Acetabular dysplasia and the risk of developing hip osteoarthritis at 2,5,8, and 10 years follow-up in a prospective nationwide cohort study (CHECK).

Objective: To assess the relationship between acetabular dysplasia (AD) and the risk of incident and end-stage radiographic hip osteoarthritis (RHOA) over 2,5,8 and 10 years. Design: Individuals (n = 1002) aged between 45 and 65 from the prospective Cohort Hip and Cohort Knee (CHECK) were studied. Anteroposterior pelvic radiographs were obtained at baseline and 2,5,8, and 10-years follow-up. False profile radiographs were obtained at baseline. AD was defined as a lateral center edge angle, an anterior center edge angle, or both <25° at baseline. The risk of developing RHOA was determined at each follow-up moment. Incident RHOA was defined by Kellgren & Lawrence (KL) grade ≥2 or total hip replacement (THR), end-stage RHOA by a KL grade ≥3 or THR. Associations were expressed in odds ratios (OR) using logistic regression with generalized estimating equations. Results: AD was associated with the development of incident RHOA at 2 years follow-up (OR 2.46, 95% CI 1.00–6.04), 5 years follow-up (OR 2.28, 95% CI 1.20–4.31), and 8 years follow-up (OR 1.86, 95%CI 1.22–2.83). AD was only associated with end-stage RHOA at 5 years follow-up (OR 3.75, 95% CI 1.02–13.77). No statistically significant associations were observed between AD and RHOA at 10-years follow-up. Conclusion: Baseline AD in individuals between 45 and 65 years is associated with an increased risk of developing RHOA within 2- and 5 years. However, this association seems to weaken after 8 years and disappears after 10 years

The meaning of life in a developing universe

The evolution of life on Earth has produced an organism that is beginning to model and understand its own evolution and the possible future evolution of life in the universe. These models and associated evidence show that evolution on Earth has a trajectory. The scale over which living processes are organized cooperatively has increased progressively, as has its evolvability. Recent theoretical advances raise the possibility that this trajectory is itself part of a wider developmental process. According to these theories, the developmental process has been shaped by a larger evolutionary process that involves the reproduction of universes. This evolutionary process has tuned the key parameters of the universe to increase the likelihood that life will emerge and develop to produce outcomes that are successful in the larger process (e.g. a key outcome may be to produce life and intelligence that intentionally reproduces the universe and tunes the parameters of ‘offspring’ universes). Theory suggests that when life emerges on a planet, it moves along this trajectory of its own accord. However, at a particular point evolution will continue to advance only if organisms emerge that decide to advance the evolutionary process intentionally. The organisms must be prepared to make this commitment even though the ultimate nature and destination of the process is uncertain, and may forever remain unknown. Organisms that complete this transition to intentional evolution will drive the further development of life and intelligence in the universe. Humanity’s increasing understanding of the evolution of life in the universe is rapidly bringing it to the threshold of this major evolutionary transition

The Temporal Singularity: time-accelerated simulated civilizations and their implications

Provided significant future progress in artificial intelligence and computing, it may ultimately be possible to create multiple Artificial General Intelligences (AGIs), and possibly entire societies living within simulated environments. In that case, it should be possible to improve the problem solving capabilities of the system by increasing the speed of the simulation. If a minimal simulation with sufficient capabilities is created, it might manage to increase its own speed by accelerating progress in science and technology, in a way similar to the Technological Singularity. This may ultimately lead to large simulated civilizations unfolding at extreme temporal speedups, achieving what from the outside would look like a Temporal Singularity. Here we discuss the feasibility of the minimal simulation and the potential advantages, dangers, and connection to the Fermi paradox of the Temporal Singularity. The medium-term importance of the topic derives from the amount of computational power required to start the process, which could be available within the next decades, making the Temporal Singularity theoretically possible before the end of the century.Comment: To appear in the conference proceedings of the AGI-18 conference (published in the Springer's Lecture Notes in AI series

Chronic Losartan Administration Reduces Mortality and Preserves Cardiac but Not Skeletal Muscle Function in Dystrophic Mice

Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy. Angiotension receptor blockade (ARB) has excellent therapeutic potential in DMD based on recent data demonstrating attenuation of skeletal muscle disease progression during 6–9 months of therapy in the mdx mouse model of DMD. Since cardiac-related death is major cause of mortality in DMD, it is important to evaluate the effect of any novel treatment on the heart. Therefore, we evaluated the long-term impact of ARB on both the skeletal muscle and cardiac phenotype of the mdx mouse. Mdx mice received either losartan (0.6 g/L) (n = 8) or standard drinking water (n = 9) for two years, after which echocardiography was performed to assess cardiac function. Skeletal muscle weight, morphology, and function were assessed. Fibrosis was evaluated in the diaphragm and heart by Trichrome stain and by determination of tissue hydroxyproline content. By the study endpoint, 88% of treated mice were alive compared to only 44% of untreated (p = 0.05). No difference in skeletal muscle morphology, function, or fibrosis was noted in losartan-treated animals. Cardiac function was significantly preserved with losartan treatment, with a trend towards reduction in cardiac fibrosis. We saw no impact on the skeletal muscle disease progression, suggesting that other pathways that trigger fibrosis dominate over angiotensin II in skeletal muscle long term, unlike the situation in the heart. Our study suggests that ARB may be an important prophylactic treatment for DMD-associated cardiomyopathy, but will not impact skeletal muscle disease

Inadequate timing of prophylactic antibiotics in orthopedic surgery. We can do better

Background and purpose There are rising concerns about the frequency of infection after arthroplasty surgery. Prophylactic antibiotics are an important part of the preventive measures. As their effect is related to the timing of administration, it is important to follow how the routines with preoperative prophylactic antibiotics are working

Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/-)) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5(-/-) developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5(-/-) compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/-) mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly

Mannose 6-Phosphate Receptor and Sortilin Mediated Endocytosis of α-Galactosidase A in Kidney Endothelial Cells

Prominent vasculopathy in Fabry disease patients is caused by excessive intracellular accumulation of globotriaosylceramide (GL-3) throughout the vascular endothelial cells causing progressive cerebrovascular, cardiac and renal impairments. The vascular lesions lead to myocardial ischemia, atherogenesis, stroke, aneurysm, thrombosis, and nephropathy. Hence, injury to the endothelial cells in the kidney is a key mechanism in human glomerular disease and endothelial cell repair is an important therapeutic target. We investigated the mechanism of uptake of α-galactosidase A (α-Gal A) in renal endothelial cells, in order to clarify if the recombinant enzyme is targeted to the lysosomes via the universal mannose 6-phosphate receptor (M6PR) and possibly other receptors. Immunohistochemical localization of infused recombinant α-Gal A in a renal biopsy from a classic Fabry disease patient showed that recombinant protein localize in the endothelial cells of the kidney. Affinity purification studies using α-Gal A resins identified M6PR and sortilin as α-Gal A receptors in cultured glomerular endothelial cells. Immunohistochemical analyses of normal human kidney with anti-sortilin and anti-M6PR showed that sortilin and M6PR were expressed in the endothelium of smaller and larger vessels. Uptake studies in cultured glomerular endothelial cells of α-Gal A labeled with fluorescence and 125I showed by inhibition with RAP and M6P that sortilin and M6PR mediated uptake of α-Gal A. Biacore studies revealed that α-Gal A binds to human M6PR with very high affinity, but M6PR also binds to sortilin in a way that prevents α-Gal A binding to sortilin. Taken together, our data provide evidence that sortilin is a new α-Gal A receptor expressed in renal endothelial cells and that this receptor together with the M6PR is able to internalize circulating α-Gal A during enzyme replacement therapy in patients with Fabry disease

Type 1 Autoimmune Pancreatitis in Europe:Clinical Profile and Response to Treatment

Background &amp; Aims: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. Methods: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. Results: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (&lt;0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054–3.387) and neither was a starting dose duration &gt;2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818–1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427–0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. Conclusions: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.</p