Cut-and-run: a new mechanism by which V(D)J recombination could trigger leukaemia and lymphoma

V(D)J recombination generates a hugely diverse repertoire of antigen receptors through the random joining of antigen receptor gene segments. Recombination is catalysed by the RAG proteins which bind to and cleave recombination signal sequences (RSSs) that flank each coding segment. Since this reaction involves the introduction of double-strand breaks in the genome, it poses a major risk to genome stability. Indeed, 35-40% of lymphoid cancers have chromosome translocations that bear the hallmarks of mistakes in the production of antigen receptor genes. Recently, V(D)J recombination was proposed to trigger genome instability by a new mechanism called reintegration, where the by-product of recombination, the excised signal circle (ESC), is reinserted back into the genome at an RSS. I examined the cleavage step of reintegration and found that an ESC stimulates cleavage of an RSS, but not vice versa. For reintegration to occur, simultaneous cleavage at an RSS and ESC is required, so this finding suggests that reintegration may not occur as frequently as others have predicted. Instead, the ESCs could trigger double-strand breaks at RSSs and cryptic RSSs throughout the genome, whilst remaining intact after each cleavage event, in a proposed new mechanism called “cut-and-run”. I then investigated the molecular basis of asymmetric cleavage, and found that it is most likely caused by RAG proteins binding to both sides of an ESC simultaneously and obscuring the cleavage site. Using transfected extrachromosomal substrates, I found that RSS-ESC cleavage is also asymmetric in vivo. Finally, analysis of an endogenous ESC revealed that it is largely intact in a pro-B cell line, consistent with the cut-and-run hypothesis. Therefore, cut-and-run could be a potent source of genomic instability in developing lymphocytes that creates broken ends for chromosome translocations

Giving Competency Its Day in Court - In re Fellman

This Note will examine the decision in In re Fellman,4 where the Superior Court of Pennsylvania determined that the issue of competency was a matter for the courts, not arbitration, to determine.5 Furthermore, this Note will explain how Fellman is consistent with cases concerning different issues, but which similarly denied arbitrators authority based upon similar reasoning

One lithium level >1.0 mmol/L causes an acute decline in eGFR: findings from a retrospective analysis of a monitoring database

Objectives Lithium is a mainstay of bipolar disorder treatment, however, there are still differences in opinion on the effects of lithium use on renal function. The aim of this analysis was to determine if there is an association between short-term exposure to various elevated lithium levels and estimated-glomerular filtration rate (eGFR) at ≤3 months, 6 months (±3 months) and 1 year (±3 months) follow-up. Setting Norfolk-wide (UK) lithium register and database. Participants 699 patients from the Norfolk database. Primary outcome measures eGFR change from baseline at ≤3 months, 6 months (±3 months) and 1 year (±3 months) after exposure to a lithium level within these ranges: 0.81–1.0 mmol/L (group 2), 1.01–1.2 mmol/L (group 3) and 1.21–2.0 mmol/L (group 4). The reference group was patients whose lithium levels never exceeded 0.8 mmol/L. Results Compared to the reference group, groups 3 and 4 showed a significant decrease in eGFR in the first 3 months after exposure (p=0.047 and p=0.040). At 6 months (±3 months) postexposure group 4 still showed a decline in eGFR, however, this result was not significant (p=0.298). Conclusions These results show for the first time that a single incident of a lithium level >1.0 mmol/L is associated with a significant decrease in eGFR in the following 3 months when compared to patients whose lithium levels never exceeded 0.8 mmol/L. It is still not known whether the kidneys can recover this lost function and the impact that more than a single exposure to a level within these ranges can have on renal function. These results suggest that lithium level monitoring should be undertaken at least every 3 months, in line with current UK guidelines and not be reduced further until the impact of more than one exposure to these lithium levels has been fully established

Paradoxical Association of C-Reactive Protein with Endothelial Function in Rheumatoid Arthritis

Background: Within the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA).Methodology/Principal Findings: Patients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P<0.01).Conclusions/Significance: These findings argue against a causal role of CRP in atherogenesis and are consistent with a protective effect of CRP on EDNO bioavailability

Left ventricular rotational mechanics in Tanzanian children with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a common inherited hemoglobinopathy. Adults with SCD manifest both systolic and diastolic cardiac dysfunction, though the age of onset of dysfunction has not been defined. Left ventricular (LV) rotational mechanics have not been studied in children with SCD. The aim of this study was to investigate whether cardiac rotational mechanics differed between children with SCD and age-matched controls. METHODS: Basal and apical LV short-axis images were acquired prospectively in 213 patients with SCD (mean age, 14.1 ± 2.6 years) and 49 controls (mean age, 13.3 ± 2.8 years) from the Muhimbili Sickle Cohort in Dar es Salaam, Tanzania. The magnitude of basal and apical rotation, net twist angle, torsion, and untwist rate were obtained by two-dimensional speckle-tracking. The timing of events was normalized to aortic valve closure. RESULTS: Mean basal rotation was significantly lower in patients with SCD compared with controls (P = .012), although no difference was observed in apical rotation (P = .37). No statistically significant differences in torsion or net twist angle were detected. Rotation rate at the apex (P = .001) and base (P = .0004) were significantly slower in subjects with SCD compared with controls. Mean peak untwisting rate was also significantly slower in patients with SCD (P = .006). No associations were found between hemoglobin concentration and apical rotation, basal rotation, net twist, and torsion. CONCLUSION: This study demonstrates alterations in LV rotational mechanics in children with SCD, including lower basal rotation, peak differential twist, and untwist rate. These abnormalities denote subclinical changes in LV systolic and diastolic performance in children with SCD. Future work may reveal an association between rotational metrics and long-term patient outcomes

Pain measurement in rheumatic and musculoskeletal diseases: where to go from here? Report from a Special Interest Group at OMERACT 2018

Objective: Establishing a research agenda on standardizing pain measurement in clinical trials in rheumatic and musculoskeletal diseases (RMDs). Methods: Discussion during a meeting at OMERACT 2018, prepared by a systematic review of existing core outcome sets and a patient online survey. Results: Several key questions were debated: is pain a symptom or a disease? are pain core (sub)domains consistent across RMDs? how to account for pain mechanistic descriptors (e.g. central sensitization) in pain measurement? Conclusion: Characterizing and assessing the spectrum of pain experience across RMDs in a standardized fashion is the future objective of the OMERACT pain working group