Acquired heart block: A possible complication of patent ductus arteriosus in a preterm infant

A large patent ductus arteriosus (PDA) is a frequently encountered clinical problem in extremely low birth weight (ELBW) infants. It leads to an increased pulmonary blood flow and in a decreased or reversed diastolic flow in the systemic circulation, resulting in complications. Here we report a possible complication of PDA not previously published. On day 8 of life, a male ELBW infant (birth weight 650 g) born at a gestational age of 23 weeks and 3 days developed an atrioventricular block (AV block). The heart rate dropped from 168/min to 90/min, and the ECG showed a Wenckebach second-degree AV block and intraventricular conduction disturbances. Echocardiography demonstrated a PDA with a large left-to-right shunt and large left atrium and left ventricle with high contractility. Within several minutes after surgical closure of the PDA, the heart rate increased, and after 30 min the AV block had improved to a 1: 1 conduction ratio. Echocardiography after 2 h revealed a significant decrease of the left ventricular and atrial dimensions. Within 12 h, the AV block completely reversed together with the intraventricular conduction disturbances. We suggest that PDA with a large left-to-right shunt and left ventricular volume overload may lead to an AV block in an ELBW infant. Surgical closure of the PDA may be indicated. Copyright (C) 2007 S. Karger AG, Basel

Addressing social issues in a universal HIV test and treat intervention trial (ANRS 12249 TasP) in South Africa: methods for appraisal

Background: The Universal HIV Test and Treat (UTT) strategy represents a challenge for science, but is also a challenge for individuals and societies. Are repeated offers of provider-initiated HIV testing and immediate antiretroviral therapy (ART) socially-acceptable and can these become normalized over time? Can UTT be implemented without potentially adding to individual and community stigma, or threatening individual rights? What are the social, cultural and economic implications of UTT for households and communities? And can UTT be implemented within capacity constraints and other threats to the overall provision of HIV services? The answers to these research questions will be critical for routine implementation of UTT strategies. Methods/design: A social science research programme is nested within the ANRS 12249 Treatment-as-Prevention (TasP) cluster-randomised trial in rural South Africa. The programme aims to inform understanding of the (i) social, economic and environmental factors affecting uptake of services at each step of the continuum of HIV prevention, treatment and care and (ii) the causal impacts of the TasP intervention package on social and economic factors at the individual, household, community and health system level. We describe a multidisciplinary, multi-level, mixed-method research protocol that includes individual, household, community and clinic surveys, and combines quantitative and qualitative methods. Discussion: The UTT strategy is changing the overall approach to HIV prevention, treatment and care, and substantial social consequences may be anticipated, such as changes in social representations of HIV transmission, prevention, HIV testing and ART use, as well as changes in individual perceptions and behaviours in terms of uptake and frequency of HIV testing and ART initiation at high CD4. Triangulation of social science studies within the ANRS 12249 TasP trial will provide comprehensive insights into the acceptability and feasibility of the TasP intervention package at individual, community, patient and health system level, to complement the trial's clinical and epidemiological outcomes. It will also increase understanding of the causal impacts of UTT on social and economic outcomes, which will be critical for the long-term sustainability and routine UTT implementation. Trial registration: Clinicaltrials.gov: NCT01509508; South African Trial Register: DOH-27-0512-3974

A Comparative Survey of the Frequency and Distribution of Polymorphism in the Genome of Xenopus tropicalis

Naturally occurring DNA sequence variation within a species underlies evolutionary adaptation and can give rise to phenotypic changes that provide novel insight into biological questions. This variation exists in laboratory populations just as in wild populations and, in addition to being a source of useful alleles for genetic studies, can impact efforts to identify induced mutations in sequence-based genetic screens. The Western clawed frog Xenopus tropicalis (X. tropicalis) has been adopted as a model system for studying the genetic control of embryonic development and a variety of other areas of research. Its diploid genome has been extensively sequenced and efforts are underway to isolate mutants by phenotype- and genotype-based approaches. Here, we describe a study of genetic polymorphism in laboratory strains of X. tropicalis. Polymorphism was detected in the coding and non-coding regions of developmental genes distributed widely across the genome. Laboratory strains exhibit unexpectedly high frequencies of genetic polymorphism, with alleles carrying a variety of synonymous and non-synonymous codon substitutions and nucleotide insertions/deletions. Inter-strain comparisons of polymorphism uncover a high proportion of shared alleles between Nigerian and Ivory Coast strains, in spite of their distinct geographical origins. These observations will likely influence the design of future sequence-based mutation screens, particularly those using DNA mismatch-based detection methods which can be disrupted by the presence of naturally occurring sequence variants. The existence of a significant reservoir of alleles also suggests that existing laboratory stocks may be a useful source of novel alleles for mapping and functional studies

Seasonal variations in the diagnosis of childhood cancer in the United States

Seasonal trends in month of diagnosis have been reported for childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL). This seasonal variation has been suggested to represent an underlying viral aetiology for these malignancies. Some studies have shown the highest frequency of diagnoses in the summer months, although this has been inconsistent. Data from the Children's Cancer Group and the Pediatric Oncology Group were analysed for seasonal incidence patterns. A total of 20 949 incident cancer cases diagnosed in the USA from 1 January 1989 through 31 December 1991 were available for analyses. Diagnosis-specific malignancies available for evaluation included ALL, acute myeloid leukaemia (AML), Hodgkin's disease, NHL, rhabdomyosarcoma, neuroblastoma, retinoblastoma, osteosarcoma, Wilms' tumour, retinoblastoma, Ewings' sarcoma, central nervous system (CNS) tumours and hepatoblastoma. Overall, there was no statistically significant seasonal variation in the month of diagnosis for all childhood cancers combined. For diagnosis-specific malignancies, there was a statistically significant seasonal variation for ALL (P = 0.01; peak in summer), rhabdomyosarcoma (P = 0.03; spring/summer) and hepatoblastoma (P = 0.01; summer); there was no seasonal variation in the diagnosis of NHL. When cases were restricted to latitudes greater than 40° (‘north’), seasonal patterns were apparent only for ALL and hepatoblastoma. Notably, 33% of hepatoblastoma cases were diagnosed in the summer months. In contrast, for latitudes less than 40° (‘south’), only CNS tumours demonstrated a seasonal pattern (P = 0.002; winter). Although these data provide modest support for a summer peak in the diagnosis of childhood ALL, any underlying biological mechanisms that account for these seasonal patterns are likely complex and in need of more definitive studies. © 1999 Cancer Research Campaig

Early gene expression changes with rush immunotherapy

<p>Abstract</p> <p>Background</p> <p>To examine whether whole genome expression profiling could reveal changes in mRNA expression of peripheral blood mononuclear cells (PBMC) from allergic patients undergoing rush immunotherapy (RIT) that might be manifest within the first few months of treatment.</p> <p>Methods</p> <p>For this study, PBMC from three allergic patients undergoing RIT were assessed at four timepoints: prior to RIT, at 1 week and 7 week post-RIT, during build-up and at 4 months, after establishment of a maintenance dose. PBMC mRNA gene expression changes over time were determined by oligonucleotide microarrays using the Illumina Human-6 BeadChip Platform, which simultaneously interrogates expression profiles of > 47,000 transcripts. Differentially expressed genes were identified using well-established statistical analysis for microarrays. In addition, we analyzed peripheral blood basophil high-affinity IgE receptor (Fc epsilon RI) expression and T-regulatory cell frequency as detected by expression of CD3⁺CD4⁺CD25bright cells at each timepoint using flow cytometry.</p> <p>Results</p> <p>In comparing the initial 2 timepoints with the final 2 timepoints and analyzing for genes with ≥1.5-fold expression change (p less than or equal to 0.05, BH-FDR), we identified 507 transcripts. At a 2-fold change (p less than or equal to 0.05, BH-FDR), we found 44 transcripts. Of these, 28 were up-regulated and 16 were down-regulated genes. From these datasets, we have identified changes in immunologically relevant genes from both the innate and adaptive response with upregulation of expressed genes for molecules including IL-1β, IL-8, CD40L, BTK and BCL6. At the 4 month timepoint, we noted a downward trend in Fc epsilon RI expression in each of the three patients and increased allergen-specific IgG4 levels. No change was seen in the frequency of peripheral T-regulatory cells expressed over the four timepoints.</p> <p>Conclusions</p> <p>We observed significant changes in gene expression early in peripheral blood samples from allergic patients undergoing RIT. Moreover, serum levels for allergen specific IgG4 also increased over the course of treatment. These studies suggest that RIT induces rapid and dynamic alterations in both innate and adaptive immunity which can be observed in the periphery of allergic patients. These alterations could be directly related to the therapeutic shift in the allergen-specific class of immunoglobulin.</p

NOD2-C2 - a novel NOD2 isoform activating NF-κB in a muramyl dipeptide-independent manner

<p>Abstract</p> <p>Background</p> <p>The innate immune system employs several receptor families that form the basis of sensing pathogen-associated molecular patterns. NOD (nucleotide-binding and oligomerization domain) like receptors (NLRs) comprise a group of cytosolic proteins that trigger protective responses upon recognition of intracellular danger signals. NOD2 displays a tandem caspase recruitment domain (CARD) architecture, which is unique within the NLR family.</p> <p>Findings</p> <p>Here, we report a novel alternative transcript of the <it>NOD2 </it>gene, which codes for a truncated tandem CARD only protein, called NOD2-C2. The transcript isoform is highest expressed in leucocytes, a natural barrier against pathogen invasion, and is strictly linked to promoter usage as well as predominantly to one allele of the single nucleotide polymorphism rs2067085. Contrary to a previously identified truncated single CARD NOD2 isoform, NOD2-S, NOD2-C2 is able to activate NF-κB in a dose dependent manner independently of muramyl dipeptide (MDP). On the other hand NOD2-C2 competes with MDPs ability to activate the NOD2-driven NF-κB signaling cascade.</p> <p>Conclusion</p> <p>NOD2 transcripts having included an alternative exon downstream of exon 3 (exon 3a) are the endogenous equivalents of a previously described <it>in vitro </it>construct with the putative protein composed of only the two N-terminal CARDs. This protein form (NOD2-C2) activates NF-κB independent of an MDP stimulus and is a potential regulator of NOD2 signaling.</p

Development of a brief multidisciplinary education programme for patients with osteoarthritis

Background Osteoarthritis (OA) is a prevalent progressive musculoskeletal disorder, leading to pain and disability. Patient information and education are considered core elements in treatment guidelines for OA; however, there is to our knowledge no evidence-based recommendation on the best approach, content or length on educational programmes in OA. Objective: to develop a brief, patient oriented disease specific multidisciplinary education programme (MEP) to enhance self-management in patients with OA. Method Twelve persons (80% female mean age 59 years) diagnosed with hand, hip or knee OA participated in focus group interviews. In the first focus group, six participants were interviewed about their educational needs, attitudes and expectations for the MEP. The interviews were transcribed verbatim and thereafter condensed. Based on results from focus group interviews, current research evidence, clinical knowledge and patients' experience, a multidisciplinary OA team (dietist, nurse, occupational therapist, pharmacist, physical therapist and rheumatologist) and a patient representative developed a pilot-MEP after having attended a work-shop in health pedagogics. Finally, the pilot-MEP was evaluated by a second focus group consisting of four members from the first focus group and six other experienced patients, before final adjustments were made. Results The focus group interviews revealed four important themes: what is OA, treatment options, barriers and coping strategies in performing daily activities, and how to live with osteoarthritis. Identified gaps between patient expectations and experience with the pilot-programme were discussed and adapted into a final MEP. The final MEP was developed as a 3.5 hour educational programme provided in groups of 6-9 patients. All members from the multidisciplinary team are involved in the education programme, including a facilitator who during the provision of the programme ensures that the individual questions are addressed. As part of an ongoing process, a patient representative regularly attends the MEP and gives feedback concerning content and perceived value. Conclusion A MEP has been developed to enhance self-management in patients with OA attending a multidisciplinary OA outpatient clinic. The effectiveness of the MEP followed by individual consultations with members of the multidisciplinary team is currently evaluated in a randomised controlled trial with respect to patient satisfaction and functioning

Identification of Rice Transcription Factors Associated with Drought Tolerance Using the Ecotilling Method

The drought tolerance (DT) of plants is a complex quantitative trait. Under natural and artificial selection, drought tolerance represents the crop survival ability and production capacity under drought conditions (Luo, 2010). To understand the regulation mechanism of varied drought tolerance among rice genotypes, 95 diverse rice landraces or varieties were evaluated within a field screen facility based on the ‘line–source soil moisture gradient’, and their resistance varied from extremely resistant to sensitive. The method of Ecotype Targeting Induced Local Lesions in Genomes (Ecotilling) was used to analyze the diversity in the promoters of 24 transcription factor families. The bands separated by electrophoresis using Ecotilling were converted into molecular markers. STRUCTURE analysis revealed a value of K = 2, namely, the population with two subgroups (i.e., indica and japonica), which coincided very well with the UPGMA clusters (NTSYS-pc software) using distance-based analysis and InDel markers. Then the association analysis between the promoter diversity of these transcription factors and the DT index/level of each variety was performed. The results showed that three genes were associated with the DT index and that five genes were associated with the DT level. The sequences of these associated genes are complex and variable, especially at approximately 1000 bp upstream of the transcription initiation sites. The study illuminated that association analysis aimed at Ecotilling diversity of natural groups could facilitate the isolation of rice genes related to complex quantitative traits

Induction of GADD34 Is Necessary for dsRNA-Dependent Interferon-β Production and Participates in the Control of Chikungunya Virus Infection

Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection