Mitochondrial genetic background plays a role in increasing risk to asthma

A number of studies suggest that mitochondrial dysfunction plays a role in the pathogenesis of asthma. To shed light for the first time on the role of the mitochondrial genome in the etiology of asthma we analyzed the mitochondrial tRNA genes and part of their flanking regions in patients with asthma compared with a set of healthy controls. We found a total of 10 mutations in 56 out of 76 asthmatic patients. Four of these mutations were not found in the control group, five were observed at a significantly lower frequency in controls, but none of the combinations of mutations detected in asthma patients was observed in the controls. Furthermore, we observed that 27.6% of the asthma patients (vs. 4% of the controls) belonged to the haplogroup U (Fisher test P = 0.00) and a positive significant correlation was found between the occurrence of the haplogroup U and the severity of the disease (Fisher test P = 0.02). Whereas further studies in larger cohorts are needed to confirm these observations we suggest that the mitochondrial genetic background plays a key role in asthma development.     

CCK-B receptor gene and response to cholecystokinin-tetrapeptide in healthy volunteers

Recent investigations suggest that genes that confer risk for panic disorder (PD) may moderate response to panicogenic agents in healthy volunteers. Given the potential role of the central cholecystokinin receptor (CCKBR) (CT) polymorphism alleles 26 and 27 in PD, the present study attempted to discern if these alleles moderated panicogenic sensitivity to the CCKBR agonist, CCK-tetrapeptide (CCK-4), in healthy volunteers. The study group consisted of 92 men and women with no personal or family history of psychiatric illness. Participants provided blood samples for genotyping of the CCKBR alleles and they received a 25 μg bolus injection of CCK-4. Behavioral, cardiovascular and hormonal responses to the peptide were assessed and analyzed with adjusted linear regression models. Carriers of the CCKBR alleles tended to have higher levels of pre-challenge anxiety and significantly higher levels of anxiety sensitivity and introversion than those without the alleles. However, they did not exhibit an enhanced panicogenic response to CCK-4. Overall, our findings do not demonstrate a role of these alleles in modulating CCK-4's panicogenicity. The significant association between the risk alleles and anxiety-related personality traits is intriguing and further exploration of this association is merited.     

Hormone secretion in transgenic rats and electrophysiological activity in their gonadotropin releasing-hormone neurons

Expression of GFP in GnRH neurons has allowed for studies of individual GnRH neurons. We have demonstrated previously the preservation of physiological function in male GnRH-GFP mice. In the present study, we confirm using biocytin-filled GFP-positive neurons in the hypothalamic slice preparation that GFP-expressing somata, axons, and dendrites in hypothalamic slices from GnRH-GFP rats are GnRH1 peptide positive. Second, we used repetitive sampling to study hormone secretion from GnRH-GFP transgenic rats in the homozygous, heterozygous, and wild-type state and between transgenic and Wistar males after ~4 yr of backcrossing. Parameters of hormone secretion were not different between the three genetic groups or between transgenic males and Wistar controls. Finally, we performed long-term recording in as many GFP-identified GnRH neurons as possible in hypothalamic slices to determine their patterns of discharge. In some cases, we obtained GnRH neuronal recordings from individual males in which blood samples had been collected the previous day. Activity in individual GnRH neurons was expressed as total quiescence, a continuous pattern of firing of either low or relatively high frequencies or an intermittent pattern of firing. In males with both intensive blood sampling (at 6-min intervals) and recordings from their GnRH neurons, we analyzed the activity of GnRH neurons with intermittent activity above 2 Hz using cluster analysis on both data sets. The average number of pulses was 3.9 ± 0.6/h. The average number of episodes of firing was 4.0 ± 0.6/h. Therefore, the GnRH pulse generator may be maintained in the sagittal hypothalamic slice preparation.     

Human viruses: discovery and emergence

There are 219 virus species that are known to be able to infect humans. The first of these to be discovered was yellow fever virus in 1901, and three to four new species are still being found every year. Extrapolation of the discovery curve suggests that there is still a substantial pool of undiscovered human virus species, although an apparent slow-down in the rate of discovery of species from different families may indicate bounds to the potential range of diversity. More than two-thirds of human viruses can also infect non-human hosts, mainly mammals, and sometimes birds. Many specialist human viruses also have mammalian or avian origins. Indeed, a substantial proportion of mammalian viruses may be capable of crossing the species barrier into humans, although only around half of these are capable of being transmitted by humans and around half again of transmitting well enough to cause major outbreaks. A few possible predictors of species jumps can be identified, including the use of phylogenetically conserved cell receptors. It seems almost inevitable that new human viruses will continue to emerge, mainly from other mammals and birds, for the foreseeable future. For this reason, an effective global surveillance system for novel viruses is needed.     

Rarity and genetic diversity in Indo-Pacific Acropora corals

Among various potential consequences of rarity is genetic erosion. Neutral genetic theory predicts that rare species will have lower genetic diversity than common species. To examine the association between genetic diversity and rarity, variation at eight DNA microsatellite markers was documented for 14 Acropora species that display different patterns of distribution and abundance in the Indo-Pacific Ocean. Our results show that the relationship between rarity and genetic diversity is not a positive linear association because, contrary to expectations, some rare species are genetically diverse and some populations of common species are genetically depleted. Our data suggest that inbreeding is the most likely mechanism of genetic depletion in both rare and common corals, and that hybridization is the most likely explanation for higher than expected levels of genetic diversity in rare species. A significant hypothesis generated from our study with direct conservation implications is that as a group, Acropora corals have lower genetic diversity at neutral microsatellite loci than may be expected from their taxonomic diversity, and this may suggest a heightened susceptibility to environmental change. This hypothesis requires validation based on genetic diversity estimates derived from a large portion of the genome.     

"There are too many, but never enough": qualitative case study investigating routine coding of clinical information in depression

Background

We sought to understand how clinical information relating to the management of depression is routinely coded in different clinical settings and the perspectives of and implications for different stakeholders with a view to understanding how these may be aligned.

Materials and Methods

Qualitative investigation exploring the views of a purposefully selected range of healthcare professionals, managers, and clinical coders spanning primary and secondary care.

Results

Our dataset comprised 28 semi-structured interviews, a focus group, documents relating to clinical coding standards and participant observation of clinical coding activities. We identified a range of approaches to coding clinical information including templates and order entry systems. The challenges inherent in clearly establishing a diagnosis, identifying appropriate clinical codes and possible implications of diagnoses for patients were particularly prominent in primary care. Although a range of managerial and research benefits were identified, there were no direct benefits from coded clinical data for patients or professionals. Secondary care staff emphasized the role of clinical coders in ensuring data quality, which was at odds with the policy drive to increase real-time clinical coding.

Conclusions

There was overall no evidence of clear-cut direct patient care benefits to inform immediate care decisions, even in primary care where data on patients with depression were more extensively coded. A number of important secondary uses were recognized by healthcare staff, but the coding of clinical data to serve these ends was often poorly aligned with clinical practice and patient-centered considerations. The current international drive to encourage clinical coding by healthcare professionals during the clinical encounter may need to be critically examined.     

Household factors influencing participation in bird feeding activity: a national scale analysis

Ameliorating pressures on the ecological condition of the wider landscape outside of protected areas is a key focus of conservation initiatives in the developed world. In highly urbanized nations, domestic gardens can play a significant role in maintaining biodiversity and facilitating human-wildlife interactions, which benefit personal and societal health and well-being. The extent to which sociodemographic and socioeconomic factors are associated with engagement in wildlife gardening activities remain largely unresolved. Using two household-level survey datasets gathered from across Britain, we determine whether and how the socioeconomic background of a household influences participation in food provision for wild birds, the most popular and widespread form of human-wildlife interaction. A majority of households feed birds (64% across rural and urban areas in England, and 53% within five British study cities). House type, household size and the age of the head of the household were all important predictors of bird feeding, whereas gross annual household income, the occupation of the head of the household, and whether the house is owned or rented were not. In both surveys, the prevalence of bird feeding rose as house type became more detached and as the age of the head of the household increased. A clear, consistent pattern between households of varying size was less evident. When regularity of food provision was examined in the study cities, just 29% of households provided food at least once a week. The proportion of households regularly feeding birds was positively related to the age of the head of the household, but declined with gross annual income. As concerns grow about the lack of engagement between people and the natural environment, such findings are important if conservation organizations are successfully to promote public participation in wildlife gardening specifically and environmentally beneficial behaviour in society more generally.     

Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model

Background

Repeated adaptive radiations are evident when phenotypic divergence occurs within lineages, but this divergence into different forms is convergent when compared across lineages. Classic examples of such repeated adaptive divergence occur in island (for example, Caribbean Anolis lizards) and lake systems (for example, African cichlids). Host-parasite systems in many respects are analogous to island systems, where host species represent isolated islands for parasites whose life cycle is highly tied to that of their hosts. Thus, host-parasite systems might exhibit interesting cases of repeated adaptive divergence as seen in island and lake systems. The feather lice of birds spend their entire life cycle on the body of the host and occupy distinct microhabitats on the host: head, wing, body and generalist. These microhabitat specialists show pronounced morphological differences corresponding to how they escape from host preening. We tested whether these different microhabitat specialists were a case of repeated adaptive divergence by constructing both morphological and molecular phylogenies for a diversity of avian feather lice, including many examples of head, wing, body and generalist forms.

Results

Morphological and molecular based phylogenies were highly incongruent, which could be explained by rampant convergence in morphology related to microhabitat specialization on the host. In many cases lice from different microhabitat specializations, but from the same group of birds, were sister taxa.

Conclusions

This pattern indicates a process of repeated adaptive divergence of these parasites within host group, but convergence when comparing parasites across host groups. These results suggest that host-parasite systems might be another case in which repeated adaptive radiations could be relatively common, but potentially overlooked, because morphological convergence can obscure evolutionary relationships.     

Signaling signatures and functional properties of anti-human CD28 superagonistic antibodies

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4⁺ T cells but not in cynomolgus T lymphocytes. The sustained Ca⁺⁺-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells.