Non-invasive stress evaluation in domestic horses (Equus caballus): impact of housing conditions on sensory laterality and immunoglobulin A.

The study aimed to evaluate sensory laterality and concentration of faecal immunoglobulin A (IgA) as non-invasive measures of stress in horses by comparing them with the already established measures of motor laterality and faecal glucocorticoid metabolites (FGMs). Eleven three-year-old horses were exposed to known stressful situations (change of housing, initial training) to assess the two new parameters. Sensory laterality initially shifted significantly to the left and faecal FGMs were significantly increased on the change from group to individual housing and remained high through initial training. Motor laterality shifted significantly to the left after one week of individual stabling. Faecal IgA remained unchanged throughout the experiment. We therefore suggest that sensory laterality may be helpful in assessing acute stress in horses, especially on an individual level, as it proved to be an objective behavioural parameter that is easy to observe. Comparably, motor laterality may be helpful in assessing long-lasting stress. The results indicate that stress changes sensory laterality in horses, but further research is needed on a larger sample to evaluate elevated chronic stress, as it was not clear whether the horses of the present study experienced compromised welfare, which it has been proposed may affect faecal IgA.

Acceptance of a medication refill reminder service in German community pharmacy practice.

Medication refill reminder services (MRRS), having the potential to support the detection of non-adherence and to promote periodic medication refilling by addressing forgetfulness, are not generally available in community pharmacy practice. Based on a new software module, a MRRS was developed. The acceptance of this service was tested in community pharmacies in Germany. Patients were recruited by trained pharmacy staff. Supported by the software, the pharmacies reminded patients to refill their prescription. After 7 months, the service was evaluated by patients and pharmacy staff. The pharmacy owners/managers were interviewed. Ten pharmacies applied the service to 148 patients, with 806 refill reminders for 391 drugs. Seventy-five patients (50.7%) chose to be reminded by a phone call, followed by text message (n=25), and email (n=18). Of all patients, 75 (50.7%) completed the paper-based questionnaire. Sixty-eight (90.7%) rated the service as good or very good and 54 (72.0%) felt more satisfied with their pharmacy. Sixty-four patients (85.3%) considered the service as supportive and wanted to continue. Thirty-nine pharmacy staff members (61.9%) answered the online questionnaire. Twenty-four (61.5%) stated that they found it difficult to use and apply the MRRS; twenty-six (66.6%) experienced technical problems. The service was rated good by 16 (41.0%) pharmacy staff members. They regarded the service helpful for some patients and wanted to continue after the end of the study. The majority of the ten interviewed pharmacy owners/managers expressed the opinion that the service was not very suitable for increasing customer loyalty and not cost-effective. Nevertheless, six (60.0%) of them wanted to continue using the service. The MRRS seems to be feasible, apart from technical difficulties. Patients rated the service as supportive, and the personal contact seems to be of high importance; most patients would like to continue the service. However, offering the service to patients turned out to be challenging in daily German community pharmacy practice.

Do patients with diabetes type 2 or chronic heart failure understand a medication plan?

A standardized medication plan (MP) was recently enacted into German law (§ 31a SGB V). The purpose of our study was to assess if patients with chronic diseases requiring polymedication understand the standardized MP and can transfer the given information into practice. 100 patients who took at least five medicines regularly were prospectively included in a cross-sectional study: 50 patients with the primary diagnosis chronic heart failure (CHF), and 50 with diabetes mellitus type 2 (DMT2). We performed a structured test-scenario studying the handling of a provided MP then evaluated the execution of the information on the MP by filling pill boxes and requested patients' opinion. An established weighted scoring system, the "Evaluation Tool to test the handling of the Medication Plan" (ET-MP) was applied to quantitate the ability of the patients to handle the MP. In addition, signs of depression, cognitive function and self-care behavior in chronic heart failure were characterized using the PHQ-9, Mini-Cog, and G9-EHFScB-9 questionnaires, respectively. The understanding of the MP was poor and irrespective of the underlying primary diagnosis. Only 32% of all patients were able to handle the MP without difficulties (ET-MP score >90%), the median ET-MP score was 83 [(IQR) 50-98]. Comprehension of the MP was better in patients aged <70 years compared to ≥70 years (p<0.01). Patients ≥10 years of education achieved higher ET-MP results than patients with <10 years of education (p<0.01). Patients with signs of cognitive impairment exhibited significantly lower ET-MP scores than patients without cognitive impairment (p<0.001). There were no significant correlations of the ET-MP score with number of daily medications, living situation, sex, the Charlson Comorbidity Index, the PHQ-9 score, and use of a dosing aid or possession of a medication list.

The pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of evacetrapib administered as monotherapy or in combination with statins.

Evacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor currently being evaluated in a late-stage cardiovascular outcome trial. Using population-based models, we analyzed evacetrapib concentration data along with high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) data from a 12-week study in dyslipidemic patients treated with evacetrapib alone or in combination with atorvastatin, simvastatin, or rosuvastatin. Evacetrapib pharmacokinetics were characterized using a two-compartment model with first-order absorption. Evacetrapib exposure increased in a less than dose-proportional manner, similar to other CETP inhibitors. No patient factors had a clinically relevant impact on evacetrapib pharmacokinetics. The relationships between evacetrapib exposure and HDL-C and LDL-C were characterized using Emax models. The theoretical maximal mean HDL-C increase and LDL-C decrease relative to baseline were 177 and 44.1%, respectively. HDL-C change from baseline was found to be negatively correlated with baseline HDL-C. A pharmacologically independent LDL-C reduction was found when evacetrapib was coadministered with statins.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e94; doi:10.1038/psp.2013.70; published online 22 January 2014.

[Risk of atherosclerosis mediated by inflammation in rheumatoid arthritis]. / Atheroskleroserisiko durch Inflammation bei rheumatoider Arthritis.

Systemic inflammation is one of the pivotal pathogenetic principles in atherogenesis and progression of atherosclerosis. Patients with rheumatoid arthritis (RA) exhibit an increased cardiovascular risk that is not explained by traditional cardiovascular risk factors but rather by a chronic systemic inflammatory reaction. Reduction of inflammatory activity in RA patients was shown to reduce cardiovascular morbidity and mortality. Besides this specific approach traditional cardiovascular risk factors need to be carefully controlled in order to improve mortality in RA patients; however, this task is difficult to implement in everyday practice as RA patients usually have decisively different medical needs that need to be addressed irrespective of the well-acknowledged limitations of medical resources, such as time and costs.

Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-γ release assays under real-life conditions.

OBJECTIVES: To characterise optimal screening strategies for latent tuberculosis infection (LTBI) prior to the initiation of anti-tumour necrosis factor therapy. METHODS: Patients in 62 German rheumatology centres were evaluated for LTBI. Each patient was screened with a tuberculin skin test (TST) and one form of an interferon-γ release assay (IGRA), either TSPOT.TB (TSPOT) or Quantiferon TB Gold (QFT). RESULTS: A total of 1529 patients with rheumatological disease were tested with a TST, 844 with TSPOT and 685 with QFT. TST was positive in 11.3% (n=173). The prevalence of LTBI was 8.0% when defined as a positive TST and no previous Bacille Calmette-Guérin (BCG) vaccination and 7.9% when based on a positive IGRA. Combining both estimates increased the prevalence of LTBI to 11.1%. Clinical risk factors for LTBI were found in 122 patients (34 with a history of prior TB, 81 close contacts and 27 with suggestive chest x-ray lesions). A compound risk factor (CRF) was defined as the presence of at least one of these three risk factors. Statistical analyses were conducted to examine the association between CRF and LTBI test outcomes. In multivariate analysis, TST was influenced by CRF (OR 6.2; CI 4.08 to 9.44, p<0.001) and BCG vaccination status (OR 2.9; CI 2.00 to 4.35, p<0.001). QFT and TSPOT were only influenced by CRF (QFT: OR 2.6; CI 1.15 to 5.98, p=0.021; TSPOT: OR 8.7; CI 4.83 to 15.82, p<0.001). ORs and the agreement of TST and IGRA test results varied by rheumatological disease. CONCLUSION: LTBI test results in an individual patient need to be considered in the context of prior BCG vaccination and clinical risk factors. In patient populations with low rates of TB incidence and BCG vaccination, the use of both TST and IGRA may maximise sensitivity in detecting LTBI but may also reduce specificity.

Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells.

MicroRNAs are often associated with the pathogenesis of many cancers, including head and neck squamous cell carcinoma (HNSCC). In particular, microRNA-21 (miR-21) appears to have a critical role in tumor cell survival, chemoresistance and HNSCC progression. In this study, we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of i nhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs effectively blocks HA-mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression but also decreases IAP expression and enhances chemosensitivity in HA-treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 has a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC.

[Cardiovascular comorbidity and its risk factors in rheumatoid arthritis]. / Kardiovaskuläre Komorbidität und ihre Risikofaktoren bei rheumatoider Arthritis.

Rheumatoid arthritis (RA) is still associated with an increased mortality mainly due to an increase in cardiovascular risk. This increase is not solely explained by traditional cardiovascular risk factors but also by disease characteristics, e.g. inflammation, positive rheumatoid factor and anti-citrullinated peptide antibodies (ACPA). Control of disease activity with disease-modifying drugs (DMARDs) was shown to reduce cardiovascular risk in RA patients. Use of non-steroidal antirheumatic drugs (NSAIDs) and glucocorticoids might be associated with an increased risk. The EULAR recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis have been established. These recommendations are based on national guidelines regarding control of traditional cardiovascular risk factors.

Peak CSF velocities in patients with symptomatic and asymptomatic Chiari I malformation.

BACKGROUND AND PURPOSE: PCMR is used to evaluate the Chiari I malformation. We compared quantitative PCMR in symptomatic and asymptomatic patients with Chiari I. MATERIALS AND METHODS: PCMR image data in an axial section near the foramen magnum in a consecutive series of patients with Chiari I malformations were evaluated. Patients were classified as symptomatic for a Chiari I if they had apnea spells and/or exertional headaches and as asymptomatic if they had symptoms not considered specific for a Chiari I malformation. The PCMR CSF flow study was obtained with the same protocol for all patients and with the neck in neutral, flexed, and extended positions. Images were inspected for CSF flow jets and synchronous bidirectional flow. Peak CSF flow velocities were calculated with commercial software. Differences between the 2 groups were tested with mixed-effects ANOVA and Wilcoxon rank sum or Fisher exact probability tests with significance set at the .05 level. RESULTS: Twenty-six patients with Chiari I were classified as symptomatic, and 24, as asymptomatic. Abnormal flow jets tended to occur more often in the symptomatic than in the asymptomatic patients (P = .054). Peak CSF velocities ranged from 2 to 20 cm/s in the symptomatic and the asymptomatic groups and did not differ significantly between the 2 groups or with neck position. CONCLUSIONS: Peak CSF flow velocities near the foramen magnum did not differentiate symptomatic and asymptomatic patients with Chiari I.

Videophone utilization as an alternative to directly observed therapy for tuberculosis.

To demonstrate whether the use of videophone technology is an effective alternative method to direct observation of tuberculosis (TB) medication administration, a retrospective chart review and data analysis were performed on records for 57 patients with active TB in two Washington state counties who utilized videophone technology for the administration of medications from 2002 through 2006. A total of US$139,546 was saved in staff salaries, benefits and travel costs. The average cost savings per patient was US$2448. The use of videophone technology is a cost-effective alternative to in-home directly observed administration of TB medication.

[Enchondroma of the hand - treatment and long-term outcome]. / Enchondrome des Handskeletts - Therapeutisches Vorgehen und funktionelle Langzeitergebnisse.

BACKGROUND: An enchondroma is with up to 90% the most common benign tumour of the hand. Functional long-term outcome studies of the several treatments do not exist. The aim of this study is thus to evaluate the information from our 147 patients about diagnostics, operative treatment and follow-up treatment. METHODS: 147 patients with 183 histologically secured enchondromas of the hand, who had been treated between 1973 and 2004, were analysed by follow-up examination and radiological findings retrospectively. RESULTS: We found 136 mono- and 11 polyostotic lesions. The proximal phalanx was afflicted most commonly (44.8%). There was no preference for one special finger, only the thumb was afflicted below average (9.8%). The most common symptoms were pain and swelling (51.7%) or pathological fracture (25%). We found 11 relapses (7.5%) after an average of 4.4 years. In two cases we found a grade 1 chondrosarcoma. 84.2% of the patients achieved a "very good" or a "good" functional long-term outcome, 11.7% a "fair" and 4.2% a "poor" outcome. CONCLUSION: Standard treatment should be the accurate extirpation of the tumour and subsequent filling of the defect with cancellous bone. Only very small, asymptomatic lesions can be treated conservatively with six-month check-up examinations.

Gastrointestinal tolerability of etoricoxib in rheumatoid arthritis patients: results of the etoricoxib vs diclofenac sodium gastrointestinal tolerability and effectiveness trial (EDGE-II).

OBJECTIVE: A randomised, double-blind study to compare the gastrointestinal (GI) tolerability, safety and efficacy of etoricoxib and diclofenac in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: A total of 4086 patients (mean age 60.8 years) diagnosed with RA were enrolled and received etoricoxib 90 mg daily (n = 2032) or diclofenac 75 mg twice daily (n = 2054). Use of gastroprotective agents and low-dose aspirin was allowed. The prespecified primary end point consisted of the cumulative rate of patient discontinuations due to clinical and laboratory GI adverse experiences (AEs). General safety was also assessed, including adjudicated thrombotic cardiovascular event data. Efficacy was evaluated using the Patient Global Assessment of Disease Status (PGADS; 0-4 point scale). RESULTS: Mean (SD; maximum) duration of treatment was 19.3 (10.3; 32.9) and 19.1 (10.4; 33.1) months in the etoricoxib and diclofenac groups, respectively. The cumulative discontinuation rate due to GI AEs was significantly lower with etoricoxib than diclofenac (5.2 vs 8.5 events per 100 patient-years, respectively; hazard ratio 0.62 (95% CI: 0.47, 0.81; p

Endovascular treatment of a ruptured aneurysm of the inferior thyroid artery. Case report and literature review.

Aneurysms of the inferior thyroid artery are rare. The natural course of these aneurysms seems to be unfavourable, why aneurysm exclusion is recommended in the literature. Open surgical repair is complex why endovascular exclusion seems to be an appealing alternative. We present a patient who developed dysphagia and respiratory distress caused by a ruptured aneurysm of the right inferior thyroid artery. Successful coil embolization of the aneurysm is described along with a review of the literature. Despite the very rare data of these aneurysms, all reported cases of endovascular treatment (n=3) showed favourable results, therefore aneurysm embolization seems to be a feasible and safe alternative to open surgery, especially in emergency cases.

A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement.

BACKGROUND: LY517717 is an oral direct inhibitor of activated factor X that is currently under clinical development. OBJECTIVES: The aims of this proof-of-concept study in patients undergoing total knee replacement (TKR) or total hip replacement (THR) were to determine whether LY517717 can safely reduce the risk of venous thromboembolism (VTE) and to identify at least one dose of LY517717 that is non-inferior to enoxaparin. METHODS: In a double-blind, parallel-arm, dose-ranging study, patients undergoing TKR or THR were randomly allocated to receive once-daily oral LY517717 (25, 50, 75, 100, 125 or 150 mg), started 6-8 h after wound closure, or s.c. enoxaparin, 40 mg, started in the evening before surgery. The primary efficacy endpoint was the composite of deep venous thrombosis (DVT), detected by mandatory bilateral venography performed at the end of the study treatment (between days 5 and 9), and objectively confirmed symptomatic DVT and/or pulmonary embolism (PE), occurring during the treatment period. The combination of major and minor bleeding was the primary safety endpoint. RESULTS: Five hundred and seven patients received at least one dose of LY517717 or enoxaparin (safety population). Three hundred and ninety-one patients had evaluable bilateral venography or experienced a clinical DVT and/or PE (primary efficacy population). LY517717 treatment resulted in a dose-dependent decrease in the incidence of thromboembolic events (P = 0.0001). The incidences of VTE with 100, 125, and 150 mg of LY517717 were 19%, 19% and 16%, respectively, compared to 21% with enoxaparin. The efficacies of 100-mg, 125-mg and 150-mg doses of LY517717 were non-inferior to that of enoxaparin according to prespecified criteria. Bleeding events were uncommon in both LY517717 and enoxaparin patients. CONCLUSIONS: Doses of 100, 125 and 150 mg of LY517717 are non-inferior to enoxaparin for the prevention of VTE after TKR or THR, and are associated with similar low rates of bleeding.

Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women.

BACKGROUND: Biological mechanisms linking diabetes and cognition continue to grow, yet the association remains controversial in elders. Whether glycosylated hemoglobin (HbA1C) level, a marker of glucose control, is predictive of the development of cognitive impairment or dementia is unknown. We determined the association between HbA1C level and risk of developing cognitive impairment in older women, mostly without diabetes. METHODS: We studied 1983 postmenopausal women (mean age, 67.2 years) with osteoporosis who had HbA1C level measured at baseline. Development of mild cognitive impairment (MCI) or dementia over 4 years was determined as part of a dementia ancillary study. We analyzed risk of MCI or dementia for every 1% of HbA1C as well as risk associated with HbA1C >or= 7%. RESULTS: The mean level of HbA1C was 5.8% (range 3.0% to 12.1%) and 86 (4.3%) women developed MCI or dementia. For every 1% increase in HbA1C, women had a greater age-adjusted likelihood of developing MCI (OR= 1.50; 95% CI 1.14-1.97) and of developing MCI or dementia (OR=1.40; 95% CI 1.08 - 1.83). For those with HbA1C level >or= 7% (n=49), the age-adjusted risk for developing MCI was increased nearly 4-fold (OR= 3.70; 95% CI 1.51-9.09) and was increased nearly 3-fold for developing MCI or dementia (OR=2.86; 95% CI 1.17-6.98). When we excluded women with diagnosed diabetes (n=53), the association between HbA1C and MCI lessened somewhat but remained elevated (unadjusted OR=1.59; 95% CI 1.01-2.50; age-adjusted OR=1.42; 95% CI 0.89-2.28). Multivariate analyses adjusted for age, education, race, depression, alcohol use and treatment with raloxifene yielded similar results. INTERPRETATION: We found an association between HbA1C level and risk of developing MCI or dementia in postmenopausal osteoporotic women primarily without diabetes. Our findings support the hypothesis that glucose dysregulation is a predictor for cognitive impairment.