Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Drug use is associated with lower plasma magnesium levels in geriatric outpatients; possible clinical relevance
    Orten-Luiten, A.C.B. van; Janse, A. ; Verspoor, E. ; Brouwer-Brolsma, E.M. ; Witkamp, R.F. - \ 2019
    Clinical Nutrition 38 (2019)6. - ISSN 0261-5614 - p. 2668 - 2676.
    Adverse drug reaction - Cardiovascular disease - Diabetes - Drug-food interaction - Magnesium deficiency - Osteoporosis

    Background: Hypomagnesemia has been associated with diabetes, cardiovascular disease, and other disorders. Drug use has been suggested as one of the risk factors for low magnesium (Mg) levels. In the elderly population, prone to polypharmacy and inadequate Mg intake, hypomagnesemia might be relevant. Therefore, we aimed to investigate associations between drug use and plasma Mg. Methods: Cross-sectional data of 343 Dutch geriatric outpatients were analysed by Cox and linear regression, while adjusting for covariates. Drug groups were coded according to the Anatomical Therapeutic Chemical classification system; use was compared to non-use. Hypomagnesemia was defined as plasma Mg < 0.75 mmol/l and <0.70 mmol/l. Results: Prevalence of hypomagnesemia was 22.2% (Mg < 0.75 mmol/l) or 12.2% (Mg < 0.70 mmol/l); 67.6% of the patients used ≥5 medications (polypharmacy). The number of different drugs used was inversely linearly associated with Mg level (beta −0.01; p < 0.01). Fully adjusted Cox regression showed significant associations of polypharmacy with hypomagnesemia (Mg < 0.75 mmol/l) (prevalence ratio (PR) 1.81; 95%CI 1.08–3.14), proton pump inhibitors (PR 1.80; 95%CI 1.20–2.72), and metformin (PR 2.34; 95%CI 1.56–3.50). Moreover, stratified analyses pointed towards associations with calcium supplements (PR 2.26; 95%CI 1.20–4.26), insulins (PR 3.88; 95%CI 2.19–6.86), vitamin K antagonists (PR 2.01; 95%CI 1.05–3.85), statins (PR 2.44; 95%CI 1.31–4.56), and bisphosphonates (PR 2.97; 95%CI 1.65–5.36) in patients <80 years; selective beta blockers (PR 2.01; 95%CI 1.19–3.40) if BMI <27.0 kg/m2; and adrenergic inhalants in male users (PR 3.62; 95%CI 1.73–7.56). Linear regression supported these associations. Conclusion: As polypharmacy and several medications are associated with hypomagnesemia, Mg merits more attention, particularly in diabetes, cardiovascular disease, and in side-effects of proton pump inhibitors and calcium supplements.

    Effect of pore size distribution and particle size of porous metal oxides on phosphate adsorption capacity and kinetics
    Suresh Kumar, Prashanth ; Korving, Leon ; Keesman, Karel J. ; Loosdrecht, Mark C.M. van; Witkamp, Geert Jan - \ 2019
    Chemical Engineering Journal 358 (2019). - ISSN 1385-8947 - p. 160 - 169.
    Adsorption kinetics - Diffusion - Particle size - Phosphate adsorption - Pore size distribution - Porous metal oxide

    Phosphate is a vital nutrient but its presence in surface waters even at very low concentrations can lead to eutrophication. Adsorption is often suggested as a step for reducing phosphate down to very low concentrations. Porous metal oxides can be used as granular adsorbents that have a high surface area and hence a high adsorption capacity. But from a practical point of view, these adsorbents also need to have good adsorption kinetics. The surface area of such adsorbents comes from pores of varying pore size and the pore size distribution (PSD) of the adsorbents can affect the phosphate adsorption kinetics. In this study, the PSD of 4 different adsorbents was correlated with their phosphate adsorption kinetics. The adsorbents based on iron and aluminium (hydr)oxide were grinded and the adsorption performance was studied as a function of their particle size. This was done to identify diffusion limitations due to the PSD of the adsorbents. The phosphate adsorption kinetics were similar for small particles of all the adsorbents. For larger particles, the adsorbents having pores larger than 10 nm (FSP and DD6) showed faster adsorption than adsorbents with smaller pores (GEH and CFH). Even though micropores (pores < 2 nm) contributed to a higher portion of the adsorbent surface area, pores bigger than 10 nm were needed to increase the rate of adsorption.

    Identification of hydroxytyrosyl oleate, a derivative of hydroxytyrosol with anti-inflammatory properties, in olive oil by-products
    Plastina, Pierluigi ; Benincasa, Cinzia ; Perri, Enzo ; Fazio, Alessia ; Augimeri, Giuseppina ; Poland, Mieke ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2019
    Food Chemistry 279 (2019). - ISSN 0308-8146 - p. 105 - 113.
    COX-2 - Hydroxytyrosyl ester - Inflammation - Macrophages - NO - Olive mill waste water - Olive oil - PGE

    Hydroxytyrosyl esters with short, medium and long acyl chains were evaluated for their ability to reduce nitric oxide (NO) production by lipopolysaccharide-stimulated RAW264.7 macrophages. Among the compounds tested, C18 esters, namely hydroxytyrosyl stearate (HtySte) and hydroxytyrosyl oleate (HtyOle), were found to decrease NO production in a concentration-dependent manner, while the other compounds, including the parent hydroxytyrosol, were ineffective in the tested concentration range (0.5–5 μM). Further study of the potential immune-modulating properties of HtyOle revealed a significant and concentration-dependent suppression of prostaglandin E2 production. At a transcriptional level, HtyOle inhibited the expression of inducible NO synthase, cyclooxygenase-2 and interleukin-1β. Moreover, HtyOle was identified for the first time in olive oil by-products by means of high performance liquid chromatography coupled with mass spectrometry. By contrast, HtyOle was not found in intact olives. Our results suggest that HtyOle is formed during oil processing and represents a significant form in which hydroxytyrosol occurs.

    Plasma citrulline concentration, a marker for intestinal functionality, reflects exercise intensity in healthy young men
    Kartaram, Shirley ; Mensink, Marco ; Teunis, Marc ; Schoen, Eric ; Witte, Gerrit ; Janssen Duijghuijsen, Lonneke ; Verschuren, Martie ; Mohrmann, Karin ; M'Rabet, Laura ; Knipping, Karen ; Wittink, Harriet ; Helvoort, Ardy van; Garssen, Johan ; Witkamp, Renger ; Pieters, Raymond ; Norren, Klaske van - \ 2019
    Clinical Nutrition 38 (2019)5. - ISSN 0261-5614 - p. 2251 - 2258.
    Citrulline - Exercise intensity - Glutamine - Intestinal fatty acid binding protein - Intestinal function

    Background & aims: Plasma citrulline concentration is considered to be a marker for enterocyte metabolic mass and to reflect its reduction as may occur during intestinal dysfunction. Strenuous exercise can act as a stressor to induce small intestinal injury. Our previous studies suggest that this comprises the intestinal ability to produce citrulline from a glutamine-rich protein bolus. In this study we investigated the effects of different exercise intensities and hydration state on citrulline and iFABP levels following a post-exercise glutamine bolus in healthy young men. Methods: Fifteen healthy young men (20–35 yrs, VO2 max 56.9 ± 3.9 ml kg−1 min−1) performed in a randomly assigned cross-over design, a rest (protocol 1) and four cycle ergometer protocols. The volunteers cycled submaximal at different percentages of their individual pre-assessed maximum workload (Wmax): 70% Wmax in hydrated (protocol 2) and dehydrated state (protocol 3), 50% Wmax (protocol 4) and intermittent 85/55% Wmax in blocks of 2 min (protocol 5). Immediately after 1 h exercise or rest, subjects were given a glutamine bolus with added alanine as an iso-caloric internal standard (7.5 g of each amino acid). Blood samples were collected before, during and after rest or exercise, up to 24 h post onset of the experiment. Amino acids and urea were analysed as metabolic markers, creatine phosphokinase and iFABP as markers of muscle and intestinal damage, respectively. Data were analysed using a multilevel mixed linear statistical model. p values were corrected for multiple testing. Results: Citrulline levels already increased before glutamine supplementation during normal hydrated exercise, while this was not observed in the dehydrated and rest protocols. The low intensity exercise protocol (50% Wmax) showed the highest increase in citrulline levels both during exercise (43.83 μmol/L ± 2.63 (p < 0.001)) and after glutamine consumption (50.54 μmol/L ± 2.62) compared to the rest protocol (28.97 μmol/L ± 1.503 and 41.65 μmol/L ± 1.96, respectively, p < 0.05). However, following strenuous exercise at 70% Wmax in the dehydrated state, citrulline levels did not increase during exercise and less after the glutamine consumption when compared to the resting condition and hydrated protocols. In line with this, serum iFABP levels were the highest with the strenuous dehydrated protocol (1443.72 μmol/L ± 249.9, p < 0.001), followed by the high intensity exercise at 70% Wmax in the hydrated condition. Conclusions: Exercise induces an increase in plasma citrulline, irrespective of a glutamine bolus. The extent to which this occurs is dependent on exercise intensity and the hydration state of the subjects. The same holds true for both the post-exercise increase in citrulline levels following glutamine supplementation and serum iFABP levels. These data indicate that citrulline release during exercise and after an oral glutamine bolus might be dependent on the intestinal health state and therefore on intestinal functionality. Glutamine is known to play a major role in intestinal physiology and the maintenance of gut health and barrier function. Together, this suggests that in clinical practice, a glutamine bolus to increase citrulline levels after exercise might be preferable compared to supplementing citrulline itself. To our knowledge this is the first time that exercise workload-related effects on plasma citrulline are reported in relation to intestinal damage.

    Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence
    Wesselink, E. ; Koekkoek, W.A.C. ; Grefte, S. ; Witkamp, R.F. ; Zanten, A.R.H. van - \ 2019
    Clinical Nutrition 38 (2019)3. - ISSN 0261-5614 - p. 982 - 995.
    ATP - Bio-energetic failure - Electron chain complex - Enzyme Q10 - Melatonin - Micronutrients

    Persistent physical impairment is frequently encountered after critical illness. Recent data point towards mitochondrial dysfunction as an important determinant of this phenomenon. This narrative review provides a comprehensive overview of the present knowledge of mitochondrial function during and after critical illness and the role and potential therapeutic applications of specific micronutrients to restore mitochondrial function. Increased lactate levels and decreased mitochondrial ATP-production are common findings during critical illness and considered to be associated with decreased activity of muscle mitochondrial complexes in the electron transfer system. Adequate nutrient levels are essential for mitochondrial function as several specific micronutrients play crucial roles in energy metabolism and ATP-production. We have addressed the role of B vitamins, ascorbic acid, α-tocopherol, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, nitrate, lipoic acid and taurine in mitochondrial function. B vitamins and lipoic acid are essential in the tricarboxylic acid cycle, while selenium, α-tocopherol, Coenzyme Q10, caffeine, and melatonin are suggested to boost the electron transfer system function. Carnitine is essential for fatty acid beta-oxidation. Selenium is involved in mitochondrial biogenesis. Notwithstanding the documented importance of several nutritional components for optimal mitochondrial function, at present, there are no studies providing directions for optimal requirements during or after critical illness although deficiencies of these specific micronutrients involved in mitochondrial metabolism are common. Considering the interplay between these specific micronutrients, future research should pay more attention to their combined supply to provide guidance for use in clinical practise. Revision number: YCLNU-D-17-01092R2.

    Side-effects related to adjuvant CAPOX treatment for colorectal cancer are associated with intermuscular fat area, not with total skeletal muscle or fat, a retrospective observational study
    Plas, R.L.C. ; Norren, K. van; Baar, H. van; Aller, C. van; Bakker, M. de; Botros, N. ; Witkamp, R.F. ; Haringhuizen, A. ; Kampman, E. ; Winkels, R.M. - \ 2018
    JCSM Clinical Reports 3 (2018)1. - ISSN 2521-3555 - 13 p.
    Aims Chemotherapeutic treatment is regularly accompanied by side‐effects. Hydrophilic chemotherapeutics such as capecitabine and oxaliplatin (CAPOX), often used in colorectal cancer treatment, predominantly accumulate in non adipose tissues. Therefore the aim of this paper was to investigate whether body composition and fat infiltration inthe muscle (muscle attenuation and intermuscular‐adipose‐tissue [IMAT] content) are associated with chemotherapy induced toxicities. Methods In this retrospective observational study, we collected data from 115 colorectal cancer patients receiving adjuvant CAPOX chemotherapy between 2006 and 2015. Information on cancer characteristics were obtained from the Netherlands Cancer Registry. Diagnostic CT scans were retrieved to assess cross‐sectional areas of skeletal muscle and adipose tissue at the third lumbar vertebrae. Information on dose‐limiting toxicity [DLT] and relative administered dose (as % of BSA‐based‐planned‐dose) were retrieved from medical charts. Associations between body composition,muscle quality and chemotherapy‐induced toxicities were determined using Cox‐regression and linear‐regression analyses. Results We found that DLT incidence was 90% in our cohort: 50% had their dose reduced, 30% their next cyclepostponed, 4% a full treatment stop and 6% was hospitalized at their first DLT. Most common were reductions in oxaliplatin dose whilst keeping the capecitabine dose constant. Cox regression analysis indicated no association between body composition or muscle quality and DLT during the first treatment cycle or time to the first DLT. Multiple linear regression showed that higher IMAT‐index and IMAT muscle percentage were associated with a lower relative administered dose of oxaliplatin. Conclusions In conclusion; only IMAT, not skeletal or fat area was associated with dose‐limiting toxicities among these CRC patients who received CAPOX treatment.
    Release of major peanut allergens from their matrix under various pH and simulated saliva conditions—Ara h2 and ara h6 are readily bio-accessible
    Koppelman, Stef J. ; Smits, Mieke ; Tomassen, Monic ; Jong, Govardus A.H. De; Baumert, Joe ; Taylor, Steve L. ; Witkamp, Renger ; Veldman, Robert Jan ; Pieters, Raymond ; Wichers, Harry - \ 2018
    Nutrients 10 (2018)9. - ISSN 2072-6643
    Allergen - Arachis hypogaea - Bio-accessibility - Peanut - Saliva

    The oral mucosa is the first immune tissue that encounters allergens upon ingestion of food. We hypothesized that the bio-accessibility of allergens at this stage may be a key determinant for sensitization. Light roasted peanut flour was suspended at various pH in buffers mimicking saliva. Protein concentrations and allergens profiles were determined in the supernatants. Peanut protein solubility was poor in the pH range between 3 and 6, while at a low pH (1.5) and at moderately high pHs (>8), it increased. In the pH range of saliva, between 6.5 and 8.5, the allergens Ara h2 and Ara h6 were readily released, whereas Ara h1 and Ara h3 were poorly released. Increasing the pH from 6.5 to 8.5 slightly increased the release of Ara h1 and Ara h3, but the recovery remained low (approximately 20%) compared to that of Ara h2 and Ara h6 (approximately 100% and 65%, respectively). This remarkable difference in the extraction kinetics suggests that Ara h2 and Ara h6 are the first allergens an individual is exposed to upon ingestion of peanut-containing food. We conclude that the peanut allergens Ara h2 and Ara h6 are quickly bio-accessible in the mouth, potentially explaining their extraordinary allergenicity.

    Understanding and improving the reusability of phosphate adsorbents for wastewater effluent polishing
    Suresh Kumar, Prashanth ; Ejerssa, Wondesen Workneh ; Wegener, Carita Clarissa ; Korving, Leon ; Dugulan, Achim Iulian ; Temmink, Hardy ; Loosdrecht, Mark C.M. van; Witkamp, Geert-Jan - \ 2018
    Water Research 145 (2018). - ISSN 0043-1354 - p. 365 - 374.
    Calcium adsorption - Phosphate adsorption - Regeneration - Reusability - Surface precipitation - Wastewater effluent

    Phosphate is a vital nutrient for life but its discharge from wastewater effluents can lead to eutrophication. Adsorption can be used as effluent polishing step to reduce phosphate to very low concentrations. Adsorbent reusability is an important parameter to make the adsorption process economically feasible. This implies that the adsorbent can be regenerated and used over several cycles without appreciable performance decline. In the current study, we have studied the phosphate adsorption and reusability of commercial iron oxide based adsorbents for wastewater effluent. Effects of adsorbent properties like particle size, surface area, type of iron oxide, and effects of some competing ions were determined. Moreover the effects of regeneration methods, which include an alkaline desorption step and an acid wash step, were studied. It was found that reducing the adsorbent particle size increased the phosphate adsorption of porous adsorbents significantly. Amongst all the other parameters, calcium had the greatest influence on phosphate adsorption and adsorbent reusability. Phosphate adsorption was enhanced by co-adsorption of calcium, but calcium formed surface precipitates such as calcium carbonate. These surface precipitates affected the adsorbent reusability and needed to be removed by implementing an acid wash step. The insights from this study are useful in designing optimal regeneration procedures and improving the lifetime of phosphate adsorbents used for wastewater effluent polishing.

    Changes in iron metabolism during prolonged repeated walking exercise in middle-aged men and women
    Terink, Rieneke ; Haaf, D. ten; Bongers, C.W.G. ; Balvers, M.G.J. ; Witkamp, R.F. ; Mensink, M. ; Eijsvogels, T.M.H. ; Klein Gunnewiek, J.M.T. ; Hopman, M.T.E. - \ 2018
    European Journal of Applied Physiology 118 (2018)11. - ISSN 1439-6319 - p. 2349 - 2357.
    Fe - Hb - Hp - Repetitive exercise

    Purpose: The aim of the present study was to assess the effect of prolonged and repeated exercise on iron metabolism in middle-aged adults and to compare differences between sexes. Methods: 50 male (58.9 ± 9.9 year) and 48 female (50.9 ± 11.2 year) individuals were monitored on 4 consecutive days at which they walked on average 8 h and 44 min per day at a self-determined pace. Blood samples were collected 1 or 2 days prior to the start of the exercise (baseline) and every day immediately post-exercise. Samples were analysed for iron, ferritin, haemoglobin, and haptoglobin concentrations. Results: Plasma iron decreased across days, while ferritin increased across days (both p < 0.001). Haptoglobin showed a decrease (p < 0.001) after the first day and increased over subsequent days (p < 0.001). Haemoglobin did not change after the first day, but increased during subsequent days (p < 0.05). At baseline, 8% of the participants had iron concentrations below minimum reference value (10 µmol/L), this increased to 43% at day 4. There was an interaction between sex and exercise days on iron (p = 0.028), ferritin (p < 0.001) and haemoglobin levels (p = 0.004), but not on haptoglobin levels. Conclusion: This study showed decreases in iron, increases in ferritin, a decrease followed by increases in haptoglobin and no change followed by increases in haemoglobin. This is most likely explained by (foot strike) haemolysis, inflammation, and sweat and urine losses. These processes resulted in iron levels below minimum reference value in a large number of our participants.

    Let thy food be thy medicine….when possible
    Witkamp, Renger F. ; Norren, Klaske van - \ 2018
    European Journal of Pharmacology 836 (2018). - ISSN 0014-2999 - p. 102 - 114.
    Food-drug interactions - Inflammation - Nutrition - Sarcopenia, Cachexia, Food-Pharma

    There is no evidence that Hippocrates, although being credited for it, ever literally stated ‘let thy food be thy medicine and thy medicine be thy food’. However, yet in line with Hippocrates’ philosophy, we are currently witnessing a reappraisal of the complementarity of nutrition and pharmacology. Recent studies not only underline the therapeutic potential of lifestyle interventions, but are also generating valuable insights in the complex and dynamic transition from health to disease. Next to this, nutritional biology can significantly contribute to the discovery of new molecular targets. It is clear that most of the current top-selling drugs used in chronic cardio-metabolic diseases modulate relatively late-stage complications, which generally indicate already longer existing homeostatic imbalances. Pharmacologists are increasingly aware that typical multifactorial disorders require subtle, multiple target pharmacological approaches, instead of the still often dominating ‘one disease - one target - one drug’ paradigm. This review discusses the recent developments in the pharma-nutrition interface and shows some relevant mechanisms, including receptors and other targets, and examples from clinical practice. The latter includes inflammatory diseases and progressive loss of muscle function. The examples also illustrate the potential of targeted combinations of medicines with nutrition and (or) other life-style interventions, to increase treatment efficacy and (or) reduce adverse effects. More attention to a potentially negative outcome of drug-food combinations is also required, as shown by the example of food-drug interactions. Together, the developments at the food-pharma interface underline the demand for intensified collaboration between the disciplines, in the clinic and in science.

    Mitochondrial dynamics in cancer-induced cachexia
    Ende, Miranda van der; Grefte, Sander ; Plas, Rogier ; Meijerink, Jocelijn ; Witkamp, Renger F. ; Keijer, Jaap ; Norren, Klaske van - \ 2018
    Biochimica et Biophysica Acta - Reviews on Cancer 1870 (2018)2. - ISSN 0304-419X - p. 137 - 150.
    Animal models - Cancer-induced cachexia - Mitochondria - Mitochondrial dynamics - Muscle

    Cancer-induced cachexia has a negative impact on quality of life and adversely affects therapeutic outcomes and survival rates. It is characterized by, often severe, loss of muscle, with or without loss of fat mass. Insight in the pathophysiology of this complex metabolic syndrome and direct treatment options are still limited, which creates a research demand. Results from recent studies point towards a significant involvement of muscle mitochondrial networks. However, data are scattered and a comprehensive overview is lacking. This paper aims to fill existing knowledge gaps by integrating published data sets on muscle protein or gene expression from cancer-induced cachexia animal models. To this end, a database was compiled from 94 research papers, comprising 11 different rodent models. This was combined with four genome-wide transcriptome datasets of cancer-induced cachexia rodent models. Analysis showed that the expression of genes involved in mitochondrial fusion, fission, ATP production and mitochondrial density is decreased, while that of genes involved ROS detoxification and mitophagy is increased. Our results underline the relevance of including post-translational modifications of key proteins involved in mitochondrial functioning in future studies on cancer-induced cachexia.

    In vitro anti-inflammatory and radical scavenging properties of chinotto (Citrus myrtifolia Raf.) essential oils
    Plastina, Pierluigi ; Apriantini, Astari ; Meijerink, Jocelijn ; Witkamp, Renger ; Gabriele, Bartolo ; Fazio, Alessia - \ 2018
    Nutrients 10 (2018)6. - ISSN 2072-6643
    Antioxidant - Citrus - Inflammation - Macrophages - Nitric oxide

    Chinotto (Citrus myrtifolia Raf.) is a widely diffused plant native from China and its fruits have a wide-spread use in confectionary and drinks. Remarkably, only little has been reported thus far on its bioactive properties, in contrast to those of the taxonomically related bergamot (Citrus bergamia Risso). The present study aimed to investigate potential in vitro anti-inflammatory and radical scavenging properties of chinotto essential oils (CEOs) and to establish to what extent their composition and bioactivities are dependent on maturation. Essential oil from half ripe chinotto (CEO2) reduced the production of nitric oxide (NO) and the expression of inflammatory genes, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6), and chemokine monocyte chemotactic protein-1 (MCP-1) by lipopolysaccharide (LPS)-stimulated RAW264,7 macrophages. Limonene, linalool, linalyl acetate, and γ-terpinene were found to be the main components in CEO2. Moreover, CEO2 showed high radical scavenging activity measured as Trolox equivalents (TE) against both 2,2′-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS). These findings show that chinotto essential oil represents a valuable part of this fruit and warrants further in vivo studies to validate its anti-inflammatory potential.

    Increasing quality of life in pulmonary arterial hypertension : is there a role for nutrition?
    Vinke, Paulien ; Jansen, Suzanne M. ; Witkamp, Renger F. ; Norren, Klaske van - \ 2018
    Heart Failure Reviews 23 (2018)5. - ISSN 1382-4147 - p. 711 - 722.
    Deficiencies - Exercise - Lifestyle - Nutrition - Pulmonary arterial hypertension - Review

    Pulmonary arterial hypertension (PAH) is a progressive disease primarily affecting the pulmonary vasculature and heart. PAH patients suffer from exercise intolerance and fatigue, negatively affecting their quality of life. This review summarizes current insights in the pathophysiological mechanisms underlying PAH. It zooms in on the potential involvement of nutritional status and micronutrient deficiencies on PAH exercise intolerance and fatigue, also summarizing the potential benefits of exercise and nutritional interventions. Pubmed/Medline, Scopus, and Web of Science were searched for publications on pathophysiological mechanisms of PAH negatively affecting physical activity potential and nutritional status, and for potential effects of interventions involving exercise or nutritional measures known to improve exercise intolerance. Pathophysiological processes that contribute to exercise intolerance and impaired quality of life of PAH patients include right ventricular dysfunction, inflammation, skeletal muscle alterations, and dysfunctional energy metabolism. PAH-related nutritional deficiencies and metabolic alterations have been linked to fatigue, exercise intolerance, and endothelial dysfunction. Available evidence suggests that exercise interventions can be effective in PAH patients to improve exercise tolerance and decrease fatigue. By contrast, knowledge on the prevalence of micronutrient deficiencies and the possible effects of nutritional interventions in PAH patients is limited. Although data on nutritional status and micronutrient deficiencies in PAH are scarce, the available knowledge, including that from adjacent fields, suggests that nutritional intervention to correct deficiencies and metabolic alterations may contribute to a reduction of disease burden.

    Associations of hyperosmolar medications administered via nasogastric or nasoduodenal tubes and feeding adequacy, food intolerance and gastrointestinal complications amongst critically ill patients : A retrospective study
    Wesselink, Evertine ; Koekkoek, Kristine W.A.C. ; Looijen, Martijn ; Blokland, Dick A. van; Witkamp, Renger F. ; Zanten, Arthur R.H. van - \ 2018
    Clinical Nutrition ESPEN 25 (2018). - ISSN 2405-4577 - p. 78 - 86.
    Diarrhea - Enteral feeding - Enteral feeding intolerance - Gastric residual volume - Gastro-intestinal symptoms - Hyperosmolar medications - Tube feeding

    Background: Adequate nutrition is essential during critical illness. However, providing adequate nutrition is often hindered by gastro-intestinal complications, including feeding intolerance. It is suggested that hyperosmolar medications could be causally involved in the development of gastro-intestinal complications. The aims of the present study were 1) to determine the osmolality of common enterally administered dissolved medications and 2) to study the associations between nasogastric and nasoduodenal administered hyperosmolar medications and nutritional adequacy as well as food intolerance and gastro-intestinal symptoms. Methods: This retrospective observational cohort study was performed in a medical-surgical ICU in the Netherlands. Adult critically ill patients receiving enteral nutrition and admitted for a minimum ICU duration of 7 days were eligible. The osmolalities of commonly used enterally administrated medications were measured using an osmometer. Patients were divided in two groups: Use of hyperosmolar medications (>500 mOsm/kg) on at least one day during the first week versus none. The associations between the use of hyperosmolar medications and nutritional adequacy were assessed using multiple logistic regression analysis. The associations between hyperosmolar medication and food intolerance as well as gastrointestinal symptoms were assessed using ordinal logistic regression. Results: In total 443 patients met the inclusion criteria. Of the assessed medications, only three medications were found hyperosmolar. We observed no associations between the use of hyperosmolar medications and nutritional adequacy in the first week of ICU admission (caloric intake β −0.27 95%CI –1.38; 0.83, protein intake β 0.32 95%CI –0.90; 1.53). In addition, no associations were found for enteral feeding intolerance, diarrhea, obstipation, gastric residual volume, nausea and vomiting in ICU patients receiving hyperosmolar medications via a nasogastric tube. A subgroup analysis of patients on duodenal feeding showed that postpyloric administration of hyperosmolar medications was associated with increased risk of diarrhea (OR 138.7 95%CI 2.33; 8245). Conclusions: Our results suggest that nasogastric administration of hyperosmolar medication via a nasogastric tube does not affect nutritional adequacy, development of enteral feeding intolerance and other gastro-intestinal complications during the first week after ICU admission. During nasoduodenal administration an increased diarrhea incidence may be encountered.

    The effect of exercise on intestinal integrity and protein permeability
    Janssen Duijghuijsen, L.M. ; Keijer, J. ; Mensink, M.R. ; Bastiaan-Net, S. ; Mes, J.J. ; Luiking, Yvette ; Wichers, H.J. ; Witkamp, R.F. ; Norren, K. van - \ 2018
    Calcium imaging of GPCR activation using arrays of reverse transfected HEK293 cells in a microfluidic system
    Roelse, Margriet ; Henquet, Maurice G.L. ; Verhoeven, Harrie A. ; Ruijter, Norbert C.A. De; Wehrens, Ron ; Lenthe, Marco S. Van; Witkamp, Renger F. ; Hall, Robert D. ; Jongsma, Maarten A. - \ 2018
    Sensors 18 (2018)2. - ISSN 1424-8220
    Cameleon YC3.6 - Cell array - GPCR - Microfluidics - NK1 receptor - Reverse transfection
    Reverse-transfected cell arrays in microfluidic systems have great potential to perform large-scale parallel screening of G protein-coupled receptor (GPCR) activation. Here, we report the preparation of a novel platform using reverse transfection of HEK293 cells, imaging by stereo-fluorescence microscopy in a flowcell format, real-time monitoring of cytosolic calcium ion fluctuations using the fluorescent protein Cameleon and analysis of GPCR responses to sequential sample exposures. To determine the relationship between DNA concentration and gene expression, we analyzed cell arrays made with variable concentrations of plasmid DNA encoding fluorescent proteins and the Neurokinin 1 (NK1) receptor. We observed pronounced effects on gene expression of both the specific and total DNA concentration. Reverse transfected spots with NK1 plasmid DNA at 1% of total DNA still resulted in detectable NK1 activation when exposed to its ligand. By varying the GPCR DNA concentration in reverse transfection, the sensitivity and robustness of the receptor response for sequential sample exposures was optimized. An injection series is shown for an array containing the NK1 receptor, bitter receptor TAS2R8 and controls. Both receptors were exposed 14 times to alternating samples of two ligands. Specific responses remained reproducible. This platform introduces new opportunities for high throughput screening of GPCR libraries.
    The role of fatty acids and their endocannabinoid-like derivatives in the molecular regulation of appetite
    Witkamp, Renger F. - \ 2018
    Molecular Aspects of Medicine 64 (2018). - ISSN 0098-2997 - p. 45 - 67.
    Intake, absorption and synthesis of fatty acids, including those produced by the intestinal microbiota are tightly monitored via specific receptors and, indirectly through their conversion into a variety of signalling molecules. The resulting information is integrated and translated to different physiological processes, including the regulation of appetite and satiation. Direct chemosensing of fatty acids takes place via interaction with free fatty acid (FFA) and other receptors. These are present in the oronasal cavity and along the entire gastrointestinal tract, in various other tissues, and, for some receptors also in brain. Results from early studies have suggested differences between fatty acids in their ability to induce the release of satiety hormones or their short-term effects on food-intake. However, more recent findings indicate that this has limited impact on long-term energy intake. Similarly, pharmacological strategies for appetite control via modulation of peripheral fatty acid binding receptors have not met their expectations. Regarding the psychobiology of eating behaviour, there has been a shift towards emphasising the importance of food reward and the cephalic phase response. Lipid-rich foods are highly energy dense. During evolution this has stimulated the development of reward mechanisms, in which fatty acids, in conjunction with carbohydrates, are major triggers. Fatty acids are also precursors of endocannabinoids and their structural congeners. The endocannabinoid system (ECS) plays a pivotal role in the homeostatic and non-homeostatic regulation of eating behaviour. In the brain it links to different endocrine and neuronal pathways, including dopaminergic circuits in the mesocorticolimbic system such as the ventral tegmental area and the nucleus accumbens, which are crucial for hedonic eating. Despite the vast progress made in the field of neurobiology it is clear that eating behaviour, one of our strongest instincts, still possess major scientific challenges. The failure, already a decade ago, of the cannabinoid-receptor type 1 (CB1) blockers for treatment of overweight and its complications may serve as an illustration that 'single-target' approaches to modulate, or even understand-, over- or undereating are very unrealistic.
    Fish oil LC-PUFAs do not affect blood coagulation parameters and bleeding manifestations : Analysis of 8 clinical studies with selected patient groups on omega-3-enriched medical nutrition
    Jeansen, Stephanie ; Witkamp, Renger F. ; Garthoff, Jossie A. ; Helvoort, Ardy van; Calder, Philip C. - \ 2018
    Clinical Nutrition 37 (2018)3. - ISSN 0261-5614 - p. 948 - 957.
    Bleeding - Coagulation - DHA - EPA - LC-PUFA - Omega-3

    Background & aims: The increased consumption of fish oil enriched-products exposes a wide diversity of people, including elderly and those with impaired health to relatively high amounts of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs). There is an ongoing debate around the possible adverse effects of n-3 LC-PUFAs on bleeding risk, particularly relevant in people with a medical history of cardiovascular events or using antithrombotic drugs. Methods: This analysis of 8 clinical intervention studies conducted with enteral medical nutrition products containing fish oil as a source of n-3 LC-PUFAs addresses the occurrence of bleeding-related adverse events and effects on key coagulation parameters (Prothrombin Time [PT], (activated) and Partial Thromboplastin Time [(a)PTT]). Results: In all the patients considered (over 600 subjects treated with the active product in total), with moderate to severe disease, with or without concomitant use of antithrombotic agents, at home or in an Intensive Care Unit (ICU), no evidence of increased risk of bleeding with use of n-3 LC-PUFAs was observed. Furthermore there were no statistically significant changes from baseline in measured coagulation parameters. Conclusion: These findings further support the safe consumption of n-3 LC-PUFAs, even at short-term doses up to 10 g/day of eicosapentaenoic acid + docosahexaenoic acid (EPA + DHA) or consumed for up to 52 weeks above 1.5 g/day, in selected vulnerable and sensitive populations such as subjects with gastrointestinal cancer or patients in an ICU. We found no evidence to support any concern raised with regards to the application of n-3 LC-PUFAs and the potentially increased risk for the occurrence of adverse bleeding manifestations in these selected patient populations consuming fish oil enriched medical nutrition.

    Eat your way to health
    Witkamp, R.F. - \ 2017
    A tomato with your coffee?
    Witkamp, R.F. ; Kleef, E. van; Zeinstra, G.G. - \ 2017
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