Half-life systematics across the N=126 shell closure: role of first-forbidden transitions in the ß decay of heavy neutron-rich nuclei.

This Letter reports on a systematic study of ß-decay half-lives of neutron-rich nuclei around doubly magic (208)Pb. The lifetimes of the 126-neutron shell isotone (204)Pt and the neighboring (200-202)Ir, (203)Pt, (204)Au are presented together with other 19 half-lives measured during the "stopped beam" campaign of the rare isotope investigations at GSI collaboration. The results constrain the main nuclear theories used in calculations of r-process nucleosynthesis. Predictions based on a statistical macroscopic description of the first-forbidden ß strength reveal significant deviations for most of the nuclei with N<126. In contrast, theories including a fully microscopic treatment of allowed and first-forbidden transitions reproduce more satisfactorily the trend in the measured half-lives for the nuclei in this region, where the r-process pathway passes through during ß decay back to stability.

Embedding integrated mental health assessment and management in general hospital settings: feasibility, acceptability and the prevalence of common mental disorder.

OBJECTIVE: To assess the feasibility and acceptability of routine web-based screening in general hospital settings, and describe the level of common mental disorder. METHOD: A service development platform to integrate mental and physical healthcare was implemented in six specialties (rheumatology, limb reconstruction, hepatitis C, psoriasis, adult congenital heart disease (ACHD), chronic pain) across three general hospitals in London, UK. Under service conditions, patients completed a web-based questionnaire comprising mental and physical patient-reported outcome measures, whilst waiting for their appointment. Feasibility was quantified as the proportion of patients who completed the questionnaire. Acceptability was quantified as the proportion of patients declining screening, and the proportion requiring assistance completing the questionnaire. The prevalence of probable depression and anxiety was expressed as the percentage of cases determined by the Patient Health Questionnaire-9 and Generalised Anxiety Disorder Questionnaire-7. RESULTS: The proportion of patients screened varied widely across specialties (40.1-98.2%). The decline rate was low (0.6-9.7%) and the minority required assistance (11.7-40.4%). The prevalence of probable depression ranged from 60.9% in chronic pain to 6.6% in ACHD. The prevalence of probable anxiety ranged from 25.1% in rheumatology to 11.4% in ACHD. CONCLUSION: Web-based screening is acceptable to patients and can be effectively embedded in routine practice. General hospital patients are at increased risk of common mental disorder, and routine screening may help identify need, inform care and monitor outcomes.

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population.

Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. (70)DERAA(74), D(70) and I(67) protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1(*)0401∼(*)0404>(*)0101∼(*)1001 ((*)0404>(*)0101: P=0.0003). HLA-DRB1(*)0401/(*)0404 compound heterozygosity conferred a risk similar to (*)0401 homozygosity (P=0.70). Protective effects of D(70) and I(67) were similar. Predictions of the D(70) model fitted the data better than those of the I(67) model. The protective effect of D(70) showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P=5.8 × 10(-4)), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P=0.0012). In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D(70) specifically protected against antibody-positive RA.

Precipitating and perpetuating factors of rheumatoid arthritis immunopathology: linking the triad of genetic predisposition, environmental risk factors and autoimmunity to disease pathogenesis.

Rheumatoid arthritis (RA) is considered to occur when genetic and environmental factors interact to trigger immunopathological changes and consequently an inflammatory arthritis. Over the last few decades, epidemiological and genetic studies have identified a large number of risk factors for RA development, the most prominent of which comprise cigarette smoking and the shared epitope alleles. These risks appear to differ substantially between anti-cyclic citrullinated peptide (ACPA)-positive and ACPA-negative disease. In this article, we will summarise the risk factors for RA development that have currently been identified, outlining the specific gene-environment and gene-gene interactions that may occur to precipitate and perpetuate autoimmunity and RA. We will also focus on how this knowledge of risk factors for RA may be implemented in the future to identify individuals at a high risk of disease development in whom preventative strategies may be undertaken.

16+ spin-gap isomer in 96Cd.

A ß-decaying high-spin isomer in (96)Cd, with a half-life T(1/2)=0.29(-0.10)(+0.11) s, has been established in a stopped beam rare isotope spectroscopic investigations at GSI (RISING) experiment. The nuclei were produced using the fragmentation of a primary beam of (124)Xe on a (9)Be target. From the half-life and the observed γ decays in the daughter nucleus, (96)Ag, we conclude that the ß-decaying state is the long predicted 16(+) "spin-gap" isomer. Shell-model calculations, using the Gross-Frenkel interaction and the πν(p(1/2),g(9/2)) model space, show that the isoscalar component of the neutron-proton interaction is essential to explain the origin of the isomer. Core excitations across the N=Z=50 gaps and the Gamow-Teller strength, B(GT) distributions have been studied via large-scale shell-model calculations using the πν(g,d,s) model space to compare with the experimental B(GT) value obtained from the half-life of the isomer.

Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.

OBJECTIVE: There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by beta-chemokines is a feature of autoimmunity, and that the CCR5Delta32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D). METHODS: We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian. RESULTS: A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08-1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75-1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98-2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00-1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5Delta32). CONCLUSIONS: These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.

Observation of isomeric decays in the r-process waiting-point nucleus 130Cd82.

The gamma decay of excited states in the waiting-point nucleus (130)Cd(82) has been observed for the first time. An 8(+) two-quasiparticle isomer has been populated both in the fragmentation of a (136)Xe beam as well as in projectile fission of 238U, making (130)Cd the most neutron-rich N = 82 isotone for which information about excited states is available. The results, interpreted using state-of-the-art nuclear shell-model calculations, show no evidence of an N = 82 shell quenching at Z = 48. They allow us to follow nuclear isomerism throughout a full major neutron shell from (98)Cd(50) to (130)Cd(82) and reveal, in comparison with (76)Ni(48) one major proton shell below, an apparently abnormal scaling of nuclear two-body interactions.

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis.

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203 269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7 Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P=0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.

A general autoimmunity gene (PTPN22) is not associated with inflammatory bowel disease in a British population.

A single-nucleotide polymorphism (C1858T) causing an amino acid substitution (R620W) in the lymphoid protein tyrosine phosphatase gene PTPN22 has been implicated in type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, juvenile idiopathic arthritis and Hashimoto's thyroiditis, thus revealing a general role for this gene in autoimmune disease. We investigated the association of the C1858T variant in an additional autoimmune disease population by performing a case-control study of 514 British individuals with inflammatory bowel disease (IBD) [294 with Crohn's disease (CD) and 220 with ulcerative colitis (UC)] and 374 normal controls. No significant differences in genotype or allele frequencies were observed between IBD, CD or UC and controls, indicating that PTPN22 does not influence risk of IBD.

Development of rheumatoid arthritis is not associated with two polymorphisms in the Crohn's disease gene CARD15.

INTRODUCTION: It has been proposed that genetic susceptibility loci for rheumatoid arthritis (RA) may be shared with other autoimmune/inflammatory diseases. Recently, common variation in the CARD15 (NOD2) gene on chromosome 16q12 has been associated with Crohn's disease (CD) in several independent populations. CARD15 is an excellent functional and positional candidate gene for RA. METHODS: Genomic DNA was obtained from 392 RA cases and 471 ethnically matched healthy controls. All samples were genotyped for two polymorphisms in CARD15, 1007fs and R702W, using 5' nuclease reporter assays. Allele frequencies were compared between cases and controls using the chi(2) test. Estimated haplotype frequencies across the two mutations were determined using the EH program. RESULTS: The allele frequency of the 1007fs variant in RA cases was 1.8% compared with 1.6% in normal controls (not significant). The frequency of the R702W variant was 4.0% in both cases and controls. Haplotypes carrying either of the two mutations accounted for 5.6% of possible haplotypes. A haplotype carrying both mutations was rare, with estimated frequency <0.01%. This study provided high power to detect an association of similar magnitude to that in Crohn's disease. These data therefore exclude the possibility that the contribution of these mutations to RA is comparable to that seen in CD. CONCLUSION: Within defined statistical parameters, we excluded a role for the CARD15 1007fs and R702W variants in RA susceptibility. These data do not preclude a role for other polymorphisms in the CARD15 gene in RA susceptibility. Results from other autoimmune and inflammatory diseases will reveal whether the CARD15 gene is in fact a common autoimmune susceptibility locus.

Structure and biology of tissue factor pathway inhibitor.

Human tissue factor pathway inhibitor (TFPI) is a modular protein comprised of three Kunitz type domains flanked by peptide segments that are less structured. The sequential order of the elements are: an N-terminal acidic region followed by the first Kunitz domain (K1), a linker region, a second Kunitz domain (K2), a second linker region, the third Kunitz domain (K3), and the C-terminal basic region. The K1 domain inhibits factor VIIa complexed to tissue factor (TF) while the K2 domain inhibits factor Xa. No direct protease inhibiting functions have been demonstrated for the K3 domain. Importantly, the Xa-TFPI complex is a much more potent inhibitor of the VIIa-TF than TFPI by itself. Furthermore, the C-terminal basic region of TFPI is required for rapid physiologic inhibition of coagulation and is needed for the inhibition of smooth muscle cell proliferation. Although a number of additional targets for attachment have been reported, the C-terminal basic region appears to play an important role in binding of TFPI to cell surfaces. A primary site of TFPI synthesis is endothelium and the endothelium-bound TFPI contributes to the antithrombotic potential of the vascular endothelium. Further, increased levels of plasma TFPI under septic conditions may represent endothelial dysfunction. We have proposed that the extravascular cells that synthesize TF also synthesize TFPI providing dual components necessary for the regulation of clotting in their microenvironment. Like the TF synthesis in these cells is augmented by serum, so is the case with the TFPI gene expression. TFPI gene knock out mice reveal embryonic lethality suggesting a possible role of this protein in early development. Since TF-induced coagulation is thought to play a significant role in many disease states, including disseminated intravascular clotting, sepsis, acute lung injury and cancer, recombinant TFPI may be a beneficial therapeutic agent in these disease states to attenuate pathologic clotting. The purpose of this review is to outline recent developments in the field related to the structural specificity and biology of TFPI.

The Saskatchewan dissemination story.

The Saskatchewan Heart Health Program (SHHP) Dissemination Phase "Building Health Promotion Capacity" is a five-year program funded by Health Canada, Saskatchewan Health and the Heart and Stroke Foundation of Saskatchewan. This phase began in July 1998 and builds on two previous SHHP phases: the provincial heart health survey (Saskatchewan Health, 1990), and the community demonstration projects (SHHP, 1998a, b, c, d). The evolution of the SHHP has occurred in a dynamic provincial context. Saskatchewan is a Canadian prairie province of one million people with most living in the southern and central parts of the province. The population is ageing and urbanizing, and the economy is shifting away from agricultural production toward a diversified service sector. In 1993, health reform created 30 Districts in southern and central Saskatchewan; the formation of three northern Districts followed five years later. All but two Districts are rural-based. Population served ranges from 2,261 to 237,274; total area ranges from 4,019 to 133,900 square kilometers.

Role of GATA motifs in tissue factor pathway inhibitor gene expression in malignant cells.

Tissue factor pathway inhibitor (TFPI) is the primary physiologic inhibitor of tissue factor-induced clotting. The TFPI gene contains three GATA motifs in the region flanking its transcription initiation sites. GATA motifs present in promoters of other genes bind GATA-2 transcription factor and thereby regulate their transcriptional expression. Both TFPI and GATA-2 transcription factor are synthesized by a variety of normal as well as malignant cells including hepatocellular carcinoma HepG2 and bladder carcinoma ECV304. Here, we studied whether the three GATA motifs flanking the transcription initiation sites regulate TFPI gene expression in HepG2 and ECV304 cells by binding to the GATA-2 transcription factor. Synthetic oligonucleotides containing GATA sequences from the TFPI regulatory region formed DNA-protein complexes with HepG2 and ECV304 nuclear extracts in an electrophoretic mobility shift assay. Using a 740-bp fragment (-496/+244) from TFPI regulatory region, the effect of base substitutions at each of the three GATA motifs was studied in a luciferase reporter gene system. TFPI promoter activity in HepG2 cells was increased 3-fold with mutation in one of the three GATA motifs and in ECV304 cells was essentially unchanged with mutations in all three GATA motifs. Thus, GATA motifs appear to serve a tissue-specific regulatory role in TFPI gene expression in malignant cells.

Synthesis and expression of tissue factor pathway inhibitor by serum-stimulated fibroblasts, vascular smooth muscle cells and cardiac myocytes.

Tissue factor pathway inhibitor (TFPI) plays an important role in regulating tissue factor (TF)-initiated blood coagulation. Since serum stimulation of fibroblasts, vascular smooth muscle cells and cardiac myocytes in culture increases the expression of TF mRNA and antigen (Ag) in these cells, we hypothesized that serum may also induce increased synthesis of TFPI in these cells to regulate the TF-induced extravascular clotting at an injury site. To test this concept, we used primary isolates of the following human cell types - fetal and adult lung fibroblasts, pulmonary and aortic smooth muscle cells, and cardiac myocytes. Serum-stimulation of these cells resulted in an increased expression of TF mRNA and Ag (8 to 10-fold). Upon serum stimulation, expression of TFPI mRNA and Ag was also increased in these cells. However, the increase in TFPI-Ag (6 to 8-fold) was significantly greater than the TFPI mRNA (2 to 3-fold). Notably, increased expression of TFPI persisted after the TF expression had declined. Further, increased synthesis of TFPI initially led to the saturation of heparin-releasable binding sites. TFPI-Ag was detected by Western blotting, 35S-metabolic labeling and activity assays on the conditioned media, heparin-released material from cells, and in cell lysates. TFPI-Ag was also detected by immunofluorescence staining of cells. Actinomycin D partially whereas cycloheximide completely prevented the serum-induced increased expression of TFPI synthesis by these cells, suggesting control primarily at the translational but some at the transcriptional level as well. The Mr of undegraded TFPI in all cases was approximately 45 kDa and was of full length. TFPI synthesized locally by fibroblasts, vascular smooth muscle cells and cardiac myocytes could play a significant role in regulating TF-initiated extravascular clotting especially since plasma TFPI that may be available at the injury site lacks a portion of the carboxyl segment and is a less efficient inhibitor.

'Unseen' on-call workload of a general surgical team.

Over a four-month period, we assessed the contribution made to the on-call workload of a general surgical team, by referrals and assessments of patients who had not been admitted under surgical care and were therefore not recorded in current audits of general surgical activity--the 'unseen workload'. Up to 5 1/2 hours per day on-call (mean 101 minutes) was spent assessing these referrals. There was a mean number of 3.6 referrals (range 1 to 7). Although 51 percent of these referrals were deemed to be non-surgical after assessment, the majority (77 percent) were believed to be appropriate. The Accident & Emergency Department referred 46 per cent of patients with only 7 percent requiring surgical management. This study shows that while hours of work are important in assessing the workload of a junior doctor on-call, the intensity of the workload is just as important in determining the impact on staff. There is a greater workload than revealed by audit of just surgical admissions and operations alone.

The complement activation assay: The test for immediate phototoxicity.

A new in vitro test for phototoxicity has been developed. Nine substances (eight photosensitizers and one non-photosensitizer) were screened for their ability to activate human complement in the presence of UV light, and all photosensitizers were found to be active. Complement activation was quantified by means of ELISA. In all cases activation was mediated by alternative, but not by classical, pathways. The results of a cell culture test performed with 5-methoxypsoralen suggest the existence of two different mechanisms of phototoxicity. This indicates that the battery of in vitro assays for phototoxicity prediction must contain at least two different tests.

The development and evaluation of in vitro tests for photoirritancy.

Photoirritancy, a reversible inflammatory reaction of the skin after chemical contact and UV radiation exposure, is increasingly observed as a side-effect of both cosmetics and certain systemic drugs. Despite the quantity of in vitro data available, none of the current animal models can be viewed as fully predictive of human exposure. It is therefore considered that the emphasis of future work should be the development and evaluation of in vitro assays. The aim of this study was to establish the interlaboratory performance of a physicochemical method, SOLATEX-PI. 12 pure chemicals at several concentrations were evaluated in the presence of UVA. In addition, a lymphoid cell assay was undertaken to allow a direct in vitro/in vitro comparison. The overall correlation between the laboratories was good when expressed in terms of a positive or negative result. However, there were some interlaboratory discrepancies, which were compounded by the lack of unequivocal in vivo data. Despite these discrepancies, both laboratories did agree on the final classification of nine of the 12 chemicals in the SOLATEX-PI system, based on the highest concentrations tested. The cellular photoirritancy assay, in contrast, predicted the correct classification for only eight of the 12 chemicals tested compared with the in vivo data supplied by IVI.