Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: sequential not parallel processes

Background\ud \ud Ankylosing spondylitis (AS) is an immune-mediated arthritis particularly targeting the spine and pelvis and is characterised by inflammation, osteoproliferation and frequently ankylosis. Current treatments that predominately target inflammatory pathways have disappointing efficacy in slowing disease progression. Thus, a better understanding of the causal association and pathological progression from inflammation to bone formation, particularly whether inflammation directly initiates osteoproliferation, is required.\ud \ud Methods\ud \ud The proteoglycan-induced spondylitis (PGISp) mouse model of AS was used to histopathologically map the progressive axial disease events, assess molecular changes during disease progression and define disease progression using unbiased clustering of semi-quantitative histology. PGISp mice were followed over a 24-week time course. Spinal disease was assessed using a novel semi-quantitative histological scoring system that independently evaluated the breadth of pathological features associated with PGISp axial disease, including inflammation, joint destruction and excessive tissue formation (osteoproliferation). Matrix components were identified using immunohistochemistry.\ud \ud Results\ud \ud Disease initiated with inflammation at the periphery of the intervertebral disc (IVD) adjacent to the longitudinal ligament, reminiscent of enthesitis, and was associated with upregulated tumor necrosis factor and metalloproteinases. After a lag phase, established inflammation was temporospatially associated with destruction of IVDs, cartilage and bone. At later time points, advanced disease was characterised by substantially reduced inflammation, excessive tissue formation and ectopic chondrocyte expansion. These distinct features differentiated affected mice into early, intermediate and advanced disease stages. Excessive tissue formation was observed in vertebral joints only if the IVD was destroyed as a consequence of the early inflammation. Ectopic excessive tissue was predominantly chondroidal with chondrocyte-like cells embedded within collagen type II- and X-rich matrix. This corresponded with upregulation of mRNA for cartilage markers Col2a1, sox9 and Comp. Osteophytes, though infrequent, were more prevalent in later disease.\ud \ud Conclusions\ud \ud The inflammation-driven IVD destruction was shown to be a prerequisite for axial disease progression to osteoproliferation in the PGISp mouse. Osteoproliferation led to vertebral body deformity and fusion but was never seen concurrent with persistent inflammation, suggesting a sequential process. The findings support that early intervention with anti-inflammatory therapies will be needed to limit destructive processes and consequently prevent progression of AS

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Efficiency of early selection for rotation-aged wood quality traits in radiata pine

A total of 360 bark-to-bark-through-pith wood strips were sampled at breast height from 180 trees in 30 open-pollinated families from two rotation-aged genetic trials to study inheritance, age-age genetic correlation, and early selection efficiency for wood quality traits in radiata pine. Wood strips were evaluated by SilviScan$^\circledR$ and annual pattern and genetic parameters for growth, wood density, microfibril angle (MFA), and stiffness (modulus of elasticity: MOE) for early to rotation ages were estimated. Annual ring growth was the largest between ages 2–5 years from pith, and decreased linearly to ages 9–10. Annual growth was similar and consistent at later ages. Wood density was the lowest near the pith, increased steadily to age 11–15 years, then was relatively stable after these ages. MFA was highest (35°) near the pith and reduced to about 10° at age 10–15 years. MFA was almost unchanged at later ages. MOE increased from about 2.5 GPa near the pith to about 20 GPa at ages 11–15 years. MOE was relatively unchanged at later ages. Wood density and MOE were inversely related to MFA. Heritability increased from zero near the pith and stabilised at ages 4 or 5 for all four growth and wood quality traits (DBH, density, MFA and MOE). Across age classes, heritability was the highest for area-weighted density and MFA, lowest for DBH, and intermediate for MOE. Age-age genetic correlations were high for the four traits studied. The genetic correlation reached 0.8 after age 7 for most traits. Early selection for density, MFA and MOE were very effective. Selection at age 7–8 has similar effectiveness as selection conducted at rotation age for MFA and MOE and at least 80% effective for wood density.Efficacité d'une sélection précoce pour les propriétés du bois adulte chez le pin radiata. Cette étude a pour objectif d'estimer les paramètres génétiques (héritabilités et corrélations juvéniles-adultes) pour différentes propriétés du bois chez le pin radiata et d'évaluer l'efficacité d'une sélection précoce. Trois cent soixante échantillons diamétraux de bois ont été prélevés dans deux dispositifs génétiques adultes sur trente familles de pin radiata issues de pollinisation libre, puis analysés avec le SilviScan$^\circledR$. Les caractéristiques annuelles de la croissance, de la densité du bois, de l'angle des microfibrilles (MFA) et de la rigidité (module d'élasticité : MOE) ont été analysées et les paramètres génétiques de ces caractères ont été estimés du stade juvénile à l'âge de la révolution. La croissance radiale est la plus forte entre 2 et 5 ans (depuis la moelle) puis décroît linéairement jusqu'à neuf–dix ans et se stabilise ensuite. La densité du bois est la plus faible près de la moelle ; elle augmente fortement jusqu'à 11–15 ans puis se stabilise. MFA est le plus élevé (35°) près de la moelle ; il diminue ensuite pour atteindre environ 10° vers 10–15 ans. MFA ne varie pratiquement plus au-delà de cet âge. MOE passe de 2.5 GPa près de la moelle à environ 20 GPa à 11–15 ans. Il se stabilise ensuite. L'évolution de la densité du bois et de MOE au cours du temps est donc inverse de celle de MFA. L'héritabilité, égale à 0 près du cœur, augmente ensuite et se stabilise vers 4–5 ans pour tous les caractères de croissance et les propriétés du bois (diamètre, densité, MFA, MOE). Quel que soit l'âge, l'héritabilité est la plus élevée pour la densité et MFA, la plus faible pour le diamètre et intermédiaire pour MOE. Les corrélations âge-âge sont fortes pour tous les caractères étudiés. Les corrélations génétiques atteignent 0.8 après 7 ans pour la plupart des caractères. Une sélection précoce pour la densité, MFA et MOE apparaît très efficace: en effet, une sélection vers 7–8 ans a la même efficacité qu'une sélection réalisée à la révolution pour MFA et MOE et cette efficacité est d'au moins 80 % pour la densité du bois

Above the line - unleashing the North's potential

Made available by the Northern Territory Library via the Publications (Legal Deposit) Act 2004 (NT).Developing Northern Australia Conference 2016. Darwin Convention Centre 20 - 22 June 2016Land and water investigations and targeted capital investment underpin economic growth in Northern Western Australia. Key factors in the attraction and retention of local remote staff in Northern Australia. Our North, whose future: what is the scope of Aboriginal workforce development? How can vocational programs respond to the challenges of globalisation, build workforce capacity in developing countries and contribute to occupational outcomes? Sponsored International Education Programs: more than an 'off the shelf' training package.Hosted by the Association for Sustainability in Business the Conference provides a platform for business, industry, academics, NGOs, special interest groups, indigenous communities and all levels of Government to participate in shaping Australia?s futur