IFIH1-GCA-KCNH7 locus: influence on multiple sclerosis risk

A recent genome-wide scan of nonsynonymous SNPs and ulterior validation in case-control and family analyses evidenced a susceptibility locus for type 1 diabetes (T1D) on chromosome 2q24.3. We aimed at testing the effect of this locus in other autoimmune diseases with complex genetic background, such as multiple sclerosis (MS). Four SNPs along the locus, rs13422767, rs2111485, rs1990760 and rs2068330, were genotyped using TaqMan MGB chemistry in 311 T1D and 412 MS patients and 535 ethnically matched healthy controls. The previously reported association of this locus was found for the first time in MS (rs2068330, G vs C: P=0.001; OR (95% CI)=0.73 (0.6-0.88)) and a trend for replication was observed in our Spanish diabetic cohort. Therefore, genes included in this locus - IFIH1 interferon induced helicase, GCA grancalcin or the potassium channel KCNH7 - are potential candidates implicated in the pathogenesis of these autoimmune diseases, although strong linkage disequilibrium in the region hampered further localization of the etiologic gene.     

Differential uptake and processing of a Haemophilus influenzae P5-derived immunogen by chinchilla dendritic cells

Dendritic cells (DCs) are potent antigen-presenting cells involved in the initiation and modulation of immune responses after immunization via their ability to process and present antigen to naive T cells. We wanted to examine the role of DCs in the development of protective immunity against nontypeable Haemophilus influenzae (NTHI)-induced experimental otitis media (OM) after intranasal immunization of chinchillas with an NTHI P5-derived synthetic peptide immunogen called LB1. As chinchilla DCs have not been described, we adapted well-established protocols to induce the differentiation of chinchilla bone marrow precursor cells into DCs, which resulted in cells that were morphologically and phenotypically similar to DCs of other species. In vitro, chinchilla DCs readily internalized LB1, upregulated expression of the maturation markers CD80 and major histocompatibility complex class II, and presented processed LB1 to primed CD3+ T cells, which resulted in antigen-specific T-cell proliferation. In vivo, LB1-activated DCs trafficked from the chinchilla nasal cavity primarily to the nasal-associated lymphoid tissues and were detected in close proximity to CD3+ T cells within this lymphoid aggregate. These data are the first to characterize chinchilla DCs and their functional properties. Furthermore, they suggest an important role for chinchilla DCs in the development of protective immunity against experimental NTHI-induced OM after intranasal immunization.     

Cervical intraepithelial neoplasia grade 2 or worse in Galicia,Spain: HPV 16 prevalence and vaccination impact

Introduction

The etiology of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) can influence the efficacy of Public Health preventive strategies. This study aimed to determine the high-risk papillomavirus (HR-HPV) prevalence in CIN2+ cases in unvaccinated women in Galicia (Spain), the expected impact of bivalent vaccination, and the distribution of HPV 16 in squamous lesions.

Material and methods

Ninety-four histologically confirmed cases of CIN2+ (2009–2010) were retrospectively studied: 23 CIN2, 58 CIN3− squamous carcinoma in situ (CIN3-CIS), 5 adenocarcinoma in situ (AIS), and 8 invasive squamous cervical cancer (SCC). Linear Array HPV Genotyping Test (Roche Diagnostics, Mannheim, Germany) was performed on the cervical specimens. Bivalent vaccination impact was calculated, based on regional vaccination coverage data, local HR-HPV prevalence, and reported efficacy (direct and cross-protection) of the vaccine.

Results

HR-HPV prevalence was 96.8%. The most frequent genotypes were HPV 16 (48.8–58.2%) and HPV 31 (9.3%–12.1%), considering single infections or single-multiple infections, respectively (hierarchical attribution). In squamous lesions, HPV 16 prevalence in women younger than 45 years of age increased in severe lesions (CIN3-CIS/SCC, OR 4.2), and was higher than in older women (OR 5.5). The vaccine could reduce the cumulative incidence of CIN2+ by 50.6% (direct protection), or by 62.7% (direct and cross-protection).

Conclusion

HPV vaccination could have a great impact in women younger than 45 years of age due to the high prevalence of HPV 16 in their lesions.     

Peptide-surface modification of poly(caprolactone) with laminin-derived sequences for adipose-derived stem cell applications

Human adipose tissue has been recognized as a source of adult stem cells for tissue engineering applications such as bone, cartilage, and soft tissue repair. For the success of these tissue-engineering approaches, a cell delivery vehicle such as a hydrogel or scaffold is required to position the stem cells at the site of need. Surface modification techniques have been instrumental in the development of scaffolds that promote cell-surface interactions. In this study, poly(caprolactone) (PCL), surfaces were modified in order to promote the attachment and proliferation of adipose-derived stem cells (ASCs). RGD, YIGSR, and IKVAV peptide sequences derived from the extracellular matrix protein laminin were each covalently attached to an aminated polymer surface using carbodiimide chemistry. The surface was characterized using scanning electron microscopy (SEM), goniometry and X-ray photoelectron spectroscopy (XPS). The attachment and proliferation of ASCs was assessed on the different peptide-treated surfaces. XPS analysis confirmed the presence of the peptide sequences on the surface of the polymer as indicated by the increase in the nitrogen/carbon ratio on the surface of the polymer. Among all peptide sequences tested, IKVAV-treated surfaces had a significantly greater number of ASCs bound 2 and 3 days after cell seeding. SEM confirmed differences in the morphology of the cells attached to the three peptide-treated surfaces. These results indicate that IKVAV is a suitable peptide sequence for use in surface modification techniques aimed at improving the attachment of ASCs to a tissue-engineered scaffold.     

Association of cardiac implantable electronic devices with survival in bifascicular block and prolonged PR interval on electrocardiogram

Purpose

Bifascicular block and prolonged PR interval on the electrocardiogram (ECG) have been associated with complete heart block and sudden cardiac death. We sought to determine if cardiac implantable electronic devices (CIED) improve survival in these patients.

Methods

We assessed survival in relation to CIED status among 636 consecutive patients with bifascicular block and prolonged PR interval on the ECG. In survival analyses, CIED was considered as a time-varying covariate.

Results

Average age was 76?±?9 years, and 99% of the patients were men. A total of 167 (26%) underwent CIED (127 pacemaker only) implantation at baseline (n?=?23) or during follow-up (n?=?144). During 5.4?±?3.8 years of follow-up, 83 (13%) patients developed complete or high-degree atrioventricular block and 375 (59%) died. Patients with a CIED had a longer survival compared to those without a CIED in the traditional, static analysis (log-rank p?<?0.0001) but not when CIED was considered as a time-varying covariate (log-rank p?=?0.76). In the multivariable model, patients with a CIED had a 34% lower risk of death (hazard ratio 0.66, 95% confidence interval 0.52–0.83; p?=?0.001) than those without CIED in the traditional analysis but not in the time-varying covariate analysis (hazard ratio 1.05, 95% confidence interval 0.79–1.38; p?=?0.76). Results did not change in the subgroup with a pacemaker only.

Conclusions

Bifascicular block and prolonged PR interval on ECG are associated with a high incidence of complete atrioventricular block and mortality. However, CIED implantation does not have a significant influence on survival when time-varying nature of CIED implantation is considered.

     

Hypersensitivity to black locust (Robinia pseudoacacia) pollen: "allergy mirages".

BACKGROUND: The allergenicity of the ornamental tree Robinia pseudoacacia, or black locust, is unknown. OBJECTIVE: To evaluate the prevalence of sensitization to R. pseudoacacia pollen, its possible allergenic cross-reactivity with other common pollens, and the potential implication of pollen panallergens (profilin, polcalcin, and 1,3-beta-glucanase) as a cause of sensitization to R. pseudoacacia pollen. METHODS: Skin prick testing with R. pseudoacacia pollen was performed in 149 patients with pollinosis. Nasal challenge with R. pseudoacacia pollen was performed in 10 patients. The prevalence of sensitization to the recombinant forms of profilin (rChe a 2), polcalcin (rChe a 3), and the N-terminal of the 1,3-beta-glucanase (rNtD of Ole e 9) was investigated. Immunoblotting, enzyme-linked immunosorbent assay, and competitive inhibition assays were performed with R. pseudoacacia pollen and recombinant pollen allergens. RESULTS: Sixty-four patients (43%) had positive skin prick test reactions to R. pseudoacacia pollen. Nasal challenge results were positive in 5 sensitized patients and negative in 4 controls and 1 sensitized patient. The allergenic profile of R. pseudoacacia pollen comprises at least the panallergen profilin, a calcium-binding protein, and a 1,3-beta-glucanase. The prevalence of sensitization to rChe a 2, rChe a 3, and rNtD of Ole e 9 was 60%, 33%, and 87%, respectively, among patients sensitized to R. pseudoacacia pollen. Binding of IgE to R. pseudoacacia extract was completely inhibited by Robinia, Chenopodium, Olea, Cupressus, and Lolium extracts. CONCLUSIONS: The high prevalence of R. pseudoacacia pollen sensitization in patients with pollinosis is likely to be due to cross-sensitization to panallergens (profilin, polcalcin, and 1,3-beta-glucanase) from other common pollens. This phenomenon may lead to a diagnosis of "allergy mirages."     

Topography of EEG complexity in human neonates: effect of the postmenstrual age and the sleep state

The topography of the EEG of human neonates is studied in terms of its power spectral density and its estimated complexity as a function of both the postmenstrual age (PMA) and the sleep state. The monopolar EEGs of three groups of seven neonates (preterm, term and older term) were recorded during active (AS) and quiet sleep (QS) from electrodes Fp1, Fp2, T3, T4, C3, C4, O1 and O2. The existence of changes between groups and sleep states in the power of delta, theta, alpha and beta bands and in the dimensional complexity of these electrodes was tested. Additionally, the nonlinearity of the EEG in each electrode and situation was analyzed. The results of the spectral measures show an increment of the power in the low frequency bands from AS to QS and with the PMA, which can be mainly traced on central and temporal electrodes. This change is shown as well by the dimensional complexity, which also presents the greatest differences in the central derivations. Moreover, the signals show evidence of nonlinearity in almost all the groups and situations, although a dynamic change from nonlinear to linear character is apparent in the central electrodes with increased PMA. As a result, it is concluded that nonlinear analysis methods provide a clear portrait of the integrated brain activity that complements the information of spectral analysis in the characterization of the brain development and the sleep states in neonates.     

Documento de consenso sobre el fenotipo mixto EPOC-asma en la EPOC

Introduction

Although asthma and COPD are different pathologies, many patients share characteristics from both entities. These cases can have different evolutions and responses to treatment. Nevertheless, the evidence available is limited, and it is necessary to evaluate whether they represent a differential phenotype and provide recommendations about diagnosis and treatment, in addition to identifying possible gaps in our understanding of asthma and COPD.

Methods

A nation-wide consensus of experts in COPD in two stages: 1) during an initial meeting, the topics to be dealt with were established and a first draft of statements was elaborated with a structured «brainstorming» method; 2) consensus was reached with two rounds of e-mails, using a Likert-type scale.

Results

Consensus was reached about the existence of a differential clinical phenotype known as «Overlap Phenotype COPD-Asthma», whose diagnosis is made when 2 major criteria and 2 minor criteria are met. The major criteria include very positive bronchodilator test (increase in FEV₁ ≥ 15% and ≥ 400 ml), eosinophilia in sputum and personal history of asthma. Minor criteria include high total IgE, personal history of atopy and positive bronchodilator test (increase in FEV₁ ≥ 12% and ≥ 200 ml) on two or more occasions. The early use of individually-adjusted inhaled corticosteroids is recommended, and caution must be taken with their abrupt withdrawal. Meanwhile, in severe cases the use of triple therapy should be evaluated. Finally, there is an obvious lack of specific studies about the natural history and the treatment of these patients.

Conclusions

It is necessary to expand our knowledge about this phenotype in order to establish adequate guidelines and recommendations for its diagnosis and treatment.     

Assessing the validity of an ELISA test for the serological diagnosis of human fascioliasis in different epidemiological situations

Objectives To improve the diagnosis of human fascioliasis caused by Fasciola hepatica and Fasciola gigantica, we evaluated the diagnostic accuracy of an enzyme‐linked immunosorbent assay (ELISA), with Fasciola antigen from the adult liver fluke, for the detection of IgG against fascioliasis in human sera. Methods The sera of 54 fascioliasis cases, originating from three endemic areas, were used in this evaluation: (i) a hyperendemic F. hepatica area where humans usually shed a great number of parasite eggs in faeces (11 sera); (ii) an epidemic F. hepatica area where humans usually shed small amounts of parasite eggs (24 sera) and (iii) an overlap area of both Fasciola species and where human shedding of parasite eggs in faeces is usually scarce or non‐existent (19 sera). One hundred and sixty‐eight patients with other parasitic infections and 89 healthy controls were also analysed. Results The respective sensitivity and specificity of this assay were 95.3% (95% confidence intervals, 82.9–99.2%) and 95.7% (95% confidence intervals, 92.3–97.5%). No correlation between egg output and the OD450 values of the F. hepatica IgG ELISA test was observed. Conclusions This test could be used both as an individual serodiagnostic test for human fascioliasis when backed up by a compatible clinical history together with a second diagnostic technique for other cross‐reactive helminth infections, and in large‐scale epidemiological studies of human fascioliasis worldwide.