The relatively high toughness, high adhesion to steel, and low internal stress of hydrogenated amorphous carbon (a-C:H) films containing Ag make them good candidate materials for various applications in sensors, tribology, and biomaterials; however, the relatively low hardness and poor tribological properties in oxidizing environments hinder their broad use. Incorporating a small amount of Si in Ag/a-C:H films may modify the film microstructure and, in turn, improve their mechanical and tribological properties. To test this hypothesis, Ag/Si/a-C:H films were synthesized by magnetron sputtering and their microstructure, composition, and mechanical/tribological properties were examined with various microanalysis techniques and mechanical testing methods. The Si content of the films was varied by controlling the rotational speed of the substrate. It is shown that the incorporation of Si in the films increases the sp 3 C, sp 3 CH, and sp 3 CH2 contents, slightly roughens the film surface, and greatly improves the mechanical and tribological properties through the formation of a SiC phase. The results of this study also show that there is a critical Si content for optimal tribological properties.

To investigate the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD-MRI) in evaluating human subcutaneous and visceral adipose tissue (AT) oxygenation status, as well as their responses to dietary salt loading/depletion, we enrolled 16 healthy subjects [mean body mass index (BMI): 24.8 ± 2.7 kg/m(2)] to conduct a dietary intervention study, beginning with a 3-day run-in period for usual diet, followed by a 7-day high-salt diet (≥ 15 g NaCl/day) and a 7-day low-salt diet (≤ 5 g NaCl/day). Abdominal BOLD-MRI scan was performed to evaluate oxygenation in waist subcutaneous and perirenal (visceral) AT. Two subjects with lower BMI were excluded because of the difficulty to identify subcutaneous AT. High salt diet led to a consistent increase in R2* signal (a parameter for increased hypoxia) both in subcutaneous and visceral AT (all P < 0.0001), which was completely regressed to baseline levels by low salt diet. In addition, subcutaneous AT R2* values at any time points, were all higher than that of visceral AT (all P < 0.0001). Pearson correlation analysis revealed that the visceral AT R2* levels were negatively associated obesity indicators (waist circumference, waist-to-hip ratio and BMI). On the contrary, although a trend towards negative associations between the subcutaneous AT R2* and obesity indicators was observed, none of the associations reached statistical significances. Thus, our data demonstrate the possibility of simultaneous detection of human subcutaneous and visceral AT oxygenation status using BOLD-MRI. In addition, there is a more close relationship visceral AT oxygenation status and the development of obesity.

The Dispatched protein, which is related to the NPC1 and PTCH1 cholesterol transporters^1,2 and to H⁺-driven transporters of the RND family^3,4, enables tissue-patterning activity of the lipid-modified Hedgehog protein by releasing it from tightly -localized sites of embryonic expression^5-10. Here we determine a cryo-electron microscopy structure of the mouse protein Dispatched homologue 1 (DISP1), revealing three Na⁺ ions coordinated within a channel that traverses its transmembrane domain. We find that the rate of Hedgehog export is dependent on the Na⁺ gradient across the plasma membrane. The transmembrane channel and Na⁺ binding are disrupted in DISP1-NNN, a variant with asparagine substitutions for three intramembrane aspartate residues that each coordinate and neutralize the charge of one of the three Na⁺ ions. DISP1-NNN and variants that disrupt single Na⁺ sites retain binding to, but are impaired in export of the lipid-modified Hedgehog protein to the SCUBE2 acceptor. Interaction of the amino-terminal signalling domain of the Sonic hedgehog protein (ShhN) with DISP1 occurs via an extensive buried surface area and contacts with an extended furin-cleaved DISP1 arm. Variability analysis reveals that ShhN binding is restricted to one extreme of a continuous series of DISP1 conformations. The bound and unbound DISP1 conformations display distinct Na⁺-site occupancies, which suggests a mechanism by which transmembrane Na⁺ flux may power extraction of the lipid-linked Hedgehog signal from the membrane. Na⁺-coordinating residues in DISP1 are conserved in PTCH1 and other metazoan RND family members, suggesting that Na⁺ flux powers their conformationally driven activities.

Objectives

To examine the long-term prevalence and predictors of weekly urinary incontinence in the Diabetes Prevention Program Outcomes Study, a follow-up study of the Diabetes Prevention Program randomized clinical trial of overweight adults with impaired glucose tolerance.

Methods

This analysis included 1778 female participants of the Diabetes Prevention Program Outcomes Study who had been randomly assigned during the Diabetes Prevention Program to intensive lifestyle intervention (n = 582), metformin (n = 589) or placebo (n = 607). The study participants completed semi-annual assessments after the final Diabetes Prevention Program visit and for 6 years until October 2008.

Results

At the study entry, the prevalence of weekly urinary incontinence was lower in the intensive lifestyle intervention group compared with the metformin and placebo groups (44.2% vs 51.8%, 48.0% urinary incontinence/week, P = 0.04); during the 6-year follow-up period, these lower rates in intensive lifestyle intervention were maintained (46.7%, 53.1%, 49.9% urinary incontinence/week; P = 0.03). Statistically adjusting for urinary incontinence prevalence at the end of the Diabetes Prevention Program, the treatment arm no longer had a significant impact on urinary incontinence during the Diabetes Prevention Program Outcomes Study. Independent predictors of lower urinary incontinence during the Diabetes Prevention Program Outcomes Study included lower body mass index (odds ratio 0.988, 95% confidence interval 0.982-0.994) and greater physical activity (odds ratio 0.999, 95% confidence interval 0.998-1.000) at the Diabetes Prevention Program Outcomes Study entry, and greater reductions in body mass index (odds ratio 0.75, 95% confidence interval 0.60-0.94) and waist circumference (odds ratio 0.998, 95% confidence interval 0.996-1.0) during the Diabetes Prevention Program Outcomes Study. Diabetes was not significantly related to urinary incontinence.

Conclusions

Intensive lifestyle intervention has a modest positive and enduring impact on urinary incontinence, and should be considered for the long-term prevention and treatment of urinary incontinence in overweight/obese women with glucose intolerance.

Aim

To examine the therapeutic/preventive potential of liposome-encapsulated spironolactone (SP; Lipo-SP) for acute lung injury (ALI) and fibrosis.

Materials & methods

Lipo-SP was prepared by the film-ultrasonic method, and physicochemical and pharmacokinetic characterized for oral administration (10 and 20 mg/kg for SP-loaded liposome; 20 mg/kg for free SP) in a mouse model bleomycin-induced ALI.

Results

Lipo-SP enhanced bioavailability of SP with significant amelioration in lung pathology. Mechanistically, SP-mediated mineralocorticoid receptor antagonism contributes to inflammatory monocyte/macrophage modulation via an inhibitory effect on Ly6C(hi) monocytosis-directed M2 polarization of alveolar macrophages. Moreover, Lipo-SP at lower dose (10 mg/kg) exhibited more improvement in body weight gain.

Conclusion

Our data highlight Lipo-SP as a promising approach with therapeutic/preventive potential for ALI and fibrosis.

Ent-kaurane diterpene compounds have attracted considerable attention in recent years due to its antitumor, antibacterial, and antiviral activities. However, the clinical development of natural kaurane diterpenes, for example, oridonin for cancer therapy has been hampered by its relatively moderate potency, limited bioavailability. Herein, we report a newly synthetic analog of natural ent-kaurane diterpene, DS2, which exhibits significantly improved activity of antiproliferation against various cancer cell lines relative to oridonin. DS2 treatment triggers the mitochondria-mediated apoptosis and cell cycle arrest in human esophageal cancer cell lines (EC9706, EC109). Interestingly, normal human esophageal epithelial cells (HEECs) and normal human liver cells (HL-7702) are both significantly more resistant to the growth inhibition by DS2 compared with esophageal cancer cells. The DS2-induced apoptosis in EC9706 cells correlated with the drop of mitochondrial membrane potential (MMP), release of cytochrome c into the cytosol and activation of caspase-9 and -3. The induction of proapoptotic proteins p21 and Bax were also observed in DS2-treated cells. The DS2-induced apoptosis was significantly attenuated by knockdown of Bax proteins. Meanwhile, the DS2 treatment caused generation of reactive oxygen species (ROS) in human esophageal cancer cells, but not in HEECs, which was attenuated by pretreatment with ROS scavenger N-acetylcysteine (NAC). More interestingly, the antioxidants pretreatment completely attenuated DS2 mediated loss of the MMP and apoptosis, as well as Bax expression and growth inhibition. In conclusion, the present study reveals that the mitochondria-mediated cell death by DS2 is associated with Bax regulation and ROS generation, and understanding the function and mechanism of DS2 will help us to design better anti-cancer drugs.

In experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing and to atherosclerotic plaque destabilization. In humans, the prognostic role of monocyte subsets in patients suffering ST-elevation MI (STEMI) is still unclear. In the present study, we aimed to determine the kinetics of the 3 monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes), as well as the subset-specific monocyte-platelet aggregates (MPA), in acute STEMI followed by primary percutaneous coronary intervention (PCI), and their relationships with cardiovascular outcomes during a 2-year follow-up.Monocyte subsets and MPA were measured in 100 STEMI patients receiving primary PCI on days 1, 2, 3, 5, and 7 of symptom onset, which were compared with 60 stable coronary heart disease patients and 35 healthy volunteers. From day 1 to day 7, significant increases in the counts of CD14++CD16+ monocytes and CD14++CD16+ MPA were observed, with peak levels on day 2. During a median follow-up of 2.0 years, 28 first cardiovascular events (defined as cardiovascular death, nonfatal ischemic stroke, recurrent MI, need for emergency or repeat revascularization, and rehospitalization for heart failure) were recorded. After adjustment for confounders, CD14++CD16+ monocytosis (day 1 [HR: 3.428; 95% CI: 1.597-7.358; P = 0.002], day 2 [HR: 4.835; 95% CI: 1.106-21.13; P = 0.04], day 3 [HR: 2.734; 95% CI: 1.138-6.564; P = 0.02], and day 7 [HR: 2.647; 95% CI: 1.196-5.861; P = 0.02]), as well as increased levels of CD14++CD16+ MPA measured on all time points (days 1, 2, 3, 5, and 7), had predictive values for adverse cardiovascular events.In conclusion, our data show the expansion of the CD14++CD16+ monocyte subset during acute phase of STEMI has predictive values for 2-year adverse cardiovascular outcomes in patients treated with primary PCI. Future studies will be warranted to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies after STEMI.

Coronary artery disease (CAD) is more frequent among individuals with dysglycemia. Preventive interventions for diabetes can improve cardiometabolic risk factors (CRFs), but it is unclear whether the benefits on CRFs are similar for individuals at different genetic risk for CAD. We built a 201-variant polygenic risk score (PRS) for CAD and tested for interaction with diabetes prevention strategies on 1-year changes in CRFs in 2,658 Diabetes Prevention Program (DPP) participants. We also examined whether separate lifestyle behaviors interact with PRS and affect changes in CRFs in each intervention group. Participants in both the lifestyle and metformin interventions had greater improvement in the majority of recognized CRFs compared with placebo (P < 0.001) irrespective of CAD genetic risk (P _interaction > 0.05). We detected nominal significant interactions between PRS and dietary quality and physical activity on 1-year change in BMI, fasting glucose, triglycerides, and HDL cholesterol in individuals randomized to metformin or placebo, but none of them achieved the multiple-testing correction for significance. This study confirms that diabetes preventive interventions improve CRFs regardless of CAD genetic risk and delivers hypothesis-generating data on the varying benefit of increasing physical activity and improving diet on intermediate cardiovascular risk factors depending on individual CAD genetic risk profile.

Sex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP). This is a secondary analysis from the DPP (1996-2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years. ILS resulted in significantly higher increases (postmenopausal women: p<0.01) or smaller decrements (men: p<0.05; premenopausal women: p<0.01) in SHBG compared with placebo or metformin. Changes in SHBG were primarily attributable to changes in adiposity. There were no consistent associations of change in SHBG with the risk of diabetes by treatment arm or participant group. Lifestyle intervention may be associated with favorable changes in circulating SHBG, which is largely due to changes in adiposity. Changes in circulating SHBG do not independently predict reductions in diabetes incidence.