Human antibodies induce arthritis in mice deficient in the low-affinity inhibitory IgG receptor FcγRIIB

Rheumatoid arthritis (RA) is a complex autoimmune disease with a poorly understood pathogenesis. The disease is associated with polyclonal B cell activation and the production of autoantibodies (autoAbs), but there is a longstanding controversy as to whether such Abs contribute to, or are secondary to, the pathogenesis of RA. To address the potential pathogenicity of human RA–associated Abs, we developed a passive transfer model involving mice deficient in the low-affinity inhibitory Fc receptor, FcγRIIB. We report that plasma or serum from patients with active RA can induce inflammation and histological lesions in FcγRIIB−/− mice consistent with arthritis, and that this pathogenic activity is caused by the immunoglobulin G–rich fraction. Our results suggest that humoral autoimmunity can contribute directly to autoimmune arthritis, and that FcγRIIB−/− mice are a promising model to evaluate the arthritogenic potential of human autoAbs

The polygenic nature of telomere length and the anti-ageing properties of lithium

Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%, with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10-5). Gene-enrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat gene, LRRC34 (p = 3.69 × 10-18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p  0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual's inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium's anti-ageing efficacy

Long term benzodiazepine use for insomnia in patients over the age of 60: discordance of patient and physician perceptions

BACKGROUND: The aim of this study was to determine and compare patients' and physicians' perceptions of benefits and risks of long term benzodiazepine use for insomnia in the elderly. METHODS: A cross-sectional study (written survey) was conducted in an academic primary care group practice in Toronto, Canada. The participants were 93 patients over 60 years of age using a benzodiazepine for insomnia and 25 physicians comprising sleep specialists, family physicians, and family medicine residents. The main outcome measure was perception of benefit and risk scores calculated from the mean of responses (on a Likert scale of 1 to 5) to various items on the survey. RESULTS: The mean perception of benefit score was significantly higher in patients than physicians (3.85 vs. 2.84, p < 0.001, 95% CI 0.69, 1.32). The mean perception of risk score was significantly lower in patients than physicians (2.21 vs. 3.63, p < 0.001, 95% CI 1.07, 1.77). CONCLUSIONS: There is a significant discordance between older patients and their physicians regarding the perceptions of benefits and risks of using benzodiazepines for insomnia on a long term basis. The challenge is to openly discuss these perceptions in the context of the available evidence to make collaborative and informed decisions

The microstructure of coaching practice:Behaviours and activities of an elite rugby union head coach during preparation and competition

The activities and behaviours of a female head coach of a national rugby union team were recorded in both training and competition, across a whole rugby season, using the newly developed Rugby Coach Activities and Behaviours Instrument (RCABI). The instrument incorporates 24 categories of behaviour, embedded within three forms of activity (training form, playing form and competitive match) and seven sub-activity types. In contrast to traditional drill-based coaching, 58.5% of training time was found to have been spent in playing form activities. Moreover, the proportion of playing form activities increased to a peak average of 83.8% in proximity to the team’s annual international championship. Uniquely, one of the coach’s most prolific behaviours was conferring with associates (23.3%), highlighting the importance of interactions with assistant coaches, medical staff and others in shaping the coaching process. Additionally, the frequencies of key behaviours such as questioning and praise were found to vary between the different activity forms and types, raising questions about previous conceptions of effective coaching practice. The findings are discussed in the light of the Game Sense philosophy and the role of the head coach

SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA

Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.

Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD

Impact of the Mitochondrial Genetic Background in Complex III Deficiency

BACKGROUND: In recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the pathogenic role of a novel homoplasmic mutation (m.15533 A>G) in the cytochrome b (MT-CYB) gene in a patient presenting with lactic acidosis, seizures, mild mental delay, and behaviour abnormalities. METHODOLOGY: Spectrophotometric analyses of the respiratory chain enzyme activities were performed in different tissues, the whole muscle mitochondrial DNA of the patient was sequenced, and the novel mutation was confirmed by PCR-RFLP. Transmitochondrial cybrids were constructed to confirm the pathogenicity of the mutation, and assembly/stability studies were carried out in fibroblasts and cybrids by means of mitochondrial translation inhibition in combination with blue native gel electrophoresis. PRINCIPAL FINDINGS: Biochemical analyses revealed a decrease in respiratory chain complex III activity in patient's skeletal muscle, and a combined enzyme defect of complexes III and IV in fibroblasts. Mutant transmitochondrial cybrids restored normal enzyme activities and steady-state protein levels, the mutation was mildly conserved along evolution, and the proband's mother and maternal aunt, both clinically unaffected, also harboured the homoplasmic mutation. These data suggested a nuclear genetic origin of the disease. However, by forcing the de novo functioning of the OXPHOS system, a severe delay in the biogenesis of the respiratory chain complexes was observed in the mutants, which demonstrated a direct functional effect of the mitochondrial genetic background. CONCLUSIONS: Our results point to possible pitfalls in the detection of pathogenic mitochondrial mutations, and highlight the role of the genetic mtDNA background in the development of mitochondrial disorders

The effect of EGM2008-based normal, normal-orthometric and Helmert orthometric height systems on the Australian levelling network

This paper investigates the normal-orthometric correction used in the definition of the Australian Height Datum, and also computes and evaluates normal and Helmert orthometric corrections for the Australian National Levelling Network (ANLN). Testing these corrections in Australia is important to establish which height system is most appropriate for any new Australian vertical datum. An approximate approach to assigning gravity values to ANLN benchmarks (BMs) is used, where the EGM2008-modelled gravity field is used to "re-construct" observed gravity at the BMs. Network loop closures (for first- and second-order levelling) indicate reduced misclosures for all height corrections considered, particularly in the mountainous regions of south eastern Australia. Differences between Helmert orthometric and normal-orthometric heights reach 44 cm in the Australian Alps, and differences between Helmert orthometric and normal heights are about 26 cm in the same region. Normal orthometric heights differ from normal heights by up to 18 cm in mountainous regions >2,000 m. This indicates that the quasigeoid is not compatible with normal-orthometric heights in Australia