Prevalence of hepatitis C virus exposure and infection among Indigenous and tribal populations: a global systematic review and meta-analysis.

OBJECTIVES: The objective of this study was to estimate prevalence of hepatitis C virus (HCV) exposure and infection among Indigenous and tribal populations globally. STUDY DESIGN: Systematic review and meta-analysis. METHODS: We systematically searched bibliographic databases and grey literature (1/01/2000-16/06/2022). Prevalence estimates were synthesised overall, by World Health Organization region and HCV-risk group. For studies with comparator populations, prevalence ratios were estimated and pooled. RESULTS: Ninety-two studies were included. Globally, among general Indigenous and tribal populations, the median prevalence of HCV antibody (HCV Ab) was 1.3% (interquartile range [IQR]: 0.3-3.8%, I2 = 98.5%) and HCV RNA was 0.4% (IQR: 0-1.3%, I2 = 96.1%). The Western Pacific Region had the highest prevalence (HCV Ab: median: 3.0% [IQR: 0.4-11.9%], HCV RNA: median 5.6% [IQR: 2.0-8.8%]). Prevalence was highest in people who injected drugs (HCV Ab: median: 59.5%, IQR: 51.5-67.6%, I2 = 96.6%; and HCV RNA: median: 29.4%, IQR: 21.8-35.2%, I2 = 97.2%). There was no association between HCV Ab prevalence and Indigenous/tribal status for general populations (prevalence ratio = 0.91; 95% CI: 0.56, 1.49) or key risk groups. CONCLUSIONS: Indigenous and tribal peoples from the Western Pacific Region and recognised at-risk sub-populations had higher HCV prevalence. HCV prevalence showed no association with Indigenous/tribal status. However, this review was limited by heterogeneity and poor quality of constituent studies, varying definitions of Indigenous/tribal status, regional data gaps, and limited studies on chronic infection (HCV RNA). Comprehensive quality evidence on HCV epidemiology in Indigenous and tribal peoples is needed to tailor preventive and treatment interventions so these populations are not left behind in elimination efforts.

Molecular cloning of crustacean hyperglycemic hormone (CHH) family members (CHH, molt-inhibiting hormone and mandibular organ-inhibiting hormone) and their expression levels in the Jonah crab, Cancer borealis.

The crustacean hyperglycemic hormone (CHH) neuropeptide family has multiple functions in the regulation of hemolymph glucose levels, molting, ion, and water balance and reproduction. In crab species, three neuroendocrine tissues: the eyestalk ganglia (medulla terminalis X-organ and -sinus gland = ES), the pericardial organ (PO), and guts synthesize a tissue-specific isoforms of CHH neuropeptides. Recently the presence of the mandibular organ-inhibiting hormone (MOIH) was reported in the stomatogastric nervous system (STNS) that regulates the rhythmic muscle movements in esophagus, cardiac sac, gastric and pyloric ports of the foregut. In this study, we aimed to determine the presence of a tissue-specific CHH isoform in the Jonah crab, Cancer borealis using PCR with degenerate primers and 5', 3' rapid amplification of cDNA ends (RACE) in the ES. PO, and STNS. The analysis of CHH sequences shows that C. borealis has one type of CHH isoform, unlike other crab species. We also isolated the cDNA sequence of molt-inhibiting hormone (MIH) in the ES and MOIH in the ES and STNS. The presence of CHH, MOIH and MIH in the sinus gland of adult females and males is confirmed by using a dot-blot assay with the putative peaks collected from RP-HPLC and anti-Cancer sera for CHH, MIH, and MOIH. The present of crustacean female sex hormone (CFSH) in the sinus gland of adult females was examined with a dot-blot assay with anti-Callinectes CFSH serum. Levels of CHH, MOIH, and MIH in the sinus gland and their expressions in the eyestalk ganglia are estimated in the adult males, where CHH is the predominant form among these neuropeptides.

Psychologists' perspectives on supported decision making in Ireland.

BACKGROUND: A new legal capacity act was introduced in Ireland in 2015. This study aimed to identify and critically examine key issues in the area of decision-making capacity from the perspective of psychologists working with adults with an intellectual disability. METHODS: A qualitative exploratory approach was employed, and the study was positioned in a social constructionist framework. Purposive and snowballing sampling methods were used to recruit 15 clinical psychologists working with adults with an intellectual disability. Data were collected with the use of individual semistructured interviews. Interview transcripts were analysed using a model of thematic analysis. RESULTS: Six themes were identified: (1) a presumption of capacity but a culture of incapacity, (2) supporting decision making as a process, (3) authenticity of decision making, (4) need for support and training, (5) contributions of psychology and (6) the way forward. CONCLUSIONS: Participants described that people with intellectual disabilities were often excluded from decision-making processes. They welcomed the functional approach to decision making, considered substituted decision making to be necessary within a support framework and described supporting decision making as a process. Systemic, resource and attitudinal challenges were identified.

An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells.

The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). Here we report the discovery and characterization of the specific KDM5 inhibitor CPI-455. The crystal structure of KDM5A revealed the mechanism of inhibition of CPI-455 as well as the topological arrangements of protein domains that influence substrate binding. CPI-455 mediated KDM5 inhibition, elevated global levels of H3K4 trimethylation (H3K4me3) and decreased the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents. These findings show that pretreatment of cancer cells with a KDM5-specific inhibitor results in the ablation of a subpopulation of cancer cells that can serve as the founders for therapeutic relapse.

Multimodal analgesia using intrathecal diamorphine, and paravertebral and rectus sheath catheters are as effective as thoracic epidural for analgesia post-open two-phase esophagectomy within an enhanced recovery program.

Thoracic epidural (TE) analgesia has been the standard of care for transthoracic esophagectomy patients since the 1990s. Multimodal anesthesia using intrathecal diamorphine, local anesthetic infusion catheters (LAC) into the paravertebral space and rectus sheaths and intravenous opioid postoperatively represent an alternative option for postoperative analgesia. While TE can provide excellent pain control, it may inhibit early postoperative recovery by causing hypotension and reducing mobilization. The aim of this study is to determine whether multimodal analgesia with LAC was effective with respect to adequate pain management, and compare its impact on hypotension and mobility. Patients receiving multimodal LAC analgesia were matched using propensity score matching to patients undergoing two-phase trans-thoracic esophagectomy with a TE over a two-year period (from January 2015 to December 2016). Postoperative endpoints that had been evaluated prospectively, including pain scores on movement and at rest, inotrope or vasoconstrictor requirements, and hypotension (systolic BP < 90 mmHg), were compared between cohorts. Out of 14 patients (13 male) that received LAC were matched to a cohort of 14 patients on age, sex, and comorbidity. Mean and maximum pain scores at rest and movement on postoperative days 0 to 3 were equivalent between the groups. In both cohorts, 50% of patients had a pain score of more than 7 on at least one occasion. Fewer patients in the LAC group required vasoconstrictor infusion (LAC: 36% vs. TE: 57%, P = 0.256) to maintain blood pressure or had episodes of hypotension (LAC: 43% vs. TE: 79%, P = 0.05). The LAC group was more able to ambulate on the first postoperative day (LAC: 64% vs. TE: 43%, P = 0.14) but these differences were not statistically significant. Within the epidural cohort, three patients had interruption of epidural due to dislodgement or failure of block compared to no disruption in the multimodal local anesthesia catheters group (P = 0.05). Therefore, multimodal anesthesia using spinal diamorphine with combined paravertebral and rectus sheath local anesthetic catheters appears to provide comparable pain relief post two-phase esophagectomy and may provide more reliable and safe analgesia than the current standard of care.

Structural and Biophysical Characterization of the Mycobacterium tuberculosis Protein Rv0577, a Protein Associated with Neutral Red Staining of Virulent Tuberculosis Strains and Homologue of the Streptomyces coelicolor Protein KbpA.

Mycobacterium tuberculosis protein Rv0577 is a prominent antigen in tuberculosis patients, the component responsible for neutral red staining of virulent strains of M. tuberculosis, a putative component in a methylglyoxal detoxification pathway, and an agonist of toll-like receptor 2. It also has an amino acid sequence that is 36% identical to that of Streptomyces coelicolor AfsK-binding protein A (KbpA), a component in the complex secondary metabolite pathways in the Streptomyces genus. To gain insight into the biological function of Rv0577 and the family of KpbA kinase regulators, the crystal structure for Rv0577 was determined to a resolution of 1.75 Å, binding properties with neutral red and deoxyadenosine were surveyed, backbone dynamics were measured, and thermal stability was assayed by circular dichroism spectroscopy. The protein is composed of four approximate repeats with a ßαßßß topology arranged radially in consecutive pairs to form two continuous eight-strand ß-sheets capped on both ends with an α-helix. The two ß-sheets intersect in the center at roughly a right angle and form two asymmetric deep "saddles" that may serve to bind ligands. Nuclear magnetic resonance chemical shift perturbation experiments show that neutral red and deoxyadenosine bind to Rv0577. Binding to deoxyadenosine is weaker with an estimated dissociation constants of 4.1 ± 0.3 mM for saddle 1. Heteronuclear steady-state {1H}-15N nuclear Overhauser effect, T1, and T2 values were generally uniform throughout the sequence with only a few modest pockets of differences. Circular dichroism spectroscopy characterization of the thermal stability of Rv0577 indicated irreversible unfolding upon heating with an estimated melting temperature of 56 °C.

Focus group study to identify the central facets of fear of hypoglycaemia in people with Type 2 diabetes mellitus.

AIMS: To determine key worries about hypoglycaemia among insulin-using adults with Type 2 diabetes using a focus group approach. METHODS: Thirteen focus groups were conducted in three diabetes outpatient care units and one peer support group was set up, in Germany. A total of 64 insulin-dependent adults with Type 2 diabetes (36.5% women, mean age 65.2 ± 11.0 years) discussed their worries about hypoglycaemia. The qualitative results were assigned into thematic categories using a bottom-up coding procedure. Participants completed the Hypoglycaemia Fear Survey and demographic measures were recorded. The results of the Hypoglycaemia Fear Survey were contrasted with the focus group findings to evaluate how accurately the Hypoglycaemia Fear Survey comprehensively captures features of fear of hypoglycaemia in Type 2 diabetes. RESULTS: Eight themes were identified: 'unconsciousness/death'; 'aloneness/ helplessness', 'fear of hurting somebody'; 'shame'; 'loss of physical control'; 'long-term complications'; 'diabetes self-management issues'; and 'impaired awareness'. A total of 30 participants (46.9%) scored ≥3 on at least one item of the Hypoglycaemia Fear Survey worry subscale, indicating elevated worries. The Hypoglycaemia Fear Survey comprehensively captured all identified themes. Self-efficacy with regard to diabetes self-management seemed to play an important role in fear of hypoglycaemia in Type 2 diabetes. CONCLUSIONS: Given that even subclinical worries can have negative effects on quality of life and diabetes self-management, emphasis should be placed on diabetes education; in particular, to help patients to develop self-efficacy concerning diabetes self-management. The Hypoglycaemia Fear Survey comprehensively captures hypoglycaemia worries in Type 2 diabetes. Additional assessment of self-efficacy might be beneficial to identify people at risk of developing hypoglycaemia worries.

Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance.

Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance.

Identification of loci associated with late-onset psoriasis using dense genotyping of immune-related regions.

BACKGROUND: Chronic plaque psoriasis can be subdivided into two groups according to the age of onset: type 1 (early onset, before 40 years) and type 2 (late onset, at or beyond 40 years). So far, 36 genetic loci have been associated with early-onset psoriasis in genome-wide association studies of white populations, while few studies have investigated genetic susceptibility to late-onset psoriasis. OBJECTIVES: To characterize the genetics underpinning late-onset psoriasis. METHODS: We genotyped 543 cases of late-onset psoriasis and 4373 healthy controls using the Immunochip array, a dense genotyping chip containing single-nucleotide polymorphisms previously associated with autoimmune diseases. Imputation using SNP2HLA and stepwise logistic regression analysis was performed for markers spanning the human leucocyte antigen gene region. RESULTS: Two loci (HLA-C and IL12B) previously associated with early-onset psoriasis showed significant association at a genome-wide threshold in the current study (P < 5 × 10(-8)). Six more loci (TRAF3IP2, IL23R, RNF114, IFIH1, IL23A and HLA-A) showed study-wide significant association (P < 2·3 × 10(-5); calculated using Genetic type 1 error calculator). Additionally, we identified an association at IL1R1 on chromosome 2q13, which is not associated with early-onset disease. CONCLUSIONS: This is the largest study to date of genetic loci in late-onset psoriasis, and demonstrates the overlap that exists with early-onset psoriasis. It also suggests that some loci are associated exclusively with late-onset psoriasis.

Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases.

Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10(-5)): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

Diffusion-weighted magnetic resonance imaging for assessment of lung lesions: repeatability of the apparent diffusion coefficient measurement.

PURPOSE: To establish repeatability of apparent diffusion coefficients (ADCs) acquired from free-breathing diffusion-weighted magnetic resonance imaging (DW-MRI) in malignant lung lesions and investigate effects of lesion size, location and respiratory motion. METHODS: Thirty-six malignant lung lesions (eight patients) were examined twice (1- to 5-h interval) using T1-weighted, T2-weighted and axial single-shot echo-planar DW-MRI (b = 100, 500, 800 s/mm(2)) during free-breathing. Regions of interest around target lesions on computed b = 800 s/mm(2) images by two independent observers yielded ADC values from maps (pixel-by-pixel fitting using all b values and a mono-exponential decay model). Intra- and inter-observer repeatability was assessed per lesion, per patient and by lesion size (> or <2 cm) or location. RESULTS: ADCs were similar between observers (mean ± SD, 1.15 ± 0.28 × 10(-3) mm(2)/s, observer 1; 1.15 ± 0.29 × 10(-3) mm(2)/s, observer 2). Intra-observer coefficients of variation of the mean [median] ADC per lesion and per patient were 11% [11.4%], 5.7% [5.7%] for observer 1 and 9.2% [9.5%], 3.9% [4.7%] for observer 2 respectively; inter-observer values were 8.9% [9.3%] (per lesion) and 3.0% [3.7%] (per patient). Inter-observer coefficient of variation (CoV) was greater for lesions <2 cm (n = 20) compared with >2 cm (n = 16) (10.8% vs 6.5% ADCmean, 11.3% vs 6.7% ADCmedian) and for mid (n = 14) vs apical (n = 9) or lower zone (n = 13) lesions (13.9%, 2.7%, 3.8% respectively ADCmean; 14.2%, 2.8%, 4.7% respectively ADCmedian). CONCLUSION: Free-breathing DW-MRI of whole lung achieves good intra- and inter-observer repeatability of ADC measurements in malignant lung tumours. KEY POINTS: • Diffusion-weighted MRI of the lung can be satisfactorily acquired during free-breathing • DW-MRI demonstrates high contrast between primary and metastatic lesions and normal lung • Apparent diffusion coefficient (ADC) measurements in lung tumours are repeatable and reliable • ADC offers potential in assessing response in lung metastases in clinical trials.

An investigation of rheumatoid arthritis loci in patients with early-onset psoriasis validates association of the REL gene.

BACKGROUND: Phenotypically diverse autoimmune conditions share common genetic susceptibility loci and underlying molecular pathways. OBJECTIVES: By systematically searching for single nucleotide polymorphisms (SNPs) associated with another autoimmune disease, rheumatoid arthritis (RA), we aimed to elucidate novel genetic markers of psoriasis. METHODS: We investigated 18 SNPs, previously confirmed as being associated with RA, in a U.K. cohort of 623 patients with early-onset psoriasis (presenting before age 40 years), comparing them with 2662 control subjects. RESULTS: Our findings confirm the association of early-onset psoriasis with REL (rs13031237, P=0·0027). The minor allele of REL had opposing effects upon susceptibility to disease in patients with psoriasis and RA. CONCLUSION: Similar exploration of additional autoimmune loci and fine mapping of such regions may provide further insight into the genetics and molecular pathophysiology of psoriasis.

Breast dynamic contrast-enhanced examinations with fat suppression: are contrast-agent uptake curves affected by magnetic field inhomogeneity?

OBJECTIVES: To investigate the effect of magnetic field heterogeneity in breast dynamic contrast-enhanced examinations with fat saturation (DCE-FS). METHODS: The magnetic field was mapped over the breasts in ten patients. DCE-FS was undertaken at 1.5 T with fast spoiled gradient echoes and spectrally selective fat saturation. Signal intensity was calculated for T1 values 25-1,200 ms both on and off resonance, and results were verified with a test object. Clinical examinations were evaluated for the predicted effects of field heterogeneity. RESULTS: Magnetic field was found to vary by 3.6 ± 1.2 ppm over the central transaxial slice and 5.1 ± 1.5 over the whole breast volume (mean ± standard deviation). Computer simulations predict a reduction in the dynamic range if field heterogeneity leads to unintended water suppression, and distortion to CA uptake curves due to fat suppression failure (for fat containing pixels). A compromise between dynamic range and fat saturation performance is required. Both water suppression and fat suppression failure are apparent in clinical examinations. CONCLUSION: Magnetic field heterogeneity is likely to reduce the sensitivity of DCE-FS by distorting the CA uptake curves because of fat suppression failure (for fat containing pixels) and by reducing the dynamic range because of unintended water suppression. KEY POINTS: • Magnetic field heterogeneity is significant in breast magnetic resonance. • Contrast-agent uptake curves are distorted by a non-uniform magnetic field. • Radiologist must be aware of possibility of distortion to interpret uptake curves correctly. • Compromise between fat suppression and dynamic range is required.

A genetic marker at the OLIG3/TNFAIP3 locus associates with methotrexate continuation in early inflammatory polyarthritis: results from the Norfolk Arthritis Register.

Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.

Rapid death after admission to palliative care.

BACKGROUND: Palliative care units provide non-curative treatment and support to patients with terminal illness. Brief end-of-life admissions are disruptive for patients and their families, and increase staff stress. Extremely rapid deaths (survival <24 h from admission) are particularly challenging for all involved. From 1 January 2010 to 23 August 2011, 256 patients died on the Palliative Care Unit (Caritas Christi) at St Vincent's Hospital Melbourne. Forty-two died within 24 h (16%), while 214 survived beyond 24 h (84%). AIMS: A retrospective chart audit was conducted, aiming to identify factors characterising those patients who died within 24 h. METHODS: Groups were compared for age, gender, country of birth, preferred language, ward of origin, primary pathology, time trends, whether an emergency code was called, Palliative Care Outcomes Collaboration (PCOC) phase, modified Karnofsky score and commencement of a syringe driver for medication. RESULTS: Results showed that admission from neurosurgery (P= 0.0001), a vascular or infective pathology (P= 0.0001), PCOC phase ≥ 3 (P= 0.0001), modified Karnofsky score ≤ 20% (P= 0.0001), and commencement of a syringe driver prior to or at admission (P= 0.0001) were all significantly associated with death within 24 h of admission. On binary logistic regression, the only independent predictor of patients likely to die in <24 h from admission was PCOC phase ≥ 3 (P= 0.002).

General practitioner's reported use of clinical guidelines for hypertension and ambulatory blood pressure.

ABPM is an invaluable clinical tool, as it has been shown to improve blood pressure control in primary care. Many clinical guidelines for hypertension advocate ambulatory blood pressure monitoring. This study aims to quantify the use of clinical guidelines for hypertension and to explore the role of ABPM in Primary Care. A questionnaire survey was sent to GPs working in the West of Ireland. 88% (n=139) of GPs use clinical guidelines that recommend the use of ABPM. 82% (n=130) of GPs find use of clinic blood pressure monitoring insufficient for the diagnosis and monitoring of hypertension. Despite good access to ABPM, GPs report lack of remuneration, 72% (n=116), cost 68% (n=108), and lack of time, 51% (n=83) as the main limiting factors to use of ABPM. GPs recognise the clinical value of ABPM, but this study identifies definite barriers to the use of ABPM in Primary Care.

Trifluoroacetyl Lysine as a Bromodomain Binding Mimic of Lysine Acetylation.

Genetic code expansion has proven invaluable to the elucidation of functions of defined protein modifications through the site-specific incorporation of noncanonical amino acids. The use of nonhydrolyzable derivatives of post-translational modifications can greatly increase site stoichiometry and half-life. Investigating acetyllysine reader domain (bromodomain) interactions with acetylated nonhistone proteins is challenging due to the limited tools available and dynamic nature of this post-translational modification. Here, we demonstrate that bromodomains bind acetyllysine peptides and those substituted with an acetyllysine derivative, trifluoroacetyllysine, with similar affinity and selectivity. Importantly, both trifluoroacetyllysine and acetyllysine can be site-specifically incorporated into proteins expressed in bacterial and mammalian cells, and the strong electron-withdrawing trifluoro substituent makes the latter resistant to deacetylation by sirtuins (SIRTs). The controlled expression of SIRT-resistant, site-specifically acetylated transcription factors expands the set of available tools for determining the function of acetylation, and it serves as a template for investigating bromodomain interactions with acetylated transcription factors.

A systematic investigation of confirmed autoimmune loci in early-onset psoriasis reveals an association with IL2/IL21.

BACKGROUND: Many autoimmune diseases share common susceptibility loci suggesting similar underlying cellular mechanisms involved in disease expression. OBJECTIVES: The purpose of this investigation was to study 21 genetic variants in 14 genes that are confirmed autoimmune loci in a cohort of patients with early-onset psoriasis. METHODS: Patients with early-onset psoriasis (n = 750) and controls (n = 3531) were genotyped using the Sequenom(®) MassArray™ iPLEX Gold platform. RESULTS: We found strong evidence of association with two variants in the IL2/IL21 (rs6822844, genotypic P = 3·3 × 10(-4) ; rs2069778, genotypic P = 7·86 × 10(-4)) region. CONCLUSIONS: The findings, although requiring replication, suggest that IL2/IL21 may play a key role in the pathogenesis of psoriasis as well as in other diverse autoimmune diseases.

Critical components of the female reproductive pathway are suppressed by the angiogenesis inhibitor AGM-1470.

Angiogenesis, the growth of new blood vessels, occurs normally in female reproductive organs. We tested the hypothesis that angiogenesis inhibition may affect fertility by studying the reproductive system in either pregnant or nonpregnant cycling mice after treatment with the angiogenesis inhibitor AGM-1470. Administration of AGM-1470 to pregnant mice resulted in complete failure of embryonic growth due to interference with decidualization, placental and yolk sac formation, and embryonic vascular development. When nonpregnant cycling female mice were chronically treated with AGM-1470, inhibition of endometrial maturation and corpora lutea was observed. These data suggest that processes in reproduction can be controlled through angiogenesis inhibition.

Association of the CCR5 gene with juvenile idiopathic arthritis.

The CC chemokine receptor 5 (CCR5) has been shown to be important in the recruitment of T-helper cells to the synovium, where they accumulate, drive the inflammatory process and the consequent synovitis and joint destruction. A 32 base-pair insertion/deletion variant (CCR5Δ32) within the gene leads to a frame shift and a nonfunctional receptor. CCR5Δ32 has been investigated for its association with juvenile idiopathic arthritis (JIA), with conflicting results. The aim of this study was to investigate whether CCR5Δ32 is associated with JIA in an UK population. CCR5Δ32 was genotyped in JIA cases (n=1054) and healthy controls (n=3129) and genotype and allele frequencies were compared. A meta-analysis of our study combined with previously published studies was performed. CCR5Δ32 was significantly associated with protection from developing JIA, in this UK data set (P(trend)=0.006, odds ratio (OR) 0.79 95% confidence interval (95% CI): 0.66-0.94). The meta-analysis of all published case-control association studies confirmed the protective association with JIA (P=0.001 OR 0.82 95% CI: 0.73-0.93). CCR5Δ32 is a functional variant determining the number of receptors on the surface of T cells, and it is hypothesized that the level of CCR5 expression could influence the migration of proinflammatory T cells into the synovium and thus susceptibility to JIA.