From cat scratch disease to endocarditis, the possible natural history of Bartonella henselae infection

BACKGROUND: Most patients with infectious endocarditis (IE) due to Bartonella henselae have a history of exposure to cats and pre-existing heart valve lesions. To date, none of the reported patients have had a history of typical cat scratch disease (CSD) which is also a manifestation of infection with B. henselae. CASE PRESENTATION: Here we report the case of a patient who had CSD and six months later developed IE of the mitral valve caused by B. henselae. CONCLUSION: Based on this unique case, we speculate that CSD represents the primary-infection of B. henselae and that IE follows in patients with heart valve lesions

Effects of Separate and Concomitant TLR-2 and TLR-4 Activation in Peripheral Blood Mononuclear Cells of Newborn and Adult Horses

Deficient innate and adaptive immune responses cause newborn mammals to be more susceptible to bacterial infections than adult individuals. Toll-like receptors (TLRs) are known to play a pivotal role in bacterial recognition and subsequent immune responses. Several studies have indicated that activation of certain TLRs, in particular TLR-2, can result in suppression of inflammatory pathology. In this study, we isolated peripheral blood mononuclear cells (PBMCs) from adult and newborn horses to investigate the influence of TLR-2 activation on the inflammatory response mediated by TLR-4. Data were analysed in a Bayesian hierarchical linear regression model, accounting for variation between horses. In general, cytokine responses were lower in PBMCs derived from foals compared with PBMCs from adult horses. Whereas in foal PBMCs expression of TLR-2, TLR-4, and TLR-9 was not influenced by separate and concomitant TLR-2 and TLR-4 activation, in adult horse PBMCs, both TLR ligands caused significant up-regulation of TLR-2 and down-regulation of TLR-9. Moreover, in adult horse PBMCs, interleukin-10 protein production and mRNA expression increased significantly following concomitant TLR-2 and TLR-4 activation (compared with sole TLR-4 activation). In foal PBMCs, this effect was not observed. In both adult and foal PBMCs, the lipopolysaccharide-induced pro-inflammatory response was not influenced by pre-incubation and co-stimulation with the specific TLR-2 ligand Pam3-Cys-Ser-Lys4. This indicates that the published data on other species cannot be translated directly to the horse, and stresses the necessity to confirm results obtained in other species in target animals. Future research should aim to identify other methods or substances that enhance TLR functionality and bacterial defence in foals, thereby lowering susceptibility to life-threatening infections during the first period of life

Functional properties and evolutionary splicing constraints on a composite exonic regulatory element of splicing in CFTR exon 12

In general, splicing regulatory elements are defined as Enhancers or Silencers depending on their positive or negative effect upon exon inclusion. Often, these sequences are usually present separate from each other in exonic/intronic sequences. The Composite Exonic Splicing Regulatory Elements (CERES) represent an extreme physical overlap of enhancer/silencer activity. As a result, when CERES elements are mutated the consequences on the splicing process are difficult to predict. Here, we show that the functional activity of the CERES2 sequence in CFTR exon 12 is regulated by the binding, in very close proximity to each other, of several SR and hnRNP proteins. Moreover, our results show that practically the entire exon 12 sequence context participate in its definition. The consequences of this situation can be observed at the evolutionary level by comparing changes in conservation of different splicing elements in different species. In conclusion, our study highlights how it is increasingly difficult to define many exonic sequences by simply breaking them down in isolated enhancer/silencer or even neutral elements. The real picture is close to one of continuous competition between positive and negative factors where affinity for the target sequences and other dynamic factors decide the inclusion or exclusion of the exon

Dietary complexity and hidden costs of prey switching in a generalist top predator

Variation in predator diet is a critical aspect of food web stability, health, and population dynamics of predator/ prey communities. Quantifying diet, particularly among cryptic species, is extremely challenging, however, and differentiation between demographic subsets of populations is often overlooked. We used prey remains and data taken postmortem from otter Lutra lutra to determine the extent to which dietary variation in a top predator was associated with biotic, spatial, and temporal factors. Biotic data (e.g., sex, weight, and length) and stomach contents were taken from 610 otters found dead across England and Wales between 1994 and 2010. Prey remains were identified to species where possible, using published keys and reference materials. Multi‐model inference followed by model prediction was applied to test for and visualize the nature of associations. Evidence for widespread decline in the consumption of eels (Anguilla anguilla ) reflected known eel population declines. An association between eel consumption and otter body condition suggested negative consequences for otter nutrition. Consumption of Cottus gobio and stickleback spp. increased, but was unlikely to compensate (there was no association with body condition). More otters with empty stomachs were found over time. Otter sex, body length, and age‐class were important biotic predictors of the prey species found, and season, region, and distance from the coast were important abiotic predictors. Our study is unique in its multivariate nature, broad spatial scale, and long‐term dataset. Inclusion of biotic data allowed us to reveal important differences in costs and benefits of different prey types, and differences between demographic subsets of the population, overlaid on spatial and temporal variation. Such complexities in otter diet are likely to be paralleled in other predators, and detailed characterization of diet should not be overlooked in efforts to conserve wild populations

Prospective risk of stillbirth and neonatal complications in twin pregnancies: systematic review and meta-analysis.

OBJECTIVE: To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane databases (until December 2015). REVIEW METHODS: Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks' gestation. RESULTS: 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies) were included. In dichorionic twin pregnancies beyond 34 weeks (15 studies, 17 830 pregnancies), the prospective weekly risk of stillbirths from expectant management and the risk of neonatal death from delivery were balanced at 37 weeks' gestation (risk difference 1.2/1000, 95% confidence interval -1.3 to 3.6; I(2)=0%). Delay in delivery by a week (to 38 weeks) led to an additional 8.8 perinatal deaths per 1000 pregnancies (95% confidence interval 3.6 to 14.0/1000; I(2)=0%) compared with the previous week. In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2.5 per 1000 perinatal deaths, which was not significant (-12.4 to 17.4/1000; I(2)=0%). The rates of neonatal morbidity showed a consistent reduction with increasing gestational age in monochorionic and dichorionic pregnancies, and admission to the neonatal intensive care unit was the commonest neonatal complication. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies. CONCLUSIONS: To minimise perinatal deaths, in uncomplicated dichorionic twin pregnancies delivery should be considered at 37 weeks' gestation; in monochorionic pregnancies delivery should be considered at 36 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014007538

Global Activation of CD8+ Cytotoxic T Lymphocytes Correlates with an Impairment in Regulatory T Cells in Patients with Generalized Vitiligo

Melanocyte-specific CD8+ cytotoxic T lymphocytes (CTLs) play a pivotal role in vitiligo-induced depigmentation. Yet, the mechanisms underlying the high frequency of generalized autoimmune disorders associated with generalized vitiligo (GV) are unknown. We hypothesized that an imbalance between activated CD8+ CTLs and regulatory T cells (Tregs) exists in patients with GV . Assessment of the circulating CD8+ CTLs and Tregs by flow cytometric analysis revealed an obvious expansion of CD8+ CTLs and a concomitant decrease in Treg cells in GV patients. The percentages of skin infiltrating CD8+ CTLs and Tregs were evaluated by immunohistochemistry and revealed dramatically increased numbers of both CD8+ CTLs and Tregs in the perilesional skin of GV patients. However, peripheral Tregs were impaired in their ability to suppress the proliferation and cytolytic capacity of autologous CD8+ T cells, suggesting that a functional failure of Tregs and the hyper-activation of CD8+ CTLs may contribute to progressive GV. Our data indicate that reduced numbers and impaired function of natural Tregs fail to control the widespread activation of CD8+ CTLs, which leads to the destruction of melanocytes and contributes to the elevated frequency of various associated autoimmune diseases. This knowledge furthers our understanding of the mechanisms of immune tolerance that are impaired in GV patients and may aid in the future development of effective immunotherapy for GV patients

Comparative genomic analysis of the arthropod muscle myosin heavy chain genes allows ancestral gene reconstruction and reveals a new type of 'partially' processed pseudogene

<p>Abstract</p> <p>Background</p> <p>Alternative splicing of mutually exclusive exons is an important mechanism for increasing protein diversity in eukaryotes. The insect <it>Mhc </it>(myosin heavy chain) gene produces all different muscle myosins as a result of alternative splicing in contrast to most other organisms of the Metazoa lineage, that have a family of muscle genes with each gene coding for a protein specialized for a functional niche.</p> <p>Results</p> <p>The muscle myosin heavy chain genes of 22 species of the Arthropoda ranging from the waterflea to wasp and <it>Drosophila </it>have been annotated. The analysis of the gene structures allowed the reconstruction of an ancient muscle myosin heavy chain gene and showed that during evolution of the arthropods introns have mainly been lost in these genes although intron gain might have happened in a few cases. Surprisingly, the genome of <it>Aedes aegypti </it>contains another and that of <it>Culex pipiens quinquefasciatus </it>two further muscle myosin heavy chain genes, called <it>Mhc3 </it>and <it>Mhc4</it>, that contain only one variant of the corresponding alternative exons of the <it>Mhc1 </it>gene. <it>Mhc3 </it>transcription in <it>Aedes aegypti </it>is documented by EST data. <it>Mhc3 </it>and <it>Mhc4 </it>inserted in the <it>Aedes </it>and <it>Culex </it>genomes either by gene duplication followed by the loss of all but one variant of the alternative exons, or by incorporation of a transcript of which all other variants have been spliced out retaining the exon-intron structure. The second and more likely possibility represents a new type of a 'partially' processed pseudogene.</p> <p>Conclusion</p> <p>Based on the comparative genomic analysis of the alternatively spliced arthropod muscle myosin heavy chain genes we propose that the splicing process operates sequentially on the transcript. The process consists of the splicing of the mutually exclusive exons until one exon out of the cluster remains while retaining surrounding intronic sequence. In a second step splicing of introns takes place. A related mechanism could be responsible for the splicing of other genes containing mutually exclusive exons.</p

Genome-Wide Data-Mining of Candidate Human Splice Translational Efficiency Polymorphisms (STEPs) and an Online Database

Variation in pre-mRNA splicing is common and in some cases caused by genetic variants in intronic splicing motifs. Recent studies into the insulin gene (INS) discovered a polymorphism in a 5' non-coding intron that influences the likelihood of intron retention in the final mRNA, extending the 5' untranslated region and maintaining protein quality. Retention was also associated with increased insulin levels, suggesting that such variants--splice translational efficiency polymorphisms (STEPs)--may relate to disease phenotypes through differential protein expression. We set out to explore the prevalence of STEPs in the human genome and validate this new category of protein quantitative trait loci (pQTL) using publicly available data.Gene transcript and variant data were collected and mined for candidate STEPs in motif regions. Sequences from transcripts containing potential STEPs were analysed for evidence of splice site recognition and an effect in expressed sequence tags (ESTs). 16 publicly released genome-wide association data sets of common diseases were searched for association to candidate polymorphisms with HapMap frequency data. Our study found 3324 candidate STEPs lying in motif sequences of 5' non-coding introns and further mining revealed 170 with transcript evidence of intron retention. 21 potential STEPs had EST evidence of intron retention or exon extension, as well as population frequency data for comparison.Results suggest that the insulin STEP was not a unique example and that many STEPs may occur genome-wide with potentially causal effects in complex disease. An online database of STEPs is freely accessible at http://dbstep.genes.org.uk/