High prevalence of asthma symptoms in Warao Amerindian children in Venezuela is significantly associated with open-fire cooking: a cross-sectional observational study

Background

The International Study on Asthma and Allergies in Childhood (ISAAC) reported a prevalence of asthma symptoms in 17 centers in nine Latin American countries that was similar to prevalence rates reported in non-tropical countries. It has been proposed that the continuous exposure to infectious diseases in rural populations residing in tropical areas leads to a relatively low prevalence of asthma symptoms. As almost a quarter of Latin American people live in rural tropical areas, the encountered high prevalence of asthma symptoms is remarkable. Wood smoke exposure and environmental tobacco smoke have been identified as possible risk factors for having asthma symptoms.

Methods

We performed a cross-sectional observational study from June 1, 2012 to September 30, 2012 in which we interviewed parents and guardians of Warao Amerindian children from Venezuela. Asthma symptoms were defined according to the ISAAC definition as self-reported wheezing in the last 12 months. The associations between wood smoke exposure and environmental tobacco smoke and the prevalence of asthma symptoms were calculated by means of univariate and multivariable logistic regression analyses.

Results

We included 630 children between two and ten years of age. Asthma symptoms were recorded in 164 of these children (26%). The prevalence of asthma symptoms was associated with the cooking method. Children exposed to the smoke produced by cooking on open wood fires were at higher risk of having asthma symptoms compared to children exposed to cooking with gas (AOR 2.12, 95% CI 1.18 - 3.84). Four percent of the children lived in a household where more than ten cigarettes were smoked per day and they had a higher risk of having asthma symptoms compared to children who were not exposed to cigarette smoke (AOR 2.69, 95% CI 1.11 - 6.48).

Conclusion

Our findings suggest that children living in rural settings in a household where wood is used for cooking or where more than ten cigarettes are smoked daily have a higher risk of having asthma symptoms.     

Findings from the Peutz-Jeghers Syndrome Registry of Uruguay

Background

Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients.

Methods

Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed.

Results and discussion

25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000.

Conclusion

The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation.     

Improved BM212 MmpL3 Inhibitor Analogue Shows Efficacy in Acute Murine Model of Tuberculosis Infection

1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED₉₉ of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery.     

Integrating ecological and genetic structure to define management units for caribou in Eastern Canada

Genetic diversity is a key parameter to delineate management units, but many organisms also display ecological characteristics that may reflect potential local adaptations. Here, we used ecological and genetic information to delineate management units for a complex system involving several ecotypes of caribou (Rangifer tarandus) from Québec and Labrador, eastern Canada. We genotyped 560 caribou at 16 microsatellite loci and used three Bayesian clustering methods to spatially delineate and characterize genetic structure across the landscape. The different approaches employed did not converge on the same solution, and differed in the number of inferred genetic clusters that best fit the dataset but also in the spatial distribution of genetic variation. We reconciled variability among the methods using a synthetic approach that considers the sum of the partitions obtained by each of them and retrieved six genetically distinct groups that differ in their spatial extent across the range of caribou in the study area. These genetic groups are not consistent with the presently defined ecological designations for this species. Combining both genetic and ecological criteria, we distinguished eight independent management units. Overall, the management units we propose should be the focus of conservation and management actions aimed to maximize genetic and ecological diversity and ensure the persistence of caribou populations inhabiting increasingly disturbed landscapes.     

Risk of Advanced Neoplasia in First-Degree Relatives with Colorectal Cancer: A Large Multicenter Cross-Sectional Study

BackgroundFirst-degree relatives (FDR) of patients with colorectal cancer have a higher risk of developing colorectal cancer than the general population. For this reason, screening guidelines recommend colonoscopy every 5 or 10 y, starting at the age of 40, depending on whether colorectal cancer in the index-case is diagnosed at <60 or ≥60 y, respectively. However, studies on the risk of neoplastic lesions are inconclusive. The aim of this study was to determine the risk of advanced neoplasia (three or more non-advanced adenomas, advanced adenoma, or invasive cancer) in FDR of patients with colorectal cancer compared to average-risk individuals (i.e., asymptomatic adults 50 to 69 y of age with no family history of colorectal cancer).ConclusionsIndividuals having two FDR with colorectal cancer showed an increased risk of advanced neoplasia compared to those with average-risk for colorectal cancer. Men had over 2-fold higher risk of advanced neoplasia than women, independent of family history. These data suggest that screening colonoscopy guidelines should be revised in the familial-risk population.     

Impact of Obstructive Sleep Apnea on the Levels of Placental Growth Factor (PlGF) and Their Value for Predicting Short-Term Adverse Outcomes in Patients with Acute Coronary Syndrome

Background

Placental growth factor (PlGF) induces angiogenesis and promotes tissue repair, and plasma PlGF levels change markedly during acute myocardial infarction (AMI). Currently, the impact of obstructive sleep apnea (OSA) in patients with AMI is a subject of debate. Our objective was to evaluate the relationships between PlGF levels and both the severity of acute coronary syndrome (ACS) and short-term outcomes after ACS in patients with and without OSA.

Methods

A total of 538 consecutive patients (312 OSA patients and 226 controls) admitted for ACS were included in this study. All patients underwent polygraphy in the first 72 hours after hospital admission. The severity of disease and short-term prognoses were evaluated during the hospitalization period. Plasma PlGF levels were measured using an electrochemiluminescence immunoassay.

Results

Patients with OSA were significantly older and more frequently hypertensive and had higher BMIs than those without OSA. After adjusting for age, smoking status, BMI and hypertension, PlGF levels were significantly elevated in patients with OSA compared with patients without OSA (19.9 pg/mL, interquartile range: 16.6–24.5 pg/mL; 18.5 pg/mL, interquartile range: 14.7–22.7 pg/mL; p<0.001), and a higher apnea-hypopnea index (AHI) was associated with higher PlGF concentrations (p<0.003). Patients with higher levels of PlGF had also an increased odds ratio for the presence of 3 or more diseased vessels and for a Killip score>1, even after adjustment.

Conclusions

The results of this study show that in patients with ACS, elevated plasma levels of PlGF are associated with the presence of OSA and with adverse outcomes during short-term follow-up.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01335087","term_id":"NCT01335087"}}NCT01335087     

Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways

A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells.     

Determination of protein markers in human serum: Analysis of protein expression in toxic oil syndrome studies

Toxic oil syndrome (TOS) is a disease that appeared in Spain in 1981. It affected more than 20 000 people and produced over 300 deaths in the first 2 years. In this paper, a prospective study on the differences in gene expression in sera between a control versus a TOS-affected population, both originally exposed to the toxic oil, is presented. Differential protein expression was analyzed by two-dimensional electrophoresis (2-DE). Several problems related with serum analysis by 2-DE were addressed in order to improve protein detection in the gel images. Three new commercial systems for albumin depletion were tested to optimize the detection of minor proteins that can be obscured by the presence of a few families of high abundance proteins (albumin, immunoglobulins). Other factors, such as the use of nonionic reductants or the presence of thiourea in the gels, were also tested. From these optimized images, a group of 329 major gel spots was located, matched and compared in serum samples. Thirty-five of these protein spots were found to be under- or overexpressed in TOS patients (> three-fold increase or decrease). Proteins in the differential spots were identified by matrix-assisted laser desorption/ionization-time of flight peptide map fingerprinting and database search. Several haptoglobin isoforms were found to be differentially expressed, showing expression phenotypes that could be related with TOS affection. Haptoglobin phenotypes have been previously reported to have important biological and clinical consequences and have been described as risk factors for several diseases.     

Identification of the autoantigen HB as the barrier-to-autointegration factor

The HB autoantigen, a 10-kDa DNA-binding protein recognized by autoantibodies only when bound to DNA, was identified by two-dimensional electrophoresis. Silver-stained protein spots corresponding to the antigen were excised from two-dimensional electrophoresis gels, digested with trypsin, and analyzed by matrix-assisted laser desorption/ionization-reflectron time of flight and nano-electrospray ionization-ion trap/mass spectrometry. Data base search identified the HB antigen as the barrier-to-autointegration factor, a cellular protein implicated in the cellular cycle that blocks autointegration and promotes intermolecular integration of retrovirus such as the Moloney murine leukemia and the human immunodeficiency type 1 virus. The physicochemical characteristics described for these proteins, their ability to bind double-stranded DNA but not single-stranded DNA, and their nuclear localization confirm that HB and barrier-to-autointegration factor are the same protein.     

M142.2 (cut-6), a novel Caenorhabditis elegans matrix gene important for dauer body shape

The cuticle of the nematode Caenorhabditis elegans is a collagenous extracellular matrix which forms the exoskeleton and defines the shape of the worm. We have characterized the C. elegans gene M142.2, and we show that this is a developmentally regulated gene important for cuticle structure. Transgenic worms expressing M142.2 promoter fused to green fluorescent protein showed that M142.2 is expressed in late embryos and L2d predauers, in the hypodermal cells which synthesize the cuticle. The same temporal pattern was seen by RT-PCR using RNA purified from specific developmental stages. A recombinant fragment of M142.2 was expressed in Escherichia coli and used to raise an antiserum. Immunohistochemistry using the antiserum localized M142.2 to the periphery of the alae of L1 and dauers, forming two longitudinal ribbons over the hypodermal cells. Loss-of-function of M142.2 by RNAi resulted in a novel phenotype: dumpy dauers which lacked alae. M142.2 therefore plays a major role in the assembly of the alae and the morphology of the dauer cuticle; because of its similarity to the other cut genes of the cuticle, we have named the gene cut-6.