Paul A M van Leeuwen

VU University Medical Center, Amsterdamo, North Holland, Netherlands

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Publications (259)1136.75 Total impact

  • International Journal of Molecular Sciences 06/2015; 16(6):12288-12306. DOI:10.3390/ijms160612288 · 2.34 Impact Factor
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    ABSTRACT: Supplementation with arginine in combination with atorvastatin is more efficient in reducing the size of an atherosclerotic plaque than treatment with a statin or arginine alone in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. We evaluated the mechanism behind this feature by exploring the role of the arginine/asymmetric dimethylarginine (ADMA) ratio, which is the substrate and inhibitor of nitric oxide synthase (NOS) and thereby nitric oxide (NO), respectively. Methods: Rabbits were fed either an arginine diet (group A, n = 9), standard rabbit chow plus atorvastatin (group S, n = 8), standard rabbit chow plus an arginine diet with atorvastatin (group SA, n = 8) or standard rabbit chow (group C, n = 9) as control. Blood was sampled and the aorta was harvested for topographic and histological analysis. Plasma levels of arginine, ADMA, cholesterol and nitric oxide were determined and the arginine/ADMA ratio was calculated. Results: The decrease in ADMA levels over time was significantly correlated to fewer aortic lesions in the distal aorta and total aorta. The arginine/ADMA ratio was correlated to cholesterol levels and decrease in cholesterol levels over time in the SA group. A lower arginine/ADMA ratio was significantly correlated to lower NO levels in the S and C group. Discussion: A balance between arginine and ADMA is an important indicator in the prevention of the development of atherosclerotic plaques.
    International Journal of Molecular Sciences 05/2015; 16(6):12230-12242. DOI:10.3390/ijms160612230 · 2.34 Impact Factor
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    ABSTRACT: Intralesional (IL) cryotherapy is a new technique for the treatment of keloid scars, in which the scar is frozen from inside. Two cryodevices are available, which were recently evaluated. Both devices showed promising results, but differed in clinical outcome. To explain these differences, more understanding of the working mechanism of both devices is required. This experimental study was designed to investigate and compare the thermal behavior of an argon gas- and a liquid nitrogen-based device. Thermal behavior constitutes: (1) minimum tissue temperature (°C), (2) the freezing rate (°C/min). The thermal behavior was measured inside and on the outer surface of the scar. Both devices were tested ex vivo and in vivo. Ex vivo, when determining the maximum freezing capacity, the argon gas device showed a higher end temperature compared to the liquid nitrogen device (argon gas: -120°C, liquid nitrogen: -140°C) and a faster freezing rate (argon gas: -1300°C/min, liquid nitrogen: -145°C/min). In vivo, measured inside the keloid, the argon gas device showed a lower end temperature than the liquid nitrogen device (argon gas: -36.4°C, liquid nitrogen: -8.1°C) and a faster freezing rate (argon gas: -14.7°C/min, liquid nitrogen: -5°C/min). The outer surface of the scar reached temperatures below -20°C with both devices as measured with the thermal camera. In conclusion, the argon gas device displayed a lower end temperature and a faster freezing rate compared to the liquid nitrogen device. Although this resulted in lower recurrence rates for the argon gas device, more hypopigmentation was seen compared to the liquid nitrogen device following treatment. Finally, the low outer surface temperatures measured with both devices, suggest that some hypopigmentation following treatment is inevitable. Copyright © 2015. Published by Elsevier Inc.
    Cryobiology 04/2015; DOI:10.1016/j.cryobiol.2015.04.004 · 1.64 Impact Factor
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    ABSTRACT: Malignancies induce disposal of arginine, an important substrate for the immune system. To sustain immune function, the tumor-bearing host accelerates arginine's intestinal-renal axis by glutamine mobilization from skeletal muscle and this may promote cachexia. Glutamine supplementation stimulates argi-nine production in healthy subjects. Arginine's intestinal-renal axis and the effect of glutamine supplementation in cancer cach-exia have not been investigated. This study evaluated the long-term adaptations of the interorgan pathway for arginine production following the onset of cachexia and the metabolic effect of glutamine supplementation in the cachectic state. Fischer-344 rats were randomly divided into a tumor-bearing group (n = 12), control group (n = 7) and tumor-bearing group receiving a glutamine-enriched diet (n = 9). Amino acid fluxes and net fractional extractions across intestine, kidneys, and liver were studied. Compared to controls, the portal-drained viscera of tumor-bearing rats took up significantly more glutamine and released significantly less citrulline. Renal metabolism was unchanged in the cachectic tumor-bearing rats compared with controls. Glutamine supplementation had no effects on intestinal and renal adaptations. In conclusion, in the cachectic state, an increase in intestinal glutamine uptake is not accompanied by an increase in renal arginine production. The adaptations found in the cachectic, tumor-bearing rat do not depend on glutamine availability.
    Nutrition and Cancer 04/2015; DOI:10.1080/01635581.2015.1029638 · 2.47 Impact Factor
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    ABSTRACT: Intralesional cryotherapy is a novel treatment for keloid scars in which the scar is frozen from inside. Published results are promising, but the treatment has only been tested in a Caucasian patient population. Therefore, the authors evaluated intralesional cryotherapy in a patient population including different Fitzpatrick skin types (I through VI). This prospective multicenter study with a 1-year follow-up included 27 patients with 29 keloid scars. Intralesional cryotherapy was administered with a disposable liquid nitrogen-based device called CryoShape. Scar assessment was performed using the Patient and Observer Scar Assessment Scale and four objective devices to determine scar color, scar elasticity, scar volume, and patient skin type. Keloid scars showed an average volume decrease of 63 percent (range, 16 to 100 percent) after 12 months, compared with baseline (p < 0.01). Recurrence was seen in seven keloids (24 percent) and hypopigmentation recovered in 69 percent of all keloid scars within 12 months. Scar assessment with the Patient and Observer Scar Assessment Scale showed an overall improvement according to both doctors and patients. In addition, complaints of pain and itching were reduced. When analyzing the results per Fitzpatrick skin type, African American patients showed a higher incidence of persistent hypopigmentation (p = 0.02). Intralesional cryotherapy for the treatment of keloid scars shows favorable results in terms of reduction of volume and complaints of pain and pruritus. However, no complete eradication was obtained in some cases and recurring scars were seen. In addition, persistent hypopigmentation proved a problem in non-Caucasian patients. Therapeutic, IV.
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    ABSTRACT: Background: Nutrition studies in the intensive care unit (ICU) have shown that adequate enteral nutrition (EN) support has clinical benefits. However, the course of amino acid concentrations in plasma has never been investigated in patients admitted with shock receiving EN. We hypothesized that plasma concentrations, when deficit, increase during EN and that persistent deficiency is associated with poor outcome. Methods: In 33 septic or cardiogenic shock patients receiving EN, plasma amino acid concentrations were measured during 5 days. Changes in amino acid concentrations, correlations with clinical outcome variables, and regression analyses were studied. Results: On ICU admission, several plasma concentrations were deficient. Plasma concentrations of almost all amino acids increased. In contrast, taurine decreased by >50%, from 47.6 µmol/L on admission to 20.0 µmol/L at day 1, and remained low at day 5. Taurine (admission) correlated with time on mechanical ventilation (R = -0.42, P = .015). Taurine decrease within 24 hours correlated with Acute Physiology and Chronic Health Evaluation II predicted mortality (R = 0.43, P = .017) and Sequential Organ Failure Assessment score (R = 0.36, P = .05). Regression analyses confirmed correlations. Conclusions: Several amino acids were deficient in plasma on ICU admission but increased during EN. Taurine concentrations declined and were associated with longer periods of mechanical ventilation and ICU support. Fast taurine decline correlated with severity of organ failure. These findings support the role of taurine during ischemia, reperfusion, and inflammation. Taurine may be an essential candidate to enrich nutrition support for critically ill patients, although more research is required. © 2015 American Society for Parenteral and Enteral Nutrition.
    Journal of Parenteral and Enteral Nutrition 01/2015; DOI:10.1177/0148607114567199 · 3.14 Impact Factor
  • Plastic &amp Reconstructive Surgery 01/2015; DOI:10.1097/PRS.0000000000001508 · 3.33 Impact Factor
  • Nikki Buijs, Paul A M van Leeuwen
    JAMA The Journal of the American Medical Association 12/2014; 312(21):2288. DOI:10.1001/jama.2014.14493 · 30.39 Impact Factor
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    ABSTRACT: Background: Keloids cause aesthetic disfigurement and physical complaints, mainly pain and pruritus. Treatment of these scars is difficult, with high recurrence rates forming the main issue. Surgical excision with adjuvant radiotherapy is considered the most efficacious treatment. At their institution, the authors have been treating keloids with a high-dose-rate brachytherapy procedure for over 10 years, using a protocol with the lowest total radiation dosage known in the literature. Methods: This prospective study included 43 patients of all Fitzpatrick skin types, with 67 keloids in total. After extralesional excision, a radiation scheme of 2 x 6 Gy was administered in two fractions: the first within 4 hours after surgery and the second within 24 hours. Scars were measured and recurrence was judged. Scar appearance was evaluated using the Patient and Observer Scar Assessment Scale. Results: The recurrence rate was 3.1 percent at a mean follow-up of 33.6 months. A significant average scar surface decrease of 56.7 percent was measured (p = 0.01). Complaints of pain and pruritus decreased by 82.9 and 87.2 percent, respectively. Patients were satisfied with the treatment in 88.6 percent of the cases and with the cosmetic result in 77.1 percent. Pigmentation problems were seen in 21.4 percent of the patients, mostly in Fitzpatrick type V and VI/African American individuals. Conclusions: The results of this prospective study show a good cosmetic outcome with a low recurrence rate. The unique radiation schedule proves the efficacy and safety of high-dose-rate brachytherapy and suggests the importance of immediate postoperative irradiation. In addition, only one outpatient treatment is required after surgery, enhancing patient convenience.
    Plastic &amp Reconstructive Surgery 09/2014; 134(3):527-534. DOI:10.1097/PRS.0000000000000415 · 3.33 Impact Factor
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    ABSTRACT: Background Intralesional (IL) cryotherapy is a new promising technique for the treatment of keloid scars, in which the scar is frozen from inside. Multiple devices are available, mostly based on a simple liquid nitrogen Dewar system, which have a limited freezing capacity. Argon gas based systems ensure accurate and highly controlled freezing and have shown effective within the field of oncologic surgery. However, this technique has never been used for treatment of keloid scars. Objective This prospective study evaluates an argon gas based system for the treatment of keloids in a patient population including all Fitzpatrick skin types with a 1 year follow-up. Methods Twenty-five patients with 30 keloid scars were included and treated with a device called Seednet. Scar quality and possible scar recurrence were assessed pre- and post-treatment (6 and 12 months) with objective devices determining scar color, scar elasticity, scar volume and patient’s skin type. In addition, scars were evaluated using the Patient and Observer Scar Assessment Scale. Results After 12 months, a significant volume reduction of 62% was obtained, p=0,05. Moreover, complaints of pain and itching were alleviated and scar quality had improved according to the Patient and Observer Scar Assessment Scale. Scar pigmentation recovered in 62% of all keloid scars within 12 months. Five out of 30 (17%) scars recurred within 12 months, 3 of which had previously been treated with liquid nitrogen-based IL cryotherapy. Both recurrence and persistent hypopigmentation were mainly seen in Afro-American patients. Conclusions Intralesional cryotherapy with the use of an argon gas based system proves to be effective in the treatment of keloid scars, yielding volume reduction and low recurrence rates. Although hypopigmentation recovered in most cases, it is strongly related to non- Caucasian patients. Finally, additional treatment of keloid scars previously unresponsive to IL cryotherapy, are predisposed to a high recurrence rate. Trial number NCT02063243.
    Journal of Plastic Reconstructive & Aesthetic Surgery 08/2014; DOI:10.1016/j.bjps.2014.08.046 · 1.47 Impact Factor
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    ABSTRACT: A serious complication seen in critically ill patients is the solidification of enteral nutrition causing gastrointestinal obstruction. It has been suggested that enteral nutrition enriched with insoluble fibers may increase the risk of this complication. Therefore, we investigate the effect of soluble and insoluble dietary fibers on the coagulation of a casein-based enteral nutrition in an artificial gastric digestion model. A 100% casein-based enteral nutrition was enriched with increasing concentrations of soluble fibers (acacia fiber, oligofructose and inulin) and insoluble fibers (soy polysaccharide, resistant starch and alpha cellulose). After digestion in an artificial gastric model, the chyme was poured over sequentially placed sieves, separating the coagulate into size fractions of larger than 2 mm, between 1 and 2 mm, and between 0.25 and 1 mm. Of these fractions we measured wet weight, dry weight and protein content. A significant effect on the fraction larger than 2 mm was considered to be clinically relevant. Addition of high concentrations soy polysaccharide and resistant starch to a casein-based enteral nutrition, did not alter the wet weight, whereas dry weight and protein content of the coagulate was significantly reduced. When high concentrations of soy polysaccharide and resistant starch are added to a 100% casein-based enteral nutrition, the coagulate consist of more water and less proteins, which may lead to an increased protein digestion and absorption in a clinical setting. The suggestion that insoluble fibers increase the risk of gastrointestinal obstruction in critically ill patients is not supported by these data.
    Food & Function 06/2014; 5(8). DOI:10.1039/c4fo00061g · 2.91 Impact Factor
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    ABSTRACT: Asymmetric dimethylarginine (ADMA) is an analog of arginine and functions as an endogenous inhibitor of the nitric oxide synthase, which forms nitric oxide. Nitric oxide is crucial for perfusion of vital organs and is an important signaling agent in the development of critical illness. The role of ADMA in the pathophysiological mechanisms underlying critical illness is widely studied in the last decades, and recently it has become clear that ADMA should not be overlooked by clinicians working at the ICU. The aim of this review is to describe new insights into the role of ADMA in critical illness and its clinical relevance. High levels of ADMA are found in critically ill patients, because of higher levels of protein methylation, increased rate of protein turnover, decreased activity of dimethylamine dimethylaminohydrolase, and impaired renal and hepatic clearance capacity. These high levels are an independent risk factor for cardiac dysfunction, organ failure, and ICU mortality. The arginine : ADMA ratio in particular is of clinical importance and the restoration of this ratio is expedient to restore several functions that are disturbed during critical illness. Elevated ADMA levels occur in critically ill patients, which is detrimental for morbidity and mortality. The arginine : ADMA ratio should be restored to maintain nitric oxide production and therewith improve the clinical outcome of the patient.
    11/2013; DOI:10.1097/MCO.0000000000000020
  • M. Visser, B.A. de Mol, P.A. van Leeuwen
    Clinical Nutrition 09/2013; 32:S27. DOI:10.1016/S0261-5614(13)60062-X · 3.94 Impact Factor
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    Nikki Buijs, Mechteld Vermeulen, Paul van Leeuwen
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    ABSTRACT: To the Editor: Heyland et al. (April 18 issue)(1) have shown that glutamine supplementation (approximately 65 g daily) of a diet that does not supply adequate energy (910 kcal) or protein (45 g) did not affect clinical outcome and increased mortality. However, the addition of a supplement that constituted 60% of total dietary protein introduced an amino acid imbalance with the potential for toxicity. Other, similar examples, such as the lack of arginine as part of dietary protein(2) or the use of essential amino acids only(3) in otherwise complete diets, have been shown to produce hyperammonemia in humans. Furthermore, glutamine . . .
    New England Journal of Medicine 08/2013; 369(5):482-5. DOI:10.1056/NEJMc1306658#SA4 · 54.42 Impact Factor
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    ABSTRACT: Delayed gastric emptying limits the administration of enteral nutrition, leading to malnutrition, which is associated with higher mortality and morbidity. Currently available prokinetics have limitations in terms of sustained efficacy and side effects. To summarise the mechanisms of action and to discuss the possible utility of gastrointestinal hormones to prevent or treat delayed gastric emptying in critically ill patients. We searched PubMed for articles discussing 'delayed gastric emptying', 'enteral nutrition', 'treatment', 'gastrointestinal hormones', 'prokinetic', 'agonist', 'antagonist' and 'critically ill patients'. Motilin and ghrelin receptor agonists initiate the migrating motor complex in the stomach, which accelerates gastric emptying. Cholecystokinin, glucagon-like peptide-1 and peptide YY have an inhibiting effect on gastric emptying; therefore, antagonising these gastrointestinal hormones may have therapeutic potential. Other gastrointestinal hormones appear less promising. Manipulation of endogenous secretion, physiological replacement and administration of gastrointestinal hormones in pharmacological doses is likely to have therapeutic potential in the treatment of delayed gastric emptying. Future challenges in this field will include the search for candidates with improved selectivity and favourable kinetic properties.
    Alimentary Pharmacology & Therapeutics 07/2013; 38(6). DOI:10.1111/apt.12421 · 4.55 Impact Factor
  • Nutritional Therapy and Metabolism 07/2013; 31(3). DOI:10.5301/NTM.2013.11329
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    ABSTRACT: Pharmaco-nutrients have beneficial effects on protective and immunological mechanisms in patients undergoing surgery, which are important for recovery after injury and in combating infectious agents. The aim of this review article was to outline the potential of the administration of nutritional substrates to surgical patients and the underlying mechanisms that make them particularly important in peri-operative care. Surgery causes a stress response, which has catabolic effects on the body's substrate stores. The amino acid glutamine is a stimulating agent for immune cells. It activates protective mechanisms through its role as a precursor for antioxidants and it improves the barrier function of the gut. Arginine also enhances the function of the immune system, since it is the substrate for T-lymphocytes. Furthermore, n-3 PUFA stabilise surgery-induced hyper-inflammation. Taurine is another substrate that may counteract the negative effects of surgical injury on acid-base balance and osmotic balance. These pharmaco-nutrients rapidly become deficient under the influence of surgical stress. Supplementation of these nutrients in surgical patients may restore their protective and immune-enhancing actions and improve clinical outcome. Moreover, pre-operative fasting is still common practice in the Western world, although fasting has a negative effect on the patient's condition and the recovery after surgery. This may be counteracted by a simple intervention such as administering a carbohydrate-rich supplement just before surgery. In conclusion, there are various nutritional substrates that may be of great value in improving the condition of the surgical patient, which may be beneficial for post-operative recovery.
    Proceedings of The Nutrition Society 02/2013; DOI:10.1017/S0029665112003047 · 4.94 Impact Factor
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    ABSTRACT: Loss of body tissue resulting in undernutrition can be caused by reduced food intake, altered metabolism, ageing, and physical inactivity. The predominant cause of undernutrition before cardiac operations is unknown. First, we explored the association of reduced food intake and inactivity with undernutrition in patients before elective cardiac operations. Second, we assessed if adding these reversible, cause-based items to the nutritional screening process improved diagnostic accuracy. A prospective observational study was performed. Undernutrition was defined by low fat-free mass index (LFFMI) measured by bioelectrical impedance spectroscopy and/or unintended weight loss (UWL). Reduced food intake was defined as the patient having a decreased appetite over the previous month. Patients admitted to hospital preoperatively were assumed to be less physically active than patients awaiting cardiac operations at home. Using these data, we developed a new tool and compared this with an existing cardiac surgery-specific tool (Cardiac Surgery-Specific Malnutrition Universal Screening Tool [CSSM]). A total of 325 patients who underwent open cardiac operations were included. Reduced food intake and inactivity were associated with undernutrition (odds ratio [OR], 4.2; 95% confidence interval [CI], 2.1-8.5 and OR, 2.0; 95% CI, 1.0-4.0). Reduced food intake and inactivity were integrated with body mass index (BMI) and UWL into a new scoring system: the Cardiac Surgery-Specific Undernutrition Screening Tool (CSSUST). Sensitivity in identification of undernourished patients was considerably higher with the CSSUST (90%) than with the CSSM (71%) (receiver operating characteristic [ROC] curve-based area under the curve [AUC], 0.79; 95% CI, 0.73-0.86 and ROC AUC, 0.71; 95% CI, 0.63-0.80). Results suggest that reduced food intake and inactivity partly explain undernutrition before cardiac operations. Our new cause-based CSSUST, which includes reduced food intake and inactivity, is superior to existing tools in identifying undernutrition in patients undergoing cardiac operations.
    The Annals of thoracic surgery 02/2013; 95(2):642-7. DOI:10.1016/j.athoracsur.2012.08.119 · 3.65 Impact Factor
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    ABSTRACT: The patients’ condition prior to surgery is of major importance for clinical outcome. It is believed nowadays that artificial nutrition in the form of a preoperative drink may improve postoperative outcome. Until now, a clear overview concerning the effects of preoperative supplementation on patients’ well-being has been lacking. The aim of this review is to summarize the results of randomized clinical trials investigating the effects of different preoperative supplements such as carbohydrate (CHO)-rich beverages, oral nutritional supplements (ONSs), immunonutrition and lemonades on clinical, metabolic and immunological parameters. We reviewed the relevant articles published between 1995 and 2012. Preoperative CHO-rich drinks appear to be safe, do not affect gastric emptying time and switch the fasted state to a fed state. Moreover, a significant reduction of postoperative insulin resistance, an improved well-being of the patient and prevention of surgery-induced immunodepression was found. For ONSs, beneficial effects were found according to muscle metabolism and strength, glucose storage and cost-effectiveness. Preoperative supplementation of immunonutrition resulted in improved immune function, restricted inflammatory response after surgery, prevention of organ damage, improved nutritional status with subsequently decreased postoperative complication rates and reduced length of hospital stay. Preoperative oral supplements have beneficial effects on many aspects of patient’s well-being and recovery. Different supplements, preferably in combination with each other, can help to reduce postoperative complications after surgery and length of hospital stay. Nutritional support must not be overlooked when considering optimal surgical care. Keywords: Preoperative, Oral supplements, Surgery, Carbohydrates,
    CAB Reviews Perspectives in Agriculture Veterinary Science Nutrition and Natural Resources 01/2013; DOI:10.1079/PAVSNNR20138015
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Publication Stats

6k Citations
1,136.75 Total Impact Points


  • 2002–2015
    • VU University Medical Center
      • • Department of Surgery
      • • Department of Pathology
      Amsterdamo, North Holland, Netherlands
    • Technische Universität München
      München, Bavaria, Germany
  • 2000–2014
    • VU University Amsterdam
      • • Department of Surgery
      • • Department of Clinical Chemistry
      Amsterdamo, North Holland, Netherlands
  • 1998–2011
    • University of Amsterdam
      • • Faculty of Medicine AMC
      • • Department of Chemistry
      • • Department of Surgery
      Amsterdam, North Holland, Netherlands
  • 2006
    • Klang General Hospital
      Krung Thep, Bangkok, Thailand
  • 2005
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 1999–2005
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Surgery
      Amsterdamo, North Holland, Netherlands
  • 1997–2000
    • Freie Universität Berlin
      Berlín, Berlin, Germany
  • 1991
    • Harvard Medical School
      • Department of Surgery
      Boston, Massachusetts, United States