Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives.

Osteogenesis imperfecta is an inherited connective tissue disorder with wide phenotypic and molecular heterogeneity. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities, including long bone bowing and scoliosis. Multidisciplinary management improves quality of life for patients with osteogenesis imperfecta. It consists of physical therapy, medical treatment and orthopaedic surgery as necessary. Medical treatment consists of bone-remodelling drug therapy. Bisphosphonates are widely used in the treatment of moderate to severe osteogenesis imperfecta, from infancy to adulthood. Other more recent drug therapies include teriparatide and denosumab. All these therapies target the symptoms and have effects on the mechanical properties of bone due to modification of bone remodelling, therefore influencing skeletal outcome and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell transplantation, targeting the specific altered pathway rather than the symptoms, are in the process of development

Burn Center Organization and Cellular Therapy Integration: Managing Risks and Costs.

The complex management of severe burn victims requires an integrative collaboration of multidisciplinary specialists in order to ensure quality and excellence in healthcare. This multidisciplinary care has quickly led to the integration of cell therapies in clinical care of burn patients. Specific advances in cellular therapy together with medical care have allowed for rapid treatment, shorter residence in hospitals and intensive care units, shorter durations of mechanical ventilation, lower complications and surgery interventions, and decreasing mortality rates. However, naturally fluctuating patient admission rates increase pressure toward optimized resource utilization. Besides, European translational developments of cellular therapies currently face potentially jeopardizing challenges on the policy front. The aim of the present work is to provide key considerations in burn care with focus on architectural and organizational aspects of burn centers, management of cellular therapy products, and guidelines in evolving restrictive regulations relative to standardized cell therapies. Thus, based on our experience, we present herein integrated management of risks and costs for preserving and optimizing clinical care and cellular therapies for patients in dire need

Repair of critical size defects in the rat cranium using ceramic-reinforced PLA scaffolds obtained by supercritical gas foaming

Bioresorbable scaffolds made Of poly(L-lactic acid) (PLA) obtained by supercritical gas foaming were recently described as suitable for tissue engineering, portraying biocompatibility with primary osteoblasts in vitro and interesting mechanical properties when reinforced with ceramics. The behavior of such constructs remained to be evaluated in vivo and therefore the present study was undertaken to compare different PLA/ceramic composite scaffolds obtained by supercritical gas foaming in a critical size defect craniotomy model in Sprague-Dawley rats. The host-tissue reaction to the implants was evaluated semiquantitatively and similar tendencies were noted for all graft substitutes: initially highly reactive but decreasing with time implanted. Complete bone-bridging was observed IS weeks after implantation with PLA/ 5 wt % beta-TCP (PLA/TCP) and PLA/5 wt % HA (PLA/HA) scaffolds as assessed by histology and radiography. We show here for the first time that this solvent-free technique provides a promising approach in tissue engineering demonstrating both the biocompatibility and osteoconcluctivity of the processed structures in vivo

Ownership and control in a competitive industry

We study a differentiated product market in which an investor initially owns a controlling stake in one of two competing firms and may acquire a non-controlling or a controlling stake in a competitor, either directly using her own assets, or indirectly via the controlled firm. While industry profits are maximized within a symmetric two product monopoly, the investor attains this only in exceptional cases. Instead, she sometimes acquires a noncontrolling stake. Or she invests asymmetrically rather than pursuing a full takeover if she acquires a controlling one. Generally, she invests indirectly if she only wants to affect the product market outcome, and directly if acquiring shares is profitable per se. --differentiated products,separation of ownership and control,private benefits of control

International Society of Sports Nutrition Position Stand: Nutritional recommendations for single-stage ultra-marathon; training and racing

Background. In this Position Statement, the International Society of Sports Nutrition (ISSN) provides an objective and critical review of the literature pertinent to nutritional considerations for training and racing in single-stage ultra-marathon. Recommendations for Training. i) Ultra-marathon runners should aim to meet the caloric demands of training by following an individualized and periodized strategy, comprising a varied, food-first approach; ii) Athletes should plan and implement their nutrition strategy with sufficient time to permit adaptations that enhance fat oxidative capacity; iii) The evidence overwhelmingly supports the inclusion of a moderate-to-high carbohydrate diet (i.e., ~60% of energy intake, 5 – 8 g⸱kg−1·d−1) to mitigate the negative effects of chronic, training-induced glycogen depletion; iv) Limiting carbohydrate intake before selected low-intensity sessions, and/or moderating daily carbohydrate intake, may enhance mitochondrial function and fat oxidative capacity. Nevertheless, this approach may compromise performance during high-intensity efforts; v) Protein intakes of ~1.6 g·kg−1·d−1 are necessary to maintain lean mass and support recovery from training, but amounts up to 2.5 g⸱kg−1·d−1 may be warranted during demanding training when calorie requirements are greater; Recommendations for Racing. vi) To attenuate caloric deficits, runners should aim to consume 150 - 400 kcal⸱h−1 (carbohydrate, 30 – 50 g⸱h−1; protein, 5 – 10 g⸱h−1) from a variety of calorie-dense foods. Consideration must be given to food palatability, individual tolerance, and the increased preference for savory foods in longer races; vii) Fluid volumes of 450 – 750 mL⸱h−1 (~150 – 250 mL every 20 min) are recommended during racing. To minimize the likelihood of hyponatraemia, electrolytes (mainly sodium) may be needed in concentrations greater than that provided by most commercial products (i.e., >575 mg·L−1 sodium). Fluid and electrolyte requirements will be elevated when running in hot and/or humid conditions; viii) Evidence supports progressive gut-training and/or low-FODMAP diets (fermentable oligosaccharide, disaccharide, monosaccharide and polyol) to alleviate symptoms of gastrointestinal distress during racing; ix) The evidence in support of ketogenic diets and/or ketone esters to improve ultra-marathon performance is lacking, with further research warranted; x) Evidence supports the strategic use of caffeine to sustain performance in the latter stages of racing, particularly when sleep deprivation may compromise athlete safety

Protection against pyrimidine dimers, p53, and 8-hydroxy-2'-deoxyguanosine expression in ultraviolet-irradiated human skin by sunscreens: difference between UVB + UVA and UVB alone sunscreens

As DNA damage induced by ultraviolet radiation plays an essential role in skin cancer induction, we pursued the measure of several DNA lesions induced by ultraviolet radiation in human skin for determining the efficacy of different topical photoprotectors. Non-exposed skin (buttocks from 20 individuals) was exposed to 10 doses of ultraviolet, which corresponded to three to four minimal erythema doses of solar-simulating radiation, and biopsies were taken at 24 h within the half and one minimal erythema dose sites and a nonirradiated, adjacent control area. We report that even suberythemal doses of ultraviolet radiation are capable of inducing substantial DNA damage, namely pyrimidine dimers, p53 induction, and the DNA base-modified product generated by oxidative stress, 8-hydroxy-2'-deoxyguanosine. All three lesions are induced in a dose-dependent manner. An additional eight individuals were treated with either ultraviolet B or ultraviolet B + ultraviolet A sunblock (sun protection factor 15) and exposed to 71/2 and 15 times the minimal erythema dose on each individual, with biopsies taken at 24 h post-ultraviolet. Pyrimidine dimer and p53 expression were rarely seen in nonirradiated skin but occasional staining was seen in all normal skin for 8-hydroxy-2'-deoxyguanosine. Applications of sunscreens to human skin before irradiation were shown to attenuate erythema but did not completely eliminate all three types of cellular damage when tested up to their sun protection factor 15. Furthermore, ultraviolet B + ultraviolet A sunscreens were less efficient than the ultraviolet B alone formulation for protection against all three lesions. These results suggest that DNA damage assessed in vivo by immunohistochemistry provides a very sensitive endpoint for determining the efficacy or photosensitivity of possible different protective measures in human skin

Human Platelet Lysate as an Alternative to Autologous Serum for Human Chondrocyte Clinical Use.

A pivotal aspect of cartilage tissue engineering resides in cell culture medium supplementation, in view of maximizing in vitro cell proliferation and preserving cellular functionality. Autologous human serum (aHS) is commonly used as an inducive supplement for safe human articular chondrocyte (HAC) proliferation prior to clinical implantation. However, practical clinical use of aHS is hindered by constraining manufacturing requirements and quality assurance-driven downstream processing. The present study investigated potential alternative use of commercial human platelet lysate (hPL) supplements in HAC manufacturing workflows related to clinical therapeutic pathways. Differential effects of hPL, aHS, and fetal bovine serum were assessed on primary cultured HAC parameters (viability, proliferative rates, and morphology) in 2-dimensional in vitro systems. A 3-dimensional HAC pellet model served for postexpansion assessment of cellular functionality, by visualizing proteoglycan production (Alcian blue staining), and by using qRT-PCR relative quantification of chondrogenic marker (SOX9, COL2-A1, and ACAN) genetic expression. We found that monolayer HAC culture with hPL or aHS supplements presented similar characteristics (elongated cell morphology and nearly identical growth kinetics). Chondrogenic activity appeared as conserved in HACs expanded with human or bovine supplements, wherein histologic analysis indicated a progressive sGAG accumulation and SOX9, COL2-A1, ACAN gene expression was upregulated in 3-dimensional HAC pellet models. This study therefore supports the use of hPL as a functional equivalent and alternative to aHS for cultured HAC batch preparation, with the potential to effectively alleviate pressure on clinical and manufacturing bottlenecks in cell therapy approaches for cartilage regeneration

Temperature evolution following joint loading promotes chondrogenesis by synergistic cues via calcium signaling.

During loading of viscoelastic tissues, part of the mechanical energy is transformed into heat that can locally increase the tissue temperature, a phenomenon known as self-heating. In the framework of mechanobiology, it has been accepted that cells react and adapt to mechanical stimuli. However, the cellular effect of temperature increase as a by-product of loading has been widely neglected. In this work, we focused on cartilage self-heating to present a 'thermo-mechanobiological' paradigm, and demonstrate how the coupling of a biomimetic temperature evolution and mechanical loading could influence cell behavior. We thereby developed a customized in vitro system allowing to recapitulate pertinent in vivo physical cues and determined the cells chondrogenic response to thermal and/or mechanical stimuli. Cellular mechanisms of action and potential signaling pathways of thermo-mechanotransduction process were also investigated. We found that co-existence of thermo-mechanical cues had a superior effect on chondrogenic gene expression compared to either signal alone. Specifically, the expression of Sox9 was significantly upregulated by application of the physiological thermo-mechanical stimulus. Multimodal transient receptor potential vanilloid 4 (TRPV4) channels were identified as key mediators of thermo-mechanotransduction process, which becomes ineffective without external calcium sources. We also observed that the isolated temperature evolution, as a by-product of loading, is a contributing factor to the cell response and this could be considered as important as the conventional mechanical loading. Providing an optimal thermo-mechanical environment by synergy of heat and loading portrays new opportunity for development of novel treatments for cartilage regeneration and can furthermore signal key elements for emerging cell-based therapies

Repair of critical size defects in the rat cranium using ceramic-reinforced PLA scaffolds obtained by supercritical gas foaming

Bioresorbable scaffolds made of poly(L-lactic acid) (PLA) obtained by supercritical gas foaming were recently described as suitable for tissue engineering, portraying biocompatibility with primary osteoblasts in vitro and interesting mechanical properties when reinforced with ceramics. The behavior of such constructs remained to be evaluated in vivo and therefore the present study was undertaken to compare different PLA/ceramic composite scaffolds obtained by supercritical gas foaming in a critical size defect craniotomy model in Sprague-Dawley rats. The host-tissue reaction to the implants was evaluated semiquantitatively and similar tendencies were noted for all graft substitutes: initially highly reactive but decreasing with time implanted. Complete bone-bridging was observed 18 weeks after implantation with PLA/ 5 wt % beta-TCP (PLA/TCP) and PLA/5 wt % HA (PLA/HA) scaffolds as assessed by histology and radiography. We show here for the first time that this solvent-free technique provides a promising approach in tissue engineering demonstrating both the biocompatibility and osteoconductivity of the processed structures in vivo