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.

Towards research combat readiness: prepared, prospective and preapproved.

Research drives the advancement of medical knowledge during war, but planning and execution are too slow to enable early data acquisition. Future conflicts are likely to be shorter and more dispersed, requiring innovation to avoid missing out on the crucial early stages. To seize the initiative, we suggest that a collection of preapproved research studies be designed, stored and maintained within the medical command structure so that they are ready for immediate implementation at the onset of future conflicts, even during the most kinetic early phases of deployment.

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification.

Heterotopic ossification (HO) is a debilitating condition defined by the de novo development of bone within non-osseous soft tissues, and can be either hereditary or acquired. The hereditary condition, fibrodysplasia ossificans progressiva is rare but life threatening. Acquired HO is more common and results from a severe trauma that produces an environment conducive for the formation of ectopic endochondral bone. Despite continued efforts to identify the cellular and molecular events that lead to HO, the mechanisms of pathogenesis remain elusive. It has been proposed that the formation of ectopic bone requires an osteochondrogenic cell type, the presence of inductive agent(s) and a permissive local environment. To date several lineage-tracing studies have identified potential contributory populations. However, difficulties identifying cells in vivo based on the limitations of phenotypic markers, along with the absence of established in vitro HO models have made the results difficult to interpret. The purpose of this review is to critically evaluate current literature within the field in an attempt identify the cellular mechanisms required for ectopic bone formation. The major aim is to collate all current data on cell populations that have been shown to possess an osteochondrogenic potential and identify environmental conditions that may contribute to a permissive local environment. This review outlines the pathology of endochondral ossification, which is important for the development of potential HO therapies and to further our understanding of the mechanisms governing bone formation.

The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia.

BACKGROUND: There has been an absence of controlled studies focusing specifically on neuroleptic treatment in the elderly schizophrenic population. Therefore, we conducted a 12-week double-blind comparison study to assess the efficacy and tolerability of clozapine and chlorpromazine in a group of elderly inpatients with chronic schizophrenia. METHOD: Forty-two elderly DSM-IV schizophrenic veterans were randomly assigned to clozapine or chlorpromazine and assessed for efficacy at baseline and at termination with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions scale (CGI). Side effects were also monitored. Medications were titrated, on the basis of clinical response and side effects, to a maximum dose of 300 mg/day of clozapine or 600 mg/day of chlorpromazine. RESULTS: The results suggest that both the chlorpromazine and clozapine groups improved their PANSS scores at termination compared with baseline, but the difference between the 2 groups was not statistically significant. The mean CGI scores reflecting severity of illness also demonstrated improvement in both groups over time. Both groups had similar incidences of side effects. One patient in each group had a life-threatening side effect. More patients taking clozapine had tachycardia and weight gain, while more chlorpromazine patients noted sedation. CONCLUSION: We concluded that both clozapine and chlorpromazine are effective treatments for psychosis and behavioral disturbances in geriatric schizophrenia. Both agents had similar incidences of side effects. With careful monitoring and titration of dosage, both clozapine and chlorpromazine were fairly well tolerated in this population.

Comparison of linear equating and prorated short forms for estimating WAIS-R FSIQ in a neuropsychological population.

Comparisons were made of estimates of the Wechsler Adult Intelligence Scale - Revised Full Scale IQ using the two-,three- and four-subtest linear equating procedures of Kaufman (1990) and Booker and Cyr (1986) with FSIQ estimates using prorating to obtain FSIQ scores. The advantage of prorating is that it affords greater clinical flexibility in selection of subtests. The participants were 64 neuropsychiatric patients who completed the full WAIS-R from which short form and FSIQ were calculated. Prorating yielded estimates of mean IQ and categorization of IQ comparable to IQs obtained by linear equating, though there was an increased likelihood of disparate results with extreme IQ scores. Prudent clinical judgment is recommended for situations involving unusual or extreme scaled score patterns, particularly when the number of subtests is small.

Factor structure of the Neurobehavioral Cognitive Status Exam (COGNISTAT) in healthy, and psychiatrically and neurologically impaired, elderly adults.

This study reports the results of factor analyses of COGNISTAT (NCSE) in a sample of elderly persons comprised of "healthy" participants with no psychiatric or neurological impairments (n = 153), individuals with psychiatric impairments (n = 70), and those with neurological impairments (n = 80). Our findings support a unitary factor structure for COGNISTAT, though a separate factor of unclear clinical or theoretical significance was suggested.

The Lie/Bet Questionnaire for screening pathological gamblers.

A 2-item questionnaire was derived from 10 DSM-IV criteria for pathological gambling. Subjects were 362 men, 191 classified as pathological gamblers and 171 as nonproblem-gambling controls. The two items were significant in sensitivity and negative predictive value and significant in specificity and positive predictive value.

Social facilitation of muricidal behavior in the rat.

A phenomenon resembling social facilitation of muricide was described. Rats, who were already established mouse killers, killed mice faster in the presence of a large number of rats continuously killing mice. Evidence was presented which supports the argument that the facilitation was transmitted through auditory rather than olfactory cues.

Effect of medroxyprogesterone and an aorta-derived cell growth inhibitor on B16 melanoma in mice.

An aorta-derived inhibitor of endothelial cell and tumor cell growth and medroxyprogesterone, which depresses collagenase expression in vivo, were tested alone and in combination against B16-F10 melanoma in C57BL/6 mice in such doses that either agent alone had little effect. Together, these agents retarded growth of subcutaneously transplanted tumor cells and reduced the number and size of pulmonary tumors after iv tumor cell injection. Of the treatments used, only the aortic factor administered alone prolonged life in mice with pulmonary tumors.

Effects of selected drugs on spontaneously occurring abnormal behavior in beagles.

A sub-population of beagles with abnormal behavioral patterns has been identified, isolated and tested for responsively to selected classes of psychoactive drugs. The abnormal behavior was ameliorated by anxiolytics and antidepressants but not by antipsychotics, an antihistaminic, an alpha-adrenergic blocker, a beta-adrenergic blocker, or an anticholinergic drug. Improvement occurred after a single dose of the anxiolytic drugs but did not occur until 10-18 days after daily dosing with standard tricylic antidepressants and the MAO inhibitor isocarboxazid. This delayed onset in beagles resembles that seen on use of these drugs in humans. The results with these drugs suggest that the abnormal behaviors of the beagles are related to anxiety and are in part depressive in nature. This colony provides an animal model of abnormal behavior which allows evaluation of the anxiolytic and antidepressant effects of drugs and estimates of the onset of action of antidepressant drugs.

Role of serotonin in the blockade of muricidal behavior by tricyclic antidepressants.

Dose-response curves for the ability of three tricyclic antidepressants, imipramine, desmethylimipramine and amitriptyline to inhibit muricidal behavior were measured after treatment with a tryptophan-free diet and after administration of p-chloroamphetamine. Both treatments, which have been reported to specifically reduce central levels of serotonin, decreased the ability of the drugs to inhibit muricide. The results suggest that all three antidepressants block muricide in part through their effects on serotonin.

Central nervous system activity of 7-substituted 1-azaphenoxathiin analogues and their oxidation products.

A number of 7-substituted 1-azaphenoxathiins and their sulfone oxidation products have been synthesized and screened for central nervous system activity. Some of the compounds have antidepressant activity, with the most active, 7-(trifluoromethyl)-1-azaphenoxathiin 10,10-dioxide (8), having similar potency to imipramine.