The impact of the duration of the integrated disease management program on COPD-related outcomes.

BACKGROUND: The aim of this study is to assess the impact of the duration of the integrated disease management (IDM) program on COPD-related outcomes in real-world setting. METHODS: A retrospective cohort study among 3771 patients with COPD who had regularly completed 4 visits of IDM program within 1 year between April 1, 2017 and December 31, 2018. CAT score as the primary outcome used to investigate the association between IDM intervention duration and improvement in CAT score. Change in CAT score from baseline to each follow-up visit determined by using least-squares means (LSMeans) approach. The cut-off value of IDM duration for improving the CAT score was determined by the Youden index. Logistic regression was used to analyze the relationship between IDM intervention duration and MCID (the minimal clinically important difference) improvement in CAT score and the factor associated CAT improvement. Risks of COPD exacerbation events (COPD-related ED visit and COPD-related hospitalization) were estimated by using the cumulative incidence curve and Cox proportional hazards models. RESULT: Among 3771 enrolled COPD patients, the majority of the study cohort were males (91.51%) and 42.7% of patients had CAT score of ≥ 10 at baseline. The mean of age was 71.47 years and the mean CAT at baseline were 10.49. The mean change from baseline in CAT score was - 0.87, - 1.19, - 1.23 and - 1.40 at 3-, 6-, 9- and 12 month follow-up (p < 0.0001 for all visits), respectively. Statistically significantly lower likelihood of achieving MCID improvement in CAT were observed at 3- and 6 month compared to 9 month (at 3 month: OR: 0.720, 95% CI 0.655-0.791; at 6 month: OR: 0.905, 95% CI 0.825-0.922). And only a modest increase likelihood of achieving MCID improvement in CAT at 12 month (OR: 1.097, 95% CI 1.001-1.201) compared with 9-month follow-up. In logistic regression on the entire cohort, CAT MCID improvement was most associated with baseline CAT scores ≥ 10, followed by frequent exacerbation in previous year (> 2 episodes/year), wheezing, and GOLD B or D at baseline. In baseline CAT ≥ 10 group, patients were more likely to achieve CAT MCID improvement and had greater decreases from baseline in CAT score observed at 3-, 6-, 9-, and 12 month compared with baseline CAT score < 10 group (all p < 0.0001). Moreover, in CAT ≥ 10 groups, patients who achieved CAT MCID improvement had lower risk of subsequent COPD exacerbation events (COPD-related ED visit: aHR: 1.196, 95% CI 0.985-1.453, p = 0.0713; COPD-related hospitalization: aHR: 1.529, 95% CI 1.215-1.924, p = 0.0003) when compared to those without. CONCLUSION: This is the first real-world study indicating the association between COPD IDM intervention duration and COPD-related outcomes. From 3 to 12 month follow-up results showed that continued improvement over time in COPD-specific health status, particularly in patients with baseline CAT score of ≥ 10. Furthermore, a reduction of the risk of subsequent COPD exacerbations were observed in patients with CAT MCID improvement.

Tiotropium/Olodaterol treatment reduces cigarette smoke extract-induced cell death in BEAS-2B bronchial epithelial cells.

BACKGROUND: Cigarette smoking is a critical risk factor for the destruction of lung parenchyma or the development of emphysema, which is characteristic of COPD. Disruption of epithelial layer integrity may contribute to lung injury following cigarette smoke extract (CSE) exposure. Tiotropium/olodaterol acts as a bronchodilator for COPD treatment; however, the effect of dual bronchodilators on epithelial cell injury and its underlying mechanism remain unclear. In this study, we evaluated the effect of tiotropium/olodaterol on CSE-mediated cell death and the underlying mechanisms. METHODS: Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis, necrosis, and autophagy were evaluated using flow cytometry. Autophagy-related protein, phosphorylated ERK, expression was determined using Western blotting. RESULTS: Tiotropium/olodaterol significantly inhibited CSE-induced cell death, mitochondria dysfunction, and autophagy, which had no significant effect on apoptosis or necrosis in BEAS-2B human bronchial epithelial cells. Moreover, tiotropium/olodaterol attenuated CSE-induced upregulation of JNK. CONCLUSIONS: CSE induced cell death and caused consistent patterns of autophagy and JNK activation in BEAS-2B human bronchial epithelial cells. Tiotropium/olodaterol treatment protected bronchial epithelial cells from CSE-induced injury and inhibited activation of autophagy and upregulation of JNK phosphorylation. These results indicate that tiotropium/olodaterol may protect epithelial cells from the deleterious effects of CSE exposure, which is associated with the regulation of autophagy and JNK activation.

Antihelminthic Niclosamide Induces Autophagy and Delayed Apoptosis in Human Non-small Lung Cancer Cells In Vitro and In Vivo.

BACKGROUND/AIM: Niclosamide is an antihe-minthic drug that has shown cytotoxic effects on non-small cell lung carcinoma (NSCLC) cells. However, the exact mechanisms underlying the anti-tumour activity of niclosamide in NSCLC cancer cells remains to be defined. The aim of this study was to evaluate the antitumor activity of niclosamide in human A549 and CL1-5 non-small cell lung cancer cells using in vitro and in vivo. MATERIALS AND METHODS: We investigated the effects of niclosamide on cell viability, apoptosis, the mitochondrial membrane potential (MMP; Δϕm), and autophagy and apoptosis-related protein expression in human A549 and CL1-5 non-small cell lung cancer cells. RESULTS: Niclosamide induced mainly caspase-independent apoptosis through apoptosis-inducible factor (AIF) translocation to the nucleus upon mitochondria damage. Moreover, niclosamide-induced autophagy may act as adaptive response against apoptosis. AMPK/AKT/mTOR pathway were involved in niclosamide-induced cell death and autophagy in response to ATP depletion. Furthermore, niclosamide efficiently suppressed tumor growth and induce autophagy in vivo. CONCLUSION: Niclosamide induced apoptosis by activating the intrinsic and caspase-independent pathway in human A549 and CL1-5 non-small cell lung cancer cells. Therefore, niclosamide is a potential candidate for anti-NSCLC therapy.

The application of miniprobe ultrasonography in the diagnosis of colorectal subepithelial lesions.

BACKGROUND: Difficulty with the proximal lesion approach and durability of endoscopic ultrasonography (EUS) instruments usually limits its application for lower gaotrointestina (GI) lesions to locoregional staging of rectal cancer. This study investigated the value of colonoscopic miniprobe ultrasonography for differential diagnosis and treatment strategy in patients with colorectal subepithelial lesions (SEL). METHODS: Miniprobe ultrasonography was Performed in 40 consecutive patients with suspected colorectal SEL or residual lesions after endoscopic resection at one medical center by the same endoscopist (C-J Lin). The EUS images and procedure records were reviewed. The final diagnosis of these lesions was confirmed by cross section imaging, histopathologic findings, or clinical follow-up. RESULTS: Miniprobe EUS allowed high-resolution imaging and a successful approach to all colorectal SEL through the working channel of a sigmoidoscope or colonoscope without breakdown of the miniprobe. Thirteen patients, suspected of having rectal carcinoid tumors (mean size, 6.9 +/- 3.3 mm), were treated radically by endoscopic mucosal resection using a transparent cap (EMRC) after EUS confirmation of no muscular invasion. Three patients had no residual or recurrent carcinoid tumor on EUS examination after previous empiric polypectomy or biopsy. EUS detected submucosal lipomas (mean size, 18.5 mm; range, 8.6-25.6 mm) in ten patients however, only two patients underwent endoscopic resection. Five patients had suspected rectal myogenic stromal tumors on EUS; three were transferred for surgical resection due to uterine myoma compression (N = 2) or mucinous adenocarcinoma of the appendix with rectal metastasis (N = 1), and two had uterine myoma detected by gynecologic ultrasound or CT. One appendiceal stone with orifice obstruction mimicking cecal submucosal tumor was proved by surgical resection. One patient had hemorrhoids proved by hemorrhoidectomy. One patient was proved to have proctitis cystica profunda by EMRC. The other six patients had various benign lesions, which were diagnosed and followed-up by EUS without progression. In thirty-five of forty patients (88%) colorectal SEL were managed uneventfully according to EUS interpretation. CONCLUSIONS: Miniprobe ultrasonography can be a useful supplement to routine colonoscopy and provide treatment guidance for suspected colorectal subepithelial lesions.

The outcome assessment of double-balloon enteroscopy for diagnosing and managing patients with obscure gastrointestinal bleeding.

Diagnosing and treating patients with obscure gastrointestinal bleeding is clinically challenging. Most lesions responsible for the origin of obscure gastrointestinal bleeding are located in the small bowel. Double-balloon enteroscopy is a novel method for exploring the small intestine and has significant therapeutic potential. This study evaluated the value of double-balloon enteroscopy in diagnosing and managing obscure gastrointestinal bleeding. From October 2003 to January 2006, a total of 20 patients (6 men, 14 women; mean age, 55.2 years old) with obscure gastrointestinal bleeding (18 obscure overt bleeding, 2 obscure occult bleeding) were investigated by double-balloon enteroscopy. A total of 29 procedures (15 via oral approach and 14 via rectal approach) were performed. The diagnostic yield, endoscopic therapeutic procedures, complications, and outcome were then assessed. Small bowel lesions potentially responsible for the bleeding were identified in 15 (75%) of 20 patients, including 9 angiodysplasias, 2 gastrointestinal stromal tumors (GISTs), 2 ulcers, 1 jejunal granulation polyp, and 1 Peutz-Jeghers polyposis. Endoscopic treatments including heater probe coagulation, polypectomy, and endoscopic mucosal resection were performed in 11 patients. Two patients with GISTs received surgical intervention. Two patients with angiodysplasias that endoscopic treatment failed underwent laparoscopic resections following tattooing. There were no complications and the procedures were tolerated well. Among the 15 patients who had a lesion identified with subsequent treatment, rebleeding occurred in 3 (20%) patients with angiodysplasias. Of the five patients in whom no definite lesion was detected, rebleeding developed in four (80%). For patients with an identified lesion that was further treated, the rebleeding rate was lower than for those with "persistent" obscure gastrointestinal bleeding (P=0.031). We conclude that double-balloon enteroscopy offers a safe and effective method for diagnosing and managing patients with obscure gastrointestinal bleeding.

The involvement of K(v)3.4 voltage-gated potassium channel in the growth of an oral squamous cell carcinoma cell line.

BACKGROUND: In our previous study, an A-type voltage-gated K(+) channel, K(v)3.4, was found more frequently expressed in oral squamous cell carcinoma (OSCC) when compared with non-cancerous matched oral tissue. An OSCC cell line, OECM-1, was found to have moderate level of K(v)3.4 expression. METHODS: To further elucidate the roles of K(v)3.4 for the involvement of neoplastic process, we amplified K(v)3.4 coding sequence by reverse transcriptase polymerase chain reaction (RT-PCR), constructed an expression vector carrying this sequence and then stably transfected into OECM-1 OSCC cells. RESULTS: We demonstrated the integration and constitutive expression of K(v)3.4 in the cell. A unique A-type current elicited by such expression in OECM-1 cells was defined by patch clamp analysis. This current pattern can be reversibly blocked by an A-type K(+) channel blocker 2 mM 4-aminopyridine (4-AP). The acquisition of K(v)3.4 activity in OECM-1 cells bestowed growth advantage. However, in 3T3 cell, transfected K(v)3.4 caused only limited increase of growth without forming transformation foci. CONCLUSION: The present study established a stable keratinocyte system carrying functional K(v)3.4 and increase of growth, by which the anti-K(v)3.4 modalities for potential OSCC control can be further investigated.

Bone mineral density in women receiving thyroxine suppressive therapy for differentiated thyroid carcinoma.

BACKGROUND AND PURPOSE: Most patients with well-differentiated thyroid carcinoma have an excellent prognosis and are likely to live long enough to be subjected to osteoporosis. The purpose of this study was to investigate the consequences of treatment with a supraphysiological dose of levothyroxine (l-T4) on bone mineral density (BMD) in Taiwanese women with differentiated thyroid cancer. METHODS: A total of 69 (44 premenopausal, 25 postmenopausal) Taiwanese women with differentiated thyroid cancer were included in this retrospective study. These patients were free of disease recurrence after initial near-total thyroidectomy and I-131 radioablation, and had undergone regular l-T4 suppressive therapy for more than 3 years (mean, 7.3 +/- 3.0 years; range, 3 to 15 years). The degree of thyroid-stimulating hormone (TSH) suppression was determined based on the mean TSH score for each patient which was determined by analysis of all available follow-up TSH data, where 1 = undetectable TSH (< 0.2 mIU/mL); 2 = subnormal TSH (0.2 to 0.39 mIU/mL); 3 = normal TSH (0.4 to 4.0 mIU/mL); and 4 = elevated TSH (> 4.0 mIU/mL). The patients were divided into a full TSH suppression group with a mean TSH score in the range 1.0 to 1.99, and a partial TSH suppression group with a mean TSH score in the range 2.0 to 2.99. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine, femoral neck, Ward's triangle and total hip. Comparisons between subgroups of patients and controls were performed by unpaired t test. Correlation between BMD and other clinical variables was assessed by Pearson's correlation analysis. RESULTS: Postmenopausal patients (aged 57.7 +/- 6.9 years) had significantly higher serum calcium levels and decreased BMD at all sites of the spine and hip as compared with premenopausal patients (aged 38.6 +/- 6.7 years) with similar BMI and duration of TSH suppression. Comparison of BMD between postmenopausal patients and BMI- and age-matched controls revealed that the patient group had decreased BMD at all sites of measurement, although this difference was not significant. This phenomenon was not observed in the premenopausal patients. Furthermore, when BMD was compared between patients categorized as having full and partial suppression of TSH, only patients with full suppression in the postmenopausal group showed a tendency to lower BMD. There was a strong correlation of BMD with age, BMI and serum calcium level. However, no correlation was found between BMD and degree of TSH suppression or duration of l-T4 suppression therapy. CONCLUSION: Women with differentiated thyroid cancer who had long-term (mean, 7.3 +/- 3.0 years) l-T4 therapy and suppressed TSH levels had no evidence of lower BMD. However, patients with full suppression in the postmenopausal group showed a tendency towards lower BMD. Therefore, careful monitoring of BMD in postmenopausal women during suppression therapy is mandatory.

Relative impact of low-density lipoprotein-cholesterol concentration and insulin resistance on carotid wall thickening in nondiabetic, normotensive volunteers.

The relative effect of an increase in low-density lipoprotein-cholesterol (LDL-C) concentration, as compared with insulin resistance and its manifestations, on intimal medial thickening (IMT) of the common carotid artery was defined in 72 healthy men and women. Insulin-mediated glucose disposal was quantified by the insulin suppression tests, in which the height of the steady-state plasma glucose (SSPG) concentration during the last 30 minutes of a 180-minute infusion of octreotide, insulin, and glucose provides an estimate of insulin resistance. IMT was determined by high-resolution B-mode ultrasonography. Univariate analyses defined statistically significant correlation coefficients between IMT and LDL-C concentration (r =.25, P <.05), SSPG concentration (r =.32, P <.01), triglycerides (TG) (r =.25, P <.05), and high-density lipoprotein-cholesterol (HDL-C) (r = -.28, P <.05) concentrations (changes associated with insulin resistance) and ratio of waist-to-hip girth (r =.29, P <.05). When forward step-wise linear regression analysis was used, concentrations of SSPG, LDL-C and HDL-C all emerged as independent predictors of IMT (P <.05). Furthermore, the magnitude of their relationship to IMT values was comparable. These results provide evidence that insulin resistance is as significant a predictor of degree of atherogenesis (estimated by IMT) of the common carotid artery as a high LDL-C concentration.