Postabsorptive and postprandial myofibrillar protein synthesis rates at rest and after resistance exercise in women with post-menopause.

Feeding and resistance exercise stimulate myofibrillar protein synthesis rates (MPS) in healthy adults. This anabolic characterization of 'healthy adults' has been namely focused on males. Therefore, the purpose of this study was to examine the temporal responses of MPS and anabolic signaling to resistance exercise alone or combined with the ingestion of protein in post-menopausal females and compare postabsorptive rates with young females. Sixteen females (60 ± 7 y; BMI = 26 ± 12 kg·m-2) completed an acute bout of unilateral resistance exercise before consuming either: a fortified whey protein supplement (WHEY) or water. Participants received primed continuous infusions of L-[ring-13C6]phenylalanine with bilateral muscle biopsies before and after treatment ingestion at 2 h and 4 h in non-exercised and exercised legs. Resistance exercise transiently increased MPS above baseline at 0-2 h in the water condition (P = 0.007). Feeding after exercise resulted in a late phase (2-4 h) increase in MPS in the WHEY condition (P = 0.005). In both conditions, exercise did not enhance the cumulative (0-4 h) MPS response. In the non-exercised leg, MPS did not differ at 0-2 h, 2-4 h, or 0-4 h of the measurement periods (all, P > 0.05). Likewise, there were no changes in the phosphorylation of p70S6K, AMPKα, or total and phosphorylated yes-associated protein on Ser127. Post-absorptive MPS were lower in pre-menopausal vs. post-menopausal females (P = 0.023). We show that resistance exercise-induced changes in MPS are temporally regulated, but do not result in greater cumulative (0-4 h) MPS in post-menopausal women.

Relationship between overweight and obesity and insufficient micronutrient intake: a nationwide study in Taiwan.

The aim of the present study is to examine whether overweight or obese people in Taiwan have an inadequate intake of selected micronutrients. A population-based study was conducted using data from the Nutrition and Health Survey in Taiwan (NAHSIT) 2013-2016. We evaluated fourteen nutrient intakes using the 24 h dietary recall method. The dietary reference intake (DRI) adherence was estimated by the prevalence of participants whose intake was lower than the recommended dietary allowance (RDA) or adequate intakes (AIs) for selected micronutrients. Body mass index (BMI) ≥ 27 kg/m2 and waist circumference (WC), with men having WC ≥ 90 cm or women having WC ≥ 80 cm, were defined as obesity. A total of 3075 participants aged 19 years and above were included. After adjusting for confounders, we found that obese women have a lower DRI adherence of vitamin C (odds ratio (OR) 0⋅73, 95 % confidence interval (CI) 0⋅56, 0⋅95) and magnesium (OR 0⋅72, 95 % CI 0⋅54, 0⋅95), compared with normal-weight women. Obese men have a higher DRI adherence of vitamin B3 (OR 1⋅70, 95 % CI 1⋅29, 2⋅23), iron (OR 1⋅46, 95 % CI 1⋅06, 2⋅00) and zinc (OR 1⋅41, 95 % CI 1⋅07, 1⋅85), compared with normal-weight men. Similar findings were found using WC to define obesity. We conclude that obese women may have insufficient intakes of vitamin A, vitamin C and magnesium.

Muscle Sodium Accumulation in Kidney Failure: Physiological Impact and Mitigation Strategies.

Skeletal muscle has recently been recognized as a nonosmotic sodium reservoir that buffers dietary sodium. The in-vivo quantification of muscle sodium is based on a novel technology, sodium magnetic resonance imaging. Studies using this technology have shown that muscle sodium accumulation may be a clinical complication of chronic kidney disease (CKD). This review aims to summarize existing evidence on muscle sodium accumulation in patients with CKD and to identify knowledge gaps and topics for further research. The literature examined in this review suggests that muscle sodium accumulation is associated with CKD progression and pathological conditions. However, the causalities between muscle sodium accumulation and its related pathological changes are still elusive mainly because it is still uncertain where and how sodium accumulates in the muscle. More research is needed to address these gaps and determine if muscle sodium is a new intervention target in CKD.

The Safety and Efficacy of Clonidine in Hemodialysis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Clonidine is a frequently prescribed long-term antihypertensive medication in hemodialysis (HD) patients in the USA, but its safety and efficacy has not been clearly established in the HD population. OBJECTIVE: To evaluate, we conducted a systematic review and meta-analysis on the safety and efficacy of clonidine in HD patients. METHODS: Keyword search of "clonidine" and "dialysis" was conducted through April 2021 in PubMed, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov databases. Inclusion criteria were as follows - study design: randomized controlled trials, cohort studies, prospective studies, retrospective studies, or case series; subjects: adult HD patients; main outcome: blood pressure (BP) and safety; language: English; and article type: peer-reviewed publications. Studies that examined the effects of clonidine in populations other than adult HD patients were excluded. Meta-analysis was performed on BP reduction outcomes. RESULTS: Eight studies met the inclusion criteria for the systematic review, including prospective pre-post studies (2), double-blind controlled trial (1), single-blinded placebo-controlled trial (1), crossover open-label clinical trial (1), retrospective analysis (1), and case report series (2). Three studies included in the meta-analysis ranged from 2 to 12 weeks duration, with a collective sample size of 24 (ages 12-77 years). Risk of bias, assessed using the ROBINS-1 tool, was high for all included studies. Significant adverse effects reported included hypotension, light-headedness, drowsiness, dry mouth, rebound hypertension, and contact dermatitis from patch application. Short-term clonidine use was associated with significant improvement in systolic BP (pooled effect: -12.985 mm Hg, 95% CI [-7.878, -18.092], p < 0.001), while changes in diastolic BP were not statistically significant (-11.119 mm Hg, 95% CI [-22.725, 0.487], p = 0.060). No data currently support the long-term efficacy of clonidine in HD patients. This study was unfunded and was developed using PRISMA guidelines and registered on PROSPERO (CRD42018112042). CONCLUSIONS: There is no evidence supporting the long-term use of clonidine in the HD population and a significant side-effect profile. There is low-quality evidence demonstrating the efficacy of clonidine in lowering BP in HD patients in short-term use, but significant safety concerns remain. Fluid removal strategies and other antihypertensives should be used over clonidine for long-term BP control in the HD population.

Targeted Hsp70 fluorescence molecular endoscopy detects dysplasia in Barrett's esophagus.

PURPOSE: The incidence of esophageal adenocarcinoma (EAC) has been increasing for decades without significant improvements in treatment. Barrett's esophagus (BE) is best established risk factor for EAC, but current surveillance with random biopsies cannot predict progression to cancer in most BE patients due to the low sensitivity and specificity of high-definition white light endoscopy. METHODS: Here, we evaluated the membrane-bound highly specific Hsp70-specific contrast agent Tumor-Penetrating Peptide (Hsp70-TPP) in guided fluorescence molecular endoscopy biopsy. RESULTS: Hsp70 was significantly overexpressed as determined by IHC in dysplasia and EAC compared with non-dysplastic BE in patient samples (n = 12) and in high-grade dysplastic lesions in a transgenic (L2-IL1b) mouse model of BE. In time-lapse microscopy, Hsp70-TPP was rapidly taken up and internalized  by human BE dysplastic patient-derived organoids. Flexible fluorescence endoscopy of the BE mouse model allowed a specific detection of Hsp70-TPP-Cy5.5 that corresponded closely with the degree of dysplasia but not BE. Ex vivo application of Hsp70-TPP-Cy5.5 to freshly resected whole human EAC specimens revealed a high (> 4) tumor-to-background ratio and a specific detection of previously undetected tumor infiltrations. CONCLUSION: In summary, these findings suggest that Hsp70-targeted imaging using fluorescently labeled TPP peptide may improve tumor surveillance in BE patients.

Dileucine ingestion is more effective than leucine in stimulating muscle protein turnover in young males: a double blind randomized controlled trial.

Leucine is regarded as an anabolic trigger for the mTORC1 pathway and the stimulation muscle protein synthesis rates. More recently, there has been an interest in underpinning the relevance of branched-chain amino acid (BCAA)-containing dipeptides and their intact absorption into circulation to regulate muscle anabolic responses. We investigated the effects of dileucine and leucine ingestion on postprandial muscle protein turnover. Ten healthy young men (age: 23 ± 3 yr) consumed either 2 g of leucine (LEU) or 2 g of dileucine (DILEU) in a randomized crossover design. The participants underwent repeated blood and muscle biopsy sampling during primed continuous infusions of l-[ring-13C6]phenylalanine and l-[15N]phenylalanine to determine myofibrillar protein synthesis (MPS) and mixed muscle protein breakdown rates (MPB), respectively. LEU and DILEU similarly increased plasma leucine net area under the curve (AUC; P = 0.396). DILEU increased plasma dileucine AUC to a greater extent than LEU (P = 0.013). Phosphorylation of Akt (P = 0.002), rpS6 (P < 0.001), and p70S6K (P < 0.001) increased over time under both LEU and DILEU conditions. Phosphorylation of 4E-BP1 (P = 0.229) and eEF2 (P = 0.999) did not change over time irrespective of condition. Cumulative (0-180 min) MPS increased in DILEU (0.075 ± 0.032%·h-1), but not in LEU (0.047 ± 0.029%·h-1; P = 0.023). MPB did not differ between LEU (0.043 ± 0.030%·h-1) and DILEU conditions (0.051 ± 0.027%·h-1; P = 0.659). Our results showed that dileucine ingestion elevated plasma dileucine concentrations and muscle protein turnover by stimulating MPS in young men.NEW & NOTEWORTHY The role of dipeptides as anabolic agents remains unresolved in humans. We show that the ingestion of 2 g dileucine increased plasma dileucine concentrations and resulted in an enhancement of muscle protein turnover by stimulating an increase in muscle protein synthesis rates in healthy young males. The ingestion of 2 g leucine, however, did not stimulate an increase in muscle protein turnover. Our work provides the first insights into the effects of dipeptides on human protein metabolism.

Early resistance training-mediated stimulation of daily muscle protein synthetic responses to higher habitual protein intake in middle-aged adults.

KEY POINTS: The ingestion of protein potentiates the stimulation of myofibrillar protein synthesis rates after an acute bout of resistance exercise. Protein supplementation (eating above the protein Recommended Dietary Allowance) during resistance training has been shown to maximize lean mass and strength gains in healthy young and older adults. Here, contractile, oxidative, and structural protein synthesis were assessed in skeletal muscle in response to a moderate or higher protein diet during the early adaptive phase of resistance training in middle-aged adults. The stimulation of myofibrillar, mitochondrial or collagen protein synthesis rates during 0-3 weeks of resistance training is not further enhanced by a higher protein diet. These results show that moderate protein diets are sufficient to support the skeletal muscle adaptive response during the early phase of a resistance training programme. ABSTRACT: Protein ingestion augments muscle protein synthesis (MPS) rates acutely after resistance exercise and can offset age-related loss in muscle mass. Skeletal muscle contains a variety of protein pools, such as myofibrillar (contractile), mitochondrial (substrate oxidation), and collagen (structural support) proteins, and the sensitivity to nutrition and exercise seems to be dependent on the major protein fraction studied. However, it is unknown how free-living conditions with high dietary protein density and habitual resistance exercise mediates muscle protein subfraction synthesis. Therefore, we investigated the effect of moderate (MOD: 1.06 ± 0.22 g kg-1  day-1 ) or high (HIGH: 1.55 ± 0.25 g kg-1  day-1 ) protein intake on daily MPS rates within the myofibrillar (MyoPS), mitochondrial (MitoPS) and collagen (CPS) protein fractions in middle-aged men and women (n = 20, 47 ± 1 years, BMI 28 ± 1 kg m-2 ) during the early phase (0-3 weeks) of a dietary counselling-controlled resistance training programme. Participants were loaded with deuterated water, followed by daily maintenance doses throughout the intervention. Muscle biopsies were collected at baseline and after weeks 1, 2 and 3. MyoPS in the HIGH condition remained constant (P = 1.000), but MOD decreased over time (P = 0.023). MitoPS decreased after 0-3 weeks when compared to 0-1 week (P = 0.010) with no effects of protein intake (P = 0.827). A similar decline with no difference between groups (P = 0.323) was also observed for CPS (P = 0.007). Our results demonstrated that additional protein intake above moderate amounts does not potentiate the stimulation of longer-term MPS responses during the early stage of resistance training adaptations in middle-aged adults.

Anti-inflammatory chemoprevention attenuates the phenotype in a mouse model of esophageal adenocarcinoma.

Barrett's esophagus (BE) is the main known precursor condition of esophageal adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is probably mediated by chronic esophageal inflammation, secondary to gastroesophageal reflux disease in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high-fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, whereas both NSAIDs were effective chemoprevention agents in the accelerated HFD-fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.

Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.

Identification of a PET Radiotracer for Imaging of the Folate Receptor-α: A Potential Tool to Select Patients for Targeted Tumor Therapy.

The aim of this study was to identify a folate receptor-α (FRα)-selective PET agent potentially suitable for the selection of patients who might profit from FRα-targeted therapies. The 6R and 6S isomers of 18F-aza-5-methyltetrahydrofolate (MTHF) were assessed regarding their binding to FRα and FRß, expressed on cancer and inflammatory cells, respectively, and compared with 18F-AzaFol, the folic acid-based analog. Methods: FR selectivity was investigated using FRα-transfected (RT16) and FRß-transfected (D4) CHO cells. The cell uptake of 18F-folate tracers was investigated, and receptor-binding affinities were determined with the nonradioactive analogs. In vitro autoradiography of the 18F-folate tracers was performed using RT16 and D4 tissue sections. Biodistribution studies and PET/CT imaging of the radiotracers were performed on mice bearing RT16 and D4 xenografts. Results: The uptake of 18F-6R-aza-5-MTHF was high when using RT16 cells (62% ± 10% of added activity) but much lower when using D4 cells (5% ± 2%). The FRα selectivity of 18F-6R-aza-5-MTHF was further demonstrated by its approximately 43-fold higher binding affinity to FRα (half-maximal inhibitory concentration [IC50], 1.8 ± 0.1 nM) than to FRß (IC50, 77 ± 27 nM). The uptake of 18F-6S-aza-5-MTHF and 18F-AzaFol was equal in both cell lines (52%-70%), with similar affinities to FRα (IC50, 2.1 ± 0.4 nM and 0.6 ± 0.3 nM, respectively) and FRß (0.8 ± 0.2 nM and 0.3 ± 0.1 nM, respectively). The autoradiography signal obtained with 18F-6R-aza-5-MTHF was 11-fold more intense for RT16 than for D4 tissue sections. Biodistribution data showed high uptake of 18F-6R-aza-5-MTHF in RT16 xenografts (81% ± 20% injected activity per gram [IA]/g 1 h after injection) but significantly lower accumulation in D4 xenografts (7.3% ± 2.1% IA/g 1 h after injection), which was also visualized using PET. The uptake of 18F-6S-aza-5-MTHF and 18F-AzaFol was similar in RT16 (53% ± 10% IA/g and 45% ± 2% IA/g, respectively) and D4 xenografts (77% ± 10% IA/g and 52% ± 7% IA/g, respectively). Conclusion: This study demonstrated FRα selectivity for 18F-6R-aza-5-MTHF but not for 18F-6S-aza-5-MTHF or 18F-AzaFol. This characteristic, together with its favorable tissue distribution, makes 18F-6R-aza-5-MTHF attractive for clinical translation to enable detection of FRα-positive cancer while preventing undesired accumulation in FRß-expressing inflammatory cells.

Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy-a preclinical study using a syngeneic breast cancer model.

PURPOSE: It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. METHODS: In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 µg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. RESULTS: [177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. CONCLUSION: Application of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.

Elimination of NF-κB signaling in Vimentin+ stromal cells attenuates tumorigenesis in a mouse model of Barrett's Esophagus.

Chronic inflammation induces Barrett's Esophagus (BE) which can advance to esophageal adenocarcinoma. Elevated levels of interleukin (IL)-1b, IL-6 and IL-8 together with activated nuclear factor-kappaB (NF-κB), have been identified as important mediators of tumorigenesis. The inflammatory milieu apart from cancer cells and infiltrating immune cells contains myofibroblasts (MFs) that express aSMA and Vimentin. As we observed that increased NF-κB activation and inflammation correlates with increased MF recruitment and an accelerated phenotype we here analyze the role of NF-κB in MF during esophageal carcinogenesis in our L2-IL-1B mouse model. To analyze the effect of NF-κB signaling in MFs, we crossed L2-IL-1B mice to tamoxifen inducible Vim-Cre (Vim-CreTm) mice and floxed RelA (p65fl/fl) mice to specifically eliminate NF-κB signaling in MF (IL-1b.Vim-CreTm.p65fl/fl). The interaction of epithelial cells and stromal cells was further analyzed in mouse BE organoids and patient-derived human organoids. Histological scoring of IL-1b.Vim-CreTm.p65fl/fl mice showed a significantly attenuated phenotype compared with L2-IL-1B mice, with mild inflammation, decreased metaplasia and no dysplasia. This correlated with decreased proliferation and increased differentiation in cardia tissue of IL-1b.Vim-CreTm.p65fl/fl compared with L2-IL-1B mice. Distinct changes of cytokines and chemokines within the local microenvironment in IL-1b.Vim-CreTm.p65fl/fl mice reflected the histopathological abrogated phenotype. Co-cultured NF-κB inhibitor treated MF with mouse BE organoids demonstrated NF-κB-dependent growth and migration. MFs are essential to form an inflammatory and procarcinogenic microenvironment and NF-κB signaling in stromal cells emerges as an important driver of esophageal carcinogenesis. Our data suggest anti-inflammatory approaches as preventive strategies during surveillance of BE patients.

Pilot study to reduce interdialytic weight gain by provision of low-sodium, home-delivered meals in hemodialysis patients.

INTRODUCTION: Patients with kidney failure undergoing maintenance hemodialysis (HD) therapy are routinely counseled to reduce dietary sodium intake to ameliorate sodium retention, volume overload, and hypertension. However, low-sodium diet trials in HD are sparse and indicate that dietary education and behavioral counseling are ineffective in reducing sodium intake. This study aimed to determine whether 4 weeks of low-sodium, home-delivered meals in HD patients reduces interdialytic weight gain (IDWG). Secondary outcomes included changes in dietary sodium intake, thirst, xerostomia, blood pressure, volume overload, and muscle sodium concentration. METHODS: Twenty HD patients (55 ± 12 years, body mass index [BMI] 40.7 ± 16.6 kg/m2 ) were enrolled in this study. Participants followed a usual (control) diet for the first 4 weeks followed by 4 weeks of three low-sodium, home-delivered meals per day. We measured IDWG, hydration status (bioimpedance), standardized blood pressure (BP), food intake (3-day dietary recall), and muscle sodium (magnetic resonance imaging) at baseline (0 M), after the 4-week period of usual diet (1 M), and after the meal intervention (2 M). FINDINGS: The low-sodium meal intervention significantly reduced IDWG when compared to the control period (-0.82 ± 0.14 kg; 95% confidence interval, -0.55 to -1.08 kg; P < 0.001). There were also 1 month (1 M) to 2 month (2 M) reductions in dietary sodium intake (-1687 ± 297 mg; P < 0.001); thirst score (-4.4 ± 1.3; P = 0.003), xerostomia score (-6.7 ± 1.9; P = 0.002), SBP (-18.0 ± 3.6 mmHg; P < 0.001), DBP (-5.9 ± 2.0 mmHg; P = 0.008), and plasma phosphorus -1.55 ± 0.21 mg/dL; P = 0.005), as well as a 0 M to 2 M reduction in absolute volume overload (-1.08 ± 0.33 L; P = 0.025). However, there were no significant changes in serum or tissue sodium (all P > 0.05). DISCUSSION: Low-sodium, home-meal delivery appears to be an effective method for improving volume control and blood pressure in HD patients. Future studies with larger sample sizes are needed to examine the long-term effects of home-delivered meals on these outcomes and to assess cost-effectiveness.

Adherence to Daily Food Guides Is Associated with Lower Risk of Metabolic Syndrome: The Nutrition and Health Survey in Taiwan.

Although nutritional health knowledge serves as the basis for the daily food guides, limited epidemiologic studies were conducted to verify whether adherence to the daily food guides reduced the prevalence of diseases. This study aims to examine whether adherence to the daily food guides relates to the lower risk of having metabolic syndrome, as well as to assess the association between levels of adherence to daily food guides and demographic characteristics. A cross-sectional study was conducted using data from the Nutrition and Health Survey in Taiwan (NAHSIT) 2014-2016. Face-to-face dietary assessments were conducted using a validated food-frequency questionnaire. Six food groups were defined according to the daily food guides in Taiwan. We constructed a daily food guide index to measure the levels of adherence to the daily food guides. Logistic regression was performed to assess the association between the levels of adherence to the daily food guides and the risk of having metabolic syndrome. A total of 2534 participants (51% of females) were included in the final analysis. After adjusting for age, sex, body mass index, education level, marital status, and family income, we found a negative correlation between the levels of adherence to daily food guides and the prevalence of metabolic syndrome. The odds ratios (ORs) for the highest versus lowest quartile of the adherence level was 0.65 (95% confidence interval (CI) = 0.48-0.88). In addition, males, younger age, lower education, divorced, separated, and widowed, and lower family income were associated with lower adherence to daily food guides. In conclusion, participants reporting better adherence to the daily food guides during the past month had a lower risk of having metabolic syndrome.

Pilot feasibility study examining the effects of a comprehensive volume reduction protocol on hydration status and blood pressure in hemodialysis patients.

INTRODUCTION: Chronic volume overload is a persistent problem in hemodialysis (HD) patients. The purpose of this study was to investigate the impacts of comprehensive volume reduction protocol on HD patient's hydration status and blood pressure (BP). METHODS: Twenty-three HD patients (age = 55.7 ± 13.3 years) completed a 6-month comprehensive volume control protocol consisting of: reducing postdialysis weight; reducing BP medication prescriptions; and weekly intradialytic counseling to reduce dietary sodium intake and interdialytic weight gain (IDWG). The primary outcome was volume overload (VO) measured by bioelectrical impedance spectroscopy. Secondary outcomes included: IDWG, postdialysis weight, estimated dry weight (EDW), dietary sodium intake, BP and BP medication prescriptions. FINDINGS: From baseline (0M) to 6 months (6M), significant improvements were noted in: VO (0M 3.9 ± 3.9 L vs. 6M 2.6 ± 3.4 L, P = 0.003), postdialysis weight (0M 89.4 ± 23.1 kg vs. 6M 87.6 ± 22.2 kg; P = 0.012), and EDW (0M 89.0 ± 23.2 vs. 6M 86.7 ± 22.5 kg., P = 0.009). There was also a trend for a reduction in monthly averaged IDWG (P = 0.053), and sodium intake (0M 2.9 ± 1.6 vs. 6M 2.3 ± 1.1 g/d, P = 0.125). Neither systolic BP (0M 162 ± 27 vs. 6M 157 ± 23 mmHg, P = 0.405) nor diastolic BP (0M 82 ± 21 vs. 6M 82 ± 19 mmHg, P = 0.960) changed, though there was a significant reduction in the total number of BP medications prescribed (0M 3.0 ± 1.0 vs. 6M 1.5 ± 1.0 BP meds; P = 0.004). DISCUSSION: Our volume reduction protocol significantly improved HD patient's hydration status. While BP did not change, the reduction in prescribed BP medication number suggests improved BP control. Despite these overall positive findings, the magnitude of change in most variables was modest. Comprehensive changes in HD clinics may be necessary to realize more clinically significant results.

CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy.

Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism of ClC-2 is currently unclear. Here, we aimed to identify the molecular mechanism of endoplasmic reticulum-associated degradation of ClC-2, and to explore the pathophysiological significance of disease-associated anomalous ClC-2 proteostasis. In both heterologous expression system and native neuronal and testicular cells, ClC-2 is subject to significant regulation by cullin-RING E3 ligase-mediated polyubiquitination and proteasomal degradation. The cullin 4 (CUL4)-damage-specific DNA binding protein 1 (DDB1)-cereblon (CRBN) E3 ubiquitin ligase co-exists in the same complex with and promotes the degradation of ClC-2 channels. The CRBN-targeting immunomodulatory drug lenalidomide and the cullin E3 ligase inhibitor MLN4924 promotes and attenuates, respectively, proteasomal degradation of ClC-2. Analyses of disease-related ClC-2 mutants reveal that aldosteronism and leukodystrophy are associated with opposite alterations in ClC-2 proteostasis. Modifying CUL4 E3 ligase activity with lenalidomide and MLN4924 ameliorates disease-associated ClC-2 proteostasis abnormality. Our results highlight the significant role and therapeutic potential of CUL4 E3 ubiquitin ligase in regulating ClC-2 proteostasis.

Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

BACKGROUND & AIMS: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. METHODS: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. RESULTS: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. CONCLUSIONS: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.

The Risk of Depression in Patients with Pemphigus: A Nationwide Cohort Study in Taiwan.

Pemphigus is a chronic dermatological disorder caused by an autoimmune response and is associated with a high proportion of comorbidities and fatalities. The aim of this study was to investigate the risk of depression in patients with pemphigus. Data were derived from the National Health Insurance Research Database recorded during the period 2000-2010 in Taiwan. Multivariate Cox proportional hazards regression models were used to analyze the data and assess the effects of pemphigus on the risk of depression after adjusting for demographic characteristics and comorbidities. Patients with pemphigus were 1.98 times more likely to suffer from depression than the control group (pemphigus, adjusted HR: 1.99, 95% CI = 1.37-2.86). People aged ≥65 years were 1.69 times more likely to suffer from depression than those aged 20-49 years (≥65 years, adjusted HR: 1.42, 95% CI = 0.92-2.21). Female and male patients with pemphigus were respectively 2.02 and 1.91 times more likely to suffer from depression than the control group (female, adjusted HR: 2.09, 95% CI = 1.24-3.54; male, adjusted HR: 1.87, 95% CI = 0.97-3.60). People with HTN, hyperlipidemia, asthma/COPD, and chronic liver disease were respectively 1.73, 2.3, 2.2, and 1.69 times more likely to suffer from depression than those without these comorbidities (HTN, adjusted HR: 0.75, 95% CI = 0.41-1.42; hyperlipidemia, adjusted HR: 1.48, 95% CI = 0.78-2.82; asthma/COPD, adjusted HR: 1.4, 95% CI = 0.72-2.69; and chronic liver disease, adjusted HR: 1.61, 95% CI = 1.07-2.43). There was a significant association between pemphigus and increased risk of depression. Female patients had a higher incidence of depression.

Resistance Exercise-induced Regulation of Muscle Protein Synthesis to Intraset Rest.

During a traditional set configuration of resistance exercise (TRD), characterized by a continuous completion of repetitions, a decrease in power output tends to occur throughout a set of repetitions. Inclusion of intraset rest, otherwise known as a cluster set configuration (CLU), counteracts this power decline. However, the effect of a CLU configuration on postexercise myofibrillar protein synthesis rates (MPS) and anabolic signaling has not been investigated. PURPOSE: We aimed to determine if any mechanistic differences exist between TRD and CLU signaling events associated with muscle anabolism. METHODS: In randomized crossover trials, eight resistance-trained participants (23 ± 1 yr, 81 ± 4.7 kg, body fat: 18% ± 1.9%; 1 repetition maximum [1RM], 150 ± 9.1 kg) performed an acute bout of CLU (4 sets × (2 × 5) repetitions, 30-s intraset rest, 90-s interset rest) and TRD (4 sets × 10 repetitions, 120-s interset rest) barbell back squats at approximately 70% 1RM with total volume load equated during primed continuous L-[ring-C6]phenylalanine infusions. Blood and muscle biopsy samples were collected at rest and after exercise at 0, 2, and 5 h. RESULTS: There was no difference in postexercise MPS between the CLU and TRD condition (P > 0.05) and no changes in phosphorylation of mTORC1 downstream targets (p70S6K and 4EBP1). Total and phosphorylated yes-associated protein on Ser127 transiently increased (P < 0.01) immediately after exercise (t = 0) in CLU (~2.1-fold) and TRD condition (~2.2-fold). CONCLUSIONS: Our results show that CLU is a viable anabolic option by preserving power output with similar MPS stimulation when compared with the TRD condition in trained young adults.

A Comparison of Intradialytic versus Out-of-Clinic Exercise Training Programs for Hemodialysis Patients.

BACKGROUND: Physical inactivity is prevalent and linked with a variety of unfavorable clinical outcomes in hemodialysis patients. To increase physical activity (PA) and improve quality of life in this population, intradialytic and out-of-clinic exercise interventions have been implemented in many studies. However, there is still a lack of consensus in the literature on which type of exercise intervention is more feasible and effective. SUMMARY: This review provides a brief overview of intradialytic and out-of-clinic exercise protocols utilized in previous studies. We also examine data related to the feasibility of each approach, and their efficacy for improving cardiovascular health, muscle mass, strength, and physical function. Key Messages: The benefits from most intradialytic and out-of-center exercise training interventions published to date have been modest or inconsistent. Furthermore, neither appears to provide a significant advantage over the other in terms of benefits for cardiovascular health, muscle mass, strength, and physical function. A significant concern is that most intradialytic and out-of-center exercise interventions are mandated exercise prescriptions that include either endurance or resistance training exercises, performed at low-moderate intensities, for a total of 60-135 min of exercise/week. This volume, intensity, and variety of exercise are far less than what is recommended in most PA guidelines. This type of structured activity is also boring for most patients. To enhance the effectiveness of exercise interventions, we suggest using the intradialytic period to provide patients guidance on how they can best incorporate more activity into their lives, based on their individual needs and barriers.