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Evidence for TRPV4 channel induced skin vasodilatation through NOS, COX, and KCa channel mechanisms with no effect on sweat rate in humans.
Fujii, N, Kenny, GP, Amano, T, Honda, Y, Kondo, N, Nishiyasu, T
European journal of pharmacology. 2019;:172462
Abstract
Transient receptor potential vanilloid 4 (TRPV4) channels exist in the endothelial cells of cutaneous blood vessels and the secretory cells of eccrine sweat glands. We assessed if exogenous TRPV4 channel activation elicits cutaneous vasodilatation and sweating in humans in vivo, and if so, whether this response is mediated by nitric oxide synthase (NOS)- cyclooxygenase (COX)- and/or Ca2+-sensitive K+ (KCa) channel-related mechanisms. In ten healthy young adults (24±2 years, 5 women), cutaneous vascular conductance and sweat rate were assessed at four dorsal forearm skin sites continuously treated with either: 1) lactated Ringer's solution (Control), 2) 20 mM L-NAME, a non-selective NOS inhibitor, 3) 10 mM ketorolac, a non-selective COX inhibitor, or 4) 50 mM TEA, a non-selective KCa channel blocker. A potent and selective TRPV4 channel agonist, GSK1016790 A (GSK101), was administered to each skin site in a dose-dependent manner (1, 10, 100, 1000 μM each for ≥30min) via intradermal microdialysis. Administration of 100 and 1000 μM GSK101 increased cutaneous vascular conductance from pre-infusion level at the Control site (48±12 and 57±9%max, respectively, P≤0.004). This response was markedly (53-83%) attenuated by NOS inhibition, COX inhibition, or KCa channel blockade (all P≤0.037), except KCa channel blockade had no effect during 1000 μM GSK101 administration. GSK101 did not influence sweat rate regardless of skin site. We showed that in human skin in vivo, exogenous activation of TRPV4 channels mediates cutaneous vasodilatation, but not sweating through NOS, COX, and KCa channel mechanisms.
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Influence of vitamin D supplementation on glycemic control in type 2 diabetics.
Abdesselem, H, Ben Salem, L, Bibi, A, Sebai, I, Jemal, M, Ounaissa, K, Amrouche, C
La Tunisie medicale. 2019;(8-9):984-989
Abstract
INTRODUCTION Several studies have suggested a benefic impact of vitamin D supplementation on glycemic control and insulin resistance among patients with type 2 diabetes mellitus. The aims of our study were to assess vitamin D status in individuals with type 2 diabetes mellitus and to investigate the effects of vitamin D supplementation on glycemic measures in patients having vitamin D deficiency. METHODS We conducted a comparative prospective study involved 100 Tunisian patients with type 2 diabetes followed at the National Institute of Nutrition and Food Technology of Tunis. Glycemic control and insulin resistance were evaluated in the beginning of the study and three months after supplementation. RESULTS Baseline mean 25-Hydroxy vitamin D (25(OH)D) level was 17.5±9.8 ng/ml. Vitamin D status was deficient in 60%, insufficient in 26% and sufficient in 14% patients. After vitamin D supplementation, mean serum 25(OH)D concentration increased significantly (p˂10-3). We observed a negative correlation between the variation of plasma 25(OH)D level and the waist circumference's variation (r=-0.266 and p=0.018). This correlation persisted after adjustment for therapeutic management. Vitamin D supplementation did significantly improve neither glycemic control nor insulin resistance parameters. CONCLUSION Vitamin D deficiency is frequent in patients with type 2 diabetes mellitus. The metabolic effects of supplementation are controversial, hence the need of expanding studies to better demonstrate these effects.
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Beneficial effects of leptin substitution on impaired eating behavior in lipodystrophy are sustained beyond 150 weeks of treatment.
Püschel, J, Miehle, K, Müller, K, Villringer, A, Stumvoll, M, Fasshauer, M, Schlögl, H
Cytokine. 2019;:400-404
Abstract
AIM: Metreleptin treatment in lipodystrophy patients improves eating behavior with increased satiety and reduced hunger. However, no data are available whether effects are maintained beyond 52 weeks of treatment. METHODS A prospective study with measurements at baseline and at >150 weeks of metreleptin treatment was performed. Five female lipodystrophy patients with indication for metreleptin were included. Behavioral aspects of hunger- and satiety regulation were assessed by validated eating behavior questionnaires and visual analog scales assessing hunger and satiety feelings before and after a standardized meal. RESULTS Hunger rated on visual analog scales at 120 min after the meal significantly decreased from 46 ± 10 mm at baseline to 17 ± 6 mm at long-term assessment. Furthermore, satiety at 5 and 120 min after the meal significantly increased from baseline to long-term assessment (5 min: 70 ± 7 mm to 87 ± 3 mm; 120 min: 43 ± 10 mm to 79 ± 8 mm). On the Three Factor Eating Questionnaire, the mean value of factor 3 (hunger) significantly decreased from 9.2 ± 0.2 at baseline to 2.6 ± 1.5 at long-term assessment. In the Inventory of Eating Behavior and Weight Problems Questionnaire, mean values for scale 2 (strength and triggering of desire to eat) and scale 7 (cognitive restraint of eating) significantly decreased from baseline (31.6 ± 4.8 and 11.4 ± 2.2, respectively) to long-term assessment (14.0 ± 2.1 and 10.0 ± 1.9). CONCLUSION First evidence is presented that long-term metreleptin treatment of >150 weeks has sustained effects on eating behavior with increased satiety, as well as reduced hunger and hunger-related measures.
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Association between hair cortisol concentration and dietary intake among normal weight preschool children predisposed to overweight and obesity.
Larsen, SC, Rohde, JF, Olsen, NJ, Händel, MN, Stougaard, M, Fahrenkrug, J, Heitmann, BL
PloS one. 2019;(3):e0213573
Abstract
BACKGROUND The association between chronically elevated cortisol, as measured by hair cortisol concentration (HCC), and dietary intake among children has generally not been explored. Moreover, it is unknown whether there is an association between parental HCC and dietary intake among their children. OBJECTIVE To examine associations between HCC and dietary intake among children, and to explore the association between parental HCC and dietary intake among their children. METHODS We conducted a cross-sectional study based on 296 children predisposed to overweight and obesity who participated in the Healthy Start study. Multiple Linear regression analyses were conducted to assess the association between HCC and total energy intake, macronutrients, fruit and vegetables, added sugar, sugar-sweetened beverages (SSB), and a diet quality index (DQI). RESULTS Among the children, we found that higher HCC was associated with a lower consumption of dietary fat (β: -0.7 g/day [95% CI: -1.3, -0.0] per 100 pg/mg HCC). We found no statistically significant association between HCC and intake of total energy, protein, carbohydrate, fruit and vegetables, added sugar, SSB or DQI. We found no association between parental HCC and intake of total energy, added sugar, selected food groups or DQI among their children. However, stratified analyses showed that paternal HCC was associated with a borderline significant lower total energy intake and significantly lower protein intake, but only among daughters (adjusted β: -42 kcal/day [95% CI: -85, 0] and -2.6 g/day [95% CI: -4.4, -0.8] per 100 pg/mg HCC, respectively). CONCLUSION Among children, chronic stress as measured by HCC may be associated with a lower fat consumption, and paternal HCC may be associated with a lower intake of energy and protein among their daughters. However, the associations observed were weak, and any clinical relevance of these findings remains questionable.
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Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients.
Cuyàs, E, Fernández-Arroyo, S, Buxó, M, Pernas, S, Dorca, J, Álvarez, I, Martínez, S, Pérez-Garcia, JM, Batista-López, N, Rodríguez-Sánchez, CA, et al
Aging. 2019;(9):2874-2888
Abstract
Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the "drug plus diet" approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body β-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response.
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Protein and energy intake improved by in-between meals: An intervention study in hospitalized patients.
Mortensen, MN, Larsen, AK, Skadhauge, LB, Høgsted, RH, Beermann, T, Cook, ME, Rasmussen, HH, Mikkelsen, BE, Holst, M
Clinical nutrition ESPEN. 2019;:113-118
Abstract
BACKGROUND/AIM: Disease related malnutrition is a major problem in hospitals. Malnutrition in hospitalized patients is caused by many factors. Among these factors are decreased appetite and early satiety, and reaching nutritional requirements in nutritional risk patients is a challenge when using ordinary energy and protein dense food. The aim of this study was to examine if total protein and energy intake in medical and surgical patients at nutritional risk could be improved by protein fortified and energy rich in-between meals. METHODS An assortment of fortified in-between meals including 10 g of protein was developed based on patient preferences and served in the Departments of Lung Medicine and Abdominal Surgery for a period of three months. Nutrition intake was recorded before and after intervention. RESULTS Food intake records were collected from a total of 92 patients, (46 before and 46 after intervention). The total amount of protein intake per in-between meal was increased from 2,6 g to 10,3 g. Total daily protein intake increased from 49% to 88% (p < 0.00) and total energy intake from 74% to 109% (p < 0.00) of requirements. CONCLUSION Protein and energy intake for surgical and medical patients at in-between meals as well as total daily intake increased significantly. Recommended average level for individually measured requirements was reached.
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Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM).
Hurwitz, HI, Tan, BR, Reeves, JA, Xiong, H, Somer, B, Lenz, HJ, Hochster, HS, Scappaticci, F, Palma, JF, Price, R, et al
The oncologist. 2019;(7):921-932
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Abstract
BACKGROUND First-line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI-BEV) or sequentially (sFOLFOXIRI-BEV, FOLFOX-BEV alternating with FOLFIRI-BEV), versus FOLFOX-BEV for mCRC. PATIENTS AND METHODS Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, or FOLFOX-BEV and treated with 4-6-month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first-line cFOLFOXIRI-BEV vs. FOLFOX-BEV) and progression-free survival (PFS; pooled first-line cFOLFOXIRI-BEV and sFOLFOXIRI-BEV vs. FOLFOX-BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety. RESULTS ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, and FOLFOX-BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI-BEV and FOLFOX-BEV did not significantly differ (p = .132); thus, the primary ORR endpoint was not met. cFOLFOXIRI-BEV and sFOLFOXIRI-BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI-BEV versus FOLFOX-BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5-0.9; p < .01). Liver resection rates were 17.2% (cFOLFOXIRI-BEV), 9.8% (sFOLFOXIRI-BEV), and 8.4% (FOLFOX-BEV). Grade ≥ 3 treatment-emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI-BEV), 86.7% (sFOLFOXIRI-BEV), and 85.6% (FOLFOX-BEV) of patients, with no increase in serious chemotherapy-associated TEAEs. CONCLUSION cFOLFOXIRI-BEV and sFOLFOXIRI-BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX-BEV, supporting triplet chemotherapy plus BEV as a first-line treatment option for mCRC. IMPLICATIONS FOR PRACTICE The combination of first-line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI-BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI-BEV or FOLFOX-BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI-BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI-BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI-BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first-line treatment options for this population.
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Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: the Components of Weight Loss in Japanese Patients with Type 2 Diabetes Mellitus) Study.
Sasaki, T, Sugawara, M, Fukuda, M
Journal of diabetes investigation. 2019;(1):108-117
Abstract
AIMS/INTRODUCTION It is unclear how changes in body composition induced by sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment correlate with metabolic profile changes. We aimed to clarify how metabolic profile changes correlate with body component changes, and if SGLT2 inhibitor treatment causes sarcopenia and bone mineral content (BMC) loss. MATERIALS AND METHODS Moderately obese Japanese type 2 diabetes patients, treated with luseogliflozin for a year, were observed prospectively and evaluated for body composition changes. We analyzed the changes in the individual body components during treatment, and their correlation with other clinical variables. RESULTS The efficacy analysis set comprised 37 of 43 enrolled patients. The total fat mass significantly decreased early in the treatment at and after week 4, with a mean decrease of -1.97 kg (95% confidence interval -2.66 to -1.28) at week 24. The visceral fat area at week 24 showed an average downward trend, although this was not significant. The changes in visceral fat area in individual patients showed a significant negative correlation with the extent of the baseline visceral fat area (r = -0.399, P = 0.023). The skeletal muscle mass index showed a significant but small change at and after week 36. The BMC profile showed a transient significant decrease only at week 12. No significant change in BMC was noted at other time-points. CONCLUSIONS Luseogliflozin treatment brought about favorable changes in body composition and metabolism of moderately obese Japanese type 2 diabetes patients, accompanied by body fat reduction, and minimal muscle and BMC reduction.
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Automated individualization of dialysate sodium concentration reduces intradialytic plasma sodium changes in hemodialysis.
Ságová, M, Wojke, R, Maierhofer, A, Gross, M, Canaud, B, Gauly, A
Artificial organs. 2019;(10):1002-1013
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Abstract
In standard care, hemodialysis patients are often treated with a center-specific fixed dialysate sodium concentration, potentially resulting in diffusive sodium changes for patients with plasma sodium concentrations below or above this level. While diffusive sodium load may be associated with thirst and higher interdialytic weight gain, excessive diffusive sodium removal may cause intradialytic symptoms. In contrast, the new hemodialysis machine option "Na control" provides automated individualization of dialysate sodium during treatment with the aim to reduce such intradialytic sodium changes without the need to determine the plasma sodium concentration. This proof-of-principle study on sodium control was designed as a monocentric randomized controlled crossover trial: 32 patients with residual diuresis of ≤1000 mL/day were enrolled to be treated by high-volume post-dilution hemodiafiltration (HDF) for 2 weeks each with "Na control" (individually and automatically adjusted dialysate sodium concentration) versus "standard fixed Na" (fixed dialysate sodium 138 mmol/L), in randomized order. Pre- and post-dialytic plasma sodium concentrations were determined at bedside by direct potentiometry. The study hypothesis consisted of 2 components: the mean plasma sodium change between the start and end of the treatment being within ±1.0 mmol/L for sodium-controlled treatments, and a lower variability of the plasma sodium changes for "Na control" than for "standard fixed Na" treatments. Three hundred seventy-two treatments of 31 adult chronic hemodialysis patients (intention-to-treat population) were analyzed. The estimate for the mean plasma sodium change was -0.53 mmol/L (95% confidence interval: [-1.04; -0.02] mmol/L) for "Na control" treatments and -0.95 mmol/L (95% CI: [-1.76; -0.15] mmol/L) for "standard fixed Na" treatments. The standard deviation of the plasma sodium changes was 1.39 mmol/L for "Na control" versus 2.19 mmol/L for "standard fixed Na" treatments (P = 0.0004). Whereas the 95% CI for the estimate for the mean plasma sodium change during "Na control" treatments marginally overlapped the lower border of the predefined margin ±1.0 mmol/L, the variability of intradialytic plasma sodium changes was lower during "Na control" versus "standard fixed Na" treatments. Thus, automated dialysate sodium individualization by "Na control" approaches isonatremic dialysis in the clinical setting.
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Neurovascular decoupling in type 2 diabetes mellitus without mild cognitive impairment: Potential biomarker for early cognitive impairment.
Yu, Y, Yan, LF, Sun, Q, Hu, B, Zhang, J, Yang, Y, Dai, YJ, Cui, WX, Xiu, SJ, Hu, YC, et al
NeuroImage. 2019;:644-658
Abstract
Type 2 diabetes mellitus (T2DM) is a significant risk factor for mild cognitive impairment (MCI) and the acceleration of MCI to dementia. The high glucose level induce disturbance of neurovascular (NV) coupling is suggested to be one potential mechanism, however, the neuroimaging evidence is still lacking. To assess the NV decoupling pattern in early diabetic status, 33 T2DM without MCI patients and 33 healthy control subjects were prospectively enrolled. Then, they underwent resting state functional MRI and arterial spin labeling imaging to explore the hub-based networks and to estimate the coupling of voxel-wise cerebral blood flow (CBF)-degree centrality (DC), CBF-mean amplitude of low-frequency fluctuation (mALFF) and CBF- mean regional homogeneity (mReHo). We further evaluated the relationship between NV coupling pattern and cognitive performance (false discovery rate corrected). T2DM without MCI patients displayed significant decrease in the absolute CBF-mALFF, CBF-mReHo coupling of CBFnetwork and in the CBF-DC coupling of DCnetwork. Besides, networks which involved CBF and DC hubs mainly located in the default mode network (DMN). Furthermore, less severe disease and better cognitive performance in T2DM patients were significantly correlated with higher coupling of CBF-DC, CBF-mALFF or CBF-mReHo, especially for the cognitive dimensions of general function and executive function. Thus, coupling of CBF-DC, CBF-mALFF and CBF-mReHo may serve as promising indicators to reflect NV coupling state and to explain the T2DM related early cognitive impairment.