STAT3 phosphorylation inhibitor Bt354 exhibits anti-neoplastic activity in glioblastoma multiforme cells.

The high mortality rate of glioblastoma multiforme (GBM), a lethal primary brain tumor, is attributable to postsurgical recurrence. STAT3, an oncogenic protein, is a signal transducer and transcription activator encourages cancer cell migration and proliferation, which results in resistance to therapy. STAT3 inhibition reduces cancer metastasis and improves patient prognosis. Bt354, a small molecule STAT inhibitor, exhibits significant cytotoxic and anti-proliferative activities against certain cancer types. Here, we demonstrated that exposure of GBM cells (U87 MG) to Bt354 had a significant, concentration-dependent growth suppression. Bt354 also induced apoptosis and downregulated the expression of the epithelial-mesenchymal transition genes. Therefore, this study suggests the potential of Bt354 for treating GBM owing to its ability to induce cytotoxicity.

Unraveling the Link between Periodontitis and Coronavirus Disease 2019: Exploring Pathogenic Pathways and Clinical Implications.

Periodontitis involves the inflammation of the periodontal tissue, leading to tissue loss, while coronavirus disease 2019 (COVID-19) is a highly transmissible respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is amplified by poor systemic health. Key facilitators of SARS-CoV-2's entry into host cells are angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). This review reveals that periodontal pockets can serve as a hotspot for virus accumulation, rendering surrounding epithelia more susceptible to infection. Given that ACE2 is expressed in oral mucosa, it is reasonable to suggest that poor periodontal health could increase the risk of COVID-19 infection. However, recent studies have not provided sufficient evidence to imply a significant effect of COVID-19 on periodontal health, necessitating further and more long-term investigations. Nevertheless, there are hypotheses linking the mechanisms of the two diseases, such as the involvement of interleukin-17 (IL-17). Elevated IL-17 levels are observed in both COVID-19 and periodontitis, leading to increased osteoclast activity and bone resorption. Lastly, bidirectional relationships between periodontitis and systemic diseases like diabetes are acknowledged. Given that COVID-19 symptoms may worsen with these conditions, maintaining good oral health and managing systemic diseases are suggested as potential ways to protect against COVID-19.

Explainable Machine Learning Techniques To Predict Amiodarone-Induced Thyroid Dysfunction Risk: Multicenter, Retrospective Study With External Validation.

BACKGROUND: Machine learning offers new solutions for predicting life-threatening, unpredictable amiodarone-induced thyroid dysfunction. Traditional regression approaches for adverse-effect prediction without time-series consideration of features have yielded suboptimal predictions. Machine learning algorithms with multiple data sets at different time points may generate better performance in predicting adverse effects. OBJECTIVE: We aimed to develop and validate machine learning models for forecasting individualized amiodarone-induced thyroid dysfunction risk and to optimize a machine learning-based risk stratification scheme with a resampling method and readjustment of the clinically derived decision thresholds. METHODS: This study developed machine learning models using multicenter, delinked electronic health records. It included patients receiving amiodarone from January 2013 to December 2017. The training set was composed of data from Taipei Medical University Hospital and Wan Fang Hospital, while data from Taipei Medical University Shuang Ho Hospital were used as the external test set. The study collected stationary features at baseline and dynamic features at the first, second, third, sixth, ninth, 12th, 15th, 18th, and 21st months after amiodarone initiation. We used 16 machine learning models, including extreme gradient boosting, adaptive boosting, k-nearest neighbor, and logistic regression models, along with an original resampling method and 3 other resampling methods, including oversampling with the borderline-synthesized minority oversampling technique, undersampling-edited nearest neighbor, and over- and undersampling hybrid methods. The model performance was compared based on accuracy; Precision, recall, F1-score, geometric mean, area under the curve of the receiver operating characteristic curve (AUROC), and the area under the precision-recall curve (AUPRC). Feature importance was determined by the best model. The decision threshold was readjusted to identify the best cutoff value and a Kaplan-Meier survival analysis was performed. RESULTS: The training set contained 4075 patients from Taipei Medical University Hospital and Wan Fang Hospital, of whom 583 (14.3%) developed amiodarone-induced thyroid dysfunction, while the external test set included 2422 patients from Taipei Medical University Shuang Ho Hospital, of whom 275 (11.4%) developed amiodarone-induced thyroid dysfunction. The extreme gradient boosting oversampling machine learning model demonstrated the best predictive outcomes among all 16 models. The accuracy; Precision, recall, F1-score, G-mean, AUPRC, and AUROC were 0.923, 0.632, 0.756, 0.688, 0.845, 0.751, and 0.934, respectively. After readjusting the cutoff, the best value was 0.627, and the F1-score reached 0.699. The best threshold was able to classify 286 of 2422 patients (11.8%) as high-risk subjects, among which 275 were true-positive patients in the testing set. A shorter treatment duration; higher levels of thyroid-stimulating hormone and high-density lipoprotein cholesterol; and lower levels of free thyroxin, alkaline phosphatase, and low-density lipoprotein were the most important features. CONCLUSIONS: Machine learning models combined with resampling methods can predict amiodarone-induced thyroid dysfunction and serve as a support tool for individualized risk prediction and clinical decision support.

3,5,2',4'-Tetramethoxystilbene, a fully methylated resveratrol analog, prevents platelet aggregation and thrombus formation by targeting the protease-activated receptor 4 pathway.

Thrombin is a potent platelet activator and a key mediator of blood coagulation, thereby playing a crucial role in cardiovascular disease. Recently, protease-activated receptor 4 (PAR4), one of thrombin receptors in human platelets, is emerging as a promising target for antiplatelet therapy. 3,5,2',4'-Tetramethoxystilbene (TMS), a resveratrol analog, have demonstrated promising effects on preventing atherosclerosis and hypertension, whereas its antiplatelet effect has never been investigated. Herein we show that TMS at concentrations of a few micromolar selectively inhibits PAR4-mediated human platelet aggregation, ATP secretion, integrin αIIbß3 activation, and signaling pathways. In a whole-blood model of arterial flow, TMS also significantly reduced in vitro thrombus formation. Analysis of the structure-activity relationships of TMS and a panel of stilbene analogs reveal that full methylation of hydroxy groups of the stilbenes is the critical structural determinant for the anti-PAR4 activity. Our results suggest that fully methylated resveratrol analogs with anti-PAR4 activity are potential candidates for development of novel antiplatelet agents.

The effect of medication therapy management service combined with a national PharmaCloud system for polypharmacy patients.

BACKGROUND: This study evaluated a medication therapy management service using the Taiwan National Health Insurance Administration's PharmaCloud system in a medical center in Taiwan. The new PharmaCloud System, launched in 2013, links a complete list of prescribed and dispensed medication from different hospitals, clinics, and pharmacies for all insured patients. METHOD: The study included patients with polypharmacy (≥5 drugs) at a medication therapy management service from March 2013 to March 2014. A structured questionnaire was designed to collect patients' baseline data and record patients' knowledge, attitudes, and practice scores before and after the service intervention. Phone follow-ups for practice and adherence scores on medication use were performed after 3 months. RESULTS: There were 152 patients recruited in the study. Scores for medication use attitudes and practice significantly increased after the service (attitudes: 40.06 ± 0.26 to 43.07 ± 0.19, p <0.001; practice: 33.42 ± 0.30 to 40.37 ± 0.30, p <0.001). The scores for medication adherence also increased from 3.02 ± 0.07 to 3.92 ± 0.02 (p <0.001). CONCLUSIONS: The PharmaCloud system facilitates accurate and efficient medication reconciliation for pharmacists in the medication therapy management service. The model improved patients' attitudes and practice of the rational use of medications and adherence with medications. Further studies are warranted to evaluate human resources, executing costs, and the cost-benefit ratio of this medication therapy management service with the PharmaCloud system.

Acute Paraplegia After Aneurysmal SAH: A Case Report of a Rare Complication and Review of the Literature.

BACKGROUND: Paraplegia after intracranial aneurysmal subarachnoid hemorrhage (SAH) is a rare condition, and its pathogenesis is still unclear. CASE DESCRIPTION: We present a case of a ruptured basilar dissecting aneurysm treated with the stent-assisted coiling procedure. Progressive weakness of the lower limbs developed within 5 days postoperatively. Spinal magnetic resonance image showed SAH accumulation in the lumbosacral area. Emergency lumbar drainage was performed, and the patient's symptoms improved dramatically. CONCLUSIONS: To the best of our knowledge, this is the first report to describe the successful treatment of paraplegia after intracranial aneurysmal SAH.

The association between urbanization and rheumatoid arthritis in Taiwan.

OBJECTIVES: To investigate the association between rheumatoid arthritis (RA) and urbanization and compare the medication selection for RA patients in urban vs. rural areas. METHODS: RA patients were identified among 1,000,000 random individuals from a 23-million-person nationwide health insurance database, and controls were matched at a 1 : 10 ratio. Taiwan's 359 townships were grouped into 7 urbanization levels. Geographic region and monthly income were also analyzed. Medication use in the most urbanized and less-urbanized areas were also compared. RESULTS: Rural dwellers had lower odds of having an RA diagnosis. The odds ratio (OR) for level 5 area residents of having an RA diagnosis was 0.62 (95% confidence interval (CI) 0.46 - 0.85; p = 0.002), and they were both 0.76 for level 6 - 7 area residents (95% CI, 0.61 - 0.95 for level 6; p = 0.017 and 0.60 - 0.96 for level 7; p = 0.021) compared to level 1 (the most urban dwellers). The ORs of having a new RA diagnosis were 0.57 (95% CI 0.41 - 0.79, p = 0.001) in eastern Taiwan and 0.33 (95% CI 0.15 - 0.69, p = 0.004) on offshore islands compared to northern Taiwan. No association was found between monthly income and RA. Urban-dwelling RA patients used more tumor necrosis factor-α antagonists (level 1 urbanization; n = 24; 2.3%) than RA patients in less-urbanized areas (level 2 - 7 urbanization n = 30; 1.3%; p = 0.038). CONCLUSION: Results of this study suggested that an RA diagnosis and treatment are associated with urbanization.

Activation of brain steroidogenesis and neurogenesis during the gonadal differentiation in protandrous black porgy, Acanthopagrus schlegelii.

The early brain development, at the time of gonadal differentiation was investigated using a protandrous teleost, black porgy. This natural model of monosex juvenile fish avoids the potential complexity of sexual dimorphism. Brain neurogenesis was evaluated by histological analyses of the diencephalon, at the time of testicular differentiation (in fish between 90 and 150 days after hatching). Increases in the number of both Nissl-stained total brain cells, and Pcna-immunostained proliferative brain cells were observed in specific area of the diencephalon, such as ventromedialis thalami and posterior preoptic area, revealing brain cell proliferation. qPCR analyses showed significantly higher expression of the radial glial cell marker blbp and neuron marker bdnf. Strong immunohistochemical staining of Blbp and extended cellular projections were observed. A peak expression of aromatase (cyp19a1b), as well as an increase in estradiol (E2 ) content were also detected in the early brain. These data demonstrate that during gonadal differentiation, the early brain exhibits increased E2 synthesis, cell proliferation, and neurogenesis. To investigate the role of E2 in early brain, undifferentiated fish were treated with E2 or aromatase inhibitor (AI). E2 treatment upregulated brain cyp19a1b and blbp expression, and enhanced brain cell proliferation. Conversely, AI reduced brain cell proliferation. Castration experiment did not influence the brain gene expression patterns and the brain cell number. Our data clearly support E2 biosynthesis in the early brain, and that brain E2 induces neurogenesis. These peak activity patterns in the early brain occur at the time of gonad differentiation but are independent of the gonads.

Osteopontin Promotes Oncostatin M Production in Human Osteoblasts: Implication of Rheumatoid Arthritis Therapy.

Accumulating evidence indicates that subchondral bone might play an essential role in rheumatoid arthritis (RA). Osteopontin (OPN) induces the production of an important proinflammatory cytokine involved in the pathogenesis of RA. This study evaluated the activation of oncostatin M (OSM) by OPN in human primary osteoblasts to understand RA pathogenesis and characterized the intracellular signaling pathways involved in this activation. Quantitative PCR, ELISA, and Western blot results indicated that stimulation of human primary osteoblasts with OPN induces OSM expression through αvß3 integrin/c-Src/platelet-derived growth factor receptor transactivation/MEK/ERK. Treatment of osteoblasts with OPN also increased c-Jun phosphorylation, AP-1 luciferase activity, and c-Jun binding to the AP-1 element on the OSM promoter, as demonstrated using chromatin immunoprecipitation assay. Moreover, inhibition of OPN expression using lentiviral-OPN short hairpin RNA resulted in the amelioration of articular swelling, cartilage erosion, and OSM expression in the ankle joint of mice with collagen-induced arthritis as shown using microcomputed tomography and immunohistochemistry staining. Our results imply that OSM expression in osteoblasts increases in response to OPN-induced inflammation in vitro. Finally, lentiviral-OPN short hairpin RNA ameliorates the inflammatory response and bone destruction in mice with collagen-induced arthritis. Therefore, OPN may be a potential therapeutic target for RA.

Infection risk in patients with rheumatoid arthritis treated with etanercept or adalimumab.

OBJECTIVES: To compare the risk of infection for rheumatoid arthritis (RA) patients who took etanercept or adalimumab medication in a nationwide population. METHODS: RA patients who took etanercept or adalimumab were identified in the Taiwan's National Health Insurance Research Database. The composite outcome of serious infections, including hospitalization for infection, reception of an antimicrobial injection, and tuberculosis were followed for 365 days. A Kaplan-Meier survival curve with a log-rank test and Cox proportional hazards regression were used to compare risks of infection between the two cohorts of tumor necrosis factor (TNF)-α antagonists users. Hazard ratios (HRs) were obtained and adjusted with propensity scores and clinical factors. Sensitivity analyses and subgroup analyses were also performed. RESULTS: In total, 1660 incident etanercept users and 484 incident adalimumab users were eligible for the analysis. The unadjusted HR for infection of the etanercept users was significantly higher than that of the adalimumab users (HR: 1.93; 95% confidence interval (CI): 1.09-3.42; p=0.024). The HRs were 2.04 (95% CI: 1.14-3.65; p=0.016) and 2.02 (95% CI: 1.13-3.61; p=0.018) after adjusting for propensity scores and for propensity scores in addition to clinical factors, respectively. The subgroup analyses revealed that HRs for composite infection was significantly higher in patient subgroups of older age, female, as well as patients who did not have DM, COPD, and hospitalization history at the baseline. CONCLUSION: In this head-to-head cohort study involving a nationwide population of patients with RA, etanercept users demonstrated a higher risk of infection than adalimumab users. Results of this study suggest the possible existence of an intra-class difference in infection risk among TNF-α antagonists.

Pharmacist-conducted medication reconciliation at hospital admission using information technology in Taiwan.

OBJECTIVES: Obtaining an accurate medication history upon admission to the hospital can be challenging and time-consuming. This study evaluated the efficacy of a medication reconciliation program, conducted by pharmacists, with the assistance of medication usage data from the Taiwan National Health Insurance (NHI). Characteristics of patients at high risk for drug discrepancies were also determined. METHODS: Patients admitted between May 2008 and September 2009 were recruited. The type and class of medication discrepancies reported by pharmacists, the medication discrepancy rate, physician acceptance rate, and time taken for the intervention were studied. The degree of harm that could have resulted from the discrepancies was independently evaluated by four pharmacists. The association between selected variables and the occurrence of drug discrepancies was analyzed. RESULTS: Among 3013 patients interviewed, the pharmacists identified 243 patients (8%) with at least one medication discrepancy between the patient's medication history and admission orders. There were 576 discrepancies identified. About 19% of the errors prevented could have potentially caused moderate to severe harm. The average time for one intervention was 18±9.8min. The number of preadmission medications, age, frequency of outpatient visits within 3 months prior to this hospital admission, and the number of specialist outpatient clinics the patient had visited within 3 months before the admission were determined to be risk factors for drug discrepancies. CONCLUSIONS: This medication reconciliation program, conducted by pharmacists, was made more efficient by medication usage data from the Taiwan NHI. Pharmacists can reconcile medications more effectively by selecting patients at high risk for unintentional drug discrepancies.

High glucose induces vascular endothelial growth factor production in human synovial fibroblasts through reactive oxygen species generation.

BACKGROUND: Diabetes is an independent risk factor of osteoarthritis (OA). Angiogenesis is essential for the progression of OA. Here, we investigated the intracellular signaling pathways involved in high glucose (HG)-induced vascular endothelial growth factor (VEGF) expression in human synovial fibroblast cells. METHODS: HG-mediated VEGF expression was assessed with qPCR and ELISA. The mechanisms of action of HG in different signaling pathways were studied using Western blotting. Knockdown of proteins was achieved by transfection with siRNA. Chromatin immunoprecipitation assays were used to study in vivo binding of c-Jun to the VEGF promoter. RESULTS: Stimulation of OA synovial fibroblasts (OASF) with HG induced concentration- and time-dependent increases in VEGF expression. Treatment of OASF with HG increased reactive oxygen species (ROS) generation. Pretreatment with NADPH oxidase inhibitor (APO or DPI), ROS scavenger (NAC), PI3K inhibitor (Ly294002 or wortmannin), Akt inhibitor, or AP-1 inhibitor (curcumin or tanshinone IIA) blocked the HG-induced VEGF production. HG also increased PI3K and Akt activation. Treatment of OASF with HG increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the VEGF promoter. CONCLUSIONS: Our results suggest that the HG increases VEGF expression in human synovial fibroblasts via the ROS, PI3K, Akt, c-Jun and AP-1 signaling pathway. GENERAL SIGNIFICANCE: We link high glucose on VEGF expression in osteoarthritis.

Evaluation of the safety and efficacy of warfarin in Taiwanese patients.

OBJECTIVE: The safety and efficacy of warfarin therapeutic range in Asians remain to be ascertained. Physicians in Taiwan consider Asians are more likely to have bleeding complications rather than thromboembolic events from warfarin. The aim of this study was to determine if the proper INR range for patients in Taiwan is different. METHODS: A retrospective study was conducted with 161 patients on warfarin therapy for more than 24 consecutive months during March 1, 2006 to Sepember 30, 2008. Total follow-up time was 3,504 patient-months. The incidence rates of thromboembolic and bleeding events for INR categories were calculated. RESULTS: The overall incidence rates of INR ranges of < 1.5, 1.5 - 1.9, 2.0 - 2.4, 2.5 - 2.9, 3.0 - 3.4, and ≥ 3.5 were 8.1, 5.6, 2.0, 7.6, 33.3, and 121.2 per 1,000 patientmonths, respectively. The overall incidence rate at INR of > 3 is higher than that at INR of < 2 or 2 - 3 (p < 0.001), with the lowest incidence rate at INR between 2.0 and 2.4. When INR was maintained at a level < 2, patients taking warfarin for secondary prevention had a significantly higher event rate compared to the primary prevention group (p < 0.05). Age greater than 73 years was a risk factor for thromboembolic events before and after covariate adjustment. CONCLUSION: An INR range of 2 - 2.4 appeared to be associated with lower complications and better clinical outcomes in Taiwanese patients treated with warfarin. Lowering the intensity of anticoagulant therapy further does not decrease the number of events.

Tobacco consumption is a reversible risk factor associated with reduced successful treatment outcomes of anti-tuberculosis therapy.

OBJECTIVE: The aim of this study was to evaluate the reversible factors that could possibly affect outcomes of anti-tuberculosis (anti-TB) treatment. METHODS: A retrospective observational nested case-control study was performed to evaluate the association of patient and clinical factors with anti-TB therapy outcomes as defined by the World Health Organization (WHO). RESULTS: To examine the impact of a variety of factors on the outcomes of anti-TB treatment, a total of 302 TB patients were included in the study. Univariate analysis revealed that age, gender, concurrent hypertension, asthma/chronic obstructive pulmonary disease, or liver disease, worsened baseline blood urea nitrogen or creatinine, ethambutol <800 mg/day, hepatitis or adverse skin reactions during therapy, smoking history, and current tobacco consumption were significant factors in decreasing both the cure rate and treatment completion rate. However, multivariate regression showed that only age, current daily tobacco consumption, baseline liver disease, and ethambutol dosage were independent factors. A high level of tobacco consumption (>20 cigarettes per day) was significantly associated with a decreased odds of cure or treatment completion (odds ratio 0.23, 95% confidence interval 0.05-0.98, p=0.047). CONCLUSIONS: As smoking significantly inhibits the effectiveness of TB treatment, the integration of smoking cessation into TB treatment programs is strongly advocated to reduce the dual global burden of smoking and TB.

Nephrotoxicity of vancomycin in patients with methicillin-resistant Staphylococcus aureus bacteraemia.

AIM: Vancomycin and teicoplanin are the two most used glycopeptides for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is suspected to have more nephrotoxicity but this has not been clearly established. The aim of this study was to assess its nephrotoxicity by a consensus definition of acute kidney injury (AKI): the risk (R), injury (I), failure (F), loss and end-stage renal disease (RIFLE) classification. METHODS: Patients with MRSA bacteraemia who were prescribed either vancomycin or teicoplanin between 2003 and 2008 were classified. Patients who developed AKI were classified by RIFLE criteria. Variables such as comorbidities, laboratory data and medical cost information were also obtained from the database. Outcomes determined were: (i) the rate of nephrotoxicity and mortality; and (ii) the association of nephrotoxicity with the length of hospital stay and costs. RESULTS: The study included 190 patients (vancomycin 33, teicoplanin 157). Fifteen patients on vancomycin and 27 patients on teicoplanin developed AKI (P = 0.0004). In the vancomycin group, four, eight and three patients were classified to RIFLE criteria R, I and F, respectively. In the teicoplanin group, 17, nine and one patient were classified to RIFLE criteria R, I and F, respectively. Kaplan-Meier analysis showed significant difference in time to nephrotoxicity for the vancomycin group compared to the teicoplanin group. No significant differences were found between the groups in terms of total mortality, length of hospital stay and costs. CONCLUSION: The study data suggest that vancomycin is associated with a higher likelihood of nephrotoxicity using the RIFLE classification.

WISP-1 increases MMP-2 expression and cell motility in human chondrosarcoma cells.

Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. WISP-1 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matricellular proteins. However, the effect of WISP-1 on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that WISP-1 increased the migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells (JJ012 cells). We also found that human chondrosarcoma tissues had significant expression of the WISP-1 which was higher than that in normal cartilage. α5ß1 monoclonal antibody and MAPK kinase (MEK) inhibitors (PD98059 and U0126) inhibited the WISP-1-induced increase of the migration and MMP-2 up-regulation of chondrosarcoma cells. WISP-1 stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK and extracellular signal-regulated kinase (ERK). In addition, NF-κB inhibitors also suppressed the cell migration and MMP-2 expression enhanced by WISP-1. Moreover, WISP-1 increased NF-κB luciferase activity and binding of p65 to the NF-κB element on the MMP-2 promoter. Taken together, our results indicated that WISP-1 enhances the migration of chondrosarcoma cells by increasing MMP-2 expression through the α5ß1 integrin receptor, FAK, MEK, ERK, p65 and NF-κB signal transduction pathway.

Impact of a continuing education program on pharmacists' knowledge and attitudes toward asthma patient care.

OBJECTIVE: The objective of this study was to evaluate the impact of an asthma continuing education program on pharmacists' knowledge and attitudes related to asthma pharmaceutical care. SUBJECTS AND METHODS: A 20-hour continuing education program was conducted by the joint efforts of the Taipei City Government, Taiwan Association of Asthma Education and Taipei Medical University Wan Fang Hospital, in a series of 4 days afternoon sessions from June 26 to July 4, 2004. One hundred and twenty-five pharmacists participated. The Asthma Knowledge Test in Mandarin and the Asthma Attitude Scale in Mandarin were developed by adapting the scale used to evaluate the impact of pharmacist continuing education programs on diabetic care. The results before and after the intervention were compared to evaluate the impact of the program. RESULTS: Of the 125 participants, 105 returned both the pre- and post-intervention questionnaires, for a response rate of 84.0%. The total score of the attitude section increased significantly from 40.04 +/- 3.35 to 42.54 +/- 2.98 (full score = 50, p < 0.001). The total score of the knowledge section also increased significantly from 7.18 +/- 1.31 to 7.56 +/- 1.15 (p = 0.008). Improvement in the attitude score was found in 70 (67.0%) subjects, and in the knowledge score in 45 (43.5%) subjects. CONCLUSION: The study demonstrated that attitude and knowledge toward asthma care improved after the continuing education program. Further study of long-term impact and direct changes in asthma pharmaceutical care practice will be necessary.

Hepatitis associated with prothionamide for treatment of multidrug-resistant tuberculosis.

Timely and intensive monitoring for, and management of, adverse effects caused by anti-tuberculosis drugs are essential components of control programs for multidrug-resistant tuberculosis (MDR-TB). This retrospective case series was conducted in northern Taiwan from January 2007 to December 2008 at Taipei Medical University-Wan Fang Hospital, a 750-bed tertiary-care center and MDR-TB referral center. Hepatitis associated with prothionamide was defined as the recurrence of hepatitis after a second prothionamide treatment re-challenge. In total, 47 patients with MDR-TB enrolled in the Directly Observed Therapy, Short Course-Plus Program were identified during the study period, and 44 (93.6%) were treated with prothionamide. Seven of these 44 patients (15.9%) developed hepatitis after being treated with prothionamide concurrent with other anti-tuberculosis agents. Hepatitis associated with prothionamide occurred in three of these seven patients (6.8%). In these three patients, hepatitis developed following treatment with prothionamide for 28 days, 39 days or 45 days. Hepatitis developed rapidly after re-challenge with prothionamide at 4 days, 4 days and 3 days, respectively. Liver function returned to the normal range after cessation of prothionamide treatment for 19 days, 27 days or 28 days. Close monitoring of liver function was necessary in MDR-TB patients who received prothionamide treatment.

Stereoelectronic effects on the transition barrier of polyproline conformational interconversion.

There has been growing interest in polyproline type II (PPII) helices since PPII helices have been found in folded and unfolded proteins and involved in a variety of biological activities. Polyproline can also form type I helices (PPI) which are very different from PPII conformation and only exist in certain organic solvents. Recent studies have shown that stereoelectronic effects play a critical role in stabilizing a PPI or PPII helix. Here, we have synthesized a series of host-guest peptides with an electron-withdrawing substituent at the 4R or 4S position of proline and used a kinetic approach to further explore stereoelectronic effects on the transition barrier of the interconversion between PPI and PPII conformations. Time-dependent circular dichroism measurements revealed that the rates of PPII --> PPI conversion were reduced upon incorporating the hydroxyl-, fluoro-, and methoxy-groups at the 4R position while the rates would be increased if these substituents were at the 4S position. We quantified the changes in transition free energy by comparing their rate constants. (4R,2S)-4-Fluoroproline and (4S,2S)-4-fluoroproline have the largest effect on the transition energy barrier for PPII --> PPI conversion. Our results provide important insights into the role of stereoelectronic effects on the PPII --> PPI transition state barrier, which has not been reported in past thermodynamic studies.