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Junctional adhesion molecule 3 (JAM3) is involved in epithelial cell junction, cell polarity, and motility. The molecular mechanisms underlying the role of JAM3 in placental dysfunction remain unclear. We hypothesized that JAM3 expression regulates trophoblast fusion, differentiation, proliferation, and apoptosis. Our results revealed that JAM3 was expressed in the cytotrophoblasts and syncytiotrophoblasts of first-trimester and term placental villi. JAM3 expression in cell–cell junctions decreased with the formation of syncytiotrophoblasts. Using trophoblasts as an in vitro model, we observed that forskolin and JAM3 knockdown significantly reduced JAM3 expression and increased syncytium formation. JAM3 knockdown additionally inhibited trophoblast proliferation and increased the number of trophoblasts in the sub-G1 and G2/M phases, indicating cell-cycle disturbance and apoptosis. Cell-cycle arrest was associated with the engagement of checkpoint kinase 2-cell division cycle 25C-cyclin-dependent kinase 1/cyclin B1 signaling. Increased expression of BIM, NOXA, XAF1, cytochrome c, and cleaved caspase-3 further indicated trophoblast apoptosis. Overexpression of JAM3 or recombinant JAM3 protein enhanced trophoblast adhesion and migration, which were inhibited by JAM3 knockdown. JAM3 knockdown induced reactive oxygen species and syncytin 2 expression in trophoblasts. Furthermore, H2O2-induced oxidative stress reduced JAM3 expression in trophoblasts and cell culture supernatants. H2O2 simultaneously induced trophoblast apoptosis. JAM3 expression was significantly decreased in the plasmas and placentas of patients with early-onset severe preeclampsia. Thus, our results show that JAM3 may not only be a structural component of trophoblast cell junctions but also regulates trophoblast fusion, differentiation, proliferation, apoptosis, and motility. Dysregulated trophoblast JAM3 expression is crucial in preeclampsia development.

High salt intake ranks among the most important risk factors for noncommunicable diseases. Western diets, which are typically high in salt, are associated with a high prevalence of obesity. High salt is thought to be a potential risk factor for obesity independent of energy intake, although the underlying mechanisms are insufficiently understood. A high salt diet could influence energy expenditure (EE), specifically diet-induced thermogenesis (DIT), which accounts for about 10% of total EE. We aimed to investigate the influence of high salt on DIT. In a randomized, double-blind, placebo-controlled, parallel-group study, 40 healthy subjects received either 6 g/d salt (NaCl) or placebo in capsules over 2 weeks. Before and after the intervention, resting EE, DIT, body composition, food intake, 24 h urine analysis, and blood pressure were obtained. EE was measured by indirect calorimetry after a 12 h overnight fast and a standardized 440 kcal meal. Thirty-eight subjects completed the study. Salt intake from foods was 6 g/d in both groups, resulting in a total salt intake of 12 g/d in the salt group and 6 g/d in the placebo group. Urine sodium increased by 2.29 g/d (p < 0.0001) in the salt group, indicating overall compliance. The change in DIT differed significantly between groups (placebo vs. salt, p = 0.023). DIT decreased by 1.3% in the salt group (p = 0.048), but increased by 0.6% in the placebo group (NS). Substrate oxidation indicated by respiratory exchange ratio, body composition, resting blood pressure, fluid intake, hydration, and urine volume did not change significantly in either group. A moderate short-term increase in salt intake decreased DIT after a standardized meal. This effect could at least partially contribute to the observed weight gain in populations consuming a Western diet high in salt.

Background This study aimed to collect data regarding patient perception and knowledge of dental implants. It was conducted with the hope that the data would provide dental professionals and policymakers with a better understanding of ways to promote implant therapy. Methods An anonymous online survey with 10 questions was distributed through 12 dental offices in Tokyo and provincial cities in Japan to assess patient perception and knowledge of dental implants. Harvard Medical School’s IRB approved this study. Results We collected data from 1172 patients (59% female, 41% male). The most common perceptions of implant therapy were that it was “expensive,” “advanced,” and “scary”. Patients’ implant knowledge came primarily from magazines or books, while professional dental societies/associations were the least sought out source of information. Patients believed that the purpose of dental implants was to avoid dentures and improve chewing function. Their primary concerns about dental implants were the cost and longevity. Approximately 12% of patients with dental implants and 61% of patients without implants did not know that bone grafts may be required and that sedation during surgery was an option. For patients who experienced sedation during the procedure, 60% of them want it for future surgeries. Patients also had limited knowledge of bone-graft materials and the effects of CBCT radiation; 75% of the patients expressed concerns over the safety of graft materials and radiation exposure. For patients with a history of dental implant therapy, 80% of them would recommend dental implants to their family and friends. Conclusions Overall, patients’ experiences with dental implant therapy were positive, but there was a lack of patient education regarding dental implants and their associated procedures. Dental professionals need to take the initiative to improve patient education.

Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of β-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial β-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 μM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells., Hsien-Ya Lin, Chia-Yu Chen, Ting-Chien Lin and colleagues perform structure-guided modifications of the compound uronic isofagomaine in order to engineer a highly specific and potent inhibitor of gut bacterial β-glucuronidases (GUSs). The authors present eight crystal structures and demonstrate in vivo efficacy of the optimised C6-alkyl derivative inhibitor in mice models. This study may enhance the development of inhibitors of microbial GUS for use in colorectal cancer therapy to minimize the undesired side effects of irinotecan treatment.

Preterm labor is associated with inflammation and infection. The mechanisms underlying the role of omega-3 fatty acid in inflammasome activation and prevention of preterm labor remain unknown. We hypothesized that omega-3 fatty acid can reduce the rate of preterm birth induced by infection and trophoblast inflammation. In the present study, we found that inflammasome-related molecules and IL-1β in trophoblasts were activated by TNF-α derived from lipopolysaccharide (LPS)-stimulated THP-1 cell-conditioned medium (CM) and recombinant TNF-α protein. The results demonstrated that stimulation with TNF-α caused lysosomal rupture in trophoblasts, which accelerated cathepsin S (CTSS) diffusion from lysosomes to the cytosol and activated NLRP1 (nacht domain-leucine-rich repeat, and pyd-containing protein 1) and absent in melanoma 2 (AIM2) inflammasomes, thereby increasing IL-1β secretion. Moreover, in response to LPS challenge, TNF-α increased trophoblast cell death and decreased cell viability through inflammasome and CTSS activation. Stearidonic acid (SDA; 18:4n−3) and docosahexaenoic acid (DHA; 22:6n−3) inhibited inflammasome-related molecule synthesis and CTSS and caspase-1 activation, which further reduced the preterm delivery rate of pregnant mice induced by LPS (92.9 compared with 69.7% (DHA); 92.9 compared with 53.5% (SDA)). Higher expression of TNF-α, IL-1β, prostaglandin E2, and CTSS, but lower resolvin D1 expression, was observed in preterm pregnant mice than in controls. Similarly, resolvin D1 was highly expressed in women with term delivery compared with women with preterm delivery. Thus, SDA and DHA may attenuate macrophage-derived TNF-α inducing CTSS and inflammasome activation, IL-1β secretion, and placental trophoblast cell death. These functions are implicated in the preventive effects of SDA and DHA on preterm labor.

This cross-sectional study aimed to examine the oral hygiene behaviors in the general population and identify factors affecting oral hygiene behaviors and plaque removal efficacy. A survey was distributed to patients through 11 dental practices in Japan, and each patient’s plaque index score (PIS) was recorded. In total, 1184 patients participated (521 women and 660 men), with 84.04% using manual toothbrushes (MTBs) and 15.96% using electric toothbrushes (ETBs). ETB users had a significantly lower PIS compared to MTB users (p = 0.0017). In addition, a statistically significant difference in the PIS was detected in relation to the frequency of brushing per day (≥2 times) and time spent on brushing (≥1 min). Some MTB users spent less than 1 min brushing, while all ETB users spent at least 1 min brushing, and extended brushing periods significantly improved the PIS for the MTB users. MTB users tend to replace brush heads more frequently than ETB users, and the frequency of replacement affected the PIS significantly (p < 0.01) for the MTB users. The status of dental treatment (first visit, in treatment versus recall) also significantly affected the PIS (p < 0.01). The ETB was more effective than the MTB in terms of better plaque removal and reduced frequency of brush head replacement.

Slit proteins have been reported to act as axonal repellents in Drosophila; however, their role in the placental microenvironment has not been explored. In this study, we found that human placental multipotent mesenchymal stromal cells (hPMSCs) constitutively express Slit2. Therefore, we hypothesized that Slit2 expressed by hPMSCs could be involved in macrophage migration during placental inflammation through membrane cognate Roundabout (Robo) receptor signaling. In order to develop a preclinical in vitro mouse model of hPMSCs in treatment of perinatal infection, RAW 264.7 cells were used in this study. Slit2 interacted with Robo4 that was highly expressed in RAW 264.7 macrophages: their interaction increased the adhesive ability of RAW 264.7 cells and inhibited migration. Lipopolysaccharide (LPS)-induced CD11bCD18 expression could be inhibited by Slit2 and by hPMSC-conditioned medium (CM). LPS-induced activation of p38 and Rap1 was also attenuated by Slit2 and by hPMSC-CM. Noticeably, these inhibitory effects of hPMSC-CM decreased after depletion of Slit2 from the CM. Furthermore, we found that p38 siRNA inhibited LPS-induced Rap1 expression in RAW 264.7 cells, indicating that Rap1 functions downstream of p38 signaling. p38 siRNA increased cell adhesion and inhibited migration through reducing LPS-stimulated CD11bCD18 expression in RAW 264.7 cells. Thus, hPMSC-derived Slit2 may inhibit LPS-induced CD11bCD18 expression to decrease cell migration and increase adhesion through modulating the activity and motility of inflammatory macrophages in placenta. This may represent a novel mechanism for LPS-induced placental infection.

Gingival hyperpigmentation in the anterior region in people with a high smile line is an esthetic concern. Gingival depigmentation can be achieved through various procedures. Most techniques have shown successful short-term results; however, recurrence is observed in 50% of patients after 2 to 4 years. A 46-year-old woman presenting with a large black zone of gingival hyperpigmentation in the anterior maxilla was treated with scalpel blade excision. At 25 years after the depigmentation procedure, the patient displayed no recurrence.

Background In pancreatic cancer, toxicities associated with current chemotherapeutic regimens remain concerning. A modified combination of gemcitabine, S-1, and leucovorin (GSL) was used as the first-line treatment for newly diagnosed locally advanced or metastatic pancreatic adenocarcinoma patients. Methods GSL was administered every 2 weeks—intravenous gemcitabine 800 mg/m2 at a fixed-dose rate of 10 mg/m2/min on day 1 and oral S-1 (80–120 mg/day) plus leucovorin 30 mg twice daily on days 1–7. We retrospectively analyzed the feasibility of GSL and patient outcomes in three medical centers in Taiwan. Results Overall, 49 patients received GSL with a median follow-up of 24.9 months from May 2015 to March 2019. The median patient age was 68 years (range, 47–83 years), with a marginally higher number of females (57.1%). Among the 44 patients who underwent image evaluation, 13 demonstrated a partial response (29.5%) and 17 presented with stable disease (38.6%). The partial response rate and stable disease rate was 26.5% and 34.7%, respectively, in the intent-to-treat analysis. The median time-to-treatment failure was 5.79 months (95% C.I., 2.63–8.94), progression-free survival was 6.94 months (95% C.I., 5.55–8.33), and overall survival time was 11.53 months (95% C.I., 9.94–13.13). For GSL treatment, the most common grade 3 or worse toxicities were anemia (18.3%), neutropenia (6.1%), nausea (4.1%), and mucositis (4.1%). Treatment discontinuation was mostly due to disease progression (65.3%). Conclusions The modified GSL therapy can be a promising and affordable treatment for patients with advanced and metastatic pancreatic cancer in Taiwan. A prospective trial of modified GSL for elderly patients is currently ongoing in Taiwan.

The objective of this study was to investigate whether human placental multipotent mesenchymal stromal cell (hPMSC)-derived Slit2 and endothelial cell Roundabout (Robo) receptors are involved in placental angiogenesis. The hPMSC-conditioned medium and human umbilical vein endothelial cells were studied for Slit2 and Robo receptor expression by immunoassay and RT-PCR. The effect of the conditioned medium of hPMSCs with or without Slit2 depletion on endothelial cells was investigated by in vitro angiogenesis using growth factor-reduced Matrigel. hPMSCs express Slit2 and both Robo1 and Robo4 are present in human umbilical vein endothelial cells. Human umbilical vein endothelial cells do not express Robo2 and Robo3. The hPMSC-conditioned medium and Slit2 recombinant protein significantly inhibit the endothelial cell migration, but not by the hPMSC-conditioned medium with Slit2 depletion. The hPMSC-conditioned medium and Slit2 significantly enhance endothelial tube formation with increased cumulated tube length, polygonal network number and vessel branching point number compared to endothelial cells alone. The tube formation is inhibited by the depletion of Slit2 from the conditioned medium, or following the expression of Robo1, Robo4, and both receptor knockdown using small interfering RNA. Furthermore, co-immunoprecipitation reveals Slit2 binds to Robo1 and Robo4. Robo1 interacts and forms a heterodimeric complex with Robo4. These results suggest the implication of both Robo receptors with Slit2 signaling, which is involved in endothelial cell angiogenesis. Slit2 in the conditioned medium of hPMSCs has functional effect on endothelial cells and may play a role in placental angiogenesis.

Background: W e investigated the combined impact of abdominal obesity and low skeletal muscle mass on cardiovascular and total mortality in an elderly Asian population. Methods: A total of 1,485 elderly individuals (≥65 years) from Elderly Nutrition and Health Survey in Taiwan (1999–2000) were enrolled, and their survival status was followed using data from the National Death Registry. Skeletal muscle mass index (SMMI) was calculated by dividing skeletal muscle mass (kg) by height squared (m 2 ). Low skeletal muscle mass was defined as the first quartile of SMMI. Abdominal obesity (high triglycerides plus waist circumference [HTGWC]) was defined as triglycerides ≥150 mg/dL and w aist circumference ≥90 cm (men) and ≥80 cm (women). The Cox proportional hazard model was used to evaluate the combined impact of abdominal obesity and low SMMI on cardiovascular and total mortality. Results: During follow -up (median 9.2 years), one third (n = 493) of subjects died from any cause, of which 34% (n = 168) were cardiovascular-related. Total and cardiovascular mortality were 4.2 and 1.4 per 100 person-years, respectively. Low SMMI and HTGWC were independently associated with total mortality in men, but only low SMMI was significantly associated in women. Those with both HTGWC and low SMMI had the highest mortality risk, with the cardiovascular mortality risk increased by >6.8-fold and 3.2-fold in men and women, respectively, compared with controls having normal SMMI and TGWC. Conclusions: Elderly indi viduals with abdominal obesity and low skeletal muscle mass have higher all-cause and cardiovascular mortality risk.

Background and aim Atrial fibrillation (AF) is an important cardiovascular disease in the elderly. The association between hyperuricemia and AF is unclear. Therefore, we aimed to investigate the prospective relationship between uric acid and development of AF in a nationally representative cohort of elderly people. Methods and results A total of 1485 elderly people (age ≥ 65 yrs) from the Elderly Nutrition and Health Survey in Taiwan (1999–2000) were without AF on “electrocardiography” at baseline. Incident AF events (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM: 427.31) were identified using data from the National Health Insurance Dataset. Hyperuricemia was defined as levels of uric acid >7.0 mg/dL in men and 6.0 mg/dL in women. A Cox proportional hazards model was used to evaluate the association between hyperuricemia and incident AF. The follow-up period was from 1999 to 2000 to 2008. During the follow-up period (median: 9.16 yrs), 90 AF events occurred (44 in men and 46 in women). Older age, elevated systolic blood pressure, being an ex-smoker, and high uric acid were positively associated with incident AF. Hyperuricemia was positively associated with incident AF in normotensive (age-adjusted hazard ratio (HR): 2.65 and 95% confidence intervals: 1.05–6.69), but not in (1.20:0.74–1.94) hypertensive individuals (systolic blood pressure ≥130 or diastolic blood pressure ≥85 or using hypertensive medicine). A significant association between hyperuricemia and AF (3.78; 1.24–11.59) remained after adjusting for other potential confounders among normotensive older persons. Conclusion Hyperuricemia is associated with the development of AF in elderly people with normal blood pressure.

Background and aim: Body mass index (BMI) has a U-shaped relationship with mortal- ity among the elderly, in contrast to the general adult population. Skeletal muscle mass may be more appropriate than BMI for classifying mortality risk among the elderly. We investigated the relationship between skeletal muscle mass and mortality among elderly Chinese persons. Method and results: A total of 1512 elderly from the Nutrition and Health Survey in Taiwanese Elderly (1999e2000) was enrolled, and the survival status was followed using data from the Na- tional Death Registry. The skeletal muscle mass index (SMMI) was calculated by dividing skeletal muscle mass by height in meters squared. The Cox proportional hazard model was used to esti- mate the association between SMMI and mortality. During the follow-up (average time: 7.9 years), one-third elderly died (n Z 506) by any cause and 25% of them was cardiovascular mor- tality (ICD-9-CM: between 390 and 459). The total mortality and cardiovascular mortality were 4.23 and 1.07 per 100 person-years. Elderly participants with the lowest SMMI had the highest total mortality and cardiovascular mortality among the four quartiles (6.72, 3.76, 3.25 and 3.50 per 100 PY for total mortality; 1.81, 0.76, 0.87, 0.93 for cardiovascular mortality). Those with a low (1st quartile) SMMI had a 2-fold increase in total mortality (1.96; 1.63e2.35) and cardiovas- cular mortality (2.16; 1.51e3.08) risk compared to those with a normal (2nd, 3rd, or 4th quartile) SMMI. Conclusions: The threshold relationship between SMMI and mortality is contrast to the reverse J- shaped relationship between BMI and total mortality. Therefore, skeletal muscle mass measure- ment may be considered with a high priority to identify elderly individuals with a high mortality risk.

The increased mortality risk of hyperhomocysteinaemia in diabetes may be mitigated by dietary quality.The Nutrition and Health Survey in Taiwan of 1999-2000 for elders formed this prospective cohort. Baseline health status, diet and anthropometry were documented and plasma homocysteine and biomarkers for B vitamins measured. Participants without diabetes (n=985) were referent for those who had diabetes or developed diabetes until 2006 (n=427). The effect of homocysteine on mortality risk during 1999-2008 was evaluated.Men, smokers and those with poorer physical function had higher homocysteine, but less so with diabetes. Diabetes incidence was unrelated to homocysteine. In hyperhomocysteinaemia (=15 vs15 μmol/L), those with diabetes had an adjusted hazard ratio (HR) (95% CI) for mortality of 1.71 (1.18-2.46); p for interaction between homocysteine and diabetes was 0.005. Without diabetes, but with hyperhomocysteinaemia and a low dietary diversity score (DDS=4 of 6), where the joint mortality hazard for the greater DDS, (4) and lower homocysteine (15) was referent, the HR was 1.80 (1.27-2.54) with significant interaction (p=0.008); by contrast, there was no joint effect with diabetes. The contribution of DDS to mortality mitigation in hyperhomocysteinaemia could not be explained by B group vitamins, even though plasma folate was low in hyperhomocysteinaemic participants. With hyperhomocysteinaemia, heart failure was a major cause of death.In non-diabetic hyperhomocysteinaemia, a more diverse diet increases survival prospects independent of B group vitamins, but not in hyperhomocysteinaemic diabetes where the cardiomyopathy may be less responsive.背景與目的：飲食品質可能減輕糖尿病患因高同半胱氨酸血症增加的死亡風 險。方法與研究設計：1999 - 2000 年臺灣老人營養健康狀況調查形成這個前瞻 世代。基線健康狀況、飲食和體位測量被記錄，血漿同半胱氨酸和B 群維生 素生物標記被測量。非糖尿病的參與者（n=985）當作那些已經有糖尿病或至 2006 年期間發生糖尿病者（n=427）之參考組，評估參與者於1999-2008 年間 同半胱氨酸對死亡風險的影響。結果：男性、吸菸者和那些身體生理功能較差 者，有較高的同半胱氨酸，但糖尿病患者並非如此。糖尿病發生率與同半胱氨 酸無關。在高同半胱氨酸寫症患者中（=15 vs15 mol/ L），患有糖尿病者， 其調整後之死亡危害比（HR）及95％信賴區間為1.71（1.18-2.46）；同半胱 氨酸與糖尿病之間的交互作用p 值0.005。非糖尿病患者，以有較高的飲食多 樣性得分（DDS4）及較低的同半胱氨酸血症者為參考組，高同半胱氨酸血 症者加上較低的DDS（=4）的聯合死亡風險更大HR 為1.80 （1.27-2.54）及 顯著的交互作用（p=0.008）；相較之下，對糖尿病並無聯合作用。儘管有高 同半胱氨酸血症的參與者其血漿葉酸濃度較低，DDS 減輕同半胱氨酸血症對 死亡的貢獻並無法被維生素B 群所解釋。心臟衰竭是高同半胱氨酸血症參與 者的主要死因。結論：在非糖尿病的高同半胱氨酸血症患者，無論維生素B 群的狀況，較多樣化的飲食可以增加存活率。但是，對高同半胱氨酸血症的糖 尿病患者，其心肌病變對飲食的反應可能較差。.

The transcription factor glial cells missing 1 (GCM1) regulates trophoblast differentiation and function during placentation. Decreased GCM1 expression is associated with pre-eclampsia, suggesting that abnormal expression of GCM1 target genes may contribute to the pathogenesis of pregnancy complications. Here we identified a novel GCM1 target gene, synapse defective 1 (SYDE1), which encodes a RhoGAP that is highly expressed in human placenta, and demonstrated that SYDE1 promotes cytoskeletal remodelling and cell migration and invasion. Importantly, genetic ablation of murine Syde1 results in small fetuses and placentas with aberrant phenotypes in the placental-yolk sac barrier, maternal-trophoblast interface, and placental vascularization. Microarray analysis revealed altered expression of renin-1, angiotensin I converting enzyme 2, angiotensin II type 1a receptor, and membrane metalloendopeptidase of the renin-angiotensin system in Syde1-knockout placenta, which may compensate for the vascular defects to maintain normal blood pressure. As pregnancy proceeds, growth restriction of the Syde1

STEAP1 (six transmembrane epithelial antigen of the prostate 1) is a transmembrane protein that functions as a potential channel or transporter protein. It is overexpressed in certain cancers and is viewed as a promising therapeutic target. However, the prognostic role of STEAP1 is still controversial, and no role for STEAP1 has yet been indicated in colorectal cancer. The aim of this study was to investigate the possible association of STEAP1 expression with colorectal cancer prognosis. STEAP1 expression was analyzed by immunohistochemical staining of a tissue array of 165 cancer specimens from primary colorectal cancer patients. The mean and medium follow-up times after surgery were 5.1 and 3.9 years, respectively. A total of 139 patients died during the 13 years of follow-up in the survey period. The prognostic value of STEAP1 with respect to overall survival was analyzed by Kaplan-Meier analysis and Cox proportional hazard models. In total, 164 samples displayed detectable STEAP1 expression in the cytoplasm and membrane. Low STEAP1 expression was correlated with poor overall survival (five-year survival: 33.7% vs. 57.0%, low expression vs. high expression, p = 0.020). Accordingly, multivariate analysis identified low STEAP1 expression as an independent risk factor (hazard ratio = 1.500, p = 0.018), especially in elderly patients or those with late stage cancers, late T values, and early N values. We suggest that analysis of STEAP1 expression by immunohistochemical staining could serve as an independent prognostic marker for colorectal patients. This finding should be validated by other investigative groups.

Over the past two decades, studies have widely examined the effectiveness of pay-for-performance (P4P) programs by conducting biochemical tests and assessing complications; however, the reported effectiveness of such programs among participants selected through purposeful sampling is controversial. Therefore, the objective of the current study was to analyze the effectiveness of a P4P program on patients' prognoses, including hospitalization for chronic diabetic complications, and all-cause mortality during specific follow-up years by using a nationwide population-based database in Taiwan. Based on 125,315 newly diagnosed type 2 diabetes patient cohort during 2002-2006, two control sets were designed by propensity-score-matching strategy according to participation of P4P program and followed up to 2012. The results indicated that full participants demonstrated the lowest risks of developing complications and all-cause mortality compared with nonparticipants. These findings confirm the long-term effect of P4P programs on full participants and reveal that this effect is not due to confounding variables. The results indicate the importance of performance management and adherence to interventions for patients with chronic diseases in a long-term observation. Comprehensive and continuous care is suggested to improve patient prognosis and quality of care.

Introduction Population aging is set to increase the elder dependency ratio, causing a rapid increase in healthcare expenditures and financial burden on the government. This study aims to construct an aging score from age-related diseases and to perform longitudinal analyses to examine the association between personal income and aging. Methods A total of 86,838 subjects drawn from a community with 384,617 residents in northern Taiwan were examined. Personal income and aging-related diseases were measured from the National Health Insurance database during 1997–2010. Multiple linear regression and stratified analyses were used. Results Our results indicate that subjects with low personal income (defined as monthly income ≤610 USD) can have high aging scores as calculated by selected aging-related diseases. In stratified analyses, moreover, subjects with low personal income tended to have higher aging scores across different anthropometric groups. The association was particularly evident in subjects >60 years old, and they were noted across multiple strata, including those of catastrophic illness as well as type of primary care setting. Conclusions This study found evidence for association between low income and aging in a population with compulsory health insurance program, where accessibility barriers were low in terms of health care resources and personal socioeconomic status. The economic inequity causes difference in aging process, which deserves for future interventions.

We studied the smooth muscle cell differentiation capability of human placental multipotent mesenchymal stromal cells (hPMSCs) and identified how endothelial cells recruit hPMSCs participating in vessel formation. hPMSCs from term placentas were induced to differentiate into smooth muscle cells under induction conditions and different matrix substrates. We assessed endothelial cells from umbilical veins for platelet-derived growth factor (PDGF)-BB expression and to induce hPMSC PDGFR-beta and STAT3 activation. Endothelial cells were co-cultured with hPMSCs for in vitro angiogenesis. Cell differentiation ability was then further assessed by mouse placenta transplantation assay. hPMSCs can differentiate into smooth muscle cells; collagen type I and IV or laminin support this differentiation. Endothelial cells expressed significant levels of PDGF-BB and activated STAT3 transcriptional activity in hPMSCs. Endothelial cell-conditioned medium induced hPMSC migration, which was inhibited by STAT3 small interfering RNA transfection or by pretreatement with PDGFR-beta-blocking antibody but not by PDGFR-alpha-blocking antibody or isotype immunoglobulin G (IgG; P0.001). hPMSCs can incorporate into endothelial cells with tube formation and promote endothelial cells, forming capillary-like networks than endothelial cells alone (tube lengths: 12 024.1 ± 960.1 vs. 9404.2 ± 584.7 pixels; P0.001). Capillary-like networks were significantly reduced by hPMSCs pretreated with PDGFR-beta-blocking antibody but not by PDGFR-alpha-blocking antibody or isotype IgG (P0.001). Transplantation of hPMSCs into mouse placentas revealed incorporation of the hPMSCs into vessel walls, which expressed alpha-smooth muscle actin, calponin, and smooth muscle myosin (heavy chain) in vivo. In conclusion, endothelial cell-hPMSC interactions occur during vessel development of placenta. Placental endothelial cell-derived PDGF-BB recruits hPMSCs involved in vascular development via PDGFR-beta/STAT3 activation.

Rac GTPase activating protein 1 (RACGAP1) plays a regulatory role in initiation of cytokinesis, control of cell growth and differentiation, and tumor malignancy, making it a potential prognostic biomarker. RACGAP1 is present in the nucleus, but a diffuse distribution in the cytoplasm also occurs. The aim of this study was to determine the impact of nuclear and cytoplasmic expression of RACGAP1 on clinical outcome to provide further evidence of a role in colorectal cancer. RACGAP1 expression was analyzed by immunohistochemistry in 166 cancer specimens from primary colorectal cancer patients. The mean follow-up time after surgery was 5.4 years (range, 0.01-13.10 years). The prognostic value of RACGAP1 on overall survival was validated by Kaplan-Meier analysis and Cox regression models. RACGAP1 is expressed in colorectal specimen and is present in both the nucleus and cytoplasm in different amounts. Colorectal cancer patients had opposite prognoses depending on the site of RACGAP1 expression. Patients with high nuclear RACGAP1 expression had poor outcomes, whereas those with high cytoplasmic RACGAP1 expression had favorable prognosis (P = .003 and P = .001, respectively). Patients with low nuclear but high cytoplasmic RACGAP1 expression had better survival compared with those with other combinations (P < .001). We suggest that RACGAP1 expression levels in the nucleus and cytoplasm, determined by immunohistochemical staining, predict opposite clinical outcomes and that both could be independent prognostic markers for colorectal cancer.

Background Many studies have investigated the association between markers for peripheral inflammation and risk of dementia, but the results have been conflicting. We aimed to evaluate the association between a specific inflammation marker, C-reactive protein (CRP), and dementia in an elderly Asian community cohort. Methods The cohort included 1436 individuals (ages 65 and older) from a national representative sample in Taiwan. Dementia incidence was identified using International Classification of Diseases , Ninth Revision codes for vascular dementia, Alzheimer disease, and nonvascular dementia. Baseline characteristics and CRP levels were determined. A Cox proportional hazard model and Fine and Grays model were adjusted for stroke and competing risk of death to estimate the association between inflammation and development of dementia. Results During 11.04 years (median) of follow-up, 607 individuals (50.77%) died and 260 individuals (18.11%) were diagnosed with dementia. Those with high CRP had a 55% higher risk of dementia (hazard ratio 1.55; 95% confidence interval 1.21–2.00) compared with those with normal CRP. After adjusting for possible confounding cardiovascular risk factors, high CRP was independently associated with vascular dementia but not Alzheimer disease. Conclusions In this prospective study of an elderly Asian community cohort with more than 10 years of follow-up, the baseline serum CRP level was associated with future development of vascular dementia, but not Alzheimer disease after adjusting for common cardiovascular risk factors, stroke, and competing risk of death.

To establish whether elderly people with impaired cognition are at greater risk for the de-velopment of type 2 diabetes.Prospective population-based cohort study.The El-derly Nutrition and Health Survey in Taiwan (NAHSIT Elderly).One thousand and four hundred ninety-three diabetes-free people=65 years were followed for incident diabetes in relation to cognitive status for up to 8 years.The association between cognitive impairment and diabetes incidence was analyzed with Cox proportional hazards models with exclusion of people who had diabetes within one year of cognitive function assessments.Cognitively-impaired women, but not men, had increased diabetes incidence density (DID). Age, gender, ethnicity and personal behavior adjusted hazard ratios (HR) and 95% confidence intervals (CI) for type 2 diabetes with normal cognition as referent were 2.43 (95% CI: 1.27-4.63) for women and 1.55 (95% CI: 0.48-5.07) for men. These gender differences and the HR significances remained with adjustments for age, ethnicity, financial status, dietary quality as a dietary diversity score, physical function, physical activity, fasting glucose, indices of body composition, body mass index, waist circumference, mid-arm muscle circumference, perceived and mental health status. There were extensive significant interactions with the covariates in women.Cognitive impairment in later life is associated with greater risk of type 2 diabetes in women and considerable potential risk enhancement.已有研究發現患有糖尿病的老人易發生認知功能障礙，對於患有認知功能障 礙的老人是否更易發生糖尿病，也就是老人糖尿病和認知功能障礙發生是否 存在雙向性影響，目前不可知。本研究的目的為觀察患有認知功能障礙的老 人是否更容易發生糖尿病。以參與1999-2000 年臺灣老人營養和健康調查中 1493 位年齡超過65 歲，且沒有糖尿病的老人為研究對象，追蹤8 年，研究糖 尿病發生率和認知功能的關係。認知功能障礙和糖尿病的發生率以Cox 比例 風險迴歸模型來分析。結果發現有認知功能障礙的女性其糖尿病發生率顯著 提高，但在男性中沒有觀察到這樣的結果。以正常認知功能組做為參照組， 在校正年齡，性別，種族和個人行為之後，認知功能障礙老年女性二型糖尿 病風險比值(HR)為2.43 (95%信賴區間: 1.27-4.63)，男性為1.55 (95%信賴區間: 0.48-5.07)。在分別校正年齡，種族，個人行為和經濟狀況，飲食品質，身體 活動功能，運動，空腹血糖值，身體質量指數，腰圍及中臂肌圍等可能影響 糖尿病發生的變數後，性別差異和風險比顯著性仍然存在。在女性中，上述 共變數對糖尿病的發生存在顯著交互作用。飲食品質差及少運動，會增加認 知功能障礙老年女性患糖尿病的風險比。

Background: Oral health is crucial to individual growth and development. However, oral health care is often overlooked in children with special health care needs (CSHCN). We investigated current oral health status and unmet dental needs of CSHCN in Taiwan. Methods: We performed a retrospective study of consecutive CSHCN cases receiving first-time comprehensive dental treatment under general anesthesia at Taipei Veterans General hospital from 2001 to 2010. We retrieved clinical data including age, sex, types, and severity of disability, caries experience index [decayed, extracted, and filled teeth (deft) index for primary dentition/decayed, missing, and filled teeth (DMFT) index for permanent dentition], malocclusion, and treatment modalities from medical charts for analysis. The correlation between different groups of CSHCN regarding the deft/DMFT indices and treatment modalities was analyzed statistically. Results: Our study included 96 children, ranging in age from 2.4 years to 14.3 years (mean age 6.8 ± 3.3 years). The deft/DMFT index was significantly higher in the younger age group (2–6 years; 13.8 ± 4.3) compared with the older group (> 6 years; 10.5 ± 5.3; p

To examine the significance of underweight and physical function as well as their interaction on mortality in the aged.Prospective cohort.The Elderly Nutrition and Health Survey in Taiwan during 1999-2000.Total of 1435 representative free-living elders (739 men and 696 women).Body composition was assessed by various anthropometrics. Physical function score (PF, ranged 0-100) was derived from the SF-36(®). Death by December 31, 2006 was the outcome measure.After 7.9 (median: 7.0) years follow-up, 381 (223 men, 158 women) of 1435 eligible participants had died. Those with the lowest PF (45) had 3.43 (hazards ratio (HR), 95% confidence interval (CI) = 2.20-5.36) times the all-cause mortality risk of the highest PF (≥58). Interactions for PF and BMI (P =0.02) and for PF and wrist circumference (P =0.09) on death were found after controlling for potential confounders. Jointly, compared to normal-BMI-highest-PF, the greatest HR for death occurred where BMI18.5 kg/m2 was combined with the lowest-PF after covariate adjustments (HR = 8.67, 95% CI = 3.77-20.0). Similarly, the lowest arm muscle circumference (MAMC)-PF had a HR of 5.22 compared to mid-MAMC-highest-PF. However, percent and absolute body fat, estimated by bioelectrical impedance, was comparable to non-sarcopenic individuals.Thin elderly Taiwanese with sarcopenia, and less skeleton, are at the most risk of death, especially if physical function is limited.

The X-linked DEAD-box RNA helicase DDX3 (DDX3X) is a multifunctional protein that has been implicated in gene regulation, cell cycle control, apoptosis, and tumorigenesis. However, the precise physiological function of Ddx3x during development remains unknown. Here, we show that loss of Ddx3x results in an early post-implantation lethality in male mice. The size of the epiblast marked by Oct3/4 is dramatically reduced in embryonic day 6.5 (E6.5) Ddx3x-/Y embryos. Preferential paternal X chromosome inactivation (XCI) in extraembryonic tissues of Ddx3x heterozygous (Ddx3x-/+) female mice with a maternally inherited null allele leads to placental abnormalities and embryonic lethality during development. In the embryonic tissues, Ddx3x exhibits developmental- and tissue-specific differences in escape from XCI. Targeted Ddx3x ablation in the epiblast leads to widespread apoptosis and abnormal growth, which causes embryonic lethality in the Sox2-cre/+;Ddx3xflox/Y mutant around E11.5. The observation of significant increases in γH2AX and p-p53Ser15 indicates DNA damage, which suggests that loss of Ddx3x leads to higher levels of genome damage. Significant upregulation of p21WAF1/Cip1 and p15Ink4b results in cell cycle arrest and apoptosis in Ddx3x-deficient cells. These results have uncovered that mouse Ddx3x is essential for both embryo and extraembryonic development.

Microvascular free flap transfer for post-oncologic reconstructive surgery in oral cancer is considered to be a challenge due to the complexity of the anatomy and function of the region. We sought to identify possible factors associated with microsurgical complications and to assess the impact of these complications in relation to patient survival. Following the inclusion and exclusion protocol, 142 patients with stage III and IV oral squamous cell carcinoma (OSCC) who underwent immediate free flap reconstruction after tumor ablation were included in the study. Clinical and surgical procedural-related factors were retrieved from a database and analyzed retrospectively; survival data were evaluated using the Kaplan-Meier method. Major complications that required re-anastomosis of the flap vessels occurred in 23 patients (16.2%); total necrosis of the flaps, regardless of salvage treatment, occurred in seven cases, with 95.1% of full flap survival. The American Society of Anesthesiologists classification, types of neck dissection, and number of flaps were regarded as strong predictors for surgical complications. Patients with these complications appeared to have a shortened survival (5-year cancer-specific survival of approximately 60%, both in stage III and IV OSCC). However, the impact of surgical complications on survival was significant only in stage III OSCC (P = 0.037). Strategies to minimize surgical complications should be used to ensure better prognoses for these patients.

Background Little is known about health care costs associated with the metabolic syndrome (MetS). Objective We assessed annualized health care costs and health outcomes for both genders in different health care settings among representative Taiwanese elders. Methods The Nutrition and Health Survey in Taiwan (1999–2000) provided 1378 individuals aged 65 years or older with known MetS status. Nutrition and Health Survey in Taiwan files were linked to National Health Insurance records (1999–2006). Student t tests and multiple regression models were used to assess expenditures in total and in 6 services: inpatient, ambulatory care, dental care, traditional Chinese medicine, emergency care, and contracted pharmacy. The Cox model was used to assess gender effect on all-cause mortality and cardiovascular disease mortality, whereas logistic regression was used for that on cardiovascular disease hospitalization. The 5 MetS component costs were evaluated by multiple regressions. Results MetS affected 29% of men and 48% of women. After full adjustment, those with MetS had 1.30 (95% CI, 1.11–1.52), men had 1.43 (95% CI, 1.20–1.70), and women had 1.19 (95% CI, 0.93–1.52) times higher costs than those without MetS. Compared with no MetS, MetS costs were increased 2.94-fold for inpatient care (95% CI, 1.23–7.10) and 1.30-fold for ambulatory care for men (95% CI, 1.12–1.52), whereas ambulatory MetS costs were increased 1.28-fold for women (95% CI, 1.05–1.57). MetS was associated with higher risk of cardiovascular disease hospitalization in men (adjusted odds ratio, 1.76; 95% CI, 1.20–2.58) but not in women (adjusted odds ratio, 1.08; 95% CI, 0.67–1.75). Among those with MetS, all-cause and cardiovascular mortality were comparable between men and women. Of the MetS components, low HDL cholesterol had the greatest affect on costs, more so in men (2.23-fold) than women (1.58-fold). Conclusions In people with MetS, service costs were greater overall, significantly for men, but not women, and these increased costs were evident for men who experienced hospitalization, but not women. At the same time, cardiovascular and all-cause mortalities were not significantly different by gender in regard to MetS in Taiwanese elders.

Hyperhomocysteinemia and cognitive impairment both predict mortality and partly because of dietary associations. We have hypothesized that for, nutritional reasons, homocysteine and cognition may act jointly to determine elder survival. In a Nutrition and Health Survey in Taiwan (1999-2000), some 1412 representative elderly were followed up for mortality up to 10 years. Cognition was assessed by the Short Portable Mental Status Questionnaire. Food and B vitamin intakes with their biomarkers, and plasma homocysteine, were measured at baseline. The possible effects of cognition on homocysteine-associated mortality were ascertained with Cox proportional-hazards models. Homocysteine was higher in those who were older, male, and single, consumed less fish and tea, and with alcohol and smoking. In models adjusted for these variables, when homocysteine exceeded 14.5 μmol/L, mortality was 1.80-fold more than when

ObjectiveTo investigate the association between cooking behaviour and long-term survival among elderly Taiwanese.DesignCohort study. The duration of follow-up was the interval between the date of interview and the date of death or 31 December 2008, when censored for survivors. Information used included demographics, socio-economic status, health behaviours, cooking frequencies, physical function, cognitive function, nutrition knowledge awareness, eating out habits and food and nutrient intakes. These data were linked to death records. Cox proportional-hazards models were used to evaluate cooking frequency on death from 1999 to 2008 with related covariate adjustments.SettingElderly Nutrition and Health Survey in Taiwan, 1999–2000.SubjectsNationally representative free-living elderly people aged ≥65 years (n 1888).ResultsDuring a 10-year follow-up, 695 participants died. Those who cooked most frequently were younger, women, unmarried, less educated, non-drinkers of alcohol, non-smokers, without chewing difficulty, had spouse as dinner companion, normal cognition, who walked or shopped more than twice weekly, who ate less meat and more vegetables. Highly frequent cooking (>5 times/week, compared with never) predicted survival (hazard ratio (HR) = 0·47; 95 % CI, 0·36, 0·61); with adjustment for physical function, cognitive function, nutrition knowledge awareness and other covariates, HR was 0·59 (95 % CI, 0·41, 0·86). Women benefited more from cooking more frequently than did men, with decreased HR, 51 % v. 24 %, when most was compared with least. A 2-year delay in the assessment of survivorship led to similar findings.ConclusionsCooking behaviour favourably predicts survivorship. Highly frequent cooking may favour women more than men.

Background Active ageing is a key to healthy ageing; shopping behaviour is an economically relevant activity of the elderly. Methods Analysis was based on the NAHSIT 1999–2000 dataset. A total of 1841 representative free-living elderly Taiwanese people were selected and information included demographics, socioeconomic status, health behaviours, shopping frequencies, physical function and cognitive function. These data were linked to official death records. Cox proportional hazard models were used to evaluate shopping frequency on death from 1999–2008 with possible covariate adjustment. Results Highly frequent shopping compared to never or rarely predicted survival (HR 0.54, 95% CI 0.43 to 0.67) with adjustment for physical function and cognitive function and other covariates HR was 0.73 (95% CI 0.56 to 0.93). Elderly who shopped every day have 27% less risk of death than the least frequent shoppers. Men benefited more from everyday shopping than women with decreased HR 28% versus 23% compared to the least. Conclusion Shopping behaviour favourably predicts survival. Highly frequent shopping may favour men more than women. Shopping captures several dimensions of personal well-being, health and security as well as contributing to the community9s cohesiveness and economy and may represent or actually confer increased longevity.

Reactive oxygen species may cause oxidative damage in the placenta, yet some mechanisms must exist to reduce or prevent such damage. We investigated whether oxidative injury to placental endothelial cells is inhibited by activation of antioxidant enzymes by paracrine factors secreted by human placental multipotent mesenchymal stromal cells (hPMSC). hPMSC-conditioned medium and umbilical endothelial cells were assayed for cytokines and cytokine receptor expression by immunoassay and real-time PCR. Endothelial cell survival was evaluated by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay and caspase 3 activity assay. tert-Butyl hydroperoxide was used to induce oxidative injury in endothelial cells, with fluorescent microscopy and flow cytometry used to detect intracellular peroxides and cell apoptosis. Western blot, real-time PCR, STAT3 DNA-binding activity assay, and STAT3 siRNA were used to assess endothelial cell antioxidant enzymes. hPMSC-conditioned medium supported endothelial cell survival and reduced endothelial cell intracellular peroxides and apoptosis. hPMSCs expressed the transcripts of the interleukin (IL) 6 cytokine family, including IL6 and leukemia-inhibitory factor. hPMSC-conditioned medium activated STAT3 expression in endothelial cells, which was inhibited by neutralizing antibody to interleukin 6 signal transducer (IL6ST) but not to IL6 or leukemia-inhibitory factor. STAT3 siRNA or manganese superoxide dismutase (SOD2) siRNA transfected into endothelial cells inhibited the antiapoptotic effect of conditioned medium. SOD2 was significantly upregulated in endothelial cells by conditioned medium via STAT3 activation that, in turn, was inhibited by IL6ST-neutralizing antibody or STAT3 siRNA. Paracrine factors secreted by hPMSCs support endothelial cell survival. STAT3 activation and SOD2 production protect against oxidative stress-induced endothelial cell damage.

BACKGROUND: Human placental mesenchymal stem cells (hPMCs) are thought to be multipotent, but their fate after in utero transplantation is not known. METHODS: hPMCs isolated from term placenta were assessed for their phenotype markers, mutilineage capacity, and immunomodulatory properties. Their engraftment potential was analyzed in a pregnant rat model after in utero transplantation at embryonic day 17. Immunohistochemistry, tracing of labeled cells, fluorescence in situ hybridization and real-time PCR were used to assess post-transplant chimerism. RESULTS: In vitro, lineage-negative, CD34-negative hPMCs differentiated into osteocytes, adipocytes, hepatocytes and endothelial cells with tube formation, and actively suppressed the rat lymphocyte proliferative response to allogeneic lymphocyte stimulation (P < 0.0001). After in utero transplantation into pregnant rats, a low level of engraftment was achieved in various fetal tissues. Engraftment occurred in more than 60% of the fetal rats. Cells persisted for at least 12 weeks after delivery and evidence was obtained to suggest differentiation into specific lineages, including hepatocytes and hematopoietic cells. However, a greater number of hPMCs migrated to the placenta than to the fetus, thus limiting the degree of cell engraftment in fetal organs. CONCLUSIONS: We conclude that hPMCs are mutipotent cells that can be engrafted long-term in immunocompetent rats after in utero transplantation.

Fusion of cytotrophoblasts into the multinucleated syncytiotrophoblast layer is essential for the development of a functional placenta. The envelope protein of a human endogenous retrovirus W (HERV-W) family member, syncytin 1, has been shown to mediate placental cell fusion. Recently, the envelope protein of another HERV family member (HERV-FRD), syncytin 2, has been identified and shown to be highly expressed in the placenta. To better understand the biology of syncytin 2, in this study we first investigated syncytin 2 gene expression in normal and preeclamptic placentas and then characterized the functions of syncytin 2. The expression of syncytin 2 gene was decreased in preeclamptic placentas and could be stimulated by the cAMP stimulant forskolin. The endoprotease furin was found to be involved in the posttranslational cleavage of syncytin 1 and 2 polypeptides into surface and transmembrane subunits. In addition, proper association of the subunits of syncytins 1 and 2 is probably required for the functional integrity of each protein, because subunit swapping of syncytins 1 and 2 failed to generate fusogenic chimeras. Finally, we demonstrated that the disulfide bridge-forming CX(2)C and CX(7)C motifs found in syncytins 1 and 2 are essential for their fusogenic activities, because mutations in the CX(2)C motif not only abolished fusogenesis but also functioned as dominant-negative mutants. Our results suggest that syncytin 2 may function as a second fusogenic protein for placental cell fusion.

Villous fibrosis is associated with oxygen deprivation in placental pathology, but the signaling networks and growth factors involved in activating the relevant cellular repair mechanisms are largely unknown. TGF is a powerful enhancer of extracellular matrix (ECM) production and an important immune suppressor that has been linked with fibrosis in several tissues. Here, cell culture methods were used to investigate possible links between hypoxia, elevated TGF beta 1, and altered ECM production in placenta. Term placental fibroblasts were isolated and cultured under hypoxia (3% O(2)) or in the presence of TGF beta 1, and the expression of fibronectin, collagen I, and collagen IV was examined using immunohistochemistry, ELISA of cell monolayers with associated ECM, and real-time RT-PCR. The effect of hypoxia on endogenous production of TGF beta 1-3 was also examined. Both TGF beta 1 and hypoxia increased fibronectin, collagen I, and collagen IV protein and mRNA in placental fibroblasts. However, TGF beta 1-3 production was not increased by culturing the cells under hypoxic conditions for 5 d. Thus, increased ECM expression under hypoxia was not mediated directly by increased TGF beta. We conclude that ECM production can be stimulated independently by hypoxia and TGF beta 1.

Human placental multipotent mesenchymal stromal cells (hPMSCs) can be isolated from term placenta, but their angiogenic ability and the regulatory pathways involved are not known. hPMSCs were shown to express integrins alpha(v), alpha(4), alpha(5), beta(1), beta(3), and beta(5) and could be induced to differentiate into cells expressing endothelial markers. Increases in cell surface integrins alpha(5) and beta(1), but not alpha(4), alpha(v)beta(3), or alpha(v)beta(5), accompanied endothelial differentiation. Vascular endothelial growth factor-A augmented the effect of fibronectin in enhancing adhesion and migration of differentiated hPMSC through integrin alpha(5)beta(1), but not alpha(v)beta(3) or alpha(v)beta(5). Formation of capillary-like structures in vitro from differentiated cells was inhibited by pre-treatment with function-blocking antibodies to integrins alpha(5) and beta(1). When hPMSCs were seeded onto chick chorioallantoic membranes (CAM), human von Willebrand factor-positive cells were observed to engraft in the chick endothelium. CAMs transplanted with differentiated hPMSCs had a greater number of vessels containing human cells and more incorporated cells per vessel compared to CAMs transplanted with undifferentiated hPMSCs, and overall angiogenesis was enhanced more by the differentiated cells. Function-blocking antibodies to integrins alpha(5) and beta(1) inhibited angiogenesis in the CAM assay. These results suggest that differentiated hPMSCs may contribute to blood vessel formation, and this activity depends on integrin alpha(5)beta(1).

Objective This study evaluated the direct and interactive effects of regional-level and individual-level characteristics on methadone maintenance treatment (MMT), after considering the individual characteristics in Taiwan. Methods This study utilized a survey research method. Opioid-dependent patients who participated in the outpatient MMT program in 2009 and met the eligibility criteria were recruited from five hospitals. The impact of MMT on self-perceived health was assessed by using questionnaires. This study assessed the participants' quality of life and treatment outcomes during 3-month follow-up visits, before evaluating the direct effects of regional and individual characteristics. Multilevel linear models were used to estimate whether regional levels influenced individual behavior and treatment outcomes. Results Three hundred thirty-four opioid-dependent patients agreed to participate in this study. After the follow-up period, 127 participants completed the study (completion rate=38%). Participants receiving MMT demonstrated significant improvements in psychological state, HIV risk-taking behavior, social functioning, and health. Regional characteristics, such as the lower than junior high school rate, low-income family rate, and related crime rates, of the study regions were negatively associated with improvements in drug abuse behavior. Conclusions This study shows that MMT can significantly improve the HIV risk-taking behavior and health of the study participants. Disadvantaged regions, however, exhibit poor treatment outcomes. This study suggests actions to minimize the treatment variations between regions.