Local injection of a hexametaphosphate formulation reduces heterotopic ossification in vivo.

Heterotopic ossification (HO), the pathological formation of ectopic bone, is a debilitating condition which can cause chronic pain, limit joint movement, and prevent prosthetic limb fitting. The prevalence of this condition has risen in the military population, due to increased survivorship following blast injuries. Current prophylaxes, which aim to target the complex upstream biological pathways, are inconsistently effective â€‹and have a range of side-effects that make them unsuitable for combat-injured personnel. As such, many patients must undergo further surgery to remove the formed ectopic bone. In this study, a non-toxic, U.S. Food and Drug Administration (FDA) -approved calcium chelator, hexametaphosphate (HMP), is explored as a novel treatment paradigm for this condition, which targets the chemical, rather that biological, â€‹bone formation pathways. This approach allows not only prevention of pathological bone formation â€‹but also uniquely facilitates reversal, which current drugs cannot achieve. Targeted, minimally invasive delivery is achieved by loading HMP into an injectable colloidal alginate. These formulations significantly reduce â€‹the length of the ectopic bone formed in a rodent model of HO, with no effect on the adjacent skeletal bone. This study demonstrates the potential of localized dissolution as a new treatment â€‹and an alternative to surgery â€‹for pathological ossification and calcification conditions.

The role of subchondral bone, and its histomorphology, on the dynamic viscoelasticity of cartilage, bone and osteochondral cores.

OBJECTIVE: Viscoelastic properties of articular cartilage have been characterised at physiological frequencies. However, studies investigating the interaction between cartilage and subchondral bone and the influence of underlying bone histomorphometry on the viscoelasticity of cartilage are lacking. METHOD: Dynamic Mechanical Analysis (DMA) has been used to quantify the dynamic viscoelasticity of bovine tibial plateau osteochondral cores, over a frequency sweep from 1 to 88 Hz. Specimens (approximately aged between 18 and 30 months) were neither osteoarthritic nor otherwise compromised. A maximum nominal stress of 1.7 MPa was induced. Viscoelastic properties of cores have been compared with that of its components (cartilage and bone) in terms of the elastic and viscous components of both structural stiffness and material modulus. Micro-computed tomography scans were used to quantify the histomorphological properties of the subchondral bone. RESULTS: Opposing frequency-dependent loss stiffness, and modulus, trends were witnessed for osteochondral tissues: for cartilage it increased logarithmically (P < 0.05); for bone it decreased logarithmically (P < 0.05). The storage stiffness of osteochondral cores was logarithmically frequency-dependent (P < 0.05), however, the loss stiffness was typically frequency-independent (P > 0.05). A linear relationship between the subchondral bone plate (SBP) thickness and cartilage thickness (P < 0.001) was identified. Cartilage loss modulus was linearly correlated to bone mineral density (BMD) (P < 0.05) and bone volume (P < 0.05). CONCLUSION: The relationship between the subchondral bone histomorphometry and cartilage viscoelasticity (namely loss modulus) and thickness, have implications for the initiation and progression of osteoarthritis (OA) through an altered ability of cartilage to dissipate energy.

Annexin-enriched osteoblast-derived vesicles act as an extracellular site of mineral nucleation within developing stem cell cultures.

The application of extracellular vesicles (EVs) as natural delivery vehicles capable of enhancing tissue regeneration could represent an exciting new phase in medicine. We sought to define the capacity of EVs derived from mineralising osteoblasts (MO-EVs) to induce mineralisation in mesenchymal stem cell (MSC) cultures and delineate the underlying biochemical mechanisms involved. Strikingly, we show that the addition of MO-EVs to MSC cultures significantly (P < 0.05) enhanced the expression of alkaline phosphatase, as well as the rate and volume of mineralisation beyond the current gold-standard, BMP-2. Intriguingly, these effects were only observed in the presence of an exogenous phosphate source. EVs derived from non-mineralising osteoblasts (NMO-EVs) were not found to enhance mineralisation beyond the control. Comparative label-free LC-MS/MS profiling of EVs indicated that enhanced mineralisation could be attributed to the delivery of bridging collagens, primarily associated with osteoblast communication, and other non-collagenous proteins to the developing extracellular matrix. In particular, EV-associated annexin calcium channelling proteins, which form a nucleational core with the phospholipid-rich membrane and support the formation of a pre-apatitic mineral phase, which was identified using infrared spectroscopy. These findings support the role of EVs as early sites of mineral nucleation and demonstrate their value for promoting hard tissue regeneration.

Visualising phase change in a brushite-based calcium phosphate ceramic.

The resorption of brushite-based bone cements has been shown to be highly unpredictable, with strong dependence on a number of conditions. One of the major factors is phase transformation, with change to more stable phases such as hydroxyapatite affecting the rate of resorption. Despite its importance, the analysis of phase transformation has been largely undertaken using methods that only detect crystalline composition and give no information on the spatial distribution of the phases. In this study confocal Raman microscopy was used to map cross-sections of brushite cylinders aged in Phosphate Buffered Saline, Foetal Bovine Serum, Dulbecco's - Minimum Essential Medium (with and without serum). Image maps showed the importance of ageing medium on the phase composition throughout the ceramic structure. When aged without serum, there was dissolution of the brushite phase concomitant to the deposition of octacalcium phosphate (OCP) around the periphery of the sample. The deposition of OCP was detectable within five days and reduced the rate of brushite dissolution from the material. The use of serum, even at a concentration of 10vol% prevented phase transformation. This paper demonstrates the value of confocal Raman microscopy in monitoring phase change in biocements; it also demonstrates the problems with assessing material degradation in non-serum containing media.

Areca nut chewing in an expatriate population in Sydney: report of two cases.

Areca nut (betel nut) consumption occurs in a variety of forms, either on its own or with the addition of a number of products. This habit is prevalent in the Indian Subcontinent and South-East Asia. Recent immigration statistics indicate that 30% of new arrivals in Australia are from these geographical regions and are known to perpetuate this custom long after migration. The objective of this paper is to highlight the variety of oral presentations that may occur as a result of areca nut consumption in these particular demographic subgroups. Dental practitioners must be familiar with the wide spectrum of oral lesions that may present in this setting. More significantly, they must be aware that some of these lesions possess the potential for malignant transformation and hence require more specific management. Best practice mandates that dental practitioners in a multicultural society must: (1) be capable of recognizing the expatriate populations in which this custom is widely practised; (2) incorporate this particular line of questioning into the routine risk factor analysis that is undertaken for every patient from these particular sub-populations; and (3) institute appropriate referral and follow-up of these lesions if required.

Morphological preservation of carbonaceous plant fossils in blueschist metamorphic rocks from New Zealand.

Morphological and chemical evidence of ancient life is widespread in sedimentary rocks retrieved from shallow depths in the Earth's crust. Metamorphism is highly detrimental to the preservation of biological information in rocks, thus limiting the geological record in which traces of life might be found. Deformation and increasing pressure/temperature during deep burial may alter the morphology as well as the composition and structure of both the organic and mineral constituents of fossils. However, microspore fossils have been previously observed in intensely metamorphosed rocks. It has been suggested that their small size, and/or the nature of the polymer composing their wall, and/or the mineralogy of their surrounding matrix were key parameters explaining their exceptional preservation. Here, we describe the remarkable morphological preservation of plant macrofossils in blueschist metamorphic rocks from New Zealand containing lawsonite. Leaves and stems can be easily identified at the macroscale. At the microscale, polygonal structures with walls mineralized by micas within the leaf midribs and blades may derive from the original cellular ultrastructure or, alternatively, from the shrinkage during burial of the gelified remnants of the leaves in an abiotic process. Processes and important parameters involved in the remarkable preservation of these fossils during metamorphism are discussed. Despite the excellent morphological preservation, the initial biological polymers have been completely transformed to graphitic carbonaceous matter down to the nanometer scale. This occurrence demonstrates that plant macrofossils may experience major geodynamic processes such as metamorphism and exhumation involving deep changes and homogenization of their carbon chemistry and structure but still retain their morphology with remarkable integrity even if they are not shielded by any hard-mineralized concretion.

Establishing a normal range for mouth opening: its use in screening for oral submucous fibrosis.

The maximal mouth opening of 700 healthy Nepalese adults, age range of 18-68 years, measured by paraclinical workers was determined as there are no data available for an Asian population. The mean value of the inter-incisal distance was 47.1 mm (range 33.7-60.4 mm) and 98% of the population surveyed fell within this range. The minimum limit of normal oral opening was determined to be 34 mm. Ten out of 13 patients with histologically confirmed oral submucous fibrosis (OSF) had a maximal oral opening of less than 34 mm. It was concluded that reduced oral opening measured by paraclinical workers as a single screening test for oral submucous fibrosis, has a sensitivity of only 77% and will detect only advanced cases. However, each of the 3 subjects from the healthy population found to have restricted mandibular opening and who agreed to be examined further had significant oral conditions, namely oral submucous fibrosis (2) and pericoronitis (1). The study confirms the value of this measurement as a screening procedure for significant oral disease by paraclinical staff particularly in developing countries where trained dental and medical personnel are scarce. Because of its limited sensitivity, measurement of mouth opening is unsatisfactory as a single screening test for OSF, as it will not detect early stages of the disease.

Oral submucous fibrosis. A review.

Oral submucous fibrosis (OSF) affects an estimated 2.5 million people, mostly in the Indian subcontinent. Limitation of oral opening resulting in difficulty in eating is the main presenting feature. Although nutritional deficiencies and immunological processes may play a part in the pathogenesis, the available epidemiological evidence indicates that chewing betel quid (containing areca nut, tobacco, slaked lime or other species) is an important risk factor for OSF. Genetically determined susceptibility could explain why only a small fraction of those using betel quid develop the disease. In OSF there is an incidence of oral cancer of 7.6 per cent for a median 10-year follow-up period. Risk markers for malignant transformation in OSF include epithelial dysplasia, silver binding nucleolar organizer region counts, and sister-chromatid exchange frequencies; p53 tumour suppressor gene mutations may be involved in these potentially malignant changes.

Epithelial growth fraction and expression of p53 tumour suppressor gene in oral submucous fibrosis.

The incidence of squamous cell carcinoma in patients with oral submucous fibrosis (OSF) exceeds 7 per cent. The proliferative cell nuclear antigen (PCNA) is a convenient marker of epithelial cell proliferation and p53 tumour suppressor gene mutations or deletions are frequent in oral cancer. The present study estimated the basal epithelial cell growth fraction using a standard immunohistological method for the detection of nuclear PCNA from 20 Nepalese patients with OSF as 31.8 per cent compared with 7.6 per cent for oral mucosa from 43 normal subjects (p < 0.001) and 39.4 per cent for 44 patients with oral cancer. The PCNA growth fraction correlated significantly with that derived by Ki-67 labelling. There was no correlation between the growth fraction and the severity of epithelial dysplasia found is OSF. Abnormal expression of p53 protein identified by immunohistochemistry with a panel of antibodies was found in 70 per cent of the OSF specimens, and 21 per cent of mucosal specimens from subjects with clinically normal mouths. PCNA-positive cells and p53 expression were restricted to the basal epithelial layer in OSF. The unexpected finding of p53 protein in clinically healthy mucosa was confined to subjects aged over 40 years who smoked tobacco, a known risk factor for oral cancer. There was no association between p53 expression and epithelial atypia scores in OSF. It is concluded that the proportion of actively cycling epithelial cells is increased in OSF and that p53 tumour suppressor gene mutations or deletions may be prevalent. Confirmation by molecular biology techniques of this genetic damage is now needed.

Health promotion mini-grants: grassroots implementation in New Mexico.

The populations of New Mexico are ethnically diverse, with large Hispanic and Native American components, and live in communities that are geographically dispersed and economically challenged. The University of New Mexico is located in Albuquerque, the state's only major urban area, and houses the state's only academic health sciences center. In 1986, the University received a grant from the W.K. Kellogg Foundation to establish health promotion/disease prevention curricula for health science students and create two Wellness Centers on campus. The Wellness Centers train students to be providers of health information and learn how to counsel and assist people with changing health-related behaviors. A campus-wide employee health promotion program was also implemented. Most of the instructional and service programs initiated by the grant have continued with stable institutional support. A later phase of the project was to encourage other agencies and organizations throughout New Mexico to adopt or expand their own health promotion initiatives. An operating premise of this phase was that local initiatives should respond to locally perceived priorities. To accomplish this, a program of mini-grants was designed to assist in creating health promotion programs within a variety of topic areas. Thirteen mini-grants were awarded to agencies representing diverse groups and cultures throughout New Mexico. Our experience with the mini-grants and the ability of organizations to sustain the activities past the period of grant support are described. The successful use of mini-grants has been reported elsewhere in the literature.

Acute respiratory failure: mortality associated with underlying disease.

The hospital and ICU course of 98 patients who required mechanical ventilatory support longer than 72 h was reviewed to determine if mortality rates were influenced by admitting diagnosis. Patients with malignant diagnoses were compared to patients with nonmalignant diagnoses and to those admitted to the ICU after myocardial infarction or cardiorespiratory arrest. Although there was no significant intergroup difference in incidence of multiple organ system failure, age, and length of ICU and hospital stay, there was a much higher incidence of sepsis (p less than .05) and mortality (p less than .01) in the cancer group. Cancer patients and their families should be made aware of the extremely poor prognosis if prolonged acute respiratory failure develops.