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Der Myokardinfarkt und die Herzinsuffizienz sind sehr häufige und oft zum Tode führende Erkrankungen, die trotz guter Kenntnis der Pathophysiologie noch nicht zufriedenstellend therapiert werden können. Im Wesentlichen besteht die Problematik darin, dass die postischämischen Umbauprozesse (Hypertrophie und Fibrose) nicht aufgehalten werden können und so beide Erkrankungen progredient verlaufen. In beiden Fällen gibt es steigende Evidenz dafür, dass durch Arginaseaktivierung ein Argininmangel erzeugt wird, der zu einer verminderten NO-Verfügbarkeit, erhöhten Superoxid-Konzentrationen und vermehrter Polyaminbildung führt. Diese drei Komponenten limitieren den Therapieerfolg. Eine mögliche Intervention stellt Citrullin dar, da es sowohl Arginaseinhibitor als auch natürlicher Arginindonor ist. An normoxen im elektrischen Feld stimulierten Herzmuskelzellen von Ratten kann Citrullin die kardiale Kontraktilität NO-abhängig steigern. Als Infarkt- bzw. Herzinsuffizienzmodell wurden retrograd perfundierte Rattenherzen einer 45 min Globalischämie mit anschließender 3 stündiger Reperfusion unterzogen. Die postischämische Herzfunktion kann unter Citrullin durch eine bessere Relaxation NO-abhängig gesteigert werden. Auch Arginin führt zu einer gesteigerten postischämischen Herzfunktion, diese wird aber im Gegensatz zu Citrullin, durch eine gesteigerte Kontraktilität bei verringerter Relaxation verursacht. Anhand von Dihydroethidiumbromid-Färbungen konnte gezeigt werden, dass Citrullin den postischämischen oxidativen Stress reduziert. Neben den funktionellen Effekten auf den Argininstoffwechsel induziert Citrullin die postischämische Expression der Arginase-I, auf Protein- und RNA-Ebene. Darüber hinaus konnte nach 3h Reperfusion auf RNA-Ebene ein antihypertropher und antifibrotischer Effekt Citrullins nachgewiesen werden. Im Gegensatz dazu zeigt Arginin ein prohypertrophes und profibrotisches Expressionsmuster. Die erhobenen Daten legen nahe, dass die postischämische Applikation von Citrullin über Arginaseinhibition und Konversion zu Arginin eine Kopplung der NO-Synthase bewirkt. Eine erhöhte linksventrikuläre NO-Verfügbarkeit sowie geringere Superoxidbildung sind die Folge, und führen zu einer besseren Herzfunktion sowie einer antihypertrophen und antifibrotischen Antwort des Myokards auf RNA-Ebene. Im Gegensatz dazu stimuliert Arginin wahrscheinlich primär die Arginase getriebene Polyaminsynthese. Dies ist zwar initial mit einer gesteigerten Kontraktilität assoziiert, zeigt aber ein profibrotisches und prohypertrophes Expressionsmuster. Myocardial infarction and heart failure are common diseases, which are highly lethal. Even the detailed knowledge of the underlying pathomechanisms does not guarantee satisfactory therapies. This is mainly caused by cardiac remodeling, hypertrophy and fibrosis, leading to impaired ventricular function. In both cases, arginase activation is considered to play a key role. Its activation causes a lack of arginine, which leads to NO-deficiency, excessive superoxide formation by uncoupled NO-synthase, and high concentrations of polyamines, a downstream product of arginase. All three components may limit the therapeutic success. A likely candidate to interfere with arginase activation is L-citrulline, a natural arginine precursor and non-competitive inhibitor of arginase. Under normoxic conditions citrulline improved load free cell shortening of isolated cardiomyocytes via increased NO-formation. In order to simulate myocardial infarction and heart failure in-vitro, retrograde perfused hearts of rats underwent 45 min of global ischemia followed by 3 h of reperfusion. Citrulline increased left ventricular NO bioavailability, thereby leading to reduced left ventricular end diastolic pressure and improved cardiac function. Arginine does also enhance postischemic heart function, but primarily due to a more powerful contraction. To quantify left ventricular superoxide-formation dihydroethidiumbromide staining has been used. Radical stress was attenuated by citrulline. Besides the functional effects on arginine metabolism, citrulline induces Aginase-I expression on RNA- and protein-level. After 3 h of reperfusion citrulline was associated with an antihypertrophic and antifibrotic RNA pattern. In contrast arginine treatment resulted in a prohypertrophic and profibrotic effect on RNA-level. Taken together, citrulline mediates cardioprotection through NOS-coupling and arginase inhibition, which has been pointed out on functional and RNA-level. Exactly the opposite is achieved by arginine treatment. Even if arginine improves postischemic heart function, it still mediates maladaptive processes, which might be explained by higher substrate offer to arginase, leading to excessive polyamine and proline formation. All in all, citrulline seems to be a highly promising candidate to interfere successfully with arginase-NOS-System. If this can be transferred into clinical practice of cardiovascular medicine remains unclear.

Der Myokardinfarkt und die Herzinsuffizienz sind sehr häufige und oft zum Tode führende Erkrankungen, die trotz guter Kenntnis der Pathophysiologie noch nicht zufriedenstellend therapiert werden können. Im Wesentlichen besteht die Problematik darin, dass die postischämischen Umbauprozesse (Hypertrophie und Fibrose) nicht aufgehalten werden können und so beide Erkrankungen progredient verlaufen. In beiden Fällen gibt es steigende Evidenz dafür, dass durch Arginaseaktivierung ein Argininmangel erzeugt wird, der zu einer verminderten NO-Verfügbarkeit, erhöhten Superoxid-Konzentrationen und vermehrter Polyaminbildung führt. Diese drei Komponenten limitieren den Therapieerfolg. Eine mögliche Intervention stellt Citrullin dar, da es sowohl Arginaseinhibitor als auch natürlicher Arginindonor ist.An normoxen im elektrischen Feld stimulierten Herzmuskelzellen von Ratten kann Citrullin die kardiale Kontraktilität NO-abhängig steigern. Als Infarkt- bzw. Herzinsuffizienzmodell wurden retrograd perfundierte Rattenherzen einer 45 min Globalischämie mit anschließender 3 stündiger Reperfusion unterzogen. Die postischämische Herzfunktion kann unter Citrullin durch eine bessere Relaxation NO-abhängig gesteigert werden. Auch Arginin führt zu einer gesteigerten postischämischen Herzfunktion, diese wird aber im Gegensatz zu Citrullin, durch eine gesteigerte Kontraktilität bei verringerter Relaxation verursacht. Anhand von Dihydroethidiumbromid-Färbungen konnte gezeigt werden, dass Citrullin den postischämischen oxidativen Stress reduziert. Neben den funktionellen Effekten auf den Argininstoffwechsel induziert Citrullin die postischämische Expression der Arginase-I, auf Protein- und RNA-Ebene. Darüber hinaus konnte nach 3h Reperfusion auf RNA-Ebene ein antihypertropher und antifibrotischer Effekt Citrullins nachgewiesen werden. Im Gegensatz dazu zeigt Arginin ein prohypertrophes und profibrotisches Expressionsmuster.Die erhobenen Daten legen nahe, dass die postischämische Applikation von Citrullin über Arginaseinhibition und Konversion zu Arginin eine Kopplung der NO-Synthase bewirkt. Eine erhöhte linksventrikuläre NO-Verfügbarkeit sowie geringere Superoxidbildung sind die Folge, und führen zu einer besseren Herzfunktion sowie einer antihypertrophen und antifibrotischen Antwort des Myokards auf RNA-Ebene. Im Gegensatz dazu stimuliert Arginin wahrscheinlich primär die Arginase getriebene Polyaminsynthese. Dies ist zwar initial mit einer gesteigerten Kontraktilität assoziiert, zeigt aber ein profibrotisches und prohypertrophes Expressionsmuster., Myocardial infarction and heart failure are common diseases, which are highly lethal. Even the detailed knowledge of the underlying pathomechanisms does not guarantee satisfactory therapies. This is mainly caused by cardiac remodeling, hypertrophy and fibrosis, leading to impaired ventricular function. In both cases, arginase activation is considered to play a key role. Its activation causes a lack of arginine, which leads to NO-deficiency, excessive superoxide formation by uncoupled NO-synthase, and high concentrations of polyamines, a downstream product of arginase. All three components may limit the therapeutic success. A likely candidate to interfere with arginase activation is L-citrulline, a natural arginine precursor and non-competitive inhibitor of arginase.Under normoxic conditions citrulline improved load free cell shortening of isolated cardiomyocytes via increased NO-formation. In order to simulate myocardial infarction and heart failure in-vitro, retrograde perfused hearts of rats underwent 45 min of global ischemia followed by 3 h of reperfusion. Citrulline increased left ventricular NO bioavailability, thereby leading to reduced left ventricular end diastolic pressure and improved cardiac function. Arginine does also enhance postischemic heart function, but primarily due to a more powerful contraction. To quantify left ventricular superoxide-formation dihydroethidiumbromide staining has been used. Radical stress was attenuated by citrulline. Besides the functional effects on arginine metabolism, citrulline induces Aginase-I expression on RNA- and protein-level. After 3 h of reperfusion citrulline was associated with an antihypertrophic and antifibrotic RNA pattern. In contrast arginine treatment resulted in a prohypertrophic and profibrotic effect on RNA-level.Taken together, citrulline mediates cardioprotection through NOS-coupling and arginase inhibition, which has been pointed out on functional and RNA-level. Exactly the opposite is achieved by arginine treatment. Even if arginine improves postischemic heart function, it still mediates maladaptive processes, which might be explained by higher substrate offer to arginase, leading to excessive polyamine and proline formation. All in all, citrulline seems to be a highly promising candidate to interfere successfully with arginase-NOS-System. If this can be transferred into clinical practice of cardiovascular medicine remains unclear.

Antibodies against citrullinated peptides are highly specific for rheumatoid arthritis. With second generation ELISA-kits, CCP-antibodies have a specificity of96 % and a sensitivity of 68 %. CCP-antibodies can be detected several years before the onset of clinical symptoms. They are, thus, ideally suited for the differential diagnosis between early forms of rheumatoid arthritis and other inflammatory arthritides. As CCP-antibodies are associated with aggressive and treatment resistant courses of rheumatoid arthritis, their high predictive value can be useful in therapeutic strategy decisions in order to verify early treatment with disease modifying drugs or biologicals in line with modern treatment approaches to start aggressive therapy early to prevent bone erosions. In contrast to their role in differential diagnosis and prediction of aggressive disease, however, CCP-antibodies are of no value in monitoring treatment as they do not change essentially over prolonged periods of time.

Free amino acids were determined quantitatively in cerebrospinal fluid of 80 boys and 69 girls (ages 1 month-14years). On the basis of the cliniclal criterions these children were considered to be ""healthy''. The total number of examined children was 2000. Cerebrospinal fluid was mixed with an equal volume of 5% sulphosalicylic acid and the amino acids were separated by ion exchange column chromatography.1. The sexspecific investigation of the 1 month -2 years old children showed that the boys had a statistical significant hgher concentration of lysine and that no statistical significant differences existed between the groups of 2-14 years old children. 2. The age specific comparison revealed that the amino acid concentrations ofaspartic acid, citrulline, histidine, lysine, serine, threonine and tyrosine were in the cerebrospinal fluid of the younger boys statistical significant higher as compared to the older boys and that the concentration of serine in the cerebrospinal fluid of the younger girls was statistical significant higher than in the group of older girls.

Free amino acids were determined quantitatively in serum from the fasting blood of healthy children from families with patients with endemic (Balkan) nephropathy. A group of healthy children of the same age served as controls. Compared with the boys from healthy families the healthy boys from families with patients of endemic (Balkan) nephropathy had statistically significantly higher concentrations of the following amino acids: alanin, citrulline, isoleucine, leucine, ornithine, phenylalanine, proline and serine. The healthy girls from families with patients with endemic (Balkan) nephropathy had statistically significantly higher concentrations of citrulline, cystine, glycine, isoleucine, methionine, ornithine, phenylalanine, proline and serine than girls in the control group.

Experimental studies have shown that in men with pathospermia the arginine content of sperm plasma is lower than in normal men. In order to find out the reason of this divergency the authors analysed the content of arginine, urea, citrulline, GAA and arginase activity in serum and in sperm plasma of 40 patients with normo-, oligo- or azoospermia. For the first time our results show that the low arginine content in pathological sperm is not due to disorder of the precursor metabolism, but to the increased arginase activity and to the increased conversion of arginine to GAA. In order to find out the mechanism of action and to develop an adequate andrological therapy detailed studies on molecular level have to be done.

The plasma amino acids of male patients with ankylosing spondylitis (ASp) and male controls were analysed and the concentrations statistically evaluated. The total concentration of all 28 amino acids in ASp-patients did not differ from the controls, but there were some distinct differences in the levels of individual amino acids, e. g. arginine and isoleucine which showed raised concentration (29% and 27%). A higher concentration was also detectable with rare amino acids, e. g. alpha-amino-adipinic acid (23%) and 1-methyl-histidine (32%). Correlation between the amino acid concentration and age was detected only in the case of citrulline. Some amino acids showed a significant correlation to one another which was sometimes evident in both groups and other times was noted in the control- or ASp-group only. If such correlations were found to be disease-dependent this finding could be helpful in the diagnosis of certain diseases.

We report the first case of lysinuric protein intolerance observed in Germany. A girl of Turkish ancestry suffered from severe dehydration at the age of 6 months after changing from breast milk to cow milk. Because of a microcytic hypochromic anaemia and erythrophagocytosis in the bone marrow a hematologic disease (Farquar's disease) was suspected. The definite diagnosis of lysinuric protein intolerance was eventually clarified by the following laboratory and clinical data: increased urinary excretion and low plasma concentration of lysine, arginine and ornithine, apathy, vomiting, diarrhea and hyperammonemia after an oral protein load, high serum LDH-activity, ferritinemia, and increased urinary excretion of orotic acid. Under therapy with citrullin and a low-protein diet the metabolic situation remained stable, even during infections. The bone marrow findings have been reported only in one further case of lysinuric protein intolerance.

Carbamyl phosphate synthetase (CPS) catalyses the synthesis of carbamyl-phosphate from ammonia and bicarbonate and is the first step in ureagenesis. The infant described in this report suffered from deficiency of this enzyme. The symptoms started on the 2nd day of life with tachycardia, apathy, irritability and metabolic alcalosis, on the 4th day coma and fits occurred due to hyperammonia (ammonia in the blood max 496 mumol/l, normally up to 150 in newborns). In hepatic tissue no activity of carbamyl phosphate synthetase could be measured (normal range 0.66-2.1 mumol/h/mg protein). Peritoneal dialysis was instituted, but the metabolic crisis could only be overcome by the following therapeutic measures: restriction of protein intake to 1.5 g/kg/d in part as a special aminoacid mixture, in part as breast milk; sufficient caloric supply (600-500 kJ/kg/d); sodium benzoate 350 mg/kg/d: arginine 2 mmol/kg/d respectively citrulline 350 mg/kg/d, and carnitine 150 mg/kg/d. By these procedures the exogenous and endogenous load of ammonia could be minimized. Electroencephalogram and mental development were normal. Acute metabolic crises with hyperammonia during catabolic states (infections) could be treated several times. At the age of 8 months, however, the patient died during such a crisis. This case shows that it is possible to achieve a normal psychomotor development in complete CPS-deficiency by adequate therapy. Catabolic states are difficult to manage.

The article reports on an infant which first in age of nine months and then again in age of 1.6 years had an episode of stupor. Laboratory investigation showed hyperammonemia and high values of transaminases. The differential diagnostic check up led to the diagnosis of citrullinemia in the age of 1.7 years by amino acid chromatography. The diagnosis could be confirmed by measuring enzyme activity in the liver. Therapy is protein-low feeding and supplementation of essential amino acids and arginine. A therapeutic trial with additional sodium benzoate did not show a positive effect. The patient made a significant step backwards in development during the second episode of stupor; however in the following months the retardation could be reduced markedly.

Whole blood, serum and deproteinized serum were stored at room temperature up to 24 h and at - 30 degrees C up to one month. The amino acid content was then determined with an automatic amino acid analyser. When whole blood is left at room temperature the concentration of citrulline, alpha-aminobutyric acid, cysteine and tryptophan remains unchanged, whereas the other amino acids show a remarkable increase or decrease. In serum stored for 24 h at room temperature, only the concentrations of aspartic and glutamic acid, serine, cysteine and phenylalanine were altered. With the exception of aspartic and glutamic acid it was possible to leave deproteinized serum up to 24 h at room temperature and up to one month at - 30 degrees C without observing a change in the concentration of the other amino acids. No change occurred, when serum was stored at - 30 degrees C for 24 h.