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Both during and after hospitalization, nutritional care with daily intake of oral nutritional supplements (ONS) improves health outcomes and decreases risk of mortality in malnourished older adults. In a post-hoc analysis of data from hospitalized older adults with malnutrition risk, we sought to determine whether consuming a specialized ONS (S-ONS) containing high protein and beta-hydroxy-beta-methylbutyrate (HMB) can also improve Quality of Life (QoL). We analyzed data from the NOURISH trial—a randomized, placebo-controlled, multi-center, double-blind study conducted in patients with congestive heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease. Patients received standard care + S-ONS or placebo beverage (target 2 servings/day) during hospitalization and for 90 days post-discharge. SF-36 and EQ-5D QoL outcomes were assessed at 0-, 30-, 60-, and 90-days post-discharge. To account for the missing QoL observations (27.7%) due to patient dropout, we used multiple imputation. Data represent differences between least squares mean (LSM) values with 95% Confidence Intervals for groups receiving S-ONS or placebo treatments. The study population consisted of 622 patients of mean age ±standard deviation: 77.9 ± 8.4 years and of whom 52.1% were females. Patients consuming placebo had lower (worse) QoL domain scores than did those consuming S-ONS. Specifically for the SF-36 health domain scores, group differences (placebo vs S-ONS) in LSM were significant for the mental component summary at day 90 (−4.23 [-7.75, −0.71]; p = 0.019), the domains of mental health at days 60 (−3.76 [-7.40, −0.12]; p = 0.043) and 90 (−4.88 [-8.41, −1.34]; p = 0.007), vitality at day 90 (−3.33 [-6.65, −0.01]; p = 0.049) and social functioning at day 90 (−4.02 [-7.48,-0.55]; p = 0.023). Compared to placebo, differences in LSM values for the SF-36 general health domain were significant with improvement in the S-ONS group at hospital discharge and beyond: day 0 (−2.72 [-5.33, −0.11]; p = 0.041), day 30 (−3.08 [-6.09, −0.08]; p = 0.044), day 60 (−3.95 [-7.13, −0.76]; p = 0.015), and day 90 (−4.56 [-7.74, −1.38]; p = 0.005). In hospitalized older adults with cardiopulmonary diseases and evidence of poor nutritional status, daily intake of S-ONS compared to placebo improved post-discharge QoL scores for mental health/cognition, vitality, social functioning, and general health. These QoL benefits complement survival benefits found in the original NOURISH trial analysis. NCT01626742. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.comnet.2006.04.012 Byline: Hung Tuan Tran, Thomas Ziegler Keywords: QoS; Overlay networks; Adaptive topological design Abstract: We present in this paper a generic design framework towards the profitable operation of a service overlay network (SON) that aims to assure inter-domain quality of services (QoS). Revealing some involved NP-hard topological design tasks, we work out efficient heuristic methods for the practical implementation of the proposed framework. The efficiency of the developed heuristic methods is tested and confirmed with extensive scrutinies and benchmarks, based on many input scenarios and comparative assessments. We also demonstrate the revenue benefits the SON operator can get in case of following our framework. Author Affiliation: Telecommunications Research Center Vienna (ftw.), Donaucity Strasse 1, A-1220 Vienna, Austria Article History: Received 29 July 2005; Revised 27 December 2005; Accepted 1 April 2006 Article Note: (footnote) [star] This work was done when the authors were with the Telecommunications Research Center Vienna, Austria. Hung Tuan Tran is now with the Fpt Information System (FIS), Hanoi, Vietnam.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.comnet.2005.11.003 Byline: Francesco Vacirca (a)(b), Thomas Ziegler (a), Eduard Hasenleithner (a) Keywords: TCP; Spurious timeout; UMTS; GPRS Abstract: This paper proposes an algorithm to identify TCP spurious retransmission timeouts by post processing of packet traces monitored in operational networks. The operational principles of the algorithm and the assumptions behind its design are explained in detail as well as the situations in which the algorithm is prone to inaccuracies. By extensive measurements in a lab testbed using realistic round trip time characteristics as observed in operational wireless networks and FTP-like as well as Web-like traffic generators, it is shown that the algorithm is accurate in detection of spurious retransmission timeouts. Subsequently, the algorithm is applied to real traffic traces captured at several interfaces of an operational UMTS and GPRS network to analyze the frequency of spurious retransmission timeouts as well as the spurious timeout probability dependent on the load situation in the network and the flow size. This investigation, to our best knowledge the first on large scale TCP traffic traces monitored in an operational UMTS network, shows that spurious timeouts are infrequent events in the considered UMTS as well as the GPRS network. Among other findings, it is additionally shown that the ratio between spurious timeouts and other congestion recovery events experienced by TCP flows is low, indicating a negligible impact of spurious timeouts on TCP performance. Author Affiliation: (a) ftw. Forschungszentrum Telekommunikation Wien, Donau-City-Strasse 1, A-1220 Vienna, Austria (b) Infocom Department, University of Roma "La Sapienza", Via Eudossiana 18, 00184 Roma, Italy Article History: Received 30 July 2005; Revised 17 November 2005; Accepted 21 November 2005 Article Note: (miscellaneous) Responsible Editor: S. Palazzo

With the experience-based hypothesis of low donor site morbidity (DSM) for free flaps from the distal femur, this cohort study aimed to evaluate the DSM according to objective and reproducible criteria. One hundred and fifty-six patients who had a flap harvest from either the medial or lateral femoral condyle region between 2005 and 2017 were included. A retrospective chart review was performed for all patients. In total, 97 patients were available for a follow-up examination. Outcomes were assessed according to objective (Knee Society Score; Larson Knee Score; OAK Score; 0–100 points), patient-reported (IKDC Score; KOOS Score; 0–100 points), and radiologic criteria (Kellgren and Lawrence Score; MRI Osteoarthritis Knee Score). The median follow-up time was 1529 days (range: 248–4,810). The mean Knee Society Score (94.8 ± 10.1), Larson Knee Score (94.5 ± 10.1), and OAK Score (95.5 ± 6.6) showed nearly unimpaired knee function. The overall patient-reported DSM was low (IKDC Score: 86.7 ± 17.4; KOOS Score: 89.3 ± 17.1). Osteochondral (OC) flaps had a significantly higher DSM, regardless of the donor site. Bone flaps did not show any relevant radiologic morbidity in the Kellgren and Lawrence Score. Besides the procedure-associated cartilage lesions at the OC donor sites, MRI Osteoarthritis Knee Score did not show any significant presence of further knee pathologies in the bilateral MRI Scans. The obvious cartilage lesions did not have a relevant impact on the knee function of most patients. The DSM for bone and soft-tissue flaps from the femoral condyle region is negligible. OC flaps are associated with a significantly higher DSM, although a clinically relevant impact on knee function was not evident in the majority of patients. [ABSTRACT FROM AUTHOR]

Hospitalized, malnourished older adults with chronic obstructive pulmonary disease (COPD) have an elevated risk of readmission and mortality. Post-hoc, sub-group analysis from the NOURISH study cohort examined the effect of a high-protein oral nutritional supplement (ONS) containing HMB (HP-HMB) in malnourished, hospitalized older adults with COPD and to identify predictors of outcomes. The NOURISH study (n = 652) was a multicenter, randomized, placebo-controlled, double-blind trial. The COPD subgroup (n = 214) included hospitalized, malnourished (based on Subjective Global Assessment), older adults (≥65 y), with admission diagnosis of COPD who received either standard-of-care plus HP-HMB (n = 109) or standard-of-care and a placebo supplement (n = 105) prescribed 2 servings/day from within 3 days of hospital admission (baseline) and up to 90 days after discharge. The primary study outcome was a composite endpoint of incidence of death or non-elective readmission up to 90-day post-discharge, while secondary endpoints included changes in hand-grip strength, body weight, and nutritional biomarkers over time. Categorical outcomes were analyzed using Cochran-Mantel-Haenszel tests, longitudinal data by repeated measures analysis of covariance; and changes from baseline by analysis of covariance. p-values ≤ 0.05 were considered statistically significant. Multivariate logistic regression was used to model predictors of the primary outcome and components. In patients with COPD, 30, 60, and 90-day hospital readmission rate did not differ, but in contrast, 30, 60, and 90-day mortality risk was approximately 71% lower with HP-HMB supplementation relative to placebo (1.83%, 2.75%, 2.75% vs. 6.67%, 9.52% and 10.48%, p = 0.0395, 0.0193, 0.0113, resp.). In patients with COPD, compared to placebo, intake of HP-HMB resulted in a significant increase in handgrip strength (+1.56 kg vs. −0.34 kg, p = 0.0413) from discharge to day 30; increased body weight from baseline to hospital discharge (0.66 kg vs. −0.01 kg, p < 0.05) and, improvements in blood nutritional biomarker concentrations. The multivariate logistic regression predictors of the death, readmission or composite endpoints in these COPD patients showed that participants who were severely malnourished (p = 0.0191) and had a Glasgow prognostic score (GPS) Score of 1 or 2 had statistically significant odds of readmission or death (p = 0.0227). Among malnourished, hospitalized patients with COPD, supplementation with HP-HMB was associated with a markedly decreased mortality risk, and improved handgrip strength, body weight, and nutritional biomarkers within a 90-day period after hospital discharge. This post-hoc, subgroup analysis highlights the importance of early identification of nutritional risk and administration of high-protein ONS in older, malnourished patients with COPD after hospital admission and continuing after hospital discharge. [ABSTRACT FROM AUTHOR]

There is a considerable degree of variation in bone mineral density (BMD) within populations. Use of plasma metabolomics may provide insight into established and novel determinants of BMD variance, such as nutrition and gut microbiome composition, to inform future prevention and treatment strategies for loss of BMD. Using high-resolution metabolomics (HRM), we examined low-molecular weight plasma metabolites and nutrition-related metabolic pathways associated with BMD. This cross-sectional study included 179 adults (mean age 49.5 ± 10.3 yr, 64% female). Fasting plasma was analyzed using ultra-high-resolution mass spectrometry with liquid chromatography. Whole body and spine BMD were assessed by dual energy X-ray absorptiometry and expressed as BMD (g/cm2) or Z-scores. Multiple linear regression, pathway enrichment, and module analyses were used to determine key plasma metabolic features associated with bone density. Of 10,210 total detected metabolic features, whole body BMD Z-score was associated with 710 metabolites, which were significantly enriched in seven metabolic pathways, including linoleic acid, fatty acid activation and biosynthesis, and glycerophospholipid metabolism. Spine BMD was associated with 970 metabolites, significantly enriched in pro-inflammatory pathways involved in prostaglandin formation and linoleic acid metabolism. In module analyses, tryptophan- and polyamine-derived metabolites formed a network that was significantly associated with spine BMD, supporting a link with the gut microbiome. Plasma HRM provides comprehensive information relevant to nutrition and components of the microbiome that influence bone health. This data supports pro-inflammatory fatty acids and the gut microbiome as novel regulators of postnatal bone remodeling. • A variety of modifiable factors, including diet, influence bone health. • Metabolomics is a novel tool to explore factors related to bone health. • Plasma linoleic acid and oxidized metabolites were inversely related to bone density. • Gut microbiome-related metabolites were also associated with bone density. • Metabolomics is a valuable method for examining regulators of bone metabolism. [ABSTRACT FROM AUTHOR]

Nutrients, such as glutamine (GLN), have been shown to effect levels of a family of protective proteins termed heat shock proteins (HSPs) in experimental and clinical critical illness. HSPs are believed to serve as extracellular inflammatory messengers and intracellular cytoprotective molecules. Extracellular HSP70 (eHSP70) has been termed a chaperokine due to ability to modulate the immune response. Altered levels of eHSP70 are associated with various disease states. Larger clinical trial data on GLN effect on eHSP expression and eHSP70's association with inflammatory mediators and clinical outcomes in critical illness are limited. Explore effect of longitudinal change in serum eHSP70, eHSP27 and inflammatory cytokine levels on clinical outcomes such as pneumonia and mortality in adult surgical intensive care unit (SICU) patients. Further, evaluate effect of parenteral nutrition (PN) supplemented with GLN (GLN-PN) versus GLN-free, standard PN (STD-PN) on serum eHSP70 and eHSP27 concentrations. Secondary observational analysis of a multicenter clinical trial in 150 adults after cardiac, vascular, or gastrointestinal surgery requiring PN support and SICU care conducted at five academic medical centers. Patients received isocaloric, isonitrogenous PN, with or without GLN dipeptide. Serum eHSP70 and eHSP27, interleukin-6 (IL-6), and 8 (IL-8) concentrations were analyzed in patient serum at baseline (prior to study PN) and over 28 days of follow up. eHSP70 declined over time in survivors during 28 days follow-up, but non-survivors had significantly higher eHSP70 concentrations compared to survivors. In patients developing pneumonia, eHSP70, eHSP27, IL-8, and IL-6 were significantly elevated. Adjusted relative risk for hospital mortality was reduced 75% (RR = 0.25, p = 0.001) for SICU patients with a faster decline in eHSP70. The area under the receiver operating characteristic curve was 0.85 (95% CI: 0.76 to 0.94) for the final model suggesting excellent discrimination between SICU survivors and non-survivors. GLN-PN did not alter eHSP70 or eHSP27 serum concentrations over time compared to STD-PN. Our results suggest that serum HSP70 concentration may be an important marker for severity of illness and likelihood of recovery in the SICU. GLN-supplemented-PN did not increase eHSP70. [ABSTRACT FROM AUTHOR]

• Linoleic acid (LNA) suppressed expression of key genes involved in osteoblast differentiation and function. • LNA impaired mitochondrial ATP production in MC3T3-E1 osteoblast precursors. • LNA induced production of oxidized LNA metabolites known to be associated with mitochondrial dysfunction in other tissues. Linoleic acid (LNA), an essential polyunsaturated fatty acid (PUFA), plays a crucial role in cellular functions. However, excessive intake of LNA, characteristic of Western diets, can have detrimental effects on cells and organs. Human observational studies have shown an inverse relationship between plasma LNA concentrations and bone mineral density. The mechanism by which LNA impairs the skeleton is unclear, and there is a paucity of research on the effects of LNA on bone-forming osteoblasts. The effect of LNA on osteoblast differentiation, cellular bioenergetics, and production of oxidized PUFA metabolites in vitro , was studied using primary mouse bone marrow stromal cells (BMSC) and MC3T3-E1 osteoblast precursors. LNA treatment decreased alkaline phosphatase activity, an early marker of osteoblast differentiation, but had no effect on committed osteoblasts or on mineralization by differentiated osteoblasts. LNA suppressed osteoblast commitment by blunting the expression of Runx2 and Osterix , key transcription factors involved in osteoblast differentiation, and other key osteoblast-related factors involved in bone formation. LNA treatment was associated with increased production of oxidized LNA- and arachidonic acid-derived metabolites and blunted oxidative phosphorylation, resulting in decreased ATP production. Our results show that LNA inhibited early differentiation of osteoblasts and this inhibitory effect was associated with increased production of oxidized PUFA metabolites that likely impaired energy production via oxidative phosphorylation. [ABSTRACT FROM AUTHOR]

• Therapy for high grade burns: immediate debridement, coverage with suitable dressings. • Post-burn scar contracture-surgery: at least one year after the burn injury. • Mobilization of Mesenchymal Stem Cells in infants is a autologous stem cell therapy. Burn injuries in newborns are particularly complex cases. Since these patients are rare, there is little experience and no existing standardized treatment. This report examines a case of accidental second to third-degree burning of the heel and toes on the left foot in a new-born girl. The burns covered an estimated 1% of the total body surface area (TBSA). After an initial debridement and 32 days of non-surgical wound therapy with Adaptic® fat gauze dressings, we were able to achieve an aesthetically and functionally satisfactory result including the complete preservation of all toes. In order to eliminate a scar contracture, we carried out a Z-plasty one year later. Modern wound treatment following the principle of less frequent dressing changes allows the burn wound to have better re-epithelialization. New findings in stem cell research indicate that the high proportion of mesenchymal stem cells (MSC) in postnatal blood is also involved in the regeneration and healing of burns. To our knowledge, this is the first case report dealing with initial non-surgical combustion therapy in a newborn. There is evidence that newborns have a much higher potential for wound healing than adults. Proper position in long-term immobilization of toes is important to prevent scar contracture and deformity. [ABSTRACT FROM AUTHOR]

Background Patients with cystic fibrosis (CF) have increased risk of vitamin D deficiency owing to fat malabsorption and other factors. Vitamin D deficiency has been associated with increased risk of pulmonary exacerbations of CF. Objectives The primary objective of this study was to examine the impact of a single high-dose bolus of vitamin D3 followed by maintenance treatment given to adults with CF during an acute pulmonary exacerbation on future recurrence of pulmonary exacerbations. Methods This was a multicenter, double-blind, placebo-controlled, intent-to-treat clinical trial. Subjects with CF were randomly assigned to oral vitamin D3 given as a single dose of 250,000 International Units (IU) or to placebo within 72 h of hospital admission for an acute pulmonary exacerbation, followed by 50,000 IU of vitamin D3 or an identically matched placebo pill taken orally every other week starting at 3 mo after random assignment. The primary outcome was the composite endpoint of the time to next pulmonary exacerbation or death within 1 y. The secondary outcomes included circulating concentrations of the antimicrobial peptide cathelicidin and recovery of lung function as assessed by the percentage of predicted forced expiratory volume in 1 s (FEV1%). Results A total of 91 subjects were enrolled in the study. There were no differences between the vitamin D3 and placebo groups in time to next pulmonary exacerbation or death at 1 y. In addition, there were no differences in serial recovery of lung function after pulmonary exacerbation by FEV1% or in serial concentrations of plasma cathelicidin. Conclusions Vitamin D3 initially given at the time of pulmonary exacerbation of CF did not alter the time to the next pulmonary exacerbation, 12-mo mortality, serial lung function, or serial plasma cathelicidin concentrations. This trial was registered at clinicaltrials.gov as NCT01426256. [ABSTRACT FROM AUTHOR]

Dietary fiber strongly impacts the microbiota. Here, we show that a low-fiber diet changes the small intestinal (SI) microbiota and impairs SI Th17, TCRαβ+CD8αβ+ and TCRαβ+CD8αα+ intraepithelial T cell development. We restore T cell development with dietary fiber supplementation, but this defect becomes persistent over generations with constant low-fiber diets. Offspring of low-fiber diet-fed mice have reduced SI T cells even after receiving a fiber-rich diet due to loss of bacteria important for T cell development. In these mice, only a microbiota transplant from a fiber-rich diet-fed mouse and a fiber-rich diet can restore T cell development. Low-fiber diets reduce segmented filamentous bacteria (SFB) abundance, impairing its vertical transmission. SFB colonization and a fiber-rich diet partially restore T cell development. Finally, we observe that low-fiber diet-induced T cell defects render mice more susceptible to Citrobacter rodentium infection. Together, these results demonstrate the importance of fiber to microbiota vertical transmission and host immune system development. [Display omitted] • Low-fiber diet changes the microbiota and impair the development of intestinal T cells • Mice fed low-fiber diet over generations have persistent defects in intestinal T cells • Low-fiber diet reduces the abundance and impairs the vertical transmission of SFB • Dietary fiber and SFB are needed for the development of CD8αβ intraepithelial T cells Royer et al. show that low-fiber diets change the small intestinal microbiota and impairs the development of intestinal T cells. This defect becomes persistent over generations of mice fed low-fiber diets due to impaired vertical transmission of SFB. This study demonstrates the importance of fiber for microbiota transmission and immune system development. [ABSTRACT FROM AUTHOR]

According to the One Plan Approach to Conservation, proposed by the IUCN SSC Conservation Planning Specialist Group (CPSG), there is, besides in situ conservation measures, also increased need for ex situ conservation breeding of threatened taxa. To gain a better overview of the current situation, we have compiled information from the zoo databases ZIMS (Zoological Information Management System) and ZTL (Zootierliste) on the husbandry of gecko species (suborder Gekkota) worldwide. Only 9.3 % (n = 201) of the 2151 currently recognized gecko species from seven families were kept according to ZIMS, of which about 20.4 % (n = 41) were classified as threatened. Most species were kept in European, North American and Australian zoos. Many of the species were kept outside the natural distributional range hotspots of geckos. However, institutions in Oceania kept mainly native geckos. The species richness of the natural distributional ranges of zoo-kept geckos was highest in Australia, Southeast Asia, Madagascar and lowest in South America. About 38.0 % (n = 25) of zoo-kept species with a successful breeding record were threatened, and most reproductive successes of threatened species have been recorded from only one institution per species. Although Gekkota is the most species-rich group among lizards (Sauria), they are still relatively poorly represented in zoological institutions, and most of the kept species are not threatened. Zoos inside and outside the distributional range can play a key role in conservation (breeding) programs, when they continue to provide their expertise and resources for the buildup of insurance colonies for threatened taxa. Preferably this is carried out in cooperation with experts and conservation centers from the species' range countries and also in cooperation with Citizen Conservation programs. [ABSTRACT FROM AUTHOR]

Summary Background The medial femoral condyle (MFC) flap is based on the descending genicular artery (DGA), which is a vessel with different variations in its course and branching patterns. Many studies have dealt with the vascular anatomy of the MFC. However, the results of the investigations differ markedly. Methods The authors performed a systematic literature search in MEDLINE for articles published until May 2017 on the vascular anatomy of the DGA. After the screening, 23 relevant studies with a similar topic were included into this comprehensive analysis. Results The systematic review examined the lengths and diameters of the individual arteries with regard to the vascularized bone flap of the MFC. The DGA is present in 94% of cases with an average length of 1.8 cm. In 63% of the investigated cases, the DGA divides into three terminal branches. The articular branch has an average length of 7.7 cm, the saphenous branch has a length of 10.7 cm, and the muscular branch has a length of 3.2 cm. Conclusion To ensure a secured survival of this free flap, a detailed understanding of the convoluted vascular anatomy above the MFC is necessary. We recommend the Dubois classification for a systematic classification of the anatomical patterns of the DGA.We present a summary of all anatomical studies dealing with the vascular supply to the MFC and the DGA to date. [ABSTRACT FROM AUTHOR]

Background: Both systemic redox status and diet quality are associated with risk outcomes in chronic disease. It is not known, however, the extent to which diet quality influences plasma thiol/disulfide redox status.Objective: The purpose of this study was to investigate the influence of diet, as measured by diet quality scores and other dietary factors, on systemic thiol/disulfide redox status.Methods: We performed a cross-sectional study of 685 working men and women (ages ≥18 y) in Atlanta, GA. Diet was assessed by 3 diet quality scores: the Alternative Healthy Eating Index (AHEI), Dietary Approaches to Stop Hypertension (DASH), and the Mediterranean Diet Score (MDS). We measured concentrations of plasma glutathione (GSH), cysteine, their associated oxidized forms [glutathione disulfide (GSSG) and cystine (CySS), respectively], and their redox potentials (EhGSSG and EhCySS) to determine thiol/disulfide redox status. Linear regression modeling was performed to assess relations between diet and plasma redox after adjustment for age, body mass index (BMI), sex, race, and history of chronic disease.Results: MDS was positively associated with plasma GSH (β = 0.02; 95% CI: 0.003, 0.03) and total GSH (GSH + GSSG) (β = 0.02; 95% CI: 0.003, 0.03), and inversely associated with the CySS:GSH ratio (β = -0.02; 95% CI: -0.04, -0.004). There were significant independent associations between individual MDS components (dairy, vegetables, fish, and monounsaturated fat intake) and varying plasma redox indexes (P < 0.05). AHEI and DASH diet quality indexes and other diet factors of interest were not significantly correlated with plasma thiol and disulfide redox measures.Conclusion: Adherence to the Mediterranean diet was significantly associated with a favorable plasma thiol/disulfide redox profile, independent of BMI, in a generally healthy working adult population. Although longitudinal studies are warranted, these findings contribute to the feasibility of targeting a Mediterranean diet to improve plasma redox status. [ABSTRACT FROM AUTHOR]

Summary Background & aims In vitro studies suggest that vitamin D may reduce hepcidin expression and pro-inflammatory cytokine release from monocytes. However, data assessing the vitamin D-mediated effects on iron recycling in healthy individuals are lacking. We aimed to examine the effect of high-dose vitamin D 3 on plasma hepcidin, inflammatory cytokine, and ferritin concentrations in healthy adults. Methods This was a pilot, double-blind, placebo-controlled trial in healthy adults (N = 28) randomized to receive a one-time oral dose of 250,000 IU of vitamin D 3 or placebo. Between- and within-group differences in plasma hepcidin, pro-inflammatory cytokine [interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1)], and ferritin concentrations at baseline and 1 week were determined using two-sample and paired t -tests, respectively. Results At baseline, plasma 25-hydroxyvitamin D [25(OH)D], hepcidin, pro-inflammatory cytokine, and ferritin concentrations did not differ between the two groups, and greater than 70% of subjects in both groups were vitamin D deficient (25(OH)D < 20 ng/mL). After 1 week, plasma hepcidin concentrations decreased by 73% from baseline in those who received vitamin D 3 (geometric mean ratio [GMR] = 0.27 (95% CI: 0.11–0.62); P = 0.005); there was no significant change in the placebo group (GMR = 0.73 (95% CI: 0.49–1.09); P = 0.11). Plasma cytokine and ferritin concentrations did not change significantly in either group. Conclusions High-dose vitamin D 3 significantly reduced plasma hepcidin concentrations in healthy adults 1 week post-dosing, without a change in plasma pro-inflammatory cytokine or ferritin concentrations. These data suggest that vitamin D may have a role in regulating iron recycling by acting independently of changes in pro-inflammatory markers. [ABSTRACT FROM AUTHOR]

Background Cystic fibrosis (CF) is a chronic catabolic disease often requiring hospitalization for acute episodes of worsening pulmonary exacerbations. Limited data suggest that vitamin D may have beneficial clinical effects, but the impact of vitamin D on systemic metabolism in this setting is unknown. Objective We used high-resolution metabolomics (HRM) to assess the impact of baseline vitamin D status and high-dose vitamin D 3 administration on systemic metabolism in adults with CF with an acute pulmonary exacerbation. Design Twenty-five hospitalized adults with CF were enrolled in a randomized trial of high-dose vitamin D 3 (250,000 IU vitamin D 3 bolus) versus placebo. Age-matched healthy subjects served as a reference group for baseline comparisons. Plasma was analyzed with liquid chromatography/ultra-high resolution mass spectrometry. Using recent HRM bioinformatics and metabolic pathway enrichment methods, we examined associations with baseline vitamin D status (sufficient vs. deficient per serum 25-hydroxyvitamin D concentrations) and the 7-day response to vitamin D 3 supplementation. Results Several amino acids and lipid metabolites differed between CF and healthy control subjects, indicative of an overall catabolic state. In CF subjects, 343 metabolites differed ( P < 0.05) by baseline vitamin D status and were enriched within 7 metabolic pathways including fatty acid, amino acid, and carbohydrate metabolism. A total of 316 metabolites, which showed enrichment for 15 metabolic pathways—predominantly representing amino acid pathways—differed between the vitamin D 3 - and placebo-treated CF subjects over time ( P < 0.05). In the placebo group, several tricarboxylic acid cycle intermediates increased while several amino acid-related metabolites decreased; in contrast, little change in these metabolites occurred with vitamin D 3 treatment. Conclusions Numerous metabolic pathways detected by HRM varied in association with vitamin D status and high-dose vitamin D 3 supplementation in adults with CF experiencing a pulmonary exacerbation. Overall, these pilot data suggest an anti-catabolic effect of high-dose vitamin D 3 in this clinical setting. [ABSTRACT FROM AUTHOR]

Summary Background Malnutrition is common in patients with active tuberculosis (TB), yet little information is available on serial dietary intake or body composition in TB disease. Objective To evaluate macronutrient intake and body composition in individuals with newly diagnosed TB over time. Design Adults with active pulmonary TB (n = 191; 23 with multidrug resistant TB (MDR-TB) and 36 culture-negative household contacts (controls) enrolled in a clinical trial of high-dose cholecalciferol (vitamin D 3 ) were studied. Macronutrient intake was determined at baseline, 8 and 16 weeks. Serial body composition was assessed by body mass index (BMI; kg/m 2 ) and bioelectrical impedance analysis (BIA) to estimate fat mass and fat-free mass. Descriptive statistics, repeated measures ANOVA for changes over time and linear regression were used. Results At baseline, mean daily energy, protein, fat and carbohydrate (CHO) intakes were significantly higher, and body weight, BMI, fat-free mass and fat mass were significantly lower, between TB subjects and controls. These remained significant after adjusting for age, gender, employment status and smoking. In all TB subjects, baseline mean daily intakes of energy, fat and protein were adequate when compared to the US Dietary Reference Intakes and protein significantly increased over time (p < 0.0001). Body weight, BMI, and fat and fat-free mass increased over time. MDR-TB patients exhibited lower body weight and fat-free mass over time, despite similar daily intake of kcal, protein, and fat. Conclusions Macronutrient intake was higher in TB patients than controls, but TB-induced wasting was evident. As macronutrient intake of TB subjects increased over time, there was a parallel increase in BMI, while body composition proportions were maintained. However, individuals with MDR-TB demonstrated concomitantly decreased body weight and fat-free mass over time versus drug-sensitive TB patients, despite increased macronutrient intake. Thus, MDR-TB appears to blunt anabolism to macronutrient intake, likely reflecting the catabolic effects of TB. [ABSTRACT FROM AUTHOR]

Summary Background Hospitalized, malnourished older adults have a high risk of readmission and mortality. Objective Evaluation of a high-protein oral nutritional supplement (HP-HMB) containing beta-hydroxy-beta-methylbutyrate on postdischarge outcomes of nonelective readmission and mortality in malnourished, hospitalized older adults. Design Multicenter, randomized, placebo-controlled, double-blind trial. Setting Inpatient and posthospital discharge. Patients Older (≥65 years), malnourished (Subjective Global Assessment [SGA] class B or C) adults hospitalized for congestive heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease. Interventions Standard-of-care plus HP-HMB ( n = 328) or a placebo supplement ( n = 324), 2 servings/day. Measurements Primary composite endpoint was 90-day postdischarge incidence of death or nonelective readmission. Other endpoints included 30- and 60-day postdischarge incidence of death or readmission, length of stay (LOS), SGA class, body weight, and activities of daily living (ADL). Results The primary composite endpoint was similar between HP-HMB (26.8%) and placebo (31.1%). No between-group differences were observed for 90-day readmission rate, but 90-day mortality was significantly lower with HP-HMB relative to placebo (4.8% vs. 9.7%; relative risk 0.49, 95% confidence interval [CI], 0.27 to 0.90; p = 0.018). The number-needed-to-treat to prevent 1 death was 20.3 (95% CI: 10.9, 121.4). Compared with placebo, HP-HMB resulted in improved odds of better nutritional status (SGA class, OR, 2.04, 95% CI: 1.28, 3.25, p = 0.009) at day 90, and an increase in body weight at day 30 ( p = 0.035). LOS and ADL were similar between treatments. Limitations Limited generalizability; patients represent a selected hospitalized population. Conclusions Although no effects were observed for the primary composite endpoint, compared with placebo HP-HMB decreased mortality and improved indices of nutritional status during the 90-day observation period. Clinical trial registration www.ClinicalTrials.gov NCT01626742 . [ABSTRACT FROM AUTHOR]

Background: Tuberculosis, including multidrug-resistant tuberculosis (MDR-TB), is a major global health problem. Individuals with tuberculosis disease commonly exhibit vitamin D deficiency, which may adversely affect immunity and the response to therapy. Objective: We determined whether adjunctive high-dose vitamin D3 supplementation improves outcomes in individuals with pulmonary tuberculosis disease. Design: The study was a double-blind, randomized, placebo-controlled, intent-to-treat trial in 199 individuals with pulmonary tuberculosis disease in Tbilisi, Georgia. Subjects were randomly assigned to receive oral vitamin D3 [50,000 IUs (1.25 mg) thrice weekly for 8 wk and 50,000 IU every other week for 8 wk] or a placebo concomitant with standard first-line antituberculosis drugs. The primary outcome was the time for the conversion of a Mycobacterium tuberculosis (Mtb) sputum culture to negative. Results: Baseline characteristics between groups were similar. Most subjects (74%) were vitamin D deficient (plasma 25-hydroxyvitamin D [25(OH)D] concentration,50 nmol/L). With vitamin D3, plasma 25(OH)D concentrations peaked at ~250 nmol/L by 8 wk and decreased to ~125 nmol/L at week 16. Adverse events and plasma calcium concentrations were similar between groups. In 192 subjects with culture-confirmed tuberculosis, an adjusted efficacy analysis showed similar median culture-conversion times between vitamin D3 and placebo groups [29 and 27 d, respectively; HR: 0.86; 95% CI: 0.63, 1.18; P = 0.33). Eight-week culture-conversion rates were also similar (84.0% and 82.1% for vitamin D3 and placebo, respectively; P = 0.99). Conclusion: A high-dose vitamin D3 regimen safely corrected vitamin D deficiency but did not improve the rate of sputum Mtb clearance over 16 wk in this pulmonary tuberculosis cohort. This trial was registered at clinicaltrials.gov at NCT00918086. [ABSTRACT FROM AUTHOR]

Four carbohydrate-derived 2-pyridyl and 2-quinolinyl substituted spiro-oxazoline ligands were prepared from 3,4,5-tri-O-benzyl-1,2-di-O-isopropylidene-β- d -fructose in four steps. Conversion of the latter compound with trimethylsilylazide followed by hydrogenation gave an anomeric mixture of 2-amino-3,4,5-tri-O-benzyl-2-deoxy-1-O-trimethylsilyl- d -fructopyranose. Amide coupling of the fructosylamines with picolinic acid and quinaldic acid, respectively afforded the corresponding anomeric amidofructosides, which were both separated and characterized by NMR spectroscopy and X-ray crystallography. Cyclization of alpha-amides was achieved by treatment of the corresponding mesylates with NaH while beta-amides were directly cyclisized with NCS and Ph 3 P to give the corresponding 2-pyridyl (PyOx) and 2-quinolyl (QuinOx) substituted spiro-oxazoline ligands, respectively. The 2-pyridyl substituted spiro-oxazoline ligands PyOx formed stable complexes with Pd(II), which were fully characterized and their structure determined by X-ray crystallography, whereas the corresponding QuinOx ligands failed to form similar Pd complexes. [ABSTRACT FROM AUTHOR]

Summary: Background & aim: To develop and evaluate a culture-specific nutrient intake assessment tool for use in adults with pulmonary tuberculosis (TB) in Tbilisi, Georgia. Methods: We developed an instrument to measure food intake over 3 consecutive days using a questionnaire format. The tool was then compared to 24 h food recalls. Food intake data from 31 subjects with TB were analyzed using the Nutrient Database System for Research (NDS-R) dietary analysis program. Paired t-tests, Pearson correlations and intraclass correlation coefficients (ICC) were used to assess the agreement between the two methods of dietary intake for calculated nutrient intakes. Results: The Pearson correlation coefficient for mean daily caloric intake between the 2 methods was 0.37 (P = 0.04) with a mean difference of 171 kcals/day (p = 0.34). The ICC was 0.38 (95% CI: 0.03–0.64) suggesting the within-patient variability may be larger than between-patient variability. Results for mean daily intake of total fat, total carbohydrate, total protein, retinol, vitamins D and E, thiamine, calcium, sodium, iron, selenium, copper, and zinc between the two assessment methods were also similar. Conclusions: This novel nutrient intake assessment tool provided quantitative nutrient intake data from TB patients. These pilot data can inform larger studies in similar populations. [Copyright &y& Elsevier]

Background: Vitamin D deficiency contributes to secondary hyperparathyroidism, which occurs early in chronic kidney disease (CKD). Objectives: We aimed to determine whether high-dose cholecalciferol supplementation for 1 y in early CKD is sufficient to maintain optimal vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] concentration >30 ng/mL) and decrease serum parathyroid hormone (PTH). A secondary aim was to determine the effect of cholecalciferol on blood pressure and serum fibroblast growth factor-23 (FGF23). Design: This was a double-blind, randomized, placebo-controlled trial. Forty-six subjects with early CKD (stages 2-3) were supplemented with oral cholecalciferol (vitamin D group; 50,000 IU/wk for 12 wk followed by 50,000 IU every other week for 40 wk) or a matching placebo for 1 y. Results: By 12 wk, serum 25(OH)D increased in the vitamin D group only [baseline (mean ± SD): 26.7 ± 6.8 to 42.8 ± 16.9 ng/mL; P < 0.05] and remained elevated at 1 y (group-by-time interaction: P < 0.001). PTH decreased from baseline only in the vitamin D group (baseline: 89.1 ± 49.3 to 70.1 ± 24.8 pg/mL; P = 0.01) at 12 wk, but values were not significantly different from baseline at 1 y (75.4 ± 29.5 pg/mL; P = 0.16; group-by-time interaction: P = 0.09). Group differences were more pronounced in participants with secondary hyperparathyroidism (group-by-time interaction: P = 0.004). Blood pressure and FGF23 did not change in either group. Conclusions: After 1 y, this oral cholecalciferol regimen was safe and sufficient to maintain serum 25(OH)D concentrations and prevent vitamin D insufficiency in early CKD. Furthermore, serum PTH improved after cholecalciferol treatment, particularly in patients who had secondary hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Background: Evidence links dietary sodium to hypertension and cardiovascular disease (CVD), but investigation of its influence on cardiovascular function is limited. Objective: We examined the relation between habitual dietary sodium and coronary flow reserve (CFR), which is a measure of overall coronary vasodilator capacity and microvascular function. We hypothesized that increased sodium consumption is associated with lower CFR. Design: Habitual daily sodium intake for the previous 12 mo was measured in 286 male middle-aged twins (133 monozygotic and di- zygotic pairs and 20 unpaired twins) by using the Willett food-frequency questionnaire. CFR was measured by positron emission tomography [N13]-ammonia, with quantitation of myocardial blood flow at rest and after adenosine stress. Mixed-effects regression analysis was used to assess the association between dietary sodium and CFR. Results: An increase in dietary sodium of 1000 mg/d was associated with a 10.0% lower CFR (95% CI: -17.0%, -2.5%) after adjustment for demographic, lifestyle, nutritional, and CVD risk factors (P = 0.01). Across quintiles of sodium consumption, dietary sodium was inversely associated with CFR (P-trend = 0.03), with the top quintile (> 1456 mg/d) having a 20% lower CFR than the bottom quintile (<732 mg Id). This association also persisted within pairs: a 1000-mg/d difference in dietary sodium between brothers was associated with a 10.3% difference in CFR after adjustment for potential confounders (P = 0.02). Conclusions: Habitual dietary sodium is inversely associated with CFR independent of CVD risk factors and shared familial and genetic factors. Our study suggests a potential novel mechanism for the adverse effects of dietary sodium on the cardiovascular system. This trial was registered at clinicaltrials.gov as NCT00017836. [ABSTRACT FROM AUTHOR]

Abstract: The three oligosaccharide octyl-S-glycosides Man-α1,6-Man-α1,4-GlcNH2-α1,S-Octyl (19), Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH2-α1,S-Octyl (27) and Man-α1,2-Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH2-α1,S-Octyl (37), related to the GPI anchor of Trypanosoma brucei were prepared by a stepwise and block-wise approach from octyl 2-azido-2-deoxy-3,6-di-O-benzyl-1-thio-α-d-glucopyranoside (8) and octyl 2-O-benzoyl-4,6-O-(1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl)-1-thio-α-d-mannopyransoside (9). Glucosamine derivative 8 was obtained from 1,3,4,6-tetra-O-acetyl-2-azido-2-desoxy-β-d-glucopyranose (1) in five steps. Mannoside 9 was converted into the corresponding imidate 12 and coupled with 8 to give disaccharide octyl-S-glycoside 13 which was further mannosylated to afford trisaccharide 19 upon deprotection. Likewise, mannoside 9 was galactosylated, converted into the corresponding imidate and coupled with 8 to give trisaccharide 25. Mannosylation of the latter afforded tetrasaccharide 27 upon deprotection. Condensation of 25 with disaccharide imidate 35 gave, upon deprotection of the intermediates, the corresponding pentasaccharide octyl-S-glycoside 37. Saccharides 19, 27 and 37 are suitable substrates for studying the enzymatic glycosylation pattern of the GPI anchor of T. brucei. [Copyright &y& Elsevier]

The content of sulfur amino acid (SAA) in a meal affects postprandial plasma cysteine concentrations and the redox potential of cysteine/cystine. Because such changes can affect enzyme, transporter, and receptor activities, meal content of SAA could have unrecognized effects on metabolism during the postprandial period. This pilot study used proton NMR (1H-NMR) spectroscopy of human plasma to test the hypothesis that dietary SAA content changes macronutrient metabolism. Healthy participants (18-36 y, 5 males and 3 females) were equilibrated for 3 d to adequate SAA, fed chemically defined meals without SAA for 5 d (depletion), and then fed isoenergetic, isonitrogenous meals containing 56 mg·kg-1 ·d-1 SAA for 4.5 d (repletion). On the first and last day of consuming the chemically defined meals, a morning meal containing 60% of the daily food intake was given and plasma samples were collected over an 8-h postprandial time course for characterization of metabolic changes by 1H-NMR spectroscopy. SAA-free food increased peak intensity in the plasma 1H-NMR spectra in the postprandia) period. Orthogonal signal correction/partial least squares-discriminant analysis showed changes in signals associated with lipids, some amino acids, and lactate, with notable increases in plasma lipid signals (TG, unsaturated lipid, cholesterol). Conventional lipid analyses confirmed higher plasma TG and showed an increase in plasma concentration of the lipoprotein lipase inhibitor, apoC-III. The results show that plasma 1H-NMR spectra can provide useful macronutrient profiling following a meal challenge protocol and that a single meal with imbalanced SAA content alters postprandial lipid metabolism. [ABSTRACT FROM AUTHOR]

Abstract: Noninvasive monitoring of intracellular targets such as enzymes, receptors, or mRNA by means of magnetic resonance imaging (MRI) is increasingly gaining relevance in various research areas. A vital prerequisite for their visualization is the development of cell-permeable imaging probes, which can specifically interact with the target that characterizes the cellular or molecular process of interest. Here, we describe a dual-labeled probe, Gd-DOTA-k(FR)-Gal-CPP, designed to report the presence of intracellular β-galactosidase (β-gal) enzyme by MRI. This conjugate consists of a galactose based core serving as cleavable spacer, incorporated between the cell-penetrating peptide D-Tat49–57 and reporter moieties (Gd-DOTA, fluorescein (FR)). We employed a facile building block approach to obtain our bimodal probe, Gd-DOTA-k(FR)-Gal-CPP. This strategy involved the preparation of the building blocks and their subsequent assembly using Fmoc-mediated solid phase synthesis, followed by the complexation of ligand 14 with GdCl3. Gd-DOTA-k(FR)-Gal-CPP showed a considerably higher relaxivity enhancement (16.8±0.6mM−1 s−1, 123MHz, ∼21°C) relative to the commercial Gd-DOTA (4.0±0.12mM−1 s−1, 123MHz, ∼21 °C). The activation of Gd-DOTA-k(FR)-Gal-CPP was based on a cellular retention strategy that required enzymatic cleavage of the delivery vector from galactose moiety following the cell internalization to achieve a prolonged accumulation of the reporter components (Gd-DOTA/FR) in the β-gal expressing cells. Cellular uptake of Gd-DOTA-k(FR)-Gal-CPP in β-gal expressing C6/LacZ and enzyme deficient parental C6 rat glioma cells was confirmed by fluorescence spectroscopy, MR imaging and ICP-AES measurements. All methods showed higher accumulation of measured reporters in C6/LacZ cells compared to enzyme deficient parental C6 cells. Fluorescence microscopy of cells labeled with Gd-DOTA-k(FR)-Gal-CPP indicated a predominantly vesicular localization of the green fluorescent conjugate around cell nuclei. This cellular distribution was most likely responsible for the observed non-specific background signal in the enzyme deficient C6 cells. Even though the specific accumulation of our bimodal probe has to be further improved, it could be already used for cell imaging by MRI and optical modalities. [Copyright &y& Elsevier]

Few data are available on plasma redox responses to sulfur amino acid (SAA) loads. In this study, we had 2 aims: to determine whether the SAA content of a meal affected postprandial plasma cysteine (Cys), cystine (CySS), or redox potential (EhCySS) in humans and whether SAA intake level (adequate or inadequate) in the days preceding the meal challenge affected these postprandial levels. Eight healthy individuals aged 18-36 y were equilibrated for 3 d to adequate SAA, fed chemically defined meals without SAA for 5 d (inadequate SM) and then fed isoenergetic, isonitrogenous meals with adequate SAA for 5 d. On the first and last days with the chemically defined meals, a morning meal containing 60% of the daily food intake was given, and plasma Cys, CySS, and ECySS were determined over an 8-h postprandial time course. Following equilibration to adequate intake, provision of the meal with SAA resulted in increased plasma Cys and CySS concentrations and more reduced plasma EhCySS compared with the postprandial values following the same meal without SM. Equilibration to inadequate SAA intake for the days preceding the meal challenge did not affect this response. The magnitude of the difference in postprandial plasma EhCySS (10 mV) due to meal content of SAA was comparable to those which alter physiologic signaling and/or are associated with disease risk. Consequently, the SAA content of meals could affect physiologic signaling and associated disease mechanisms in the postprandial period by changes in Cys, CySS, or EhCySS. [ABSTRACT FROM AUTHOR]

Treatment of disodium maleonitriledithiolate with 1,2:3,4-di- O -isopropylidene-6- O -trifluoromethanesulfonyl-α- d -galactopyranose gives 2,3-bis(6-deoxy-1,2:3,4-di- O -isopropylidene-6-thio-α- d -galactopyranos-6-yl)maleonitrile in 87% yield. Heating of the latter with magnesium bis(butan-1-olate) in butan-1-ol affords [2,3,7,8,12,13,17,18-octakis(6-deoxy-1,2:3,4-di- O -isopropylidene-6-thio-α- d -galactopyranos-6-yl)porphyrazinato]magnesium(II) in 53% yield. The glycoconjugated porphyrazine has an absorbance maximum at 673 nm and is a candidate as photosensitizer for photodynamic therapy. [ABSTRACT FROM AUTHOR]

Following massive small bowel resection in animal models, the remnant intestine undergoes a dynamic growth response termed intestinal adaptation. Cell growth and proliferation are intimately linked to cellular and extracellular thiol/disulfide redox states, as determined by glutathione (GSH) and GSH disulfide (GSSG) (the major cellular redox system in tissues), and cysteine (Cys) and its disulfide cystine (CySS) (the major redox system in plasma), respectively. The study was designed to determine whether dietary supplementation with sulfur amino acids (SM) leads to a greater reduction in thiol/ disulfide redox state in plasma and small bowel and colonic mucosa and alters gut mucosal growth in an established rat model of short bowel syndrome (SBS). Adult rats underwent 80% jejunal-ileal resection (RX) or small bowel transection (surgical control) and were pair-fed either isonitrogenous, isocaloric SAA-adequate (control) or SM-supplemented diets 1218% increase vs. control diet). Plasma and gut mucosal samples were obtained after 7 d and analyzed for Cys, CySS, GSH, and GSSG concentrations by HPLC. Redox status (Eb) of the Cys/CySS and GSH/GSSG couples were calculated using the Nernst equation. SAA supplementation led to a greater reduction in Eh GSH/GSSG in jejunal and ileal mucosa of resected rats compared with controls. Resected SM-supplemented rats showed increased ileal adaptation (increased full-thickness wet weight, DNA, and protein content compared with RX control-fed rats; increased mucosal crypt depth and villus height compared with all other study groups). These data suggest that SM supplementation has a trophic effect on ileal adaptation after massive small bowel resection in rats. This finding may have translational relevance as a therapeutic strategy in human SBS. [ABSTRACT FROM AUTHOR]

Summary: Background: Glutamine (Gln) may become conditionally indispensable during critical illness. The short-term metabolic effects of enteral versus parenteral Gln supplementation are unknown in this clinical setting. Objectives: We studied metabolic effects of intravenous (IV) alanyl-Gln dipeptide (AG) supplementation and enteral (EN) AG supplementation on plasma Gln concentration, antioxidant status, plasma lymphocyte subset number, gut permeability and nitrogen balance in adult critically ill patients requiring tube feeding compared to a control group not receiving Gln supplementation. Methods: In a double-blind, pilot clinical trial, 44 medical and surgical ICU patients received identical Gln-free tube feedings 24h/day and were randomized to either isonitrogenous control (n =15), EN AG (n =15) or IV AG (n =14) groups (AG). Twelve patients were discontinued from the study. The goal AG dose was 0.5g/kg/day. Biochemical and metabolic endpoints were measured at baseline and on day 9 (plasma Gln, antioxidant indices, lymphocyte subsets; serum IGF-1 and IGF-binding protein-3; intestinal permeability). Nitrogen balance was determined between study days 6 and 8. Results: Illness severity indices, clinical demographics, enteral energy and nitrogen intake and major biochemical indices were similar between groups during study. Plasma Gln was higher in the IV AG (565±119μM, mean±SEM) vs the EN AG (411±27μM) group by day 9 (p =0.039); however, subjects in the IV AG group received a higher dose of AG (IV AG 0.50 versus EN AG 0.32±0.02g/kg/day; p <0.001). EN AG subjects showed a significant increase in plasma α-tocopherol levels over time and maintained plasma γ-tocopherol concentrations. There were no differences between groups for plasma concentrations of vitamin C, glutathione, malondialdehyde (MDA), T-lymphocyte subsets, intestinal permeability or nitrogen balance. Conclusions: This study showed that alanyl-Gln administration by enteral or parenteral routes did not appear to affect antioxidant capacity or oxidative stress markers, T-lymphocyte subset (CD-3, CD-4, CD-8) number, gut barrier function or whole-body protein metabolism compared to unsupplemented ICU patients requiring enteral tube feeding. Enteral Gln appeared to maintain plasma tocopherol levels in this pilot metabolic study. [Copyright &y& Elsevier]

Abstract: Cu(I)-catalyzed 1,3-dipolar cycloaddition (click reaction) of 1molequiv of N,N′-di-prop-2-ynyl-phthalamide (1a), N,N′-di-prop-2-ynyl-isophthalamide (1b), and pyridine-2,6-dicarboxylic acid bis-prop-2-ynylamide (1c), respectively with 2molequiv of 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl azide (2a), 2-azidoethyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (2b), and 2-azidoethyl 2,3,4,6-tetra-O-acetyl-α-d-mannopyranoside (2c), respectively, afforded the corresponding bis-cycloadducts 3–5, containing two 1,2,3-triazole moieties each, in 38–76% yield. Reaction of 1molequiv of 2c with 1molequiv of 1c under otherwise identical conditions gave the mono-cycloadduct 6, containing one 1,2,3-triazole and one 2-propynylamide moiety, in 77% yield. Reaction of 6 with 2a afforded 7, containing two different sugar moieties, in 67% yield. [Copyright &y& Elsevier]

Abstract: Little is known about the relative sensitivities of antioxidant systems in nuclei, mitochondria, and cytoplasm. The present study examined the oxidation of the thiol-dependent antioxidant systems in these subcellular compartments under conditions of limited energy supply of human colonic epithelial HT-29 cells induced by depletion of glucose (Glc) and glutamine (Gln) from the culture medium. Increased oxidation of dichlorofluoroscein (DCF) indicated an increased level of reactive oxygen species (ROS). Redox Western blot analysis showed oxidation of cytosolic thioredoxin-1 (Trx1) and mitochondrial thioredoxin-2 (Trx2) by 24 h, but little oxidation of nuclear Trx1. The Trx1 substrate, redox factor-1 (Ref-1), was also oxidized in cytosol but was reduced in nuclei. Protein S-glutathionylation (PrSSG), expressed as a ratio of protein thiol (PrSH), was also increased in the cytosol, while nuclear PrSSG/PrSH was not. Taken together, the data show that oxidative stress induced by depletion of Glc and Gln affects the redox states of proteins in the cytoplasm and mitochondria more than those in the nucleus. These results indicate that the nuclear compartment has better protection against oxidative stress than cytoplasm or mitochondria. These results further suggest that energy and/or substrate supply may contribute to sensitivity of mitochondrial and cytoplasmic systems to oxidative damage. [Copyright &y& Elsevier]

Glutathione (GSH) concentration affects cell proliferation and apoptosis in intestinal and other cell lines in vitro. However, in vivo data on gut mucosal GSH redox status and cell turnover are limited. We investigated the effect of altered GSH redox status on the ileal mucosa in a rat model of short bowel syndrome following massive small bowel resection (SBR). Rats underwent 80% mid-jejunoileal resection (RX) or small bowel transection (TX; as operative controls), with administration of either saline or D, L-buthionine-sulfoximine (BSO), a specific inhibitor of cellular GSH synthesis. Ileal mucosal redox, morphology, and indices of cell proliferation and apoptosis were determined at different days after surgery. Ileal GSH redox status was assessed by GSH and GSH disulfide (GSSG) concentrations and the redox potential of GSH/GSSG (Eh). Ileal lipid peroxidation [free malondialdehyde (MDA)] was measured as an index of lipid peroxidation. BSO markedly decreased ileal mucosal GSH, oxidized GSH/GSSG Eh, and increased MDA content without inducing morphological damage as assessed by light or electron microscopy. As expected, SBR stimulated adaptive growth of ileal villus height and total mucosal height at 7 d after surgery, but this response was unaffected by BSO treatment despite a modest increase in crypt cell apoptosis. Ileal cell proliferation (crypt cell bromodeoxyuridine incorporation) increased at 2 d after SBR but was unaffected by BSO. Collectively, our in vivo data show that marked depletion of ileal GSH and oxidation of the GSH redox pool does not alter indices of ileal epithelial proliferation or SBR-induced ileal mucosal adaptive growth. [ABSTRACT FROM AUTHOR]

Glutathione (GSH) concentration affects cell proliferation and apoptosis in intestinal and other cell lines in vitro. However, in vivo data on gut mucosal GSH redox status and cell turnover are limited. We investigated the effect of altered GSH redox status on the ileal mucosa in a rat model of short bowel syndrome following massive small bowel resection (SBR). Rats underwent 80% mid-jejunoileal resection (RX) or small bowel transection (TX; as operative controls), with administration of either saline or D, L-buthionine-sulfoximine (BSO), a specific inhibitor of cellular GSH synthesis. Ileal mucosal redox, morphology, and indices of cell proliferation and apoptosis were determined at different days after surgery. Ileal GSH redox status was assessed by GSH and GSH disulfide (GSSG) concentrations and the redox potential of GSH/GSSG (Eh). Ileal lipid peroxidation [free malondialdehyde (MDA)] was measured as an index of lipid peroxidation. BSO markedly decreased ileal mucosal GSH, oxidized GSH/GSSG Eh, and increased MDA content without inducing morphological damage as assessed by light or electron microscopy. As expected, SBR stimulated adaptive growth of ileal villus height and total mucosal height at 7 d after surgery, but this response was unaffected by BSO treatment despite a modest increase in crypt cell apoptosis. Ileal cell proliferation (crypt cell bromodeoxyuridine incorporationl increased at 2 d after SBR but was unaffected by BSO. Collectively, our in vivo data show that marked depletion of ileal GSH and oxidation of the GSH redox pool does not alter indices of ileal epithelial proliferation or SBR-induced ileal mucosal adaptive growth. [ABSTRACT FROM AUTHOR]

Background: The cytokine response to operative trauma may be altered in obesity. Thus, we monitored changes in systemic and adipose tissue content of interleukin 6 (IL-6) and in insulin resistance in nonobese versus severely obese patients before and immediately after abdominal operations. Methods: At the beginning and the end of operation, blood samples and biopsies consisting of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were collected from 13 nonobese and 33 severely obese patients. Systemic concentrations of glucose, insulin, and IL-6, as well as adipose tissue content of IL-6, were determined. Results: Plasma IL-6 concentration and adipose tissue content of IL-6 increased, compared with baseline in patients after operation (plasma, 13- and 5.7-fold; VAT, 270- and 210-fold; SAT, 79- and 8.2-fold in severely obese vs nonobese patients, respectively). The increase in IL-6 in plasma and in both VAT and SAT was exaggerated in severely obese patients, compared with nonobese patients. Increases after operation in plasma IL-6 concentrations were correlated positively to the corresponding increases in both SAT and VAT IL-6 content (r = 0.57 and 0.66, respectively). Also, we found a positive correlation between the worsening of insulin resistance and increases in both plasma and SAT IL-6 concentrations (r = 0.40 and 0.51, respectively). Conclusions: Circulating IL-6 concentrations both at baseline and after operation are related strongly to abdominal adipose tissue content of content of IL-6 and are exaggerated in severely obese persons. After operation, worsening of insulin resistance is associated with increasing plasma and adipose tissue content of IL-6. [Copyright &y& Elsevier]

Low molecular weight thiol/disulfide redox pools are dependent upon extracellular cysteine (Cys) availability. We determined whether dietary sulfur amino acid (SAA) deficiency induces oxidative stress in vivo, as determined by redox state of major thiol/disulfide couples in plasma [Cys/cystine (CySS)] and intestinal mucosa [glutathione (GSH)/glutathione disulfide (GSSG)]. Rats were fed isocaloric, isonitrogenous semipurified diets: either SAA-adequate (control), SAA-deficient, or SAA-supplemented, pair-fed to intake of the SAA-deficient group. Reference rats consumed standard rat food ad libitum. After 7 d, plasma and gut mucosal samples were analyzed for Cys, CySS, GSH and GSSG, and the redox potentials of Cys/CySS and GSH/GSSG were determined. Mean daily food intake in the pair-fed rats was similar (approximately one-half of reference-rat intake). Body weight decreased in all pair-fed groups, but rats fed the SAA-deficient diet lost significantly more body weight. Dietary SAA deficiency decreased GSH concentrations in both plasma and gut mucosa, increased plasma GSSG, and oxidized plasma and gut mucosal GSH/GSSG redox and plasma Cys/CySS redox. SAA supplementation resulted in a more reducing plasma Cys/CySS redox potential. Reference rats exhibited similar tissue and plasma GSH/GSSG redox as rats that ate semipurified SAA-adequate rat food, which provided similar net SAA intake. Our in vivo data show that inadequate dietary SAA intake oxidizes the thiol/disulfide redox status in rat-gut mucosa and plasma. Such oxidation of redox pools is associated with oxidative stress and the onset or progression of several pathological conditions. Thus, dietary SAA deficiency could contribute to the progression of disease by causing an oxidation of these components. [ABSTRACT FROM AUTHOR]

The production of inflammatory mediators by abdominal adipose tissue may link obesity and insulin resistance. We determined the influence of systemic levels of interleukin-6 and C-reactive protein on insulin sensitivity after weight loss via Roux-en-Y gastric bypass surgery. Severely obese individuals (n = 15) were evaluated at baseline and at 6 months after surgery. Insulin sensitivity was determined by frequently sampled intravenous glucose tolerance testing at the same time points. Visceral and subcutaneous adipose tissue volumes were quantified by computed tomography. Interleukin-6 and C-reactive protein were measured by enzyme-linked immunoassay in plasma and in adipose tissue biopsies. Correlation analysis was used to determine associations between insulin sensitivity and other outcome variables. Significance was set at P < 0.05. Plasma interleukin-6 concentrations were significantly correlated to the IL-6 content of subcutaneous adipose tissue (r = 0.71). At 6 months postsurgery, subcutaneous and visceral adipose tissue volumes were significantly reduced (34.7% and 44.1%, respectively) and insulin sensitivity had improved by 160.9%. Significant longitudinal correlations were found between insulin sensitivity and plasma C-reactive protein (r = −0.61), but not plasma interleukin-6 at 6 months. These findings offer insights that link obesity and insulin resistance via the activity of inflammatory mediators. [Copyright &y& Elsevier]

Myopathies related to critical illness have received increasing recognition over the past decade and are common in patients even after a brief period in the intensive care unit. Recent studies have revealed that myopathies in the critically ill may in fact be more prevalent than neuropathies and that morbidity and mortality may be greater. Protein catabolism, an increase in urinary nitrogen loss, and muscle wasting are observed in critical illness myopathy. Muscle biopsies in critically ill patients demonstrate low glutamine levels, low protein/DNA levels, and high concentrations of extracellular water. The increased flux of glutamine in muscle in these patients is thought to be insufficient to meet the body's requirement for glutamine, and thus in critical illness this amino acid may be classified as "conditionally essential." Three subtypes of critical illness myopathy have been described that are often grouped together as acute quadriplegic myopathy: thick-filament myopathy, critical illness myopathy, and necrotizing myopathy. These can be differentiated based on clinical features and muscle biopsy. Treatments for critical illness myopathies range from primary prevention, i.e., avoiding myopathy-inducing drugs, to novel nutritional therapies, such as glutamine and glutathione supplementation. One should be particularly vigilant for the development of myopathies in critically ill alcoholic patients, who may have a chronic alcoholic myopathy at baseline. In the past decade, advances have been made in characterizing and identifying patients with myopathies due to critical illness. However, additional studies must be performed in order to develop appropriate therapies for this potentially devastating disorder. [ABSTRACT FROM AUTHOR]

Two weeks after 70% enterectomy, glutamine (Gln) transport is downregulated in rabbit residual bowel due to a decrease in system B(0) activity. Providing epidermal growth factor (EGF) and growth hormone (GH) restores Gln transport by increasing systems A and B(0,+) activities. We hypothesized that changes in Na(+)-dependent broad-spectrum neutral amino acid transporter (ATB(0)/ASCT2) protein and mRNA expression correlate with system B(0) activity. New Zealand White rabbits underwent 70% jejunoileal resection or no resection. Resected rabbits immediately received parenteral EGF, GH, both, or neither agent for 2 wk. Tissues harvested from jejunum, ileum, and colon were subjected to Western and Northern blot analyses for ATB(0)/ASCT2 protein and mRNA. In all tissues, ATB(0)/ASCT2 mRNA was reduced by approximately 50% in resected rabbits compared with nonresected controls. Similar reductions in protein amount occurred in the ileum and cecum. None of the growth factor treatments restored ATB(0)/ASCT2 protein, but GH treatment increased ATB(0)/ASCT2 mRNA abundance 250% in the residual ileum. Because changes in the ATB(0)/ASCT2 protein amount paralleled those in the system B(0) activity in this model, it is likely that this is the protein responsible for this transport system. The increase in mRNA abundance in rabbits treated with GH for 2 wk may be a harbinger of subsequent increases in transporter protein and activity. Unlike reported upregulation of transporters in human colon after small bowel resection, ATB(0)/ASCT2 protein and mRNA expression in rabbit colon are decreased, suggesting different regulatory pathways. [ABSTRACT FROM AUTHOR]

Wnts are morphogens with well recognized functions during embryogenesis. Aberrant Wnt signaling has been demonstrated to be important in colorectal carcinogenesis. However, the role of Wnt in regulating normal intestinal epithelial cell proliferation is not well established. Here we determine that Wnt11 is expressed throughout the mouse intestinal tract including the epithelial cells. Conditioned media from Wnt11-secreting cells stimulated proliferation and migration of IEC6 intestinal epithelial cells. Co-culture of Wnt11-secreting cells with IEC6 cells resulted in morphological transformation of the latter as evidenced by the formation of foci, a condition also accomplished by stable transfection of IEC6 with a Wnt11-expressing construct. Treatment of IEC6 cells with Wnt11 conditioned media failed to induce nuclear translocation of β-catenin but led to increased activities of protein kinase C and Ca2+ /calmodulin-dependent protein kinase II. Inhibition of protein kinase C resulted in a decreased ability of Wnt11 to induce foci formation in IEC6 cells. Finally, E-cadherin was redistributed in Wnt11-treated IEC6 cells, resulting in diminished E-cadherin-mediated cell-cell contact. We conclude that Wnt11 stimulates proliferation, migration, cytoskeletal rearrangement, and contact-independent growth of IEC6 cells by a β-eatenin-independent mechanism. These findings may help understand the molecular mechanisms that regulate proliferation and migration of intestinal epithelial cells. [ABSTRACT FROM AUTHOR]

Epithelial cell apoptosis is an important regulator of normal gut mucosal turnover; however, excessive apoptosis may inhibit mucosal restitution during pathophysiologic states. Apoptosis is induced by oxidative stress and cytokines, but regulation by specific nutrients has been infrequently studied under these conditions. Glutamine (Gln) is an important metabolic fuel for intestinal epithelial cells and a precursor to the antioxidant glutathione (GSH), which has antiapoptotic effects. In cultured intestinal epithelial cells, Gln depletion increases oxidant-induced apoptosis. This study examined whether Gln protects against apoptosis induced by the cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) in the human colon carcinoma cell line, HT-29. TRAIL-induced apoptosis in HT-29 cells was characterized by an increase in the percentage of cells in the sub-G1 fraction by flow cytometry, nuclear condensation and the activation of caspase-8 and caspase-3. TRAIL-induced apoptosis was completely prevented by Gln, but not inhibited by other amino acids, including the GSH constituents, glutamate, cysteine and glycine. Similar antiapoptotic effects of Gln occurred when apoptosis was induced by a combination of tumor necrosis factor-alpha and interferon-gamma. Cellular GSH was oxidized during TRAIL-induced apoptosis. This effect was completely blocked by Gln, however, inhibition of GSH synthesis with buthionine sulfoximine did not alter Gln antiapoptotic effects. Furthermore, glutamate prevented GSH oxidation in response to TRAIL but did not protect against TRAIL-induced apoptosis. These results show that Gln specifically protects intestinal epithelial cells against cytokine-induced apoptosis, and that this occurs by a mechanism that is distinct from the protection against oxidative stress mediated by cellular GSH. [ABSTRACT FROM AUTHOR]

Redox mechanisms function in regulation of cell growth, and variation in redox state of plasma thiol/disulfide couples occurs in various physiologic conditions, including diabetes, chemotherapy, and aging. The present study was designed to determine whether a systematic variation in extracellular thiol/disulfide redox state (Eh) over a range (0 mV to −150 mV) that occurs in human plasma altered proliferation of cultured cells. Experiments were performed with a human colon carcinoma cell line (Caco2), which grows slowly in the absence of serum and responds to peptide growth factors with increased rate of cell division. The extracellular redox states were established by varying concentrations of cysteine and cystine, maintaining constant pool size in terms of cysteine equivalents. Incorporation of 5-bromo-2-deoxyuridine (BrdU) was used to measure DNA synthesis and was lowest at the most oxidized extracellular Eh (0 mV). Incorporation increased as a function of redox state, attaining a 100% higher value at the most reduced condition (−150 mV). Addition of insulin-like growth factor-1 (IGF-1) or epidermal growth factor (EGF) increased the rate of BrdU incorporation at more oxidizing redox conditions (0 to −80 mV) but had no effect at −150 mV. Cellular GSH was not significantly affected by variation in extracellular Eh. In the absence of growth factors, extracellular Eh values were largely maintained for 24 h. However, IGF-1 or EGF stimulated a change in extracellular redox to values similar to that for cysteine/cystine redox in plasma of young, healthy individuals. The results show that extracellular thiol/disulfide redox state modulates cell proliferation rate and that this control interacts with growth factor signaling apparently independently of cellular glutathione. [Copyright &y& Elsevier]

Glutathione (GSH) has a central role in the maintenance of the thiol-disulfide redox state in mammalian cells. GSH synthesis can be physiologically limited by the availability of cysteine (Cys), and Cys and its precursors are variable in the human diet. The purpose of this study was to determine the effect of severe Cys deficiency and readdition of Cys on the redox state of the GSH/glutathione disulfide (GSSG) pool in human colon carcinoma HT29 cells. Cells were cultured in Cys- (and cystine-)limiting medium for 48 h followed by culture in medium containing either Cys or cystine for 24 h. GSH and GSSG were measured by HPLC. Cys limitation decreased cellular GSH and GSSG concentrations with an associated >80 mV oxidation of the GSH/GSSG redox state. Upon addition of either Cys or its disulfide cystine (CySS), redox of GSH/GSSG recovered in 4 h, whereas GSH concentration continued to increase over 12 h. Maximal GSH concentrations attained were 200% of control cell values. These results show that severe Cys deficiency can have marked effects on cellular redox state but that redox recovers rapidly upon resupply. The magnitude of oxidation during Cys limitation in this cell model is sufficient to result in a >100-fold change in the reduced/oxidized ratio of redox-sensitive dithiol/disulfide motifs in proteins. If redox changes occur in vivo in association with variations in dietary Cys and its precursors, these changes could have important physiologic effects through altered redox signaling and control of cell proliferation and apoptosis. [ABSTRACT FROM AUTHOR]