Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair.

Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. INTRODUCTION: Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. METHODS: To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. RESULTS: This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. CONCLUSION: There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.

The geographic availability and associated utilization of dual-energy X-ray absorptiometry (DXA) testing among older persons in the United States.

UNLABELLED: Using national Medicare data from 1999-2006, we evaluated the relationship between travel distance and receipt of dual-energy X-ray absorptiometry (DXA). After adjusting for potentially confounding factors, travel distance was strongly associated with DXA testing. Rural residents were most strongly dependent on the availability of DXAs performed in physician offices. INTRODUCTION: Medicare reimbursement for DXAs performed in non-facility settings (e.g., physician offices) decreased in 2007. With declining reimbursement, some DXA providers may cease providing this service, which would increase travel distance for some people. The impact of travel distance on access to DXA is unclear. METHODS: Using national Medicare data, we identified claims for DXA to evaluate trends in the number and locations of DXAs performed. Travel distance was the distance from beneficiaries' residence and the nearest DXA provider. Binomial regression evaluated the relationship between travel distance and receipt of DXA. RESULTS: In 2006, 2.9 million DXAs were performed, a 103% increase since 1999. In 2005-2006, 8.0% of persons were tested at non-facility sites versus 4.2% at facility sites. The remainder (88%) had no DXA. Persons traveling 5-9, 10-24, 25-39, and 40-54, and > or = 55 miles were less likely to receive DXA (adjusted risk ratios = 0.92, 0.79, 0.43, 0.32, and 0.26, respectively, < 5 miles referent). Rural residents were more dependent than urban residents on the availability of DXA from non-facility providers. CONCLUSION: Approximately two-thirds of DXAs in 2005-2006 were performed in non-facility settings (e.g., physician offices). Rural residents would have preferentially reduced access to DXA if there were fewer non-facility sites.

Scleroderma is associated with differences in individual routes of drug metabolism: a study with dapsone, debrisoquin, and mephenytoin.

Exposure to certain environmental agents may induce a scleroderma-like syndrome in a small proportion of individuals. Differences in susceptibility could involve metabolic activation of a protoxin, with affected patients having a greater converting ability. This possibility was investigated in 84 patients with scleroderma and 108 control subjects with in vivo probes of specific pathways of metabolism. Scleroderma was associated with reduced hydroxylating activity for dapsone and S-mephenytoin, whereas the ability to hydroxylate debrisoquin and N-acetyl dapsone was similar in both groups. Logistic regression confirmed these associations based on the shift in frequency distribution. Individuals who were poor metabolizers for mephenytoin and only modest N-hydroxylators of dapsone had a tenfold increased risk of scleroderma (p = 0.008). Thus this combined metabolic impairment may be causally involved in the development of scleroderma or, alternatively, the disease may produce inhibition of selected metabolizing enzymes in a subset of patients.

Prospective analysis of sinus symptoms and correlation with paranasal computed tomography scan.

OBJECTIVES: We designed a prospective study to determine whether there is a correlation between the severity of sinus symptoms and the severity of computed tomography (CT) scan evidence of rhinosinusitis. METHODS: Acute and chronic rhinosinusitis patients rated their symptoms and had a CT scan of the sinuses taken the same day. A Likert severity scale and standardized CT scoring system were used. Data were analyzed by nonparametric methods with Kendall's rank correlation coefficient. RESULTS: The severity of 5 symptoms correlated with severity of disease on CT scan. Headache and facial pain or pressure had no correlation. CONCLUSION: The certainty of a clinical diagnosis of rhinosinusitis requiring treatment is enhanced in patients with high symptom severity scores for fatigue, sleep disturbance, nasal discharge, nasal blockage, or decreased sense of smell. Isolated headache and facial pain or pressure are less reliable predictors of CT scan findings supporting the diagnosis rhinosinusitis.

Highly conserved gene expression profiles in humans with allergic rhinitis altered by immunotherapy.

BACKGROUND: Atopic diseases, resulting from hypersensitivity to a wide variety of allergens, affect 10-20% of the population. Immunotherapy is an effective treatment for atopic diseases, but its mechanisms are not fully understood. OBJECTIVE: We studied gene expression profiles in the peripheral blood mononuclear cells (PBMC) and examined whether the individuals with allergic rhinitis (AR) have a unique gene expression profile and how the immunotherapy affect the gene expression profiles. METHODS: We used cDNA microarray and 'expression analysis systemic explorer' to examine the gene expression profiles in the PBMC of atopic subjects and other groups. RESULTS: We identified a highly conserved gene expression profile in atopic subjects that permitted their accurate segregation from control or autoimmune subjects. A major feature of this profile was the under-expression of a variety of genes that encode proteins required for apoptosis and over-expression of genes that encode proteins critical for stress responses and signal transduction. We also identified 563 genes that can segregate individuals with AR based upon receipt of immunotherapy. CONCLUSION: There is a highly conserved gene expression profile in the PBMC of individuals with AR. This profile can be used to identify individuals with AR and to evaluate responses to immunotherapy. Quantitative endpoints, such as gene expression, may assist clinicians faced with clinical decisions in the diagnosis of patients and the evaluation of response to therapy. The knowledge of the possible genetic basis for immunotherapy efficacy may also lead to novel therapeutic approaches for atopic diseases.

The evolution of a case of overlap syndrome with systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus.

An unusual case of overlap syndrome which evolved over a 12-year period is described. The patient initially presented with limited cutaneous systemic sclerosis. She then developed seropositive erosive rheumatoid arthritis and subsequently vasculitis with positive lupus serology. There was no evidence that she had mixed or undifferentiated connective tissue disease, and antibody to ribonuclearprotein was negative. This unusual combination of connective tissue disorders in one patient is reported and the literature is reviewed.

Metabolism of diethylstilbestrol: identification of a catechol derived from dienestrol.

The enzymatic oxidation of E-3,4-bis-(p-hydroxyphenyl)-hex-3-ene (diethylstilbestrol) by either mushroom tyrosinase or rat liver microsomes in the presence of NADPH and air yields a catechol. Upon further oxidation of both compounds with periodate and condensation of the resulting o-quinones with o-phenylenediamine, phenazines are produced. The phenazines derived from the products of both the plant and animal enzyme systems are identical to the product obtained by oxidation of diethylstilbestrol with potassium nitrosodisulfonate and condensation of the o-quinone produced with o-phenylenediamine. High and low resolution mass spectra of the phenazine are consistent with its derivation from a catechol having two fewer hydrogens than diethylstilbestrol.

Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma.

OBJECTIVE: Free radical-induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a potential mechanism of the pathogenesis of scleroderma. However, because reliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have previously described a series of bioactive prostaglandin F2-like compounds, termed F2-isoprostanes, produced in vivo in humans by the non-cyclooxygenase, free radical-catalyzed, peroxidation of arachidonic acid and have shown them to be a reliable measure of lipid peroxidation in vivo. In the present study, we determined whether scleroderma is associated with enhanced oxidative stress. METHODS: As a measure of oxidative stress, we determined urinary concentrations of a tetranor-dicarboxylic acid metabolite of F2-isoprostanes (F2IP-M) by mass spectrometry in 8 patients with scleroderma (representing a wide spectrum of disease, including limited disease with refractory digital ulceration or pulmonary hypertension, and diffuse disease) and in 10 healthy control subjects. RESULTS: F2IP-M concentrations were significantly higher in patients with scleroderma (mean +/- SEM 3.41 +/- 0.64 ng/mg of creatinine) than in healthy controls (1.22 +/- 0.14 ng/mg of creatinine) (P = 0.002). These elevations occurred in patients with limited disease and in those with diffuse disease. CONCLUSION: The increased level of urinary F2IP-M supports the hypothesis that free radical-induced oxidative injury occurs in scleroderma and provides a biologic marker whose relationship to disease activity and disease therapy may be important. These findings may also provide a rationale for exploring whether antioxidant therapy may influence the natural course of the disease.