Hsp27 negatively regulates cell death by interacting with cytochrome c.

Mammalian cells respond to stress by accumulating or activating a set of highly conserved proteins known as heat-shock proteins (HSPs). Several of these proteins interfere negatively with apoptosis. We show that the small HSP known as Hsp27 inhibits cytochrome-c-mediated activation of caspases in the cytosol. Hsp27 does not interfere with granzyme-B-induced activation of caspases, nor with apoptosis-inducing factor-mediated, caspase-independent, nuclear changes. Hsp27 binds to cytochrome c released from the mitochondria to the cytosol and prevents cytochrome-c-mediated interaction of Apaf-1 with procaspase-9. Thus, Hsp27 interferes specifically with the mitochondrial pathway of caspase-dependent cell death.

Pulmonary and thoracic infection by Fusobacterium nucleatum. / Infección pulmonar y torácica por Fusobacterium nucleatum.

INTRODUCTION: Fusobacterium nucleatum is an anaerobic bacillus that is part of the oral microbiota and dental pla que. This can cause local and potentially remote infections, which are exceptional in pediatrics. Ob jective: To present the case of a patient with lung injury with chest wall invasion by Fusobacterium nucleatum. CLINICAL CASE: An 11-year-old female immunocompetent patient who consulted due to a two-week history of cough, night sweats, without fever or weight loss, and increased volume at the left spleen thoracic level. There was no history of chest wall trauma or travel outside the country. Two weeks before the onset of symptoms, she was treated for dental caries. Imaging studies and CT scan showed left spleen pneumonia, which invades the pleura and the chest wall. A minimal thoracotomy was performed, releasing a thick, foul-smelling liquid. The studies for common germs and tubercu losis were negative. Hematology ruled out tumor lesions. The anaerobic study reported the develo pment of Fusobacterium nucleatum. The patient was treated with penicillin followed by amoxicillin presenting good clinical and radiological responses. The dental procedure was suspected as the cause of infection. CONCLUSIONS: Fusobacterium nucleatum can occasionally cause remote or extra-oral in fections in immunocompetent patients, such as pneumonia with chest wall invasion, therefore it is necessary to bear it in mind.

Small stress protein Hsp27 accumulation during dopamine-mediated differentiation of rat olfactory neurons counteracts apoptosis.

The small stress protein Hsp27 is expressed during mammalian neural development. We have analyzed the role of this protein in immortalized rat olfactory neuroblasts. In the presence of dopamine a fraction of these cells differentiate into neurons while the remaining cells undergo apoptosis. We report here that the dopamine induced differentiation and apoptosis are associated with a transient and specific accumulation of Hsp27. Moreover, transfection experiments have shown that Hsp27 overexpression drastically decreases the fraction of cells undergoing apoptosis. In contrast, reduction of the endogenous level of Hsp27 led to abortion of differentiation and, therefore, drastically increased the number of apoptotic cells. Furthermore, in the normal cell population we show that Hsp27 accumulation takes place only in differentiating cells that were not undergoing apoptosis. We therefore conclude that Hsp27 may represent a key protein that controls the decision of olfactory precursor cells to undergo either differentiation or cell death.

Enfermedad neumocócica invasiva por serotipo 38, reporte de caso clínico / Invasive pneumococcal disease by serotype 38, a clinical case report

La enfermedad neumocócica invasiva (ENI) es causa de morbimortalidad prevenible en pediatría. Con la introducción de vacunas antineumocócicas conjugadas disminuyó la prevalencia de ENI en 61,9% en los menores de 2 años, y se produjo un cambio en la distribución de serotipos y un aumento de ENI por serotipos no vaccinales. En este contexto, es relevante la vigilancia epidemiológica de los serotipos emergentes causantes de ENI en la población. Se presentará el caso de una lactante de 11 meses con diagnóstico de meningitis causada por neumococo serotipo 38, su evolución y consecuencias clínicas, y se realiza un análisis de la situación epidemiológica actual.

In pediatrics,invasive pneumococcal disease is a preventable cause ofmorbidity andmortality.The introduction of conjugated pneumococcal vaccines has reduced the prevalence of invasive pneumococcal disease by 61.9% in the under two's and has brought about a change in the distribution of serotypes and a rise in invasive pneumococcal disease caused by non-vaccine serotypes.This being the case,itis very importanttomonitorthe epidemiology ofthe emerging serotypes causing the disease in the population.We presentthe case of an 11 month old infant diagnosed with meningitis caused by serotype 38, describing his clinical course andclinical consequences; andweperforman analysis ofthepresent epidemiologica lsituation

Assessment of dietary exposure to annatto (E160b), nitrites (E249-250), sulphites (E220-228) and tartaric acid (E334) in the French population: the second French total diet study.

The results of the assessment of the dietary exposure to annatto, nitrites, tartaric acid and sulphites within the framework of the second French total diet study (TDS) are reported. These 4 additives were selected from the Bemrah et al. study [Bemrah N, Leblanc JC, Volatier JL. 2008. Assessment of dietary exposure in the French population to 13 selected food colours, preservatives, antioxidants, stabilizers, emulsifiers and sweeteners. Food Addit Contam B. 1(1):2-14] on 13 food additives which identified a possible health risk for annatto, sulphites and nitrites and a lack of data for tartaric acid. Among the composite samples selected for the whole TDS, 524 were analysed for additives (a sample was analysed for a given additive when it was identified as a major contributor for this additive only): 130 for tartaric acid, 135 for nitrites, 59 for annatto and 200 for sulphites. Estimated concentrations (minimum lower bound to maximum upper bound) vary nationally from 0 to 9 mg/kg for annatto, 0 to 420 mg/kg for tartaric acid, 0 to 108 mg/kg for sulphites and 0 to 3.4 mg/kg for nitrites. Based on the analytical results, the dietary exposure was calculated for adults and children, separately, using lower bound and upper bound assumptions. The European ADIs for these 4 additives were not exceeded except for the dietary exposure for sulphites among 2.9% of the adult population, where the major contributors were alcoholic drinks and especially wine under both hypotheses (lower and upper bound).

Activated factor X cleaves factor VIII at arginine 562, limiting its cofactor efficiency.

BACKGROUND: Factor VIII (FVIII) and its activated form (FVIIIa) are subject to proteolysis that dampens their cofactor function. Among the proteases that attack FVIII (activated factor X (FXa), activated protein C (APC) and plasmin), only APC cleaves within the FVIII A2 domain at R562 to fully abolish FVIII activity. OBJECTIVES: We investigated the possible involvement of the FXa cleavage at R562 within the A2 domain in the process of FVIII inactivation. METHODS: An antibody (GMA012/R8B12) that recognizes the carboxy-terminus extremity of the A2 domain (A2C) was used to evaluate FXa action. A molecule mutated at R562 was also generated to assess the functional role of this particular residue. RESULTS AND CONCLUSIONS: The appearance of the A2C domain as a function of time evidenced the identical cleavage within the A2 domain of FVIII and FVIIIa by FXa. This cleavage required phospholipids and occurred within minutes. In contrast, the isolated A2 domain was not cleaved by FXa. Von Willebrand factor and activated FIX inhibited the cleavage in a dose-dependent manner. Mutation R562K increased both the FVIII specific activity and the generation of FXa due to an increase in FVIII catalytic efficiency. Moreover, A2C fragment could not be identified from FVIII-R562K cleavage. In summary, this study defines a new mechanism for A2 domain-mediated FVIII degradation by FXa and implicates the bisecting of the A2 domain at R562.

Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation.

The small heat shock proteins (sHsps) from human (Hsp27) and mouse (Hsp25) form large oligomers which can act as molecular chaperones in vitro and protect cells from heat shock and oxidative stress when overexpressed. In addition, mammalian sHsps are rapidly phosphorylated by MAPKAP kinase 2/3 at two or three serine residues in response to various extracellular stresses. Here we analyze the effect of sHsp phosphorylation on its quaternary structure, chaperone function, and protection against oxidative stress. We show that in vitro phosphorylation of recombinant sHsp as well as molecular mimicry of Hsp27 phosphorylation lead to a significant decrease of the oligomeric size. We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. In parallel, Hsp27 and its mutants were analyzed for their ability to confer resistance against oxidative stress when overexpressed in L929 and 13.S.1.24 cells. While wild type Hsp27 confers resistance, the triple mutant S15D,S78D,S82D cannot protect against oxidative stress effectively. These data indicate that large oligomers of sHsps are necessary for chaperone action and resistance against oxidative stress whereas phosphorylation down-regulates these activities by dissociation of sHsp complexes to tetramers.

Factores de riesgo para carcinoma basocelular. Estudio de casos-controles en Córdoba / Risk factors for basal cell carcinoma. Case-control study in Cordoba

El carcinoma basocelular es una enfermedad compleja. Su etiología es todavía poco clara y a pesar de su frecuencia hay pocos datos sobre factores de riesgo. Nosotros evaluamos factores de riesgo potenciales para carcinoma basocelular en una población de Córdoba (Argentina). Este estudio de casos y controles incluyó a 88 casos nuevos de carcinoma basocelular, y 88 controles pareados por sexo y edad. Los siguientes factores de riesgo fueron significativos en el análisis multivariado: fototipos I, II y III, exposición solar recreativa alta después de los 20 años de edad, exposición solar alta en vacaciones en la playa y la presencia de queratosis actínicas.

Basal cell carcinoma is undoubtedly a complex disease. Its etiology is still unclear and despite its frequency, there is a paucity of data on its risk factors. We assessed potential risk factors for basal cell carcinoma in a population from Córdoba (Argentina). This case-control study involved 88 newly diagnosed cases and 88 controls, matched by age and sex. The following risk factors were significant in the multivariate analysis: skin type I-II-III, high recreational sun exposure after 20 years of age, high sun exposure for beach holidays and actinic keratosis.