Ageing in the musculoskeletal system.

The extent of ageing in the musculoskeletal system during the life course affects the quality and length of life. Loss of bone, degraded articular cartilage, and degenerate, narrowed intervertebral discs are primary features of an ageing skeleton, and together they contribute to pain and loss of mobility. This review covers the cellular constituents that make up some key components of the musculoskeletal system and summarizes discussion from the 2015 Aarhus Regenerative Orthopaedic Symposium (AROS) (Regeneration in the Ageing Population) about how each particular cell type alters within the ageing skeletal microenvironment.

The effects of shoe type on lower limb venous status during gait or exercise: A systematic review.

This systematic review evaluated the literature pertaining to the effect of shoes on lower limb venous status in asymptomatic populations during gait or exercise. The review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed-NCBI, EBSCO Host, Cochrane Library and Science Direct databases were searched (March 2019) for words around two concepts: shoes and venous parameters. The inclusion criteria were as follows: (1) the manuscript had to be published in an English-language peer-reviewed journal and the study had to be observational or experimental and (2) the study had to suggest the analysis of many types of shoes or orthotics on venous parameters before, during and/or after exercise. Out of 366 articles, 60 duplications were identified, 306 articles were analyzed, and 13 articles met the eligibility criteria after screening and were included. This review including approximately 211 participants. The methodological rigor of these studies was evaluated with the modified Downs and Black quality index. Nine studies investigated the effect of shoes on blood flow parameters, two on venous pressure and two on lower limb circumferences with exercise. Evidence was found that unstable shoes or shoes with similar technology, sandals, athletic or soft shoes, and customized foot orthotics elicited more improvement in venous variables than high-heeled shoes, firm shoes, ankle joint immobilization and barefoot condition. These venous changes are probably related to the efficiency of muscle pumps in the lower limbs, which in turn seem to be dependent on shoe features associated with changes in the kinetics, kinematics and muscle activity variables in lower limbs during gait and exercise.

Endothelial cells and angiogenesis in the horse in health and disease-A review.

The cardiovascular system is the first functional organ in the embryo, and its blood vessels form a widespread conductive network within the organism. Blood vessels develop de novo, by the differentiation of endothelial progenitor cells (vasculogenesis) or by angiogenesis, which is the formation of new blood vessels from existing ones. This review presents an overview of the current knowledge on physiological and pathological angiogenesis in the horse including studies on equine endothelial cells. Principal study fields in equine angiogenesis research were identified: equine endothelial progenitor cells; equine endothelial cells and angiogenesis (heterogeneity, markers and assessment); endothelial regulatory molecules in equine angiogenesis; angiogenesis research in equine reproduction (ovary, uterus, placenta and conceptus, testis); angiogenesis research in pathological conditions (tumours, ocular pathologies, equine wound healing, musculoskeletal system and laminitis). The review also includes a table that summarizes in vitro studies on equine endothelial cells, either describing the isolation procedure or using previously isolated endothelial cells. A particular challenge of the review was that results published are fragmentary and sometimes even contradictory, raising more questions than they answer. In conclusion, angiogenesis is a major factor in several diseases frequently occurring in horses, but relatively few studies focus on angiogenesis in the horse. The challenge for the future is therefore to continue exploring new therapeutic angiogenesis strategies for horses to fill in the missing pieces of the puzzle.

Blood Flow Restriction Therapy: From Development to Applications.

Blood flow restriction (BFR) has been shown to produce beneficial adaptations to skeletal muscle. These adaptations have been documented in the civilian and military populations. BFR therapy may provide patients a safe method to begin strength training at earlier stages of rehabilitation to allow for earlier and more effective return to activity and improved military readiness. The purpose was to review BFR therapy physiology, complications, side effects, standardized treatment algorithms, and long-term patient outcomes.

Role of hydrogen sulfide in the musculoskeletal system.

Hydrogen sulfide (H2S) has been known as a gasotransmitter, and it contributes to various physiological and pathological processes. Multiple enzymes such as cystathionine-ß-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-Mercaptopyruvate sulfurtransferase (MST) produce endogenous H2S, and these are differentially expressed in the various tissue systems including the skeletal system. However, abnormal H2S production is associated with deregulation of the signaling cascade and imbalanced tissue homeostasis. Several studies have previously provided evidence showing the essential regulatory action of H2S in skeletal homeostasis. In this review, we have emphasized the novel function of H2S in both bone and skeletal muscle anabolism, in particular. Additionally, we also reviewed the molecular and epigenetic basis of H2S signaling in bone development and skeletal muscle function.

Reappraisal of patterns of nonmarine cryptodiran turtle carotid circulation: evidence from osteological correlates and soft tissues.

The turtle cranial circulation has been employed as an important source of phylogenetic information, but recent conflicting hypotheses of relationship within Testudinata suggest reevaluation of the utility of characters drawn from this complex. As a component of a comprehensive character analysis, the osteological correlates of the nonmarine cryptodiran turtle carotid circulation are herein subjected to high-resolution X-ray computed tomography, reassessed, and statistically investigated. Three different patterns of osteological correlates, indicating three disparate cranial circulatory patterns, are described, and this finding is corroborated by evidence from circulatory soft tissues. Members of the Trionychia and Kinosternoidea exhibit patterns that differ from the more widespread condition found in testudinoid taxa. This result differs from previous work, which has indicated the presence of only two major cranial circulatory patterns, and suggests that while cranial circulatory features may be phylogenetically informative, the information contained within them indicates patterns of relationship different from those previously hypothesized.

Endothelial function and exercise training: evidence from studies using animal models.

This review summarizes and examines the evidence from experiments using animal models to determine the effect of endurance exercise training on endothelium-dependent dilation in the arterial circulation. The response of the endothelium to exercise training is complex and depends on a number of factors that include the duration of the training program, the size of the artery/arteriole, the anatomical location of the artery/arteriole, and the health of the individual. In healthy animals, short-term exercise training appears to cause enhanced endothelium-dependent dilation in some vascular beds, but it returns to normal levels as the duration of the training program increases. In general, evidence supports the notion that exercise training causes greater increases in endothelium-dependent dilation in various disease states than in healthy individuals. The evidence of a generalized effect of training on arterial endothelium in all regions of the body is inconsistent and appears to depend on the animal model used. Available results indicate that training duration, artery size, and anatomical location interact in ways not fully understood at this time to determine whether and to what extent endothelium-dependent dilation will be enhanced by exercise training.

Applications of Doppler imaging in the musculoskeletal system.

Pathological conditions affecting the musculoskeletal system often result in alterations of regional blood flow. The assessment of a Doppler signal in inflammatory or infective processes complements the grayscale findings, helping to evaluate the severity of disease. Doppler imaging can also be used to determine therapeutic response or help guide injections. In addition, Doppler interrogation enables vascular characterization of solid masses. The presence of a Doppler signal can also help differentiate solid from cystic lesions. This article reviews the wide range of applications for Doppler imaging of the musculoskeletal system.

Muscle-derived stem cells for musculoskeletal tissue regeneration and repair.

Muscle recently has been identified as a good source of adult stem cells that can differentiate into cells of different lineages. The most well-known muscle progenitor cells are satellite cells, which not only contribute to the replenishment of the myogenic cell pool but also can become osteoblasts, adipocytes and chondrocytes. Other populations of stem cells that appear to be distinct from satellite cells also have been discovered recently. Muscle-derived stem cells (MDSCs) can be divided into two major categories based on these cells' varied abilities to differentiate into myogenic lineages. Interestingly, MDSCs that can differentiate readily into myogenic cells are usually CD45-. In contrast, MDSCs with less myogenic potential are CD45+. Various lines of evidence suggest that different populations of MDSCs are closely related. Furthermore, MDSCs appear to be closely related to endothelial cells or pericytes of the capillaries surrounding myofibers. When used in tissue engineering applications, MDSCs--particularly those genetically engineered to express growth factors--have been demonstrated to possess great potential for the regeneration and repair of muscle, bone and cartilage. Further research is necessary to delineate the relationship between different populations of MDSCs and between MDSCs and other adult stem cells, to investigate their developmental origin, and to determine the regulatory pathways and factors that control stem cell self-renewal, proliferation and differentiation. This knowledge could greatly enhance the usefulness of muscle-derived stem cells, as well as other adult stem cells, for tissue repair and regeneration applications.

Future and new developments in musculoskeletal ultrasound.

Improvements in high-resolution gray-scale imaging and clinical expertise performing musculoskeletal ultrasound will undoubtedly continue. Development of digital beam formers, two-dimensional arrays along with exploitation of nonlinear techniques to achieve higher resolution and use of ultrasound contrast to improve flow sensitivity will all contribute to the utility of ultrasound in the musculoskeletal system. It behooves the radiologic community to become familiar with these techniques, not only for economic reasons, but also because of the rich complement of future applications of this modality. The few potential applications mentioned here may only scratch the surface of what is possible. In addition to improved images of tissue morphology, ultrasound may play a role in functional and quantitative assessment of soft tissues. It may likewise play a role in the evaluation of prosthetic implants, bone mineralization, and cartilage integrity. Thus, the role of this modality in future musculoskeletal applications may significantly impact clinical diagnosis and therapy.

The impact of musculoskeletal changes on the dynamics of the calf muscle pump.

Many articles have been published on assessing and treating chronic venous insufficiency and venous leg ulcers; most recommend correcting the underlying cause. These same articles often fail to examine and address a common factor or cofactor of venous hypertension--musculoskeletal changes. Frequently, these changes accompany major injuries, neurological disease, vascular insufficiency, debilitating diseases, myositis, and bone and joint pain and can adversely affect the dynamics of the calf muscle pump. The calf muscles rapidly waste and weaken with disuse--even a change in gait related to a painful ulcer can exacerbate venous hypertension and cause calf muscle disuse atrophy. This article reviews the cause and effect of musculoskeletal changes on the hemodynamics of the calf muscle pump. Recommendations for changes in practice will be based on the identification of the underlying cause of chronic venous insufficiency related to these musculoskeletal changes.

Use of the vascularized iliac-crest flap in musculoskeletal lesions.

Bone loss was in the past treated by several methods, such as bone distraction and the use of nonvascularized or tissue-bank bone grafts. With the advent of modern microsurgical techniques, the vascularized bone flap has been used with good results; it resolves local nutritional problems, repairs soft tissue that is often damaged by severe trauma, and treats bone loss due to tumors, pseudarthroses, and osteomyelitis. This paper reports the authors' experience with the use of vascularized iliac-crest flaps to treat orthopedic pathologies in five patients with traumatic bone loss (<10 cm), three with osteomyelitis, and three with atrophic nonunion. In all cases, the same surgeon obtained a vascularized iliac-crest flap with a pedicle based on the deep iliac circumflex artery. All flaps consolidated within a mean period of 3 months. These findings demonstrate that the use of an iliac-crest flap is a treatment option in cases of bone loss and that it is associated with good functional results and minimal donor-site morbidity.

Pseudoaneurysms in haemophilia.

The incidence of bleeding as a result of a pseudoaneurysm in haemophilia is very low. The diagnosis should be suspected if the patient has a history of arterial trauma. Pseudoaneurysms can appear anywhere where trauma occurs. This can include arterial access for catheterization, blunt trauma or penetrating trauma. The diagnosis should be confirmed using Duplex ultrasonography, computed tomography (CT) angiogram or conventional angiogram. Many options exist for the treatment of pseudoaneurysms. Although surgery was the gold standard treatment in the past (surgical ligation with or without distal bypass), several less invasive treatment options are popular today. They include covered stent, ultrasound probe compression and ultrasound-guided thrombin injection. So far, only 14 pseudoaneurysms have been reported in patients with haemophilia: nine were located in the musculoskeletal system (four in the hand, four in the knee, one in the ankle), whereas five were non-musculoskeletal. Early diagnosis and treatment of this complication is vital. Endovascular treatment offers a minimally invasive treatment option. If arterial embolization fails to solve the pseudoaneurysm, open vascular surgery with surgical ligation with or without distal bypass should be performed. Whatever the procedure, a correct surgical haemostasis must be achieved by the infusion of factor concentrate (recombinant or plasma-derived) at the right dose and tranexamic acid. The advent of activated prothrombin complex concentrates and recombinant factor VIII (rFVIIa) has made invasive procedures possible in haemophilia patients with high-titre inhibitors.

Mechanics of the foot Part 2: A coupled solid-fluid model to investigate blood transport in the pathologic foot.

A coupled computational model of the foot consisting of a three-dimensional soft tissue continuum and a one-dimensional (1D) transient blood flow network is presented in this article. The primary aim of the model is to investigate the blood flow in major arteries of the pathologic foot where the soft tissue stiffening occurs. It has been reported in the literature that there could be up to about five-fold increase in the mechanical stiffness of the plantar soft tissues in pathologic (e.g. diabetic) feet compared with healthy ones. The increased stiffness results in higher tissue hydrostatic pressure within the plantar area of the foot when loaded. The hydrostatic pressure acts on the external surface of blood vessels and tend to reduce the flow cross-section area and hence the blood supply. The soft tissue continuum model of the foot was modelled as a tricubic Hermite finite element mesh representing all the muscles, skin and fat of the foot and treated as incompressible with transversely isotropic properties. The details of the mechanical model of soft tissue are presented in the companion paper, Part 1. The deformed state of the soft tissue continuum because of the applied ground reaction force at three foot positions (heel-strike, midstance and toe-off) was obtained by solving the Cauchy equations based on the theory of finite elasticity using the Galerkin finite element method. The geometry of the main arterial network in the foot was represented using a 1D Hermite cubic finite element mesh. The flow model consists of 1D Navier-Stokes equations and a nonlinear constitutive equation to describe vessel radius-transmural pressure relation. The latter was defined as the difference between the fluid and soft tissue hydrostatic pressure. Transient flow governing equations were numerically solved using the two-step Lax-Wendroff finite difference method. The geometry of both the soft tissue continuum and arterial network is anatomically-based and was developed using the data derived from visible human images and magnetic resonance images of a healthy male volunteer. Simulation results reveal that a two-fold increase in tissue stiffness leads to about 28% reduction in blood flow to the affected region.

The role of small molecules in musculoskeletal regeneration.

The uses of bone morphogenetic proteins and parathyroid hormone therapeutics are fraught with several fundamental problems, such as cost, protein stability, immunogenicity, contamination and supraphysiological dosage. These downsides may effectively limit their more universal use. Therefore, there is a clear need for alternative forms of biofactors to obviate the drawbacks of protein-based inductive factors for bone repair and regeneration. Our group has studied small molecules with the capacity to regulate osteoblast differentiation and mineralization because their inherent physical properties minimize limitations observed in protein growth factors. For instance, in general, small molecule inducers are usually more stable, highly soluble, nonimmunogenic, more affordable and require lower dosages. Small molecules with the ability to induce osteoblastic differentiation may represent the next generation of bone regenerative medicine. This review describes efforts to develop small molecule-based biofactors for induction, paying specific attention to their novel roles in bone regeneration.

Visualization of treatment response in tumors by use of dynamic contrast-enhanced magnetic resonance imaging.

Our goal in this study was to present a method for generating functional parametric maps of hemodynamic parameters in tumors and a visualization method for assessing treatment response by use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). A total of 13 patients with musculoskeletal tumors were included in this study. First, tumor blood flow (F(T)) maps were generated from DCE-MRI data by use of deconvolution analysis, and K(1), k(2), and f were obtained from a two-compartment model, where K(1) and k(2) denote the rate constant for the transfer of contrast agent from blood to tissue and from tissue to blood, respectively, and f is the fraction of the blood volume. Images were generated by application of the linear least squares method pixel by pixel. Furthermore, the images of the distribution volume (V(d)) and permeability-surface area product (PS) were obtained from the relations V(d) = K(1)/k(2) and PS = -F(T) x ln(1 - K(1)/(F(T)), respectively. Second, two-dimensional (2D) plots were generated with V(d) and K(1) placed on the x- and y-axes, and three-dimensional (3D) plots were generated by the addition of PS on the z-axis. In the case of good responders whose biopsied specimens revealed tumor necrosis greater than 90%, both 2D and 3D plots gradually approached the origin after an increasing number of treatments. On the other hand, in the case of non-responders whose biopsied specimens showed little chemotherapeutic effect, large changes were not observed in either plot. In conclusion, our method will be promising for evaluating the treatment response in tumors visually.

Rapid fat-suppressed isotropic steady-state free precession imaging using true 3D multiple-half-echo projection reconstruction.

Three-dimensional projection reconstruction (3D PR)-based techniques are advantageous for steady-state free precession (SSFP) imaging for several reasons, including the capability to achieve short repetition times (TRs). In this paper, a multi-half-echo technique is presented that dramatically improves the data-sampling efficiency of 3D PR sequences while it retains this short-TR capability. The k-space trajectory deviations are measured quickly and corrected on a per-sample point basis. A two-pass RF cycling technique is then applied to the dual-half-echo implementation to generate fat/water-separated images. The resultant improvement in the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) was demonstrated in volunteer studies. Volumetric images with excellent spatial resolution, coverage, and contrast were obtained with high speed. The non-contrast-enhanced SSFP studies show that this technique has promising potential for MR angiography (MRA).

Skeletal muscle capillary geometry: adaptation to chronic hypoxia.

The potential for gas and metabolite exchange across the capillary bed is determined largely by the capillary length and surface area available for blood-tissue transfer. It has been suggested that chronic exposure to hypoxia increases capillary tortuosity; however, the degree of orientation of capillaries in muscles of sea level animals chronically exposed to hypoxia has never been quantified rigorously. An augmented capillary tortuosity would increase capillary length per volume of muscle fiber, Jv(c,f), irrespective of whether new capillaries are formed. To resolve this issue, female rats (278 +/- 5 g) were maintained for 5 months in a temperate environment at 3800 m (PIO2 = 91 Torr). Capillary tortuosity and Jv(c,f) were estimated from transverse and longitudinal sections in perfusion-fixed M. Soleus and M. Gastrocnemius. Values were compared with weight-matched controls (274 +/- 7 g). Neither capillary density (normalized to sarcomere length 2.1 microns, hypoxic = 1292 +/- 79, control = 1282 +/- 43 mm-2) nor capillary-to-fiber ratio (hypoxic = 2.50 +/- 0.15, control = 2.57 +/- 0.05) were changed after altitude exposure. Capillary tortuosity was a function of sarcomere length in all animals and this relationship was not changed by hypoxia. Capillary length per volume of muscle fiber was unchanged (hypoxic = 1541 +/- 72, control = 1531 +/- 44 mm-2) as was mean capillary diameter. We conclude that chronic exposure to 3800 m does not change capillary tortuosity or surface area in rat M. Soleus or M. Gastrocnemius.

Improved musculoskeletal angiography with large volume contrast injection and priscoline.

Previously published studies of musculoskeletal angiography have not discussed the technical details of how the angiograms were performed. In the present report, two series of 57 consecutive angiograms were compared with respect to radiologic quality and clinical usefulness. The second series differed from the first in closer consultation between angiographer and orthopaedist and the use of intra-arterial Priscoline, large volume contrast injection, multiple views, geometric magnification, and photographic subtraction. These efforts were rewarded by greater vascular detail and better delineation of tumors on the angiograms. Especially with respect to soft tissue lesions, the surgeon found the studies more accurate and more useful in planning surgical management.