A pilot investigation to optimise methods for a future satiety preload study

Preload studies are used to investigate the satiating effects of foods and food ingredients. However, the design of preload studies is complex, with many methodological considerations influencing appetite responses. The aim of this pilot investigation was to determine acceptability, and optimise methods, for a future satiety preload study. Specifically, we investigated the effects of altering (i) energy intake at a standardised breakfast (gender-specific or non-gender specific), and (ii) the duration between mid-morning preload and ad libitum lunch meal, on morning appetite scores and energy intake at lunch. Participants attended a single study visit. Female participants consumed a 214-kcal breakfast (n = 10) or 266-kcal breakfast (n = 10), equivalent to 10% of recommended daily energy intakes for females and males, respectively. Male participants (n = 20) consumed a 266-kcal breakfast. All participants received a 250-ml orange juice preload 2 h after breakfast. The impact of different study timings was evaluated in male participants, with 10 males following one protocol (protocol 1) and 10 males following another (protocol 2). The duration between preload and ad libitum lunch meal was 2 h (protocol 1) or 2.5 h (protocol 2), with the ad libitum lunch meal provided at 12.00 or 13.00, respectively. All female participants followed protocol 2. Visual analogue scale (VAS) questionnaires were used to assess appetite responses and food/drink palatability. Correlation between male and female appetite scores was higher with the provision of a gender-specific breakfast, compared to non-gender-specific breakfast (Pearson correlation of 0.747 and 0.479, respectively). No differences in subjective appetite or ad libitum energy intake were found between protocols 1 and 2. VAS mean ratings of liking, enjoyment, and palatability were all > 66 out of 100 mm for breakfast, preload, and lunch meals. The findings of this pilot study confirm the acceptability of this methodology for future satiety preload studies. Appetite scores increased from preload to ad libitum lunch meal; however, no specific differences were found between protocols. The results highlight the importance of considering energy intake prior to preload provision, with a gender-specific breakfast improving the correlation between male and female appetite score responses to a morning preload

Evaluation of gut modulatory and bronchodilator activities of Amaranthus spinosus Linn.

Background The aqueous-methanolic extract of Amaranthus spinosus (A. spinosus Linn.,) whole plant, was studied for its laxative, spasmolytic and bronchodilator activities to validate some of its medicinal uses. Methods The crude extract of A. spinosus was studied in-vivo for bronchodilator and laxative activities and in-vitro using isolated tissue preparations which were mounted in tissue baths assembly containing physiological salt solutions, maintained at 37°C and aerated with carbogen, to assess the spasmolytic effect and to find out the possible underlying mechanisms. Results In the in-vivo experiments in mice, the administration of A. spinosus increased fecal output at doses of 100 and 300 mg/kg showing laxative activity. It also inhibited carbachol-induced bronchospasm in anesthetized rats at 1, 3, 10 and 30 mg/kg indicative of bronchodilator activity. When tested on isolated gut preparations, the plant extract showed a concentration-dependent (0.01-10.0 mg/ml) spasmogenic effect in spontaneously contracting rabbit jejunum and guinea-pig ileum. The spasmogenic effect was partially blocked in tissues pretreated with atropine (0.1 μM). When tested on K+ (80 mM)-induced sustained contractions in isolated rabbit jejunum, the plant extract caused complete relaxation and also produced a shift in the Ca++ concentration-response curves (CRCs) towards right, similar to diltiazem. In rabbit trachea, the plant extract completely inhibited K+ (80 mM) and carbachol (CCh, 1 μM)-induced contractions at 1 mg/ml but pretreatment of tissue with propranolol (1 μM), caused around 10 fold shift in the inhibitory CRCs of the plant extract constructed against CCh-induced contraction. The plant extract (up to 0.3 mg/ml) also increased both force and rate of spontaneous contractions of isolated guinea-pig atria, followed by relaxation at higher concentration (1.0-5.0 mg/ml). The cardio-stimulant effect was abolished in the presence of propranolol, similar to that of isoprenaline. Activity-directed fractionation revealed that the spasmolytic component(s) was separated in the organic fraction, whereas the spasmogenic component was concentrated in the aqueous fraction. Conclusion These results indicate that A. spinosus possesses laxative activity partially mediated through cholinergic action. The spasmolytic effect was mediated through calcium channel blocking (CCB), while bronchodilator activity through a combination of β-adrenergic and CCB pathways, which may explain the traditional uses of A. spinosus in gut and airways disorders

Effect of different protein sources on satiation and short-term satiety when consumed as a starter

<p>Abstract</p> <p>Background</p> <p>Because the source of protein may play a role in its satiating effect, we investigated the effect of different proteins on satiation and short-term satiety.</p> <p>Methods</p> <p>Two randomized single-blind cross-over studies were completed. In the first study, we investigated the effect of a preload containing 20 g of casein, whey, pea protein, egg albumin or maltodextrin vs. water control on food intake 30 min later in 32 male volunteers (25 ± 4 yrs, BMI 24 ± 0.4 kg/m²). Subjective appetite was assessed using visual analogue scales at 10 min intervals after the preload. Capillary blood glucose was measured every 30 min during 2 hrs before and after the ad libitum meal. In the second study, we compared the effect of 20 g of casein, pea protein or whey vs. water control on satiation in 32 male volunteers (25 ± 0.6 yrs, BMI 24 ± 0.5 kg/m²). The preload was consumed as a starter during an ad libitum meal and food intake was measured. The preloads in both studies were in the form of a beverage.</p> <p>Results</p> <p>In the first study, food intake was significantly lower only after casein and pea protein compared to water control (P = 0.02; 0.04 respectively). Caloric compensation was 110, 103, 62, 56 and 51% after casein, pea protein, whey, albumin and maltodextrin, respectively. Feelings of satiety were significantly higher after casein and pea protein compared to other preloads (P < 0.05). Blood glucose response to the meal was significantly lower when whey protein was consumed as a preload compared to other groups (P < 0.001). In the second study, results showed no difference between preloads on ad libitum intake. Total intake was significantly higher after caloric preloads compared to water control (P < 0.05).</p> <p>Conclusion</p> <p>Casein and pea protein showed a stronger effect on food intake compared to whey when consumed as a preload. However, consuming the protein preload as a starter of a meal decreased its impact on food intake as opposed to consuming it 30 min before the meal.</p

Valsartan Improves Adipose Tissue Function in Humans with Impaired Glucose Metabolism: A Randomized Placebo-Controlled Double-Blind Trial

<div><h3>Background</h3><p>Blockade of the renin-angiotensin system (RAS) reduces the incidence of type 2 diabetes mellitus. In rodents, it has been demonstrated that RAS blockade improved adipose tissue (AT) function and glucose homeostasis. However, the effects of long-term RAS blockade on AT function have not been investigated in humans. Therefore, we examined whether 26-wks treatment with the angiotensin II type 1 receptor blocker valsartan affects AT function in humans with impaired glucose metabolism (IGM).</p> <h3>Methodology/Principal Findings</h3><p>We performed a randomized, double-blind, placebo-controlled parallel-group study, in which 38 subjects with IGM were treated with valsartan (VAL, 320 mg/d) or placebo (PLB) for 26 weeks. Before and after treatment, an abdominal subcutaneous AT biopsy was collected for measurement of adipocyte size and AT gene/protein expression of angiogenesis/capillarization, adipogenesis, lipolytic and inflammatory cell markers. Furthermore, we evaluated fasting and postprandial AT blood flow (ATBF) (¹³³Xe wash-out), systemic inflammation and insulin sensitivity (hyperinsulinemic-euglycemic clamp). VAL treatment markedly reduced adipocyte size (<em>P</em><0.001), with a shift toward a higher proportion of small adipocytes. In addition, fasting (<em>P</em> = 0.043) and postprandial ATBF (<em>P</em> = 0.049) were increased, whereas gene expression of angiogenesis/capillarization, adipogenesis and macrophage infiltration markers in AT was significantly decreased after VAL compared with PLB treatment. Interestingly, the change in adipocyte size was associated with alterations in insulin sensitivity and reduced AT gene expression of macrophage infiltration markers. VAL did not alter plasma monocyte-chemoattractant protein (MCP)-1, TNF-α, adiponectin and leptin concentrations.</p> <h3>Conclusions/Significance</h3><p>26-wks VAL treatment markedly reduced abdominal subcutaneous adipocyte size and AT macrophage infiltration markers, and increased ATBF in IGM subjects. The VAL-induced decrease in adipocyte size was associated with reduced expression of macrophage infiltration markers in AT. Our findings suggest that interventions targeting the RAS may improve AT function, thereby contributing to a reduced risk of developing cardiovascular disease and type 2 diabetes.</p> <h3>Trial Registration</h3><p>Trialregister.nl NTR721 (ISRCTN Registry: ISRCTN<a href="http://www.controlled-trials.com/isrctn/pf/42786336">42786336</a>)</p> </div

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer

Life Cycle Management of Infrastructures

By definition, life cycle management (LCM) is a framework “of concepts, techniques, and procedures to address environmental, economic, technological, and social aspects of products and organizations in order to achieve continuous ‘sustainable’ improvement from a life cycle perspective” (Hunkeler et al.\ua02001). Thus, LCM theoretically integrates all sustainability dimensions, and strives to provide a holistic perspective. It also assists in the efficient and effective use of constrained natural and financial resources to reduce negative impacts on society (Sonnemann and Leeuw\ua02006; Adibi et al.\ua02015). The LCM of infrastructures is the adaptation of product life cycle management (PLM) as techniques to the design, construction, and management of infrastructures. Infrastructure life cycle management requires accurate and extensive information that might be generated through different kinds of intelligent and connected information workflows, such as building information modeling (BIM)

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Obesity and neuroinflammatory phenotype in mice lacking endothelial megalin

BACKGROUND: The multiligand receptor megalin controls the brain uptake of a number of ligands, including insulin and leptin. Despite the role of megalin in the transport of these metabolically relevant hormones, the role of megalin at the blood–brain-barrier (BBB) has not yet been explored in the context of metabolic regulation. METHODS: Here we investigate the role of brain endothelial megalin in energy metabolism and leptin signaling using an endothelial cell-specific megalin deficient (EMD) mouse model. RESULTS: We found megalin is important to protect mice from developing obesity and metabolic syndrome when mice are fed a normal chow diet. EMD mice developed neuroinflammation, by triggering several pro-inflammatory cytokines, displayed reduced neurogenesis and mitochondrial deregulation. CONCLUSIONS: These results implicate brain endothelial megalin expression in obesity-related metabolic changes through the leptin signaling pathway proposing a potential link between obesity and neurodegeneration. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-017-0800-2) contains supplementary material, which is available to authorized users

Evaluation of prognostic risk models for postoperative pulmonary complications in adult patients undergoing major abdominal surgery: a systematic review and international external validation cohort study

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society