal pneumonia

Prevalencia de la obesidad en la población atendida en asistencia primaria de Girona, 1995–1999

ResumenObjetivosEstimar y comparar la prevalencia de la obesidad y el sobrepeso en la población de Girona, entre 1995 y 1999, estratificando geográficamente por sexo y edad.MétodosMedidas directas de talla y peso correspondientes a 24.554 usuarios mayores de 14 años (10.595 varones y 13.959 mujeres) atendidos en cuatro áreas básicas de salud (ABS): Girona 1, Girona 4, Salt y Camprodon, así como en un centro de atención primaria (CAP) de la provincia de Girona. Se calculó el índice de masa corporal (IMC) como el cociente entre el peso y la talla al cuadrado. La obesidad se define como los grados II y III del índice de Garrow (IMC ≥ 30 kg/m2) y el sobrepeso como el grado I (25 kg/m2 ≤ IMC < 30 kg/m2). Al no utilizarse una muestra aleatoria de sujetos, el cálculo de prevalencias y de sus errores estándar se corrigió mediante el uso de ponderaciones adecuadas. La comparación de las prevalencias entre dos ABS distintas para cada sexo se realizó utilizando un contraste paramétrico de diferencia de proporciones. La comparación entre las prevalencias de un determinado grado del índice de Garrow, controlando por sexo y edad, se llevó a cabo utilizando una regresión logística jerárquica.ResultadosLa prevalencia de la obesidad se estimó en 15,6% entre los varones de 20 a 74 años (desde el 14,0% en Girona 1 hasta el 22,4% en Camprodon) y en un 17,5% entre las mujeres (un 15,6% en Girona 1 y un 22,7% en Camprodon), un 16,7% de promedio ponderado. La prevalencia del sobrepeso se sitúa en el 44% en varones y en un 33% en mujeres, un 37,8% de promedio ponderado. Existe una gradación en las prevalencias de la obesidad, con diferencias estadísticamente significativas: Girona 1, Salt, Girona 4, Camprodon y Sils.ConclusionesLas estimaciones de la prevalencia de la obesidad y sobrepeso obtenidas en este trabajo no están tan alejadas como se creía de las estimadas en poblaciones de nuestro entorno. De hecho, podrían ser muy similares a las estimadas en la Unión Europea y, para algunos grupos de edad, incluso a las de Estados Unidos.AbstractObjectivesTo estimate the prevalence of obesity and overweight in the population of Girona (Spain) between 1995 and 1999 and to divide the prevalences in geographical areas according to age and sex.MethodsHeight and weight were directly measures in 24,554 health care consumers older than 14 years (10,595 men and 13,959 women) treated in four primary health care areas: Girona 1, Girona 4, Salt and Camprodon and in one primary health care center in the province of Girona. Body mas index (BMI) was calcuted by dividing weight in kilograms bye height in meters squared. Obesity was defined as grades II and III of Garrow's index (BMI ≥ 30 kg/m2) and overweight as degree I (25 kg/m2 ≥ BMI < 30 kg/m2). Because the sample was not randomized, the prevalences were adequately weighted. The comparison between prevalences in two different primary health care areas for each sex (in the same Garrow's index and age group) was carried out using a parametric test of differences in proportions (Student's t-test). A hierarchical logistic regression was used to compare prevalences in the same grade Garrow's index, controlling for age and sex.ResultsThe prevalence of obesity was estimated as 15.6% in men aged from 20-74 years (from 14.0% in Girona 1 to 22.4% in Camprodon) and 17.5% for women (15.6% in Girona 1, 22.7% in Camprodon). The weighted mean was 16.7%. The prevalence of overweight was 44% in men and 33% in women and the weighted mean was 37.8%. The prevalence of obesity was graduated with statistically significant differences between Girona 1, Salt, Girona 4, Camprodon and Sils.ConclusionsThe estimates of the prevalences of obesity and overweight obtained in this study were closer to those of other studies in similar populations than previously believed. Inde-ed, the prevalences may be similar to those of the European Union and, in some age groups, to those of the United States

A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes

Nitro-fatty acids (NO2-FA) are electrophilic lipid mediators derived from unsaturated fatty acid nitration. These species are produced endogenously by metabolic and inflammatory reactions and mediate anti-oxidative and anti-inflammatory responses. NO2-FA have been postulated as partial agonists of the Peroxisome Proliferator-Activated Receptor gamma (PPARγ), which is predominantly expressed in adipocytes and myeloid cells. Herein, we explored molecular and cellular events associated with PPARγ activation by NO2-FA in monocytes and macrophages. NO2-FA induced the expression of two PPARγ reporter genes, Fatty Acid Binding Protein 4 (FABP4) and the scavenger receptor CD36, at early stages of monocyte differentiation into macrophages. These responses were inhibited by the specific PPARγ inhibitor GW9662. Attenuated NO2-FA effects on PPARγ signaling were observed once cells were differentiated into macrophages, with a significant but lower FABP4 upregulation, and no induction of CD36. Using in vitro and in silico approaches, we demonstrated that NO2-FA bind to FABP4. Furthermore, the inhibition of monocyte FA binding by FABP4 diminished NO2-FA-induced upregulation of reporter genes that are transcriptionally regulated by PPARγ, Keap1/Nrf2 and HSF1, indicating that FABP4 inhibition mitigates NO2-FA signaling actions. Overall, our results affirm that NO2-FA activate PPARγ in monocytes and upregulate FABP4 expression, thus promoting a positive amplification loop for the downstream signaling actions of this mediator.Fil: Lamas Bervejillo, M.. Universidad de la República; UruguayFil: Bonanata, Julieta. Universidad de la República; UruguayFil: Franchini, Gisela Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Richeri, A.. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayFil: Marqués, J.M.. Universidad de la República; UruguayFil: Freeman, B.A.. University of Pittsburgh; Estados UnidosFil: Schopfer, Francisco Jose. University of Pittsburgh; Estados UnidosFil: Coitiño, E.L.. Universidad de la República; UruguayFil: Córsico, Betina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Rubbo, H.. Universidad de la República; UruguayFil: Ferreira, A.M.. Universidad de la República; Urugua

The three-dimensional randomly dilute Ising model: Monte Carlo results

We perform a high-statistics simulation of the three-dimensional randomly dilute Ising model on cubic lattices $L^3$ with $L\le 256$. We choose a particular value of the density, x=0.8, for which the leading scaling corrections are suppressed. We determine the critical exponents, obtaining $\nu = 0.683(3)$, $\eta = 0.035(2)$, $\beta = 0.3535(17)$, and $\alpha = -0.049(9)$, in agreement with previous numerical simulations. We also estimate numerically the fixed-point values of the four-point zero-momentum couplings that are used in field-theoretical fixed-dimension studies. Although these results somewhat differ from those obtained using perturbative field theory, the field-theoretical estimates of the critical exponents do not change significantly if the Monte Carlo result for the fixed point is used. Finally, we determine the six-point zero-momentum couplings, relevant for the small-magnetization expansion of the equation of state, and the invariant amplitude ratio $R^+_\xi$ that expresses the universality of the free-energy density per correlation volume. We find $R^+_\xi = 0.2885(15)$.Comment: 34 pages, 7 figs, few correction

Electromagnetic-field quantization and spontaneous decay in left-handed media

We present a quantization scheme for the electromagnetic field interacting with atomic systems in the presence of dispersing and absorbing magnetodielectric media, including left-handed material having negative real part of the refractive index. The theory is applied to the spontaneous decay of a two-level atom at the center of a spherical free-space cavity surrounded by magnetodielectric matter of overlapping band-gap zones. Results for both big and small cavities are presented, and the problem of local-field corrections within the real-cavity model is addressed.Comment: 15 pages, 5 figures, RevTe

Relationship between damage and mortality in juvenile-onset systemic lupus erythematosus: Cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry (RELESSER)

Objectives: To identify patterns (clusters) of damage manifestation within a large cohort of juvenile SLE (jSLE) patients and evaluate their possible association with mortality. Methods: This is a multicentre, descriptive, cross-sectional study of a cohort of 345 jSLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestation were identified and compared. Results: Mean age (years) ± S.D. at diagnosis was 14.2 ± 2.89; 88.7% were female and 93.4% were Caucasian. Mean SLICC/ACR DI ± S.D. was 1.27 ± 1.63. A total of 12 (3.5%) patients died. Three damage clusters were identified: Cluster 1 (72.7% of patients) presented a lower number of individuals with damage (22.3% vs. 100% in Clusters 2 and 3, P < 0.001); Cluster 2 (14.5% of patients) was characterized by renal damage in 60% of patients, significantly more than Clusters 1 and 3 (P < 0.001), in addition to increased more ocular, cardiovascular and gonadal damage; Cluster 3 (12.7%) was the only group with musculoskeletal damage (100%), significantly higher than in Clusters 1 and 2 (P < 0.001). The overall mortality rate in Cluster 2 was 2.2 times higher than that in Cluster 3 and 5 times higher than that in Cluster 1 (P < 0.017 for both comparisons). Conclusions: In a large cohort of jSLE patients, renal and musculoskeletal damage manifestations were the two dominant forms of damage by which patients were sorted into clinically meaningful clusters. We found two clusters of jSLE with important clinical damage that were associated with higher rates of mortality, especially for the cluster of patients with predominant renal damage. Physicians should be particularly vigilant to the early prevention of damage in this subset of jSLE patients with kidney involvement

Associated factors to serious infections in a large cohort of juvenile-onset systemic lupus erythematosus from Lupus Registry (RELESSER).

Objective: To assess the incidence of serious infection (SI) and associated factors in a large juvenile-onset systemic lupus erythematosus (jSLE) retrospective cohort. Methods: All patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet =4 ACR-97 SLE criteria and disease onset <18 years old (jSLE), were retrospectively investigated for SI (defined as either the need for hospitalization with antibacterial therapy for a potentially fatal infection or death caused by the infection). Standardized SI rate was calculated per 100 patient years. Patients with and without SI were compared. Bivariate and multivariate logistic and Cox regression models were built to calculate associated factors to SI and relative risks. Results: A total of 353 jSLE patients were included: 88.7% female, 14.3 years (± 2.9) of age at diagnosis, 16.0 years (± 9.3) of disease duration and 31.5 years (±10.5) at end of follow-up. A total of 104 (29.5%) patients suffered 205 SI (1, 55.8%; 2-5, 38.4%; and =6, 5.8%). Incidence rate was 3.7 (95%CI: 3.2–4.2) SI per 100 patient years. Respiratory location and bacterial infections were the most frequent. Higher number of SLE classification criteria, SLICC/ACR DI score and immunosuppressants use were associated to the presence of SI. Associated factors to shorter time to first infection were higher number of SLE criteria, splenectomy and immunosuppressants use. Conclusions: The risk of SI in jSLE patients is significant and higher than aSLE. It is associated to higher number of SLE criteria, damage accrual, some immunosuppressants and splenectomy