Genetic background determines severity of Loxl1-mediated systemic and ocular elastosis in mice.

Pseudoexfoliation syndrome (PEX) is a systemic, age-related disorder characterized by elastosis and extracellular matrix deposits. Its most significant ocular manifestation is an aggressive form of glaucoma associated with variants in the gene encoding lysyl oxidase-like 1 (LOXL1). Depending upon the population, variants in LOXL1 can impart risk or protection for PEX, suggesting the importance of genetic context. As LOXL1 protein levels are lower and the degree of elastosis is higher in people with PEX, we studied Loxl1-deficient mice on three different genetic backgrounds: C57BL/6 (BL/6), 129S×C57BL/6 (50/50) and 129S. Early onset and high prevalence of spontaneous pelvic organ prolapse in BL/6 Loxl1-/- mice necessitated the study of mice that were <2 months old. Similar to pelvic organ prolapse, most elastosis endpoints were the most severe in BL/6 Loxl1-/- mice, including skin laxity, pulmonary tropoelastin accumulation, expansion of Schlemm's canal and dilation of intrascleral veins. Interestingly, intraocular pressure was elevated in 50/50 Loxl1-/- mice, depressed in BL/6 Loxl1-/- mice and unchanged in 129S Loxl1-/- mice compared to that of control littermates. Overall, the 129S background was protective against most elastosis phenotypes studied. Thus, repair of elastin-containing tissues is impacted by the abundance of LOXL1 and genetic context in young animals.

An Effective and Safe Novel Treatment of Opioid Use Disorder: Unilateral Transcranial Photobiomodulation.

Background: The opioid epidemic is a global tragedy even with current treatments, and a novel, safe, and effective treatment would be welcomed. We report here our findings from our second randomized controlled trial to evaluate unilateral transcranial photobiomodulation as a treatment for opioid use disorder. Methods: We enrolled 39 participants with active opioid cravings at 2 sites, 19 received the active treatment which consisted of a 4-min twice weekly (every 3 or 4 days) application of a light-emitting diode at 810 nm with an irradiance of 250 mW/cm2 and a fluence of 60 J/cm2 to the forehead over either the left or right dorsolateral prefrontal cortex with a fluence to the brain of 2.1 J/cm2. Twenty participants received a sham treatment with the same device with foil over the bulb. The side of the treatment was based on Dual-Brain Psychology, which posits that one hemisphere is more affected by past maltreatments and is more prone to anxiety and drug cravings that the other hemisphere. We treated the hemisphere with the more positive hemispheric emotional valence (HEV) by 2 tests for HEV. Results: Our primary outcome was changes in pre-treatment opioid craving scale (OCS) minus baseline, and we found using a mixed model that the active group had a highly significant treatment * time benefit over the sham group, p < 0.0001, effect size at the last follow-up of 1.5. The active treatment benefited those not on buprenorphine as well as those not on it. The TimeLine Follow Back measure of opioid use was significantly better in the actively treated group, p = 0.0001, with an effect size of 0.45. We observed no adverse effects. Conclusion: Active unilateral transcranial photobiomodulation to the brain hemisphere with the better HEV was better than sham in the reduction of opioid cravings and opioid use to a very significant degree in a RCT of 39 participants at 2 independent sites. In the active group those on buprenorphine and those not on it both had improvements in cravings over the study. No adverse responses were reported in either group. ClinicalTrials.gov Identifier: NCT04340622.

A Novel Treatment of Opioid Cravings With an Effect Size of .73 for Unilateral Transcranial Photobiomodulation Over Sham.

BACKGROUND: Opioid use disorders (OUDs) are an epidemic causing catastrophic consequences to individuals, families, and society despite treatments including psychotherapy, substitution therapy or receptor blockers, and psychoeducation. We have developed a novel treatment that combines unilateral transcranial photobiomodulation (t-PBM) to the hemisphere with a more positive valence by Dual Brain Psychology (DBP). METHODS: We used a randomized, double blind, placebo-controlled protocol in which 22 patients with significant opioid cravings and a history of recent or current OUD attended three 1-h weekly sessions. After baseline measures of opioid craving and other psychometrics, subjects received two unilateral t-PBM applications (810 nm CW LED, 250 mW/cm2, 60 J/cm2, 4 min) or a sham (foil-covered LED) at F3 or F4. Prior to any treatment we used two tests to determine which hemisphere was more associated with a negative outlook and cravings and treated that side before the more positive hemisphere. Primary outcome measure was an opioid craving scale (OCS). Secondary outcomes were weekly Hamilton Depression (HDRS) and Anxiety (HARS) Rating Scales prior to treatments and at follow-up. RESULTS: Immediately after treatment the OCS improved significantly for both the sham and active treatments, but one week later the active treatment showed a 51.0% (SD 33.7) decrease in OCS while a week after the sham treatments there was a decrease of only 15.8% (SD 35.0) (by Wilcoxon Sign Rank Test, p = 0.004) and by a mixed model it was p = 0.0071. The effect size for the differences between active and sham was 0.73. For the active treatment from before and after treatment the effect size was 1.51 and for the sham, 0.45. The HDRS improved from a baseline of 15.1 to 8.8 (SD 10.3) a week after the active treatment and to 13.3 (SD 12.9) after the sham (p = 0.0071). HARS improved from 14.7 to 8.0 (SD 13.2) after the active treatments and to 14.3 (SD 16.0) after the sham, p = 0.08. Active treatment of the positive hemisphere after the negative hemisphere significantly improved the OCS, but there was no significant difference after the sham treatment. One patient complained of 2 h of abdominal bloating and dropped out; no other adverse effects were observed. DISCUSSION: Unilateral t-PBM to the hemisphere with a more positive hemispheric emotional valence was an effective and safe treatment for opioid cravings as well as for depression and anxiety. Our results also lend support to the underlying premises of DBP.

Development of advanced signal processing and source imaging methods for superparamagnetic relaxometry.

Superparamagnetic relaxometry (SPMR) is a highly sensitive technique for the in vivo detection of tumor cells and may improve early stage detection of cancers. SPMR employs superparamagnetic iron oxide nanoparticles (SPION). After a brief magnetizing pulse is used to align the SPION, SPMR measures the time decay of SPION using super-conducting quantum interference device (SQUID) sensors. Substantial research has been carried out in developing the SQUID hardware and in improving the properties of the SPION. However, little research has been done in the pre-processing of sensor signals and post-processing source modeling in SPMR. In the present study, we illustrate new pre-processing tools that were developed to: (1) remove trials contaminated with artifacts, (2) evaluate and ensure that a single decay process associated with bounded SPION exists in the data, (3) automatically detect and correct flux jumps, and (4) accurately fit the sensor signals with different decay models. Furthermore, we developed an automated approach based on multi-start dipole imaging technique to obtain the locations and magnitudes of multiple magnetic sources, without initial guesses from the users. A regularization process was implemented to solve the ambiguity issue related to the SPMR source variables. A procedure based on reduced chi-square cost-function was introduced to objectively obtain the adequate number of dipoles that describe the data. The new pre-processing tools and multi-start source imaging approach have been successfully evaluated using phantom data. In conclusion, these tools and multi-start source modeling approach substantially enhance the accuracy and sensitivity in detecting and localizing sources from the SPMR signals. Furthermore, multi-start approach with regularization provided robust and accurate solutions for a poor SNR condition similar to the SPMR detection sensitivity in the order of 1000 cells. We believe such algorithms will help establishing the industrial standards for SPMR when applying the technique in pre-clinical and clinical settings.

Breaking up prolonged sitting time with walking does not affect appetite or gut hormone concentrations but does induce an energy deficit and suppresses postprandial glycaemia in sedentary adults.

Breaking up periods of prolonged sitting can negate harmful metabolic effects but the influence on appetite and gut hormones is not understood and is investigated in this study. Thirteen sedentary (7 female) participants undertook three 5-h trials in random order: (i) uninterrupted sitting (SIT), (ii) seated with 2-min bouts of light-intensity walking every 20 min (SIT + LA), and (iii) seated with 2-min bouts of moderate-intensity walking every 20 min (SIT + MA). A standardised test drink was provided at the start of each trial and an ad libitum pasta test meal provided at the end of each trial. Subjective appetite ratings and plasma acylated ghrelin, peptide YY, insulin, and glucose were measured at regular intervals. Area under the curve (AUC) was calculated for each variable. AUC values for appetite and gut hormone concentrations were unaffected in the activity breaks conditions compared with uninterrupted sitting (linear mixed modelling: p > 0.05). Glucose AUC was lower in SIT + MA than in SIT + LA (p = 0.004) and SIT (p = 0.055). There was no difference in absolute ad libitum energy intake between conditions (p > 0.05); however, relative energy intake was lower in SIT + LA (39%; p = 0.011) and SIT + MA (120%; p < 0.001) than in SIT. In conclusion, breaking up prolonged sitting does not alter appetite and gut hormone responses to a meal over a 5-h period. Increased energy expenditure from activity breaks could promote an energy deficit that is not compensated for in a subsequent meal.

Magnetic relaxometry as applied to sensitive cancer detection and localization.

BACKGROUND: Here we describe superparamagnetic relaxometry (SPMR), a technology that utilizes highly sensitive magnetic sensors and superparamagnetic nanoparticles for cancer detection. Using SPMR, we sensitively and specifically detect nanoparticles conjugated to biomarkers for various types of cancer. SPMR offers high contrast in vivo, as there is no superparamagnetic background, and bones and tissue are transparent to the magnetic fields. METHODS: In SPMR measurements, a brief magnetizing pulse is used to align superparamagnetic nanoparticles of a discrete size. Following the pulse, an array of superconducting quantum interference detectors (SQUID) sensors detect the decaying magnetization field. NP size is chosen so that, when bound, the induced field decays in seconds. They are functionalized with specific biomarkers and incubated with cancer cells in vitro to determine specificity and cell binding. For in vivo experiments, functionalized NPs are injected into mice with xenograft tumors, and field maps are generated to localize tumor sites. RESULTS: Superparamagnetic NPs developed here have small size dispersion. Cell incubation studies measure specificity for different cell lines and antibodies with very high contrast. In vivo animal measurements verify SPMR localization of tumors. Our results indicate that SPMR possesses sensitivity more than 2 orders of magnitude better than previously reported.

Modeling the efficiency of a magnetic needle for collecting magnetic cells.

As new magnetic nanoparticle-based technologies are developed and new target cells are identified, there is a critical need to understand the features important for magnetic isolation of specific cells in fluids, an increasingly important tool in disease research and diagnosis. To investigate magnetic cell collection, cell-sized spherical microparticles, coated with superparamagnetic nanoparticles, were suspended in (1) glycerine-water solutions, chosen to approximate the range of viscosities of bone marrow, and (2) water in which 3, 5, 10 and 100% of the total suspended microspheres are coated with magnetic nanoparticles, to model collection of rare magnetic nanoparticle-coated cells from a mixture of cells in a fluid. The magnetic microspheres were collected on a magnetic needle, and we demonstrate that the collection efficiency versus time can be modeled using a simple, heuristically-derived function, with three physically-significant parameters. The function enables experimentally-obtained collection efficiencies to be scaled to extract the effective drag of the suspending medium. The results of this analysis demonstrate that the effective drag scales linearly with fluid viscosity, as expected. Surprisingly, increasing the number of non-magnetic microspheres in the suspending fluid results increases the collection of magnetic microspheres, corresponding to a decrease in the effective drag of the medium.

Commensal microbiota stimulate systemic neutrophil migration through induction of serum amyloid A.

Neutrophils serve critical roles in inflammatory responses to infection and injury, and mechanisms governing their activity represent attractive targets for controlling inflammation. The commensal microbiota is known to regulate the activity of neutrophils and other leucocytes in the intestine, but the systemic impact of the microbiota on neutrophils remains unknown. Here we utilized in vivo imaging in gnotobiotic zebrafish to reveal diverse effects of microbiota colonization on systemic neutrophil development and function. The presence of a microbiota resulted in increased neutrophil number and myeloperoxidase expression, and altered neutrophil localization and migratory behaviours. These effects of the microbiota on neutrophil homeostasis were accompanied by an increased recruitment of neutrophils to injury. Genetic analysis identified the microbiota-induced acute phase protein serum amyloid A (Saa) as a host factor mediating microbial stimulation of tissue-specific neutrophil migratory behaviours. In vitro studies revealed that zebrafish cells respond to Saa exposure by activating NF-κB, and that Saa-dependent neutrophil migration requires NF-κB-dependent gene expression. These results implicate the commensal microbiota as an important environmental factor regulating diverse aspects of systemic neutrophil development and function, and reveal a critical role for a Saa-NF-κB signalling axis in mediating neutrophil migratory responses.

Identification of the tyrosine-protein phosphatase non-receptor type 2 as a rheumatoid arthritis susceptibility locus in europeans.

OBJECTIVES: Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA. METHODS: A cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data. RESULTS: Significant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4×10(-9)). CONCLUSIONS: This study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase) with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene.

Development of antibody-tagged nanoparticles for detection of transplant rejection using biomagnetic sensors.

Organ transplantation is a life-saving procedure and the preferred method of treatment for a growing number of disease states. The advent of new immunosuppressants and improved care has led to great advances in both patient and graft survival. However, acute T-cell-mediated graft rejection occurs in a significant quantity of recipients and remains a life-threatening condition. Acute rejection is associated with decrease in long-term graft survival, demonstrating a need to carefully monitor transplant patients. Current diagnostic criteria for transplant rejection rely on invasive tissue biopsies or relatively nonspecific clinical features. A noninvasive way is needed to detect, localize, and monitor transplant rejection. Capitalizing on advances in targeted contrast agents and magnetic-based detection technology, we developed anti-CD3 antibody-tagged nanoparticles. T cells were found to bind preferentially to antibody-tagged nanoparticles, as identified through light microscopy, transmission electron microscopy, and confocal microscopy. Using mouse skin graft models, we were also able to demonstrate in vivo vascular delivery of T-cell targeted nanoparticles. We conclude that targeting lymphocytes with magnetic nanoparticles is conducive to developing a novel, noninvasive strategy for identifying transplant rejection.

Investigation of rheumatoid arthritis genetic susceptibility markers in the early rheumatoid arthritis study further replicates the TRAF1 association with radiological damage.

OBJECTIVE: The TRAF1 genetic region conferring susceptibility to rheumatoid arthritis (RA) has been reported to associate with radiological damage. We aimed to test RA genetic susceptibility markers for association with a continuous measure of radiological damage over time using longitudinal modeling techniques. METHODS: Sixty-seven RA susceptibility variants were genotyped in 474 patients in the Early Rheumatoid Arthritis Study (ERAS) using Sequenom MassArray technology. Correlation between genetic markers and Larsen score was assessed longitudinally using zero-inflated negative binomial regression to include repeat measurements in the same individual at different timepoints. Genetic markers associated with radiological damage in ERAS were tested using the same modeling techniques on previously published data from the Norfolk Arthritis Register (NOAR). RESULTS: The single marker associated longitudinally with Larsen score in ERAS (p = 0.02) and in NOAR (p = 0.04) was rs2900180 at the TRAF1 locus. Analysis of individual timepoints in ERAS showed that rs2900180 displays its effect primarily on the extent of Larsen score early in the disease course. Combined longitudinal analysis of the 2 cohorts suggests further association of several loci with Larsen score (KIF5A, PTPN22, AFF3, TAGAP) and therefore a significant accumulation of RA severity markers among RA susceptibility markers (p = 0.016). CONCLUSION: The marker rs2900180 is associated with the extent of radiological damage in the ERAS cohort. This represents the second independent study correlating rs2900180 at the TRAF1 locus with radiological severity in RA. Replication in a large dataset is required to establish the role of other RA susceptibility loci in disease severity.

Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease.

INTRODUCTION: The largest genetic risk to develop rheumatoid arthritis (RA) arises from a group of alleles of the HLA DRB1 locus ('shared epitope', SE). Over 30 non-HLA single nucleotide polymorphisms (SNPs) predisposing to disease have been identified in Caucasians, but they have never been investigated in West/Central Africa. We previously reported a lower prevalence of the SE in RA patients in Cameroon compared to European patients and aimed in the present study to investigate the contribution of Caucasian non-HLA RA SNPs to disease susceptibility in Black Africans. METHODS: RA cases and controls from Cameroon were genotyped for Caucasian RA susceptibility SNPs using Sequenom MassArray technology. Genotype data were also available for 5024 UK cases and 4281 UK controls and for 119 Yoruba individuals in Ibadan, Nigeria (YRI, HapMap). A Caucasian aggregate genetic-risk score (GRS) was calculated as the sum of the weighted risk-allele counts. RESULTS: After genotyping quality control procedures were performed, data on 28 Caucasian non-HLA susceptibility SNPs were available in 43 Cameroonian RA cases and 44 controls. The minor allele frequencies (MAF) were tightly correlated between Cameroonian controls and YRI individuals (correlation coefficient 93.8%, p = 1.7E-13), and they were pooled together. There was no correlation between MAF of UK and African controls; 13 markers differed by more than 20%. The MAF for markers at PTPN22, IL2RA, FCGR2A and IL2/IL21 was below 2% in Africans. The GRS showed a strong association with RA in the UK. However, the GRS did not predict RA in Africans (OR = 0.71, 95% CI 0.29 - 1.74, p = 0.456). Random sampling from the UK cohort showed that this difference in association is unlikely to be explained by small sample size or chance, but is statistically significant with p<0.001. CONCLUSIONS: The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in West/Central Africa. The genetic risk of developing RA conferred by a set of 28 Caucasian susceptibility SNPs is significantly different between the UK and Africa with p<0.001. Taken together, these observations strengthen the hypothesis that the genetic architecture of RA susceptibility is different in different ethnic backgrounds.

Correlation of C-reactive protein haplotypes with serum C-reactive protein level and response to anti-tumor necrosis factor therapy in UK rheumatoid arthritis patients: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort.

INTRODUCTION: In many European countries, restrictions exist around the prescription of anti-tumor necrosis factor (anti-TNF) treatments for rheumatoid arthritis (RA). Eligibility and response to treatment is assessed by using the disease activity score 28 (DAS28) algorithm, which incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Although DAS28-CRP provides a more reliable measure of disease activity, functional variants exist within the CRP gene that affect basal CRP production. METHODS: DNA samples from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) were genotyped for rs1205, rs1800947, and rs3091244 by using either TaqMan or the Sequenom MassARRAY iPLEX system. RESULTS: Baseline CRP measurements were available for 599 samples with 442 also having data 6 months after treatment with an anti-TNF. For these 442 samples, the study had > 80% power to detect a clinically meaningful difference of 0.6 DAS28 Units for an allele frequency of 5%. Estimated haplotype frequencies corresponded with previous frequencies reported in the literature. Overall, no significant association was observed between any of the markers investigated and baseline CRP levels. Further, CRP haplotypes did not correlate with baseline CRP (P = 0.593), baseline DAS28-CRP (P = 0.540), or change in DAS28-CRP after treatment with an anti-TNF over a 6-month period (P = 0.302). CONCLUSIONS: Although CRP genotype may influence baseline CRP levels, in patients with very active disease, no such association was found. This suggests that genetic variation at the CRP locus does not influence DAS28-CRP, which may continue to be used in determining eligibility for and response to anti-TNF treatment, without adjusting for CRP genotype.

LRP1-dependent endocytic mechanism governs the signaling output of the bmp system in endothelial cells and in angiogenesis.

RATIONALE: Among the extracellular modulators of Bmp (bone morphogenetic protein) signaling, Bmper (Bmp endothelial cell precursor-derived regulator) both enhances and inhibits Bmp signaling. Recently we found that Bmper modulates Bmp4 activity via a concentration-dependent, endocytic trap-and-sink mechanism. OBJECTIVE: To investigate the molecular mechanisms required for endocytosis of the Bmper/Bmp4 and signaling complex and determine the mechanism of Bmper's differential effects on Bmp4 signaling. METHODS AND RESULTS: Using an array of biochemical and cell biology techniques, we report that LRP1 (LDL receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a coreceptor of Bmp4 to mediate the endocytosis of the Bmper/Bmp4 signaling complex. Furthermore, we demonstrate that LRP1-dependent Bmper/Bmp4 endocytosis is essential for Bmp4 signaling, as evidenced by the phenotype of lrp1-deficient zebrafish, which have abnormal cardiovascular development and decreased Smad1/5/8 activity in key vasculogenic structures. CONCLUSIONS: Together, these data reveal a novel role for LRP1 in the regulation of Bmp4 signaling by regulating receptor complex endocytosis. In addition, these data introduce LRP1 as a critical regulator of vascular development. These observations demonstrate Bmper's ability to fine-tune Bmp4 signaling at the single-cell level, unlike the spatial regulatory mechanisms applied by other Bmp modulators.

Magnetic Relaxometry with an Atomic Magnetometer and SQUID Sensors on Targeted Cancer Cells.

Magnetic relaxometry methods have been shown to be very sensitive in detecting cancer cells and other targeted diseases. Superconducting Quantum Interference Device (SQUID) sensors are one of the primary sensor systems used in this methodology because of their high sensitivity with demonstrated capabilities of detecting fewer than 100,000 magnetically-labeled cancer cells. The emerging technology of atomic magnetometers (AM) represents a new detection method for magnetic relaxometry with high sensitivity and without the requirement for cryogens. We report here on a study of magnetic relaxometry using both AM and SQUID sensors to detect cancer cells that are coated with superparamagnetic nanoparticles through antibody targeting. The AM studies conform closely to SQUID sensor results in the measurement of the magnetic decay characteristics following a magnetization pulse. The AM and SQUID sensor data are well described theoretically for superparamagnetic particles bound to cells and the results can be used to determine the number of cells in a cell culture or tumor. The observed fields and magnetic moments of cancer cells are linear with the number of cells over a very large range. The AM sensor demonstrates very high sensitivity for detecting magnetically labeled cells does not require cryogenic cooling and is relatively inexpensive.

Imaging of Her2-targeted magnetic nanoparticles for breast cancer detection: comparison of SQUID-detected magnetic relaxometry and MRI.

Both magnetic relaxometry and magnetic resonance imaging (MRI) can be used to detect and locate targeted magnetic nanoparticles, noninvasively and without ionizing radiation. Magnetic relaxometry offers advantages in terms of its specificity (only nanoparticles are detected) and the linear dependence of the relaxometry signal on the number of nanoparticles present. In this study, detection of single-core iron oxide nanoparticles by superconducting quantum interference device (SQUID)-detected magnetic relaxometry and standard 4.7 T MRI are compared. The nanoparticles were conjugated to a Her2 monoclonal antibody and targeted to Her2-expressing MCF7/Her2-18 (breast cancer cells); binding of the nanoparticles to the cells was assessed by magnetic relaxometry and iron assay. The same nanoparticle-labeled cells, serially diluted, were used to assess the detection limits and MR relaxivities. The detection limit of magnetic relaxometry was 125 000 nanoparticle-labeled cells at 3 cm from the SQUID sensors. T(2)-weighted MRI yielded a detection limit of 15 600 cells in a 150 µl volume, with r(1) = 1.1 mm(-1) s(-1) and r(2) = 166 mm(-1) s(-1). Her2-targeted nanoparticles were directly injected into xenograft MCF7/Her2-18 tumors in nude mice, and magnetic relaxometry imaging and 4.7 T MRI were performed, enabling direct comparison of the two techniques. Co-registration of relaxometry images and MRI of mice resulted in good agreement. A method for obtaining accurate quantification of microgram quantities of iron in the tumors and liver by relaxometry was also demonstrated. These results demonstrate the potential of SQUID-detected magnetic relaxometry imaging for the specific detection of breast cancer and the monitoring of magnetic nanoparticle-based therapies.

Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap.

OBJECTIVES: Rheumatoid arthritis (RA) shares some similar clinical and pathological features with juvenile idiopathic arthritis (JIA); indeed, the strategy of investigating whether RA susceptibility loci also confer susceptibility to JIA has already proved highly successful in identifying novel JIA loci. A plethora of newly validated RA loci has been reported in the past year. Therefore, the aim of this study was to investigate these single nucleotide polymorphisms (SNP) to determine if they were also associated with JIA. METHODS: Thirty-four SNP that showed validated association with RA and had not been investigated previously in the UK JIA cohort were genotyped in JIA cases (n=1242), healthy controls (n=4281), and data were extracted for approximately 5380 UK Caucasian controls from the Wellcome Trust Case-Control Consortium 2. Genotype and allele frequencies were compared between cases with JIA and controls using PLINK. A replication cohort of 813 JIA cases and 3058 controls from the USA was available for validation of any significant findings. RESULTS: Thirteen SNP showed significant association (p<0.05) with JIA and for all but one the direction of association was the same as in RA. Of the eight loci that were tested, three showed significant association in the US cohort. CONCLUSIONS: A novel JIA susceptibility locus was identified, CD247, which represents another JIA susceptibility gene whose protein product is important in T-cell activation and signalling. The authors have also confirmed association of the PTPN2 and IL2RA genes with JIA, both reaching genome-wide significance in the combined analysis.

Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort.

OBJECTIVE: A number of rheumatoid arthritis (RA) susceptibility genes have been identified in recent years. Given the overlap in phenotypic expression of synovial joint inflammation between RA and psoriatic arthritis (PsA), the authors explored whether RA susceptibility genes are also associated with PsA. METHODS: 56 single nucleotide polymorphisms (SNPs) mapping to 41 genes previously reported as RA susceptibility loci were selected for investigation. PsA was defined as an inflammatory arthritis associated with psoriasis and subjects were recruited from the UK and Ireland. Genotyping was performed using the Sequenom MassArray platform and frequencies compared with data derived from large UK control collections. RESULTS: Significant evidence for association with susceptibility to PsA was found toa SNP mapping to the REL (rs13017599, p(trend)=5.2×10(4)) gene, while nominal evidence for association (p(trend)<0.05) was found to seven other loci including PLCL2 (rs4535211, p=1.7×10(-3)); STAT4 (rs10181656, p=3.0×10(-3)) and the AFF3, CD28, CCL21, IL2 and KIF5A loci. Interestingly, three SNPs demonstrated opposite effects to those reported for RA. CONCLUSIONS: The REL gene, a key modulator of the NFκB pathway, is associated with PsA but the allele conferring risk to RA is protective in PsA suggesting that there are fundamental differences in the aetiological mechanisms underlying these two types of inflammatory arthritis.