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BackgroundIschemic stroke poses a major threat to human health and represents the third leading cause of death worldwide and in Taiwan. Post-acute care (PAC) training has been reported to be beneficial for post-index stroke events. However, knowledge is still lacking on the outcome of stroke events with cardiac origin. The focus of the current study is to investigate the effectiveness of PAC in this subgroup of patients as well as identify key baseline pointers that are capable of early prediction of patients' physical recovery. In addition, the authors hypothesize that the routinely arranged non-invasive carotid duplex that evaluates the characteristics of the carotid lumen could play a significant role in providing an early outcome prediction.MethodsFor the current research, 142 ischemic stroke patients with underlying cardiac arrhythmia (atrial fibrillation) were retrospectively recruited. The patients' basic demographics, neuroimaging, carotid duplex, and basic biochemistry datasets were accurately documented. The pre and post-admission National Institutes of Health Stroke Scale (NIHSS) (6-month follow-ups), Barthel Index, and mRS score (12-month follow-ups) were also recorded. All statistical analyses were performed using R for Windows (version 3.6.3). Barthel Index, NIHSS, and mRS scores obtained before and after hospitalization were compared to determine the patients' outcomes and were classified as improved or unimproved. A multivariate logistic analysis was designed and applied to assess the significance of risk factors and to obtain the odds ratios (ORs). The receiver operating characteristic (ROC) curve and the Youden Index was used to find the important cut-off point information, and the area under the curve (AUC) was calculated to provide accuracy.ResultsThe average age of the 142 ischemic stroke patients enrolled in the current study was about 66 years, of which 88 patients were male and 54, female. Many of them had other comorbidities: 86 patients had mixed hyperlipidemia (60.56%), 115 had hypertension (80.99%), and 49 suffered from diabetes mellitus (34.51%). The mRS showed an improvement in the condition of only 40 patients (28.175%), whereas the Barthel Index showed improvement in 71 patients (50%), and 68 patients (47.89%) showed recovery on the NIHSS. The Barthel Index and NIHSS were selected because they already had an almost equal number of samples among the improved and unimproved groups (50%), rather than mRS, which had a lower number (28.17%) of improved cases. While conducting the EuroQol-5 Dimension (EQ-5D) assessment, anxiety/depression stood out as the most prominent issue, affecting 44 patients (30.99%). Self-care was another factor that was involved in the ongoing improvement of 36 patients (25.35%). Multivariate logistic analysis of both NIHSS and Barthel Index showed improvement with a contralateral plaque index statistical significance (P

Background and objectives: The objective of this study is to elucidate peripheral occlusion artery disease (PAOD) as a risk factor for cellulitis. Materials and Methods: This is a retrospective population-based cohort study. The database is the Longitudinal Health Insurance Database, which covers two million beneficiaries from the entire population of the 2010 registry for beneficiaries in Taiwan. The PAOD group is composed of patients who were newly diagnosed with PAOD from 2001 to 2014. The non-PAOD group is composed of patients who were never diagnosed with PAOD from 2001 to 2015. All patients were followed until the onset of cellulitis, death, or until the end of 2015. Results: Finally, 29,830 patients who were newly diagnosed with PAOD were included in the PAOD group, and 29,830 patients who were never diagnosed with PAOD were included in the non-PAOD group. The incidence densities (ID) of cellulitis were 26.05 (95% CI = 25.31–26.80) patients per 1000 person-years in the PAOD group and 49.10 (95% CI = 48.04–50.19) in the non-PAOD group. The PAOD group had an increased risk of cellulitis (adjusted HR = 1.94, 95% CI = 1.87–2.01) compared to the non-PAOD group. Conclusions: Patients with PAOD were associated with a higher risk of subsequent cellulitis compared to patients without PAOD.

Abstract Background DNA methylation of Cadherin 13 (CDH13), a tumor suppressor gene is associated with gene repression and carcinogenesis. We determined the relation of dietary fat and sex with CDH13 cg02263260 methylation in Taiwanese adults. Methods Data of 870 eligible participants (430 men and 440 women) between 30 and 70 years were obtained from the Taiwan Biobank (TWB) database. The association of dietary fat and sex with CDH13 cg02263260 methylation was determined using multiple linear regression. Results The association between sex and cg02263260 methylation was significant: beta-coefficient (β) = 0.00532; 95% confidence interval (CI) = 0.00195–0.00868. Moreover, the interaction between sex and dietary fat on cg02263260 methylation was significant (P-value = 0.0145). After stratification by sex, the association of dietary fat with cg02263260 methylation was significant only in women. Specifically, high dietary fat was positively associated with cg02263260 methylation in women (β = 0.00597; 95% CI = 0.00061–0.01133) and the test for trend was significant (P-value = 0.0283). Conclusion High fat intake was significantly associated with higher cg02263260 methylation in women and the test for trend was significant. These findings suggest that the association of fat intake and CDH13 cg02263260 might vary by sex and CDH13 cg02263260 methylation levels in women might increase as fat intake increases.

This study evaluated the association between long-term low-dose aspirin use and decreased risk of pneumonia in patients with cardio-cerebra-vascular ischemic diseases (CCVDs). This retrospective cohort study used records from Taiwan's National Health Insurance Research Database of claims made between 1997 and 2013. After propensity score matching (PSM), patients who took a low dose of aspirin for more than 90 days within 1 year of diagnosis with CCVDs were identified as the exposure group (n = 15,784). A matched total of 15,784 individuals without aspirin use were selected for the non-aspirin group. The main outcome was the development of pneumonia after the index date. Multivariable Cox regression analysis and Kaplan–Meier survival analysis were performed to estimate the adjusted hazard ratio (aHR) and cumulative probability of pneumonia. The result after PSM indicated a lower hazard ratio for pneumonia in aspirin users (aHR = 0.890, 95% confidence interval = 0.837–0.945). Therefore, patients with CCVDs who took aspirin had a lower risk of developing pneumonia than those who did not. In conclusion, this population-based cohort study demonstrated that long-term low-dose aspirin use is associated with a slightly decreased risk of pneumonia in patients with CCVDs.

Colorectal cancer (CRC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Fibroblast growth factor receptor 4 (FGFR4) is a receptor tyrosine kinase that has been shown to play a key role in cancer development and prognosis via the activation of its downstream oncogenic signaling pathways. The present study aimed to explore the impact of FGFR4 gene polymorphisms on the risk and progression of CRC. Three FGFR4 single-nucleotide polymorphisms (SNPs), including rs1966265, rs351855, and rs7708357, were evaluated in 413 CRC cases and 413 gender- and age-matched cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of CRC between the case and control group. However, while assessing the clinicopathological parameters, patients of rectal cancer possessing at least one minor allele of rs1966265 (AG and GG; AOR, 0.236; p = 0.046) or rs351855 (GA and AA; AOR, 0.191; p = 0.022) were found to develop less metastasis as compared to those who are homozygous for the major allele. Further analyses using the datasets from the Genotype-Tissue Expression (GTEx) Portal and The Cancer Genome Atlas (TCGA) revealed that rs351855 regulated FGFR4 expression in many human tissues, and increased FGFR4 levels were associated with the occurrence, advanced stage, and distal metastasis of colon adenocarcinoma. These data suggest that the amino acid change in combination with altered expression levels of FGFR4 due to genetic polymorphisms may affect CRC progression.

Background and objectives: We aimed to evaluate the correlation between periodontal disease (PD) and following ocular diseases via the National Health Insurance Research Database in Taiwan. Materials and Methods: A retrospective cohort study was conducted. Subjects were regarded as having PD according to the diagnostic codes. For comparison, each subject with PD was matched to one non-PD individual from the database after exclusion. The main outcome was defined as the development of infectious keratitis, endophthalmitis, orbital cellulitis, lacrimal duct infection, uveitis and infectious scleritis. Cox proportional hazard regression was used to yield the adjusted hazard ratios (aHR) of ocular diseases between the study and control groups. Results: A total of 426,594 subjects were enrolled in both the study and control groups. In the multivariable analysis, significantly higher rates of infectious keratitis (aHR: 1.094, 95% CI: 1.030–1.161), uveitis (aHR: 1.144, 95% CI: 1.074–1.218) and infectious scleritis (aHR: 1.270, 95% CI: 1.114–1.449) were found in the study group. Concerning the PD interval, infectious keratitis (aHR: 1.159, 95% CI: 1.041–1.291) and infectious scleritis (aHR: 1.345, 95% CI: 1.055–1.714) would significantly occur in PD patients with an interval shorter than two years, individuals with a PD interval that ranged from two to five years were under a higher risk of developing uveitis (aHR: 1.184, 95% CI: 1.065–1.315) and infectious scleritis (aHR: 1.386, 95% CI: 1.125–1.708), and the rate of uveitis (aHR: 1.149, 95% CI: 1.038–1.272) was significantly higher if PD persisted more than five years. Conclusions: The presence of PD was moderately associated with the risk of developing infectious keratitis, uveitis and infectious scleritis.

Background and objectives: Breast cancer is a common cancer in women and has been the fourth leading cause of death in Taiwanese women. Risk factors for breast cancer include family history of breast cancer, genetic factors, and not breastfeeding. Several studies have reported an association between repeated inflammation at a young age, especially among lactating women, and cancer; however, the number of studies about the association of mastitis and breast cancer in nonlactating women is still limited. Therefore, the aim of this study was to determine the relationship between mastitis in women aged ≥40 years and breast cancer. Materials and Methods: This was a retrospective cohort study design. The data source was the Longitudinal Health Insurance Database 2010 (LHID 2010), comprising data collected by Taiwan’s National Health Insurance program. Cases of newly diagnosed mastitis in women aged ≥40 years (ICD-9-CM code = 611.0) were selected from the years 2010 to 2012. Women not diagnosed with mastitis were selected as the control group, and their data for the years 2009 to 2013 were obtained through the database. In addition, the non-mastitis group was matched 1:10 by age. Results: A total of 8634 participants were selected from the LHID 2010, which included 734 cases with mastitis and 7900 cases without mastitis. After adjustment for age, hypertension, hyperlipidemia, diabetes, hypothyroidism, and autoimmune diseases, the Cox proportional hazard model showed that patients with mastitis had a higher risk of breast cancer (aHR = 3.71, 95% CI = 1.9–7.02) compared with the non-mastitis group. The Kaplan–Meier curve also showed that women with mastitis had a higher risk of developing breast cancer. Conclusions: This study confirmed that women with mastitis have a higher risk of developing breast cancer. Therefore, women aged ≥40 years could reduce breast cancer risk by taking precautions to prevent mammary gland infection and mastitis.

Background and objectives: High-density lipoprotein cholesterol (HDL-C) is important for improving risk estimates of atherosclerotic cardiovascular disease. We investigated the effect of omnivore and diverse vegetarian diets in connection with exercise on HDL-C. Materials and Methods: Historical data of 9588 biobank participants (4025 exercisers and 5563 non-exercisers) aged 30−70 years were categorized as omnivores (n = 8589), former vegetarians (n = 544), lacto-ovo vegetarians (n = 417), and strict vegetarians (n = 38). We used multiple linear regression for analyses. Results: HDL-C levels were higher in exercisers compared to non-exercisers. Compared with omnivores, strict vegetarians had decreased levels of HDL-C (β = −5.705; p = 0.001) followed by lacto-ovo vegetarians (β = −3.900; p < 0.001) and former vegetarians (β = −0.329; p = 0.475). The test for trend was significant (p < 0.001). After categorization by exercise modalities, the β-value was −13.984 for strict vegetarians, −4.419 for lacto-ovo vegetarians, and −1.864 for former vegetarians, respectively (p < 0.05). There was an interaction between diet and exercise (p = 0.009). Omnivores who exercised regularly had significantly higher HDL-C, whereas strict vegetarians who exercised regularly had significantly lower HDL-C. Conclusions: In summary, strict vegetarian diets in conjunction with regular exercise might not serve as healthful behaviors to be implemented in everyday life considering the negative impact on HDL-C.

BACKGROUND:Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Human WW domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene in multiple cancers. We hypothesize that genetic variations in WWOX are associated with HCC risk. METHODOLOGY/PRINCIPAL FINDINGS:Five single-nucleotide polymorphisms (SNPs) of the WWOX gene were evaluated from 708 normal controls and 354 patients with HCC. We identified a significant association between a WWOX single nucleotide polymorphism (SNP), rs73569323, and decreased risk of HCC. After adjustment for potential confounders, patients with at least one T allele at rs11545028 of WWOX may have a significantly smaller tumor size, reduced levels of α-fetoprotein and alanine aminotransferase (ALT). Moreover, the A allele at SNP rs12918952 in WWOX conferred higher risk of vascular invasion. Additional in silico analysis also suggests that WWOX rs12918952 polymorphism tends to affect WWOX expression, which in turn contributes to tumor vascular invasion. CONCLUSIONS:In conclusion, genetic variations in WWOX may be a significant predictor of early HCC occurrence and a reliable biomarker for disease progression.

Nuclear localization of β-catenin is known to associate with malignant transformation of many squamous cell carcinomas. The aim of this study was to compare β-catenin expression in normal human oral epithelium and areca quid chewing associated oral squamous cell carcinomas (OSCCs) and further to explore the potential mechanisms that may lead to induce β-catenin expression. Methods: A total of 40 areca quid chewing-associated OSCCs and 10 normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, extracellular signal-regulated protein kinase inhibitor PD98059, glutathione precursor N-acetyl-l-cysteine (NAC), tyrosine kinase inhibitor herbimycin-A, p38 inhibitor SB203580, and phosphatidylinositaol 3-kinase inhibitor LY294002 were added to find the possible regulatory mechanisms. Results: β-catenin expression was significantly higher in OSCC specimens than that in normal oral epithelial specimens (p

Invasive lobular cancer (ILC) tends to be significantly larger in size with significantly more positive lymph nodes, whereas ILC has a significantly more favorable outcome, compared to stage-matched invasive ductal carcinoma (IDC). The mechanism accounting for such differences remains elusive. Based on morphological, immunohistochemical, and molecular studies of over 1,000 cases of human breast cancers, we hypothesize that the differences may result from the structural and/or functional differences of their surrounding myoepithelial cell layers, which dictate lobular and ductal tumor cells to follow different pathways of invasion or metastasis. The background, rationale, supportive data, and implications of our hypothesis are presented and discussed.

Background: There is an upward trend for parents to resort to assisted reproductive technology (ART) treatment due to delayed childbirth or birth difficulties.Objective: This study investigates the pregnancy health and birth outcomes of women who underwent ART and analyzes the factors that influence birth weight to become

Chinese herbs have been and still are widely used as important remedies in Oriental medicine. Over the recent years, a variety of biologically active constituents have been isolated from these sources and confirmed to have multifunctional activity in experimental studies. Honokiol is a small-molecule polyphenol isolated from the genus Magnolia. It is accompanied by other related polyphenols, including magnolol, with which it shares certain biological properties. Recently, honokiol and magnolol have been found to have anti-oxidative, anti-inflammatory, anti-tumor, and anti-microbial properties in preclinical models, without appreciable toxicity. These findings have increased interest in bringing honokiol and magnolol to the clinic as novel therapeutic agents in dermatology. In this review, the findings concerning the major mechanisms of action of honokiol and magnolol are described. Knowledge of the multiple activities of honokiol and magnolol can assist with the development of honokiol and magnolol derivatives and the design of clinical trials that will maximize the potential benefit of honokiol and magnolol in the patient setting for dermatologic disorders.

Human breast cancer represents a group of highly heterogeneous lesions consisting of about 20 morphologically distinct subtypes with substantially different molecular and/or biochemical signatures, clinical courses, and prognoses. This study analyzed the possible correlation between the morphological presentations of breast cancer and two hypothesized models of carcinogenesis, in order to identify the intrinsic mechanism(s) and clinical implications of breast cancer heterogeneity.

Our previous studies revealed that pregnancy associated breast cancer (PABC) had significantly reduced nuclear p63 expression in myoepithelia, while intense cytoplasmic p63 expression in associated epithelia. Our current study assessed these epithelia using immunohistochemistry with a panel of aggressiveness and invasiveness related markers and comparative genomic hybridization (array-CGH) with over 30,000 DNA probes. These epithelia showed several unique alterations, including (1) immunohistochemical and morphological resemblance to invasive cancer, (2) significant gain in copy numbers of DNA coding genes for morphogenesis, angiogenesis, and metastasis, and (3) significant loss in copy numbers of DNA coding genes for tumor suppressors, cell adhesion, and macromolecular complex assembly or intra-cellular trafficking. Detected array-CGH alterations correlated well with in vivo expression of a number of corresponding proteins tested. These findings suggest that aberrant sub-cellular localization of p63 expression in normal or hyperplastic appearing epithelial cells may significant contribute to increased invasiveness and aggressiveness of these cells.

The fractional concentration of exhaled nitric oxide (FENO) has been reported to be elevated in asthma and many other lung diseases. The present study investigated reference values and determinants of FENO in a Taiwanese non-smoking, healthy adult population. Methods: We used a chemiluminescence analyzer according to American Thoracic Society/European Respiratory Society recommendations to measure FENO values in 356 adults who received a health check-up and a detailed respiratory questionnaire at Taichung Veterans General Hospital, Taiwan. Among the volunteers, 249 fulfilled our definition of healthy adults: no history of smoking or physician-diagnosed asthma; no recent upper airway infection; no chronic respiratory symptoms; and no allergic rhinitis and urticaria. Results: Among the 249 non-smoking and non-asthmatic adults, the mean (5th to 95th percentile reference range) FENO was 27.9 (12.5–58.0) parts per billion. In multivariate regression analyses, age and lung function (forced vital capacity or forced expiratory volume in 1 second) were associated positively with FENO values. Sex, height, weight, and ambient NO values were not associated significantly with FENO values. Conclusion: Age and lung function were predictors of FENO in this population, and these factors should be considered for clinical applications of FENO measurements.

Heme oxygenase-1 (HO-1) is known as an oxidative stress responsive protein that is upregulated by various physiologic and endogenous stimuli. HO-1 has been proposed to provide an important cellular response that protects cells against oxidative damage. Areca quid chewing is a major risk factor in the development and further progression of oral squamous cell carcinoma (OSCC). The aim of the present study was to investigate the difference in HO-1 expression in normal human oral epithelium and OSCC, and further explore the potential mechanism that may lead to HO-1 expression. Methods: Thirty-five OSCC and 10 normal epithelium specimens were examined by immunohistochemistry and analyzed by clinicopathologic profiles. The oral epithelial GNM cell line was challenged with arecoline, a major areca nut alkaloid, by reverse-transcriptase polymerase chain reaction. Furthermore, tobacco smoke carcinogen benzo[a]pyrene (BaP) and glutathione (GSH) precursor N-acetyl-L-cysteine were added to find the possible regulatory mechanisms. Results: HO-1 expression was significantly higher in OSCC specimens (p < 0.05). No significant difference in HO-1 expression was observed with respect to age, sex, T category, and stage (p > 0.05). The high HO-1 expression was associated with lymph node metastasis (p = 0.005). In addition, arecoline was found to elevate HO-1 mRNA in a dose-dependent manner (p < 0.05). The addition of BaP enhanced arecoline-induced HO-1 expression (p < 0.05). Moreover, addition of NAC markedly inhibited arecoline-induced HO-1 expression (p < 0.05). Conclusion: Taken together, these results suggest that HO-1 expression is significantly upregulated in OSCC from areca quid chewers, and arecoline may be responsible for enhanced HO-1 expression in vivo. The compounds of cigarette smoke may act synergistically in the pathogenesis of areca-quid-chewing-associated OSCC. The regulation of HO-1 expression induced by arecoline is critically dependent on intracellular GSH concentration.

Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of osteoarthritis (OA). Here, we investigated the intracellular signaling pathways involved in CCL2-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human OA synovial fibroblasts (OASFs).Stimulation of OASFs with CCL2 induced VCAM-1 expression. CCL2-mediated VCAM-1 expression was attenuated by CCR2 inhibitor (RS102895), PKCδ inhibitor (rottlerin), p38MAPK inhibitor (SB203580), and AP-1 inhibitors (curcumin and tanshinone IIA). Stimulation of cells with CCL2 increased PKCδ and p38MAPK activation. Treatment of OASFs with CCL2 also increased the c-Jun phosphorylation and c-Jun binding to the AP-1 element on the VCAM-1 promoter. Moreover, CCL2-mediated CCR2, PKCδ, p38MAPK, and AP-1 pathway promoted the adhesion of monocytes to the OASFs monolayer.Our results suggest that CCL2 increases VCAM-1 expression in human OASFs via the CCR2, PKCδ, p38MAPK, c-Jun, and AP-1 signaling pathway. The CCL2-induced VCAM-1 expression promoted monocytes adhesion to human OASFs.

BACKGROUND: Angiogenesis is essential for the progression of osteoarthritis (OA). Hepatocyte growth factor (HGF) is an angiogenic mediator, and it shows elevated levels in regions of OA. However, the relationship between HGF and vascular endothelial growth factor (VEGF-A) in OA synovial fibroblasts (OASFs) is mostly unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we found that stimulation of OASFs with HGF induced concentration- and time-dependent increases in VEGF-A expression. Pretreatment with PI3K inhibitor (Ly294002), Akt inhibitor, or mTORC1 inhibitor (rapamycin) blocked the HGF-induced VEGF-A production. Treatment of cells with HGF also increased PI3K, Akt, and mTORC1 phosphorylation. Furthermore, HGF increased the stability and activity of HIF-1 protein. Moreover, the use of pharmacological inhibitors or genetic inhibition revealed that c-Met, PI3K, Akt, and mTORC1 signaling pathways were potentially required for HGF-induced HIF-1α activation. CONCLUSIONS/SIGNIFICANCE: Taken together, our results provide evidence that HGF enhances VEGF-A expression in OASFs by an HIF-1α-dependent mechanism involving the activation of c-Met/PI3K/Akt and mTORC1 pathways.