Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss.

The existing suite of therapies for bone diseases largely act to prevent further bone loss but fail to stimulate healthy bone formation and repair. We describe an endogenous osteopeptide (PEPITEM) with anabolic osteogenic activity, regulating bone remodeling in health and disease. PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength. Simultaneously, PEPITEM stimulates an inhibitory paracrine loop: promoting osteoblast release of the decoy receptor osteoprotegerin, which sequesters RANKL, thereby limiting osteoclast activity and bone resorption. In disease models, PEPITEM therapy halts osteoporosis-induced bone loss and arthritis-induced bone damage in mice and stimulates new bone formation in osteoblasts derived from patient samples. Thus, PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss, promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover.

The Species Effect: Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse.

The deterioration of osteoblast-led bone formation and the upregulation of osteoclast-regulated bone resorption are the primary causes of bone diseases, including osteoporosis. Numerous circulating factors play a role in bone homeostasis by regulating osteoblast and osteoclast activity, including the sphingolipid-sphingosine-1-phosphate (S1P). However, to date no comprehensive studies have investigated the impact of S1P activity on human and murine osteoblasts and osteoclasts. We observed species-specific responses to S1P in both osteoblasts and osteoclasts, where S1P stimulated human osteoblast mineralisation and reduced human pre-osteoclast differentiation and mineral resorption, thereby favouring bone formation. The opposite was true for murine osteoblasts and osteoclasts, resulting in more mineral resorption and less mineral deposition. Species-specific differences in osteoblast responses to S1P were potentially explained by differential expression of S1P receptor 1. By contrast, human and murine osteoclasts expressed comparable levels of S1P receptors but showed differential expression patterns of the two sphingosine kinase enzymes responsible for S1P production. Ultimately, we reveal that murine models may not accurately represent how human bone cells will respond to S1P, and thus are not a suitable model for exploring S1P physiology or potential therapeutic agents.

The Ying and Yang of Sphingosine-1-Phosphate Signalling within the Bone.

Bone remodelling is a highly active and dynamic process that involves the tight regulation of osteoblasts, osteoclasts, and their progenitors to allow for a balance of bone resorption and formation to be maintained. Ageing and inflammation are risk factors for the dysregulation of bone remodelling. Once the balance between bone formation and resorption is lost, bone mass becomes compromised, resulting in disorders such as osteoporosis and Paget's disease. Key molecules in the sphingosine-1-phosphate signalling pathway have been identified for their role in regulating bone remodelling, in addition to its more recognised role in inflammatory responses. This review discusses the accumulating evidence for the different, and, in certain circumstances, opposing, roles of S1P in bone homeostasis and disease, including osteoporosis, Paget's disease, and inflammatory bone loss. Specifically, we describe the current, often conflicting, evidence surrounding S1P function in osteoblasts, osteoclasts, and their precursors in health and disease, concluding that S1P may be an effective biomarker of bone disease and also an attractive therapeutic target for disease.

A detailed methodology for a three-dimensional, self-structuring bone model that supports the differentiation of osteoblasts towards osteocytes and the production of a complex collagen-rich mineralised matrix.

Background: There are insufficient in vitro bone models that accommodate long-term culture of osteoblasts and support their differentiation to osteocytes. The increased demand for effective therapies for bone diseases, and the ethical requirement to replace animals in research, warrants the development of such models.Here we present an in-depth protocol to prepare, create and maintain three-dimensional, in vitro, self-structuring bone models that support osteocytogenesis and long-term osteoblast survival (>1 year). Methods: Osteoblastic cells are seeded on a fibrin hydrogel, cast between two beta-tricalcium phosphate anchors. Analytical methods optimised for these self-structuring bone model (SSBM) constructs, including RT-qPCR, immunofluorescence staining and XRF, are described in detail. Results: Over time, the cells restructure and replace the initial matrix with a collagen-rich, mineralising one; and demonstrate differentiation towards osteocytes within 12 weeks of culture. Conclusions: Whilst optimised using a secondary human cell line (hFOB 1.19), this protocol readily accommodates osteoblasts from other species (rat and mouse) and origins (primary and secondary). This simple, straightforward method creates reproducible in vitro bone models that are responsive to exogenous stimuli, offering a versatile platform for conducting preclinical translatable research studies.

Ringed seal (Pusa hispida) breeding habitat on the landfast ice in northwest Alaska during spring 1983 and 1984.

There has been significant sea ice loss associated with climate change in the Pacific Arctic, with unquantified impacts to the habitat of ice-obligate marine mammals such as ringed seals (Pusa hispida). Ringed seals maintain breathing holes and excavate subnivean lairs on sea ice to provide protection from weather and predators during birthing, nursing, and resting. However, there is limited baseline information on the snow and ice habitat, distribution, density, and configuration of ringed seal structures (breathing holes, simple haul-out lairs, and pup lairs) in Alaska. Here, we describe historic field records from two regions of the eastern Chukchi Sea (Kotzebue Sound and Ledyard Bay) collected during spring 1983 and 1984 to quantify baseline ringed seal breeding habitat and map the distribution of ringed seal structures using modern geospatial tools. Of 490 structures located on pre-established study grids by trained dogs, 29% were pup lairs (25% in Kotzebue Sound and 33% in Ledyard Bay). Grids in Ledyard Bay had greater overall density of seal structures than those in Kotzebue Sound (8.6 structures/km2 and 7.1 structures/km2), but structures were larger in Kotzebue Sound. Pup lairs were located in closer proximity to other structures and characterized by deeper snow and greater ice deformation than haul-out lairs or simple breathing holes. At pup lairs, snow depths averaged 74.9 cm (range 37-132 cm), with ice relief nearby averaging 76 cm (range 31-183 cm), and ice deformation 29.9% (range 5-80%). We compare our results to similar studies conducted in other geographic regions and discuss our findings in the context of recent declines in extent and duration of seasonal cover of landfast sea ice and snow deposition on sea ice. Ultimately, additional research is needed to understand the effects of recent environmental changes on ringed seals, but our study establishes a baseline upon which future research can measure pup habitat in northwest Alaska.

[3-hydroxy-3-methylglutaryl-CoA lyase deficiency: a case report and literature review]. / Anorexia nerviosa como causa de fallo hepático agudo. A propósito de un caso.

INTRODUCTION: 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is an autosomal recessive disorder that usually presents in the neonatal period with vomiting, metabolic acidosis, hypoglycemia and absent ketonuria. Few cases are reported in the literature, and optimal dietary management and long term outcome are not fully understood. CASE REPORT: We report a 2 year old girl with HMG-CoA-lyase deficiency who had limited fasting tolerance on a low protein diet, with several recurrent hospital admissions with severe hypoketotic hypoglycaemia and metabolic acidosis. We also review the dietary management and outcome of other reported cases in the literature. DISCUSSION: In order to define optimal dietary treatment, it is important to collect higher numbers of case studies with detailed dietary management, fasting times and outcome.

Habitat selection and seasonal movements of young bearded seals (Erignathus barbatus) in the Bering Sea.

The first year of life is typically the most critical to a pinniped's survival, especially for Arctic phocids which are weaned at only a few weeks of age and left to locate and capture prey on their own. Their seasonal movements and habitat selection are therefore important factors in their survival. During a cooperative effort between scientists and subsistence hunters in October 2004, 2005, and 2006, 13 female and 13 male young (i.e., age <2) bearded seals (Erignathus barbatus) were tagged with satellite-linked dive recorders (SDRs) in Kotzebue Sound, Alaska. Shortly after being released, most seals moved south with the advancing sea-ice through the Bering Strait and into the Bering Sea where they spent the winter and early spring. The SDRs of 17 (8 female and 9 male) seals provided frequent high-quality positions in the Bering Sea; their data were used in our analysis. To investigate habitat selection, we simulated 20 tracks per seal by randomly selecting from the pooled distributions of the absolute bearings and swim speeds of the tagged seals. For each point in the observed and simulated tracks, we obtained the depth, sea-ice concentration, and the distances to sea-ice, open water, the shelf break and coastline. Using logistic regression with a stepwise model selection procedure, we compared the simulated tracks to those of the tagged seals and obtained a model for describing habitat selection. The regression coefficients indicated that the bearded seals in our study selected locations near the ice edge. In contrast, aerial surveys of the bearded seal population, predominantly composed of adults, indicated higher abundances in areas farther north and in heavier pack ice. We hypothesize that this discrepancy is the result of behavioral differences related to age. Ice concentration was also shown to be a statistically significant variable in our model. All else being equal, areas of higher ice concentration are selected for up to about 80%. The effects of sex and bathymetry were not statistically significant. The close association of young bearded seals to the ice edge in the Bering Sea is important given the likely effects of climate warming on the extent of sea-ice and subsequent changes in ice edge habitat.

Serologic survey for Brucella spp., phocid herpesvirus-1, phocid herpesvirus-2, and phocine distemper virus in harbor seals from Alaska, 1976-1999.

Harbor seals (Phoca vitulina richardsi) were captured in the coastal regions of Southeast Alaska, Gulf of Alaska, Prince William Sound (PWS), and Kodiak Island during 1976-1999. Blood was collected from 286 seals. Sera were tested for evidence of exposure to Brucella spp., phocid herpesvirus-1 (PhoHV-1), phocid herpesvirus-2 (PhHV-2), and phocine distemper virus (PDV). Antibody prevalence rates were 46% (46/100) for Brucella spp., 93% (225/243) for PhoHV-1, 0% (0/286) for PhHV-2, and 1% (2/160) for PDV. Antibody prevalence for Brucella spp. was directly related to host age. Antibody prevalence for PhoHV-1 was higher in PWS as compared to the other three regions. No evidence of mortality attributable to these four agents was observed during the course of this study. Based on the results of this survey, none of these agents is considered a significant mortality factor in harbor seals from the four regions of coastal Alaska included in the study.

Observations on the workshop as a means of improving communication between holders of traditional and scientific knowledge.

Traditional ecological knowledge (TEK) and the information and insights it offers to natural resource research and management have been given much attention in recent years. On the practical question of how TEK is accessed and used together with scientific knowledge, most work to date has examined documentation and methods of recording and disseminating information. Relatively little has been done regarding exchanges between scientific and traditional knowledge. This paper examines three workshop settings in which such exchanges were intended outcomes. The Barrow Symposium on Sea Ice, the Exxon Valdez Oil Spill Restoration Program Synthesis/Information Workshops, and the Alaska Beluga Whale Committee illuminate certain features of the preparation, format, and context of workshops or series of workshops and their eventual outcomes and influence. The examples show the importance of long-term relationships among participants and thorough preparation before the actual workshop. Further research should look more systematically at the factors that influence the success of a given workshop and the various ways in which participants perceive success.