Trabecular bone density in premenopausal rheumatoid arthritis patients

Objective. This study was undertaken to compare trabecular bone mineral density (BMD) in premenopausal rheumatoid arthritis. (RA) patients and normal age-matched controls.Method. A protocol was designed to record age, duration of disease, use of corticosteroids (CS) and/ or slow-acting antirheumatic drug (SAARD) therapy together with duration of such therapy. BMD was measured using the Hologic QDR 1 000 dual energy X-ray absorptiometer. The first four lumbar vertebrae and the left femur were measured in 56 RA patients and 165 controls. Height and weight were measured. Comparisons were made between RA patients and controls, as well as between subgroups of RA patients based on CS therapy.Results. Patients with RA had significantly lower BMD (P < 0.05) at all the sites than the normal controls. The mean duration of RA at the time of study was 60 months (standard deviation 58 months). Thirteen RA patients had used CS in doses less than 10 mg daily for 6 months or longer (mean 19 months), while 25 patients had been on SAARD for an excess of 6 months (mean 23 months). The CS-treated patients had significantly lower BMD than untreated subjects at the femoral neck and inter-trochanteric region (P < 0.05), but not at the lumbar spine. However, when compared with normal controls, the CS-treated subgroups had significantly lower BMD at the lumbar spine and all femoral areas. Trochanteric BMD was the best determinant of the RA group, with a sensitivity of 65% and specificity of 77%. The positive predictive value was 16%, while the negative predictive value was 10%. Using Bayes' theorem, the prevalence of osteopenia in RA was found to be6%.Conclusion. We conclude that generalised bone loss is a systemic feature of RA and that loss at the spine and femur may be aggravated by CS therapy

A dynamic network approach for the study of human phenotypes

The use of networks to integrate different genetic, proteomic, and metabolic datasets has been proposed as a viable path toward elucidating the origins of specific diseases. Here we introduce a new phenotypic database summarizing correlations obtained from the disease history of more than 30 million patients in a Phenotypic Disease Network (PDN). We present evidence that the structure of the PDN is relevant to the understanding of illness progression by showing that (1) patients develop diseases close in the network to those they already have; (2) the progression of disease along the links of the network is different for patients of different genders and ethnicities; (3) patients diagnosed with diseases which are more highly connected in the PDN tend to die sooner than those affected by less connected diseases; and (4) diseases that tend to be preceded by others in the PDN tend to be more connected than diseases that precede other illnesses, and are associated with higher degrees of mortality. Our findings show that disease progression can be represented and studied using network methods, offering the potential to enhance our understanding of the origin and evolution of human diseases. The dataset introduced here, released concurrently with this publication, represents the largest relational phenotypic resource publicly available to the research community.Comment: 28 pages (double space), 6 figure

Significance of herpesvirus immediate early gene expression in cellular immunity to cytomegalovirus infection

Interstitial pneumonia linked with reactivation of latent human cytomegalovirus due to iatrogenic immunosuppression can be a serious complication of bone marrow transplantation therapy of aplastic anaemia and acute leukaemia1. Cellular immunity plays a critical role in the immune surveillance of inapparent cytomegalovirus infections in man and the mouse1−7. The molecular basis of latency, however, and the interaction between latently or recurrently infected cells and the immune system of the host are poorfy understood. We have detected a so far unknown antigen in the mouse model. This antigen is found in infected cells in association with the expression of the herpesvirus 'immediate early' genes and is recognized by cytolytic T lymphocytes (CTL)8. We now demonstrate that an unexpectedly high proportion of the CTL precursors generated in vivo during acute murine cytomegalovirus infection are specific for cells that selectively synthesize immediate early proteins, indicating an immunodominant role of viral non-structural proteins

Contrasting environmental drivers of adult and juvenile growth in a marine fish: implications for the effects of climate change

Many marine fishes have life history strategies that involve ontogenetic changes in the use of coastal habitats. Such ontogenetic shifts may place these species at particular risk from climate change, because the successive environments they inhabit can differ in the type, frequency and severity of changes related to global warming. We used a dendrochronology approach to examine the physical and biological drivers of growth of adult and juvenile mangrove jack (Lutjanus argentimaculatus) from tropical north-western Australia. Juveniles of this species inhabit estuarine environments and adults reside on coastal reefs. The Niño-4 index, a measure of the status of the El Niño-Southern Oscillation (ENSO) had the highest correlation with adult growth chronologies, with La Niña years (characterised by warmer temperatures and lower salinities) having positive impacts on growth. Atmospheric and oceanographic phenomena operating at ocean-basin scales seem to be important correlates of the processes driving growth in local coastal habitats. Conversely, terrestrial factors influencing precipitation and river runoff were positively correlated with the growth of juveniles in estuaries. Our results show that the impacts of climate change on these two life history stages are likely to be different, with implications for resilience and management of populations

Predictability and epidemic pathways in global outbreaks of infectious diseases: the SARS case study

Background: The global spread of the severe acute respiratory syndrome (SARS) epidemic has clearly shown the importance of considering the long-range transportation networks in the understanding of emerging diseases outbreaks. The introduction of extensive transportation data sets is therefore an important step in order to develop epidemic models endowed with realism. Methods: We develop a general stochastic meta-population model that incorporates actual travel and census data among 3 100 urban areas in 220 countries. The model allows probabilistic predictions on the likelihood of country outbreaks and their magnitude. The level of predictability offered by the model can be quantitatively analyzed and related to the appearance of robust epidemic pathways that represent the most probable routes for the spread of the disease. Results: In order to assess the predictive power of the model, the case study of the global spread of SARS is considered. The disease parameter values and initial conditions used in the model are evaluated from empirical data for Hong Kong. The outbreak likelihood for specific countries is evaluated along with the emerging epidemic pathways. Simulation results are in agreement with the empirical data of the SARS worldwide epidemic. Conclusions: The presented computational approach shows that the integration of long-range mobility and demographic data provides epidemic models with a predictive power that can be consistently tested and theoretically motivated. This computational strategy can be therefore considered as a general tool in the analysis and forecast of the global spreading of emerging diseases and in the definition of containment policies aimed at reducing the effects of potentially catastrophic outbreaks.Comment: 21 pages, 2 tables, 7 figure

Mutational Biases and Selective Forces Shaping the Structure of Arabidopsis Genes

Recently features of gene expression profiles have been associated with structural parameters of gene sequences in organisms representing a diverse set of taxa. The emerging picture indicates that natural selection, mediated by gene expression profiles, has a significant role in determining genic structures. However the current situation is less clear in plants as the available data indicates that the effect of natural selection mediated by gene expression is very weak. Moreover, the direction of the patterns in plants appears to contradict those observed in animal genomes. In the present work we analized expression data for >18000 Arabidopsis genes retrieved from public datasets obtained with different technologies (MPSS and high density chip arrays) and compared them with gene parameters. Our results show that the impact of natural selection mediated by expression on genes sequences is significant and distinguishable from the effects of regional mutational biases. In addition, we provide evidence that the level and the breadth of gene expression are related in opposite ways to many structural parameters of gene sequences. Higher levels of expression abundance are associated with smaller transcripts, consistent with the need to reduce costs of both transcription and translation. Expression breadth, however, shows a contrasting pattern, i.e. longer genes have higher breadth of expression, possibly to ensure those structural features associated with gene plasticity. Based on these results, we propose that the specific balance between these two selective forces play a significant role in shaping the structure of Arabidopsis genes

Preliminary Definitions for Sacroiliac Joint Pathologies in the OMERACT Juvenile Idiopathic Arthritis MRI Score (OMERACT JAMRIS-SIJ).

Objective: To develop definitions for the assessment of MRI pathologies of the sacroiliac joints (SIJ) in juvenile idiopathic arthritis (JIA). Methods: An OMERACT consensus-driven methodology consisting of iterative surveys and focus group meetings within an international group of rheumatologists and radiologists. Results: Two domains, inflammation and structural, were identified. Definitions for bone marrow edema, joint space inflammation, capsulitis and enthesitis were derived for joint inflammation; sclerosis, erosion, fatty lesion and ankylosis were defined for assessing structural joint changes. Conclusion: Preliminary consensus-driven definitions for inflammation and structural elements have been derived, underpinning the ongoing development of the JAMRIS-SIJ score

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well

FLPe functions in zebrafish embryos

To assay the efficiency of the FLP/FRT site-specific recombination system in Danio rerio, a construct consisting of a muscle-specific promoter driving EGFP flanked by FRT sites was developed. FLPe capped RNA was microinjected into transgenic single cell stage zebrafish embryos obtained by crossing hemizygous transgenic males with wild-type females. By 48 h post fertilization (hpf), the proportion of embryos displaying green fluorescence following FLPe RNA microinjection was significantly lower (7.7%; P < 0.001) than would be expected from a cross in the absence of the recombinase (50%). Embryos that retained fluorescence displayed marked mosaicism. Inheritance of the excised transgene in non-fluorescent, transgenic embryos was verified by PCR analysis and FLPe-mediated recombination was confirmed by DNA sequencing. Sperm derived from confirmed transgenic males in these experiments was used to fertilize wild-type eggs to determine whether germline excision of the transgene had occurred. Clutches sired by FLPe-microinjected males contained 0–4% fluorescent embryos. Transgenic males that were phenotypically wild-type produced no fluorescent progeny, demonstrating complete excision of the transgene from their germline. FLPe microinjected males that retained some fluorescent muscle expression produced a small proportion of fluorescent offspring, suggesting that in mosaic males not all germline cells had undergone FLPe-mediated transgene excision. Our results show that FLPe, which is derived from Saccharomyces cerevisiae, is an efficient recombinase in zebrafish maintained at 28.5°C

Stability of Yellow Fever Virus under Recombinatory Pressure as Compared with Chikungunya Virus

Recombination is a mechanism whereby positive sense single stranded RNA viruses exchange segments of genetic information. Recent phylogenetic analyses of naturally occurring recombinant flaviviruses have raised concerns regarding the potential for the emergence of virulent recombinants either post-vaccination or following co-infection with two distinct wild-type viruses. To characterize the conditions and sequences that favor RNA arthropod-borne virus recombination we constructed yellow fever virus (YFV) 17D recombinant crosses containing complementary deletions in the envelope protein coding sequence. These constructs were designed to strongly favor recombination, and the detection conditions were optimized to achieve high sensitivity recovery of putative recombinants. Full length recombinant YFV 17D virus was never detected under any of the experimental conditions examined, despite achieving estimated YFV replicon co-infection levels of ∼2.4×106 in BHK-21 (vertebrate) cells and ∼1.05×105 in C710 (arthropod) cells. Additionally YFV 17D superinfection resistance was observed in vertebrate and arthropod cells harboring a primary infection with wild-type YFV Asibi strain. Furthermore recombination potential was also evaluated using similarly designed chikungunya virus (CHIKV) replicons towards validation of this strategy for recombination detection. Non-homologus recombination was observed for CHIKV within the structural gene coding sequence resulting in an in-frame duplication of capsid and E3 gene. Based on these data, it is concluded that even in the unlikely event of a high level acute co-infection of two distinct YFV genomes in an arthropod or vertebrate host, the generation of viable flavivirus recombinants is extremely unlikely