Ultrasound-Guided Injections of HYADD4 for Knee Osteoarthritis Improves Pain and Functional Outcomes at 3, 6, and 12 Months without Changes in Measured Synovial Fluid, Serum Collagen Biomarkers, or Most Synovial Fluid Biomarker Proteins at 3 Months.

BACKGROUND: Prior studies have demonstrated improved efficacy when intra-articular (IA) therapeutics are injected using ultrasound (US) guidance. The aim of this study was to determine if clinical improvement in pain and function after IA hyaluronic acid injections using US is associated with changes in SF volumes and biomarker proteins at 3 months. METHODS: 49 subjects with symptomatic knee OA, BMI < 40, and KL radiographic grade II or III participated. Subjects with adequate aspirated synovial fluid (SF) volumes received two US-guided IA-HA injections of HYADD4 (24 mg/3 mL) 7 days apart. Clinical evaluations at 3, 6, and 12 months included WOMAC, VAS, PCS scores, 6 MWD, and US-measured SF depth. SF and blood were collected at 3 months and analyzed for four serum OA biomarkers and fifteen SF proteins. RESULTS: Statistical differences were observed at 3, 6, and 12 months compared to baseline values, with improvements at 12 months for WOMAC scores (50%), VAS (54%), and PCS scores (24%). MMP10 levels were lower at 3 months without changes in SF volumes, serum levels of C2C, COMP, HA, CPII, or SF levels of IL-1 ra, IL-4, 6, 7, 8, 15, 18, ILGFBP-1, 3, and MMP 1, 2, 3, 8, 9. Baseline clinical features or SF biomarker protein levels did not predict responsiveness at 3 months. CONCLUSIONS: Clinical improvements were observed at 12 months using US needle guidance for IA HA, whereas only one SF protein biomarker protein was different at 3 months. Larger studies are needed to identify which SF biomarkers will predict which individual OA patients will receive the greatest benefit from IA therapeutics.

Synovial Fluid Cytokines, Chemokines and MMP Levels in Osteoarthritis Patients with Knee Pain Display a Profile Similar to Many Rheumatoid Arthritis Patients.

BACKGROUND: There are currently no effective disease-modifying drugs to prevent cartilage loss in osteoarthritis and synovial fluid is a potentially valuable source of biomarkers to understand the pathogenesis of different types of arthritis and identify drug responsiveness. The aim of this study was to compare the differences between SF cytokines and other proteins in patients with OA (n = 21) to those with RA (n = 27) and normal knees (n = 3). METHODS: SF was obtained using ultrasound (US) guidance and an external pneumatic compression device. RA patients were categorized as active (n = 20) or controlled (n = 7) based upon SF white blood cell counts (> or <300 cells/mm3). Samples were cryopreserved and analyzed by multiplex fluorescent bead assays (Luminex). Between-group differences of 16 separate biomarker proteins were identified using ANOVA on log10-transformed concentrations with p values adjusted for multiple testing. RESULTS: Only six biomarkers were significantly higher in SF from active RA compared to OA-TNF-α, IL-1-ß IL-7, MMP-1, MMP-2, and MMP-3. Only MMP-8 levels in RA patients correlated with SF WBC counts (p < 0.0001). Among OA patients, simultaneous SF IL-4, IL-6, IL-8, and IL-15 levels were higher than serum levels, whereas MMP-8, MMP-9, and IL-18 levels were higher in serum (p < 0.05). CONCLUSION: These results support the growing evidence that OA patients have a pro-inflammatory/catabolic SF environment. SF biomarker analysis using multiplex testing and US guidance may distinguish OA phenotypes and identify treatment options based upon targeted inflammatory pathways similar to patients with RA.

A comparison of specific IgE and skin prick test results to common environmental allergens using the HYTEC™ 288.

Although skin-prick testing (SPT) is commonly used by allergists in the evaluation of allergy, in-vitro testing for specific IgE (sIgE) is an attractive alternate because it can be performed remotely and is of utility when SPT is contraindicated, as in patients on anti-histamines, or with dermatitis or severe eczema. It is, however, necessary to determine the extent of correlation between the in-vitro and in-vivo methods. In this study, we examined the qualitative concordance between SPT and sIgE as measured on the HYTEC™288 platform for 10 commonly encountered inhalant allergens in 232 subjects, and analysed the performance characteristics for the HYTEC™288. Overall concordance between SPT and sIgE was >70% for all allergens tested. Sensitivity ranged from 25% to 95%, depending on the allergen, while specificity was significantly higher for all allergens (78-97%). NPV was >85% for all allergens tested, while PPV was more variable, ranging from 22% to 88%. These results are similar to findings in other studies comparing SPT with sIgE. Lack of concordance in a percentage of samples might be partly attributed to differences in allergen preparations for SPT and HYTEC™ 288. Follow-up studies utilizing identical allergen preparations for both in-vivo and in-vitro testing may address these discrepancies.

Rituximab as successful adjunct treatment in a patient with disseminated nontuberculous mycobacterial infection due to acquired anti-interferon-γ autoantibody.

An acquired immune deficiency due to interferon gamma (IFN-γ) autoantibodies was diagnosed in a 78-year-old Japanese man with treatment-refractory disseminated nontuberculous mycobacterial infection. In addition to standard antimycobacterial therapy, he was successfully treated with rituximab to eliminate B cells and thereby the autoantibody. Subsequently, he obtained a sustained remission from infection.

The acute toxicity, tissue distribution, and histopathology of inhaled ricin in Sprague Dawley rats and BALB/c mice.

Ricin is a highly toxic ribosome-inactivating protein derived from the castor bean (Ricinus communis). Due to the relative ease of producing ricin, it is characterized as a category B priority pathogen by the Center for Disease Control and Prevention. The purpose of this study was to compare the acute toxicity, associated histopathology, as well as the regional respiratory tract deposition and clearance kinetics of inhaled ricin in rats and mice using a single pure preparation. Acute toxicity was evaluated in five groups of six animals per species exposed nose-only to ricin aerosols and followed up to 7 days post-exposure. Tissues were collected for histopathology. The calculated median lethal doses (LD50s) were 0.24 µg/kg (rats) and 0.58 µg/kg (mice). Histological changes were noted in nose, larynges, trachea, lung, thymus, and spleen of both species. Pulmonary deposition in rats inhaling 94-99 ng/L ricin for 20 min (low dose) or 40 min (high dose) were 45.9 and 96 ng/g lung, respectively. Clearance was best described by a single-component negative exponential function. Estimated lung doses were 0.38 and 1.43 µg/g·h among the low and high dose rats, respectively. In mice inhaling 94 ng/L ricin for 20 min, pulmonary deposition was 91.1 ng/g lung and the estimated tissue dose was 1.72 µg/g·h. No ricin was detected in extra-respiratory tract tissue or in excreta. Results of this study demonstrate differences exist in pulmonary deposition, clearance rates, and tissue dose and histopathological changes between rats and mice inhaling ricin.

Brevetoxin inhalation alters the pulmonary response to influenza A in the male F344 rat.

Epidemiological studies demonstrated that the number of emergency-room visits for respiratory indications increases during periods of Florida Red Tides. The purpose of this study was to examine whether or not repeated brevetoxin inhalation, as may occur during a Florida Red Tide, affects pulmonary responses to influenza A. Male F344 rats were divided into four groups: (1) sham aerosol/no influenza; (2) sham aerosol/influenza; (3) brevetoxin/no influenza; and (4) brevetoxin/influenza. Animals were exposed by nose-only inhalation to vehicle or 50 µg brevetoxin-3/m3, 2 h/d for 12 d. On d 6 of aerosol exposure, groups 2 and 4 were administered 10,000 plaque-forming units of influenza A, strain HKX-31 (H3N2), by intratracheal instillation. Subgroups were euthanized at 2, 4, and 7 d post influenza treatment. Lungs were evaluated for viral load, cytokine content, and histopathologic changes. Influenza virus was cleared from the lungs over the 7-d period; however, there was significantly more virus remaining in the group 4 lungs compared to group 2. Influenza virus significantly increased interleukins-1α and -6 and monocyte chemotactic protein-1 in lung; brevetoxin exposure significantly enhanced the influenza-induced response. At 7 d, the severity of perivascular and peribronchiolar inflammatory cell infiltrates was greatest in group 4. Bronchiolitis persisted, with low incidence and severity, only in group 4 at d 7. These results suggest that repeated inhalation exposure to brevetoxin may delay virus particle clearance and recovery from influenza A infection in the rat lung.