Hans Leweling

Multiple sclerosis and nutrition

Benefits from any particular diet in multiple sclerosis (MS) have not yet been proven. It is, however, frequent that malnutrition may potentially exacerbate the symptoms of MS. There is some evidence that a high intake of saturated fat increases the incidence of MS. Epidemiological studies imply that unsaturated fatty acids may have a positive effect on the course of MS. However, the results of controlled studies are ambiguous. A meta-analysis of three small controlled clinical trials suggests a benefit from linoleic acid. Intake of Vitamin D is associated with a lower incidence of MS. In MS, the risk of osteoporosis is high, and prophylactic vitamin D and calcium should be considered at an early stage. The role of minerals, trace elements, antioxidants, vitamins or fish oil is unclear. The possible relationships between diet and MS have not been subjected to adequate study. It seems possible that in the future, diets or dietary supplements may become recommended forms of treatment for MS.

Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design

This paper documents dose-dependent effects of ornithine aspartate (OA) on postprandial hyperammonemia and plasma amino acids. Ten patients with cirrhosis were randomized to undergo 1 out of 4 infusion series. Each series consisted of four 8-h infusions (09:00 h-17:00 h), with placebo (NaCl), 5 g, 20 g or 40 g of OA being administered on separate days in varying sequences. This 4-fold crossover design was double-blind. On infusion days, patients received 2 oral protein loads (0.25 g/kg at 09:00 h and 0.5 g/kg at 13:00 h). Venous blood samples were drawn every 2 h and the 24-h urine was collected. In addition to measuring plasma ammonia and amino acids, the urea production rate, serum glucose and serum insulin were analyzed. A significant postprandial rise in the ammonia concentration was noted during the infusions of placebo and 5 g of OA but did not occur with the dosages of 20 g (after the second protein load) and 40 g (after both protein loads). Furthermore, the latter dose, compared with placebo, significantly reduced plasma ammonia after the minor protein load. Urea production rate increased when 20 g or 40 g of OA was administered. Of the amino acids involved in the metabolic pathways of ornithine and/or aspartate, glutamate showed a rise in its plasma level following infusion of 40 g of OA, whereas glutamine did not. Concentrations of methionine, phenylalanine, tyrosine, threonine, serine and glycine declined progressively with increasing doses of OA (5-40 g). The highest dose of the drug caused hyperglycemia and hyperinsulinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Pragmatic Management of Hyperglycaemia in Acute Ischaemic Stroke: Safety and Feasibility of Intensive Intravenous Insulin Treatment

Background: In patients with acute ischaemic stroke, hyperglycaemia has been retrospectively associated with negative outcome. There is an ongoing discussion as to which treatment algorithm, if any, provides the most effective prospective intervention. Here we test the safety and feasibility of an intravenous insulin-only infusion protocol designed for pragmatic routine clinical use. Methods: 40 ischaemic stroke patients with onset <24 h ago, admitted to our stroke unit, were randomized either to the study regimen (50 IU insulin in 50 ml 0.9% saline solution applied intravenously via a perfusor pump), with the aim of reaching and maintaining blood glucose levels between 4.44 mmol/l (80 mg/dl) and 6.11 mmol/l (110 mg/dl), or were treated with insulin subcutaneously if concentrations were above 11.10 mmol/l (200 mg/dl). Treatment was continued for 5 days. Primary outcome was the number of hypoglycaemic (<3.33 mmol/l; <60 mg/dl) and severe hyperglycaemic (>16.65 mmol/l; >300 mg/dl) events. Results: Hypoglycaemic events were significantly more common in patients treated intensively (total n = 25; incidence rate ratio, IRR = 5.3; 95% CI = 1.2–22.4; p < 0.05). Symptomatic events were rare (total n = 5). Severe hyperglycaemia was associated with conventional treatment (IRR = 4.9; 95% CI = 1.5–15.9; p < 0.05). Though those treated intensively attained near-normoglycaemic levels quicker and had significantly lower blood glucose levels over the study period (6.49 ± 2.19 mmol/l vs. 8.01 ± 3.06 mmol/l; 95% CI = –1.78 to –1.28, p < 0.0005), treatment imposes considerable strain on both patients and caregivers. Conclusions: The intensive intravenous insulin infusion protocol effectively lowers blood glucose levels with an increased risk of manageable hypoglycaemic events. However, a highly motivated and trained staff seems essential, limiting feasibility outside of specialty care settings.

Hyperammonemia-induced depletion of glutamate and branched-chain amino acids in muscle and plasma

BACKGROUND/AIMS Exogenous hyperammonemia is known to decrease the plasma levels of branched-chain amino acids (BCAA). To investigate whether changes in intracellular amino acid concentrations of muscle are associated with and may, at least in part, mediate this effect, experiments were carried out on a total of 60 male Wistar rats. METHODS Five groups were formed in a randomized manner. Group A: no treatment; groups B1 and B2: 2-hour and 6-hour continuous central-venous infusions, respectively, of sodium salts; groups C1 and C2: 2-hour and 6-hour infusions of ammonium salts. We obtained venous blood samples and muscle biopsies. Plasma ammonia, whole blood glucose, serum insulin, blood pH, and amino acids in plasma as well as in the intracellular water of muscle were measured. RESULTS As compared with control group A, groups C1 and C2 displayed a 3.3- and a 4-fold increase, respectively, in the plasma ammonium concentration. Regarding insulin, the ammonium-infused rats were similar to group A but not to the sodium-infused B groups, which had significantly lower insulin concentrations. Administering ammonium brought about a decline in BCAA concentrations in plasma after 2 hours and in muscle after 6 hours. The ammonium-induced fall in intracellular BCAA values was preceded by an increase of glutamine as well as by a decrease of glutamate and alanine in both plasma and muscle. CONCLUSIONS It is pointed out that the inter-group differences in serum insulin, although possibly accounting for some of the findings, can by no means explain the entire pattern of amino acid concentrations seen after the ammonium infusions. Instead, our results agree with the hypothesis that hyperammonemia indirectly lowers the plasma levels of BCAA by stimulating glutamine synthesis, thus reducing the intracellular glutamate pool, which is likely to be restored, at least in part, by an intensified BCAA transamination. Clarification is needed as to whether carbon skeletons derived from valine and isoleucine additionally contribute to replenishing the glutamate pool.

Bioimpedance Analysis Parameters and Epicardial Adipose Tissue Assessed by Cardiac Magnetic Resonance Imaging in Patients With Heart Failure

There is increasing evidence that body composition should be considered as a systemic marker of disease severity in congestive heart failure (CHF). Prior studies established bioelectrical impedance analysis (BIA) as an objective indicator of body composition. Epicardial adipose tissue (EAT) quantified by cardiac magnetic resonance (CMR) is the visceral fat around the heart secreting various bioactive molecules. Our purpose was to investigate the association between BIA parameters and EAT assessed by CMR in patients with CHF. BIA and CMR analysis were performed in 41 patients with CHF and in 16 healthy controls. Patients with CHF showed a decreased indexed EAT (22 ± 5 vs. 34 ± 4 g/m2, P < 0.001) and phase angle (PA) (5.5° vs. 6.4°, P < 0.02) compared to healthy controls. Linear regression analysis showed a significant correlation of CMR indexed EAT with left ventricular ejection fraction (LV‐EF) (r = 0.56, P < 0.001), PA (r = 0.31, P = 0.01), total body muscle mass (TBMM) (r = 0.41, P = 0.001), fat‐free mass (FFM) (r = 0.30, P = 0.02), and intracellular water (ICW) (0.47, P = 0.0003). Multivariable analysis demonstrated that LV‐EF was the only independent determinant of indexed EAT (P < 0.0001). Receiver operating characteristic curve analysis indicated good predictive performance of PA and EAT (area under the curve (AUC) = 0.86 and 0.82, respectively) with respect to cardiac death. After a follow‐up period of 5 years, 8/41 (19.5%) patients suffered from cardiac death. Only indexed EAT <22 g/m2 revealed a statistically significant higher risk of cardiac death (P = 0.02). EAT assessed by CMR correlated with the BIA‐derived PA in patients with CHF. EAT and BIA‐derived PA might serve as additional prognostic indicators for survival in these patients. However, further clinical studies are needed to elucidate the prognostic relevance of these new findings.

Aminosäurenaufnahme und -abgabe kolorektaler Karzinome des Menschen

Uber den Aminosaurenaustausch menschlicher Tumoren informieren nur wenige Arbeiten. Um diesen Austausch in vivo zu kennzeichnen, wurden 21 Patienten mit resezierbaren kolorektalen Karzinomen wah-rend

Inert gas rebreathing: the effect of haemoglobin based pulmonary shunt flow correction on the accuracy of cardiac output measurements in clinical practice.

Background:  Cardiac output (CO) is an important cardiac parameter, however its determination is difficult in clinical routine. Non‐invasive inert gas rebreathing (IGR) measurements yielded promising results in recent studies. It directly measures pulmonary blood flow (PBF) which equals CO in absence of significant pulmonary shunt flow (QS). A reliable shunt correction requiring the haemoglobin concentration (cHb) as only value to be entered manually has been implemented. Therefore, the aim of the study was to evaluate the effect of various approaches to QS correction on the accuracy of IGR.

Protein- und Aminosäurenstoffwechsel bei Leberinsuffizienz—Infusionstherapeutische und diätetische Folgerungen

Die heutigen Tendenzen und Richtlinien bezuglich der Versorgung leberinsuffizienter Patienten mit Eiweis bzw. Aminosauren ergeben sich uberwiegend aus metabolischen Erkenntnissen und kontrollierten klinischen Studien der letzten 10 Jahre; sie kontrastieren in quantitativer und qualitativer Hinsicht mit alteren Vorstellungen. Subtile Methoden der Beschreibung des Proteinhaushalts und des Ernahrungszustands (Abschnitt 1) haben zusammen mit einer verbesserten Diagnostik fruher Phanomene der hepatischen Enzephalopathie (HE) annahernd zufriedenstellende Effektivitatskriterien nutritiver Masnahmen geliefert. Des weiteren ist die rationale Basis dieser Masnahmen durch neue Einblicke in den Aminosauren— und Ammoniakstoffwechsel (Abschnitt 2) wie auch in die Entstehungsweise der HE (Abschnitt 3) stabiler und breiter geworden. Das hepatologisch konzipierte Aminosaurengemische bei entsprechend gefahrdeten Kranken eine risikofreie und effiziente parenterale Ernahrung ermoglichen, wuste man schon zu Beginn der vergangenen Dekade. Davon zu unterscheiden ist das erst in jungster Zeit ausreichend legitimierte Bestreben, durch Anwendung solcher Aminosaurengemische prakomatose und komatose Zustande nicht nur zu vermeiden, sondern auch adjuvant zu behandeln (Abschnitt 4). Auf dem Sektor der oralen Ernahrung lief die Entwicklung ungefahr parallel, wobei allerdings das Fazit aus den bislang verfugbaren Befunden mehr die Prophylaxe der HE als deren Therapie betrifft (Abschnitt 5).

Haemodilution in acute ischaemic stroke comparison of two haemodilution regimen

In a prospective study we randomly allocated 50 patients with acute ischaemic stroke in the area of the middle cerebral artery within 12 hours after onset to two moderate hypervolemic haemodilution regimen consisting of 500 ml of 10% hydroxyethyl starch per day for 10 days. In the high haematocrit group the target haematocrit of 41-42% was achieved by 0-3 phlebotomies and additional replacement of that volume with the colloid in 3 days. In the low haematocrit group with 1-4 phlebotomies a target haematocrit of 37-38% was reached in 4 days. The groups did not differ regarding age, risk factors, haematocrit and neurological score. The improvement of the disturbed blood rheology was more pronounced in the low haematocrit group. One death occurred in each group. The neurological score showed a significantly greater increase in the low haematocrit group with +59% at day 5 and +125% at day 11; the data for the high haematocrit group were +34% and +89% respectively. We calculated a correlation (r = 0.36, p less than 0.02) between the rise in neurological score and the reduction of haematocrit. Our data suggest but not do prove that an early start on moderate hypervolemic haemodilution is beneficial in patients with acute ischaemic stroke and disturbed blood rheology.

Intra- and extracellular amino acid concentrations in portacaval-shunted rabbits. Role of hyperammonemia and effects of branched-chain amino acid-enriched parenteral nutrition.

SummaryIntra- and extracellular amino acid concentrations were measured in rabbits in order to elucidate the possible role of hyperammonemia in lowering the postabsorptive plasma levels of branched-chain amino acids (BCAA) and to assess the effects of BCAA-enriched total parenteral nutrition (TPN) on the amino acid pattern of muscle. The pathophysiological part of this paper deals with portacaval anastomosis (PCA) and is aimed at substantiating or rejecting our hypothesis that excessive ammonia — by stimulating glutamine synthesis — reduces the intracellular glutamate pool which is then restored, at least in part, by an intensified BCAA degradation. Regarding infusion therapy, we were mainly interested in whether an amino acid solution adapted to the metabolism in liver cirrhosis causes an accumulation of BCAA in muscle or modifies the intracellular content of glutamate and glutamine.Eighteen rabbits did not undergo surgery and served as controls (group A), while 30 were given a portacaval end-to-side anastomosis (group B). Two weeks after creating the PCA, venous blood samples were taken and muscle biopsies (Bergströms technique) were performed postabsorptively. An 18-h TPN was then started, the regimen administered included dextrose, fat and, in addition, either a conventional (group B1, n=15) or an adapted amino acid solution (group B2, n=15). We obtained second blood specimens and muscle biopsies at the end of the infusion period. With the control animals, the same time schedule for blood sampling and muscle biopsies was followed.Fourteen days after the operation, the PCA rabbits displayed a mean plasma ammonia level 5.1 times higher than that measured in the controls (p≤0.001). Conventional blood chemistry did not reveal any impairment of liver cell integrity or over-all hepatic function, whereas the nutritional state of the shunted animals worsened, as indicated by body weight and biochemical variables. Since in the PCA rabbits, the total amino acid pools of muscle and plasma were seen to be increased and decreased, respectively, the results concerning the individual amino acids are given in terms of both the absolute and percentage values, the latter more often revealing high levels of statistical significance. PCA induced a marked rise in the intra- and extracellular concentrations of glutamine, while the values of glutamate and alanine showed a decline in muscle and plasma. The extracellular levels of methionine, phenylalanine, and tyrosine were raised, while those of the BCAA were diminished. During TPN, the intracellular concentrations of glutamate and glutamine fell in the animal group B 1 but remained stable in group B2. Only a slight and insignificant accumulation of BCAA occurred in the latter group. Secondary findings confirmed that conventional TPN aggravates the pre-existing increase in the plasma levels of methionine and phenylalanine, and that BCAA-enriched TPN results in almost normalized values of these amino acids.In conclusion, the PCA-induced alterations in the intracellular amino acid concentrations support the above-formulated hypothesis concerning the role of hyperammonemia in lowering plasma BCAA values, the preferential maintenance of intra-, rather than extracellular BCAA levels being a well-known fact. The largely stable concentrations of BCAA in muscle during BCAA-enriched TPN may indicate in intensified utilization of these amino acids, which probably involves ammonia detoxification. The observation that this type of TPN prevented a fall in the muscular levels of glutamate and glutamine fits into this concept.ZusammenfassungIn der vorliegenden Studie an Kaninchen wurden intra- und extrazelluläre Aminosäurenkonzentrationen gemessen, um erstens zu untersuchen, ob die postabsorptive Verminderung der verzweigtkettigen Aminosäuren (VAS) im Plasma durch die Hyperammoniämie bedingt oder mitbedingt sein dürfte, und zweitens festzustellen, wie ein total parenterales Ernährungsregime mit hohem Gehalt an VAS das muskuläre Aminosäurenmuster beeinflußt. Gegenstand des pathophysiologischen Teils der Arbeit ist der Stoffwechsel nach Anlage einer portokavalen Anastomose (PKA). Hier geht es um die Stützung oder Widerlegung unserer Hypothese, daß vermehrt vorhandenes Ammoniak durch Stimulation der Glutaminbildung den intrazellulären Glutamat-Pool verkleinert, und dies mit der Konsequenz eines forcierten Abbaus der VAS zur wenigstens partiellen Erhaltung der Glutamatkonzentration. Was die Infusionstherapie betrifft, so interessierte vorrangig, ob eine den metabolischen Besonderheiten bei Leberzirrhose angepaßte Aminosäurenlösung die VAS in der Muskulatur akkumulieren läßt und ob eine solche Lösung die intrazellulären Glutamat- bzw. Glutaminspiegel modifiziert.Von insgesamt 48 Kaninchen dienten 18 nicht operierte als Kontrolltiere (Gruppe A), während 30 eine portokavale End-zu-Seit-Anastomose erhielten (Gruppe B). Zwei Wochen nach Herstellung der PKA wurden postabsorptiv venöse Blutproben entnommen und — nach der Methode von Bergström et al. - Muskelbiopsien durchgeführt. Unmittelbar danach begann eine 18stündige totale parenterale Ernährung (TPE). Wir applizierten als Hauptnährstoffe Glukose, Fett und ein Aminosäurengemisch, wobei das letztere entweder eine konventielle (Gruppe B 1, n= 5) oder eine adaptierte Zusammensetzung hatte (Gruppe B 2, n=15). Gegen Ende der Infusionsphase erfolgten zum zweitenmal Blutabnahmen und Muskelbiopsien. Die Kontrolltiere unterlagen bezüglich der Blut- und Muskelproben dem gleichen Zeitplan wie die operierten.14 Tage nach der Operation boten die Kaninchen mit PKA im Schnitt einen 5,1fach höheren Ammoniakspiegel als die Kontrolltiere (p<0,001). Die konventionellen blutchemischen Befunde ergaben keinen Hinweis auf eine Beeinträchtigung der Leberzellintegrität oder des allgemeinen Funktionsniveaus der Leber. Demgegenüber hatte sich der Ernährungszustand nach Anlage des Shunts verschlechtert (Körpergewicht, biochemische Parameter). Da bei den Tieren mit PKA die Gesamtmenge der Aminosäuren in den Muskelzellen vermindert und im Plasma vermehrt war, werden in dieser Arbeit die Spiegel der einzelnen Aminosäuren doppelt angegeben, nämlich als Absolut- und als Prozentwerte; die prozentualen Konzentrationen zeigten häufiger als die absoluten hochsignifikante Veränderungen. Die PKA verursachte eine erhebliche Zunahme der intra- und extrazellulären Glutaminspiegel, während für Glutamat und Alanin in der Muskulatur sowie im Plasma herabgesetzte Werte resultieren. Die Spiegel von Methionin, Phenylalanin und Tyrosin waren extrazellulär gesteigert, die der VAS verringert. Unter der TPE fielen intrazellulär die Konzentrationen von Glutamin und Glutamat in der Gruppe B 1 ab, blieben jedoch in der Gruppe B 2 konstant; die intrazellulären VAS akkumulierten in der letzten Gruppe nur sehr gering und ohne Signifikanz. Darüber hinaus bestätigten die Versuche, daß eine Standard-TPE bereits bestehende Konzentrationserhöhungen von Methionin und Phenylalanin im Plasma deutlich akzentuiert, während ein mit VAS angereichertes Infusionsregime die Spiegel dieser Aminosäuren annähernd in die Referenzbereiche bringt.Wir meinen, daß die durch eine PKA herbeigeführte Abweichungen des intrazellulären Aminosäurenmusters die eingangs formulierte Hypothese stützen, derzufolge die Hyperammoniämie zur Senkung der Plasmaspiegel der VAS zumindest beiträgt; dabei darf die bekannte Tendenz des Organismus, eher den intra- als den extrazellulären Pool der VAS aufrechtzuerhalten, nicht außer acht bleiben. Die bei TPE mit hohem Angebot an VAS weitgehend unbeeinflußten Konzentrationen derselben in der Muskulatur sprechen für eine intensivierte Nutzung dieser Aminosäuren, unter anderem wohl zum Zweck der Ammoniakentgiftung. Im übrigen paßt die Beobachtung, daß eine Abnahme der intrazellulären Spiegel von Glutamat und Glutamin durch die adaptierte TPE verhindert werden konnte, in das vorgetragene Konzept.