The Importance of Craniofacial Sutures in Biomechanical Finite Element Models of the Domestic Pig

Craniofacial sutures are a ubiquitous feature of the vertebrate skull. Previous experimental work has shown that bone strain magnitudes and orientations often vary when moving from one bone to another, across a craniofacial suture. This has led to the hypothesis that craniofacial sutures act to modify the strain environment of the skull, possibly as a mode of dissipating high stresses generated during feeding or impact. This study tests the hypothesis that the introduction of craniofacial sutures into finite element (FE) models of a modern domestic pig skull would improve model accuracy compared to a model without sutures. This allowed the mechanical effects of sutures to be assessed in isolation from other confounding variables. These models were also validated against strain gauge data collected from the same specimen ex vivo. The experimental strain data showed notable strain differences between adjacent bones, but this effect was generally not observed in either model. It was found that the inclusion of sutures in finite element models affected strain magnitudes, ratios, orientations and contour patterns, yet contrary to expectations, this did not improve the fit of the model to the experimental data, but resulted in a model that was less accurate. It is demonstrated that the presence or absence of sutures alone is not responsible for the inaccuracies in model strain, and is suggested that variations in local bone material properties, which were not accounted for by the FE models, could instead be responsible for the pattern of results

Increased dynamics in the 40-57 Ω-loop of the G41S variant of human cytochrome c promote its pro-apoptotic conformation

Thrombocytopenia 4 is an inherited autosomal dominant thrombocytopenia, which occurs due to mutations in the human gene for cytochrome c that results in enhanced mitochondrial apoptotic activity. The Gly41Ser mutation was the first to be reported. Here we report stopped-flow kinetic studies of azide binding to human ferricytochrome c and its Gly41Ser variant, together with backbone amide H/D exchange and 15N-relaxation dynamics using NMR spectroscopy, to show that alternative conformations are kinetically and thermodynamically more readily accessible for the Gly41Ser variant than for the wild-type protein. Our work reveals a direct conformational link between the 40-57 Ω-loop in which residue 41 resides and the dynamical properties of the axial ligand to the heme iron, Met80, such that the replacement of glycine by serine promotes the dissociation of the Met80 ligand, thereby increasing the population of a peroxidase active state, which is a key non-native conformational state in apoptosis

Genotype, haplotype and copy-number variation in worldwide human populations

Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups(1-3). Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms ( SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected-including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas-the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62552/1/nature06742.pd

Evolution of active galactic nuclei

[Abriged] Supermassive black holes (SMBH) lurk in the nuclei of most massive galaxies, perhaps in all of them. The tight observed scaling relations between SMBH masses and structural properties of their host spheroids likely indicate that the processes fostering the growth of both components are physically linked, despite the many orders of magnitude difference in their physical size. This chapter discusses how we constrain the evolution of SMBH, probed by their actively growing phases, when they shine as active galactic nuclei (AGN) with luminosities often in excess of that of the entire stellar population of their host galaxies. Following loosely the chronological developments of the field, we begin by discussing early evolutionary studies, when AGN represented beacons of light probing the most distant reaches of the universe and were used as tracers of the large scale structure. This early study turned into AGN "Demography", once it was realized that the strong evolution (in luminosity, number density) of the AGN population hindered any attempt to derive cosmological parameters from AGN observations directly. Following a discussion of the state of the art in the study of AGN luminosity functions, we move on to discuss the "modern" view of AGN evolution, one in which a bigger emphasis is given to the physical relationships between the population of growing black holes and their environment. This includes observational and theoretical efforts aimed at constraining and understanding the evolution of scaling relations, as well as the resulting limits on the evolution of the SMBH mass function. Physical models of AGN feedback and the ongoing efforts to isolate them observationally are discussed next. Finally, we touch upon the problem of when and how the first black holes formed and the role of black holes in the high-redshift universe.Comment: 75 pages, 35 figures. Modified version of the chapter accepted to appear in "Planets, Stars and Stellar Systems", vol 6, ed W. Keel (www.springer.com/astronomy/book/978-90-481-8818-5). The number of references is limited upon request of the editors. Original submission to Springer: June 201

Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club

This consensus article reviews the various aspects of the non-pharmacological management of osteoporosis, including the effects of nutriments, physical exercise, lifestyle, fall prevention, and hip protectors. Vertebroplasty is also briefly reviewed. Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. The topic also includes surgical procedures for the treatment of peripheral and vertebral fractures and the post-fracture rehabilitation. The present document is the result of a consensus, based on a systematic review and a critical appraisal of the literature. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fibres exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. This is also true for vertebroplasty and kyphoplasty. Several randomized controlled studies had reported a short-term advantage of vertebroplasty over medical treatment for pain relief, but these findings have been questioned by recent sham-controlled randomized clinical studies

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Global burden of peripheral artery disease and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Peripheral artery disease is a growing public health problem. We aimed to estimate the global disease burden of peripheral artery disease, its risk factors, and temporospatial trends to inform policy and public measures. Methods Data on peripheral artery disease were modelled using the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 database. Prevalence, disability-adjusted life years (DALYs), and mortality estimates of peripheral artery disease were extracted from GBD 2019. Total DALYs and age-standardised DALY rate of peripheral artery disease attributed to modifiable risk factors were also assessed. Findings In 2019, the number of people aged 40 years and older with peripheral artery disease was 113 million (95% uncertainty interval [UI] 99·2–128·4), with a global prevalence of 1·52% (95% UI 1·33–1·72), of which 42·6% was in countries with low to middle Socio-demographic Index (SDI). The global prevalence of peripheral artery disease was higher in older people, (14·91% [12·41–17·87] in those aged 80–84 years), and was generally higher in females than in males. Globally, the total number of DALYs attributable to modifiable risk factors in 2019 accounted for 69·4% (64·2–74·3) of total peripheral artery disease DALYs. The prevalence of peripheral artery disease was highest in countries with high SDI and lowest in countries with low SDI, whereas DALY and mortality rates showed U-shaped curves, with the highest burden in the high and low SDI quintiles. Interpretation The total number of people with peripheral artery disease has increased globally from 1990 to 2019. Despite the lower prevalence of peripheral artery disease in males and low-income countries, these groups showed similar DALY rates to females and higher-income countries, highlighting disproportionate burden in these groups. Modifiable risk factors were responsible for around 70% of the global peripheral artery disease burden. Public measures could mitigate the burden of peripheral artery disease by modifying risk factors. Funding Bill & Melinda Gates Foundation

The buccinator during mastication: A functional and anatomical evaluation in minipigs

Objective: The buccinator muscle forms the lateral wall of the oral cavity. It is presumed to aid mastication by maintaining bolus position. Such a function would involve thickening the cheek, possibly compressing the alveolar bone and contributing to malocclusions. However, neither buccinator deformation nor its effect on pressure has been demonstrated. Our objective was to evaluate buccinator EMG during feeding, its changes in length and thickness, and the pressure exerted on its alveolar attachment, using miniature pigs as an animal model. Methods: EMG of the buccinator and other oral muscles was recorded with fine-wire electrodes. Anteroposterior length and mediolateral thickness of the buccinator were evaluated with implanted sonomicrometry crystals, and pressure was measured by flat transducers placed beneath the mandibular origin of the buccinator. Recordings were made during feeding and muscle stimulation. Tissues were collected postmortem for histology. Results: During mastication, buccinator EMG showed regular peaks that preceded those of the jaw closers. Pattern differences clearly distinguished working and balancing sides. The buccinator shortened and thickened when it contracted. Positive pressures were observed at the mandibular attachment of the buccinator, increasing when the muscle was active. Histological evaluation showed a complex interweaving of fibres closely associated with salivary tissue. Conclusions: Buccinator contraction does thicken the cheek, and during mastication this activity takes place just as the closing stroke begins. In addition to controlling the bolus, there may be an effect on salivation. Despite the fact that the muscle pulls on its attachment, the local mechanical environment at the alveolar bone is one of positive pressure. (C) 2010 Elsevier Ltd. All rights reserved.559627638NIDCR [DE08513]National Council for Scientific and Technological Development-BrazilNIDCR [DE08513

Osteoprotegerin, a crucial regulator of bone metabolism, also regulates B cell development and function

Osteoprotegerin (OPG) is a CD40-regulated gene in B cells and dendritic cells (DCs). We investigated the role of OPG in the immune system by generating opg-/- mice. Like its role as a regulator of bone metabolism, OPG also influences processes in the immune system, notably in B cell development. Ex vivo, opg-/- pro-B cells have enhanced proliferation to IL-7, and in opg-/- spleen, there is an accumulation of type 1 transitional B cells. Furthermore, opg-/- bone marrow-derived DCs are more effective in stimulating allogeneic T cells than control DCs. When challenged with a T-dependent Ag, opg-/- mice had a compromised ability to sustain an IgG3 Ag-specific response. Thus, in the immune system, OPG regulates B cell maturation and development of efficient Ab responses