Plasma Ornithine Levels Research Articles

A panel of four plasma amino acids is a promising biomarker for newly diagnosed bladder cancer

BackgroundMetastasis and recurrence are the main causes of death in post-operative bladder cancer (BC), emphasizing the importance of exploring early-stage diagnostic markers. Serum biomarkers constitute a promising diagnostic approach for asymptomatic stage cancer as they are non-invasive, have high accuracy and low cost. AimsTo correlate concentrations of plasma amino acids with BC progression to assess their utility as an early-stage diagnostic. MethodsNewly diagnosed BC patients (n=95) and normal controls (n=96) were recruited during the period from 1 December 2018 to 30 December 2020. General and food frequency questionnaires established their basic information and dietary intake data. Venous blood samples were collected from fasting subjects and used to detect levels of plasma amino acids by liquid chromatography-mass spectrometry. Verification was performed on the GSE13507 transcriptome gene expression matrix of BC from Gene Expression Omnibus (GEO) database. ResultsEleven amino acids have been identified as altered in the plasma of newly diagnosed BC patients compared to controls (P < 0.05). Adjusted by gender, education, smoking and other factors, plasma ornithine level (OR = 0.256, 95% CI: 0.104 ∼ 0.630) is a protective factor for BC, plasma levels of methionine (OR = 3.460, 95% CI: 1.384 ∼ 8.651), arginine (OR = 3.851, 95% CI: 1.542 ∼ 9.616), and glutamate (OR = 3.813, 95% CI: 1.543 ∼ 9.419) are all risk factors for BC. ROC analysis demonstrated that the combination of plasma ornithine, methionine, arginine and glutamate could accurately diagnose BC (AUC = 0.84, 95% CI: 0.747 ∼ 0.833). In addition, the mRNA level of arginase 1 was decreased (P < 0.05), while the inducible nitric oxide synthase was increased significantly, which may be linked with the disturbance of arginine metabolism in BC patients. Further analysis of GEO database confirmed the role of arginine metabolism. ConclusionA biomarker panel containing four amino acids may provide a feasible strategy for the early diagnosis of BC. However, further validation is required through prospective studies.

Plasma urea cycle metabolite levels and the risk of moyamoya disease.

Urea cycle metabolites are expected to be the biomarkers for cerebrovascular diseases. However, the effects of circulating urea cycle metabolites on the risk of MMD and its subcategories remain unclear. The aim of this study was to prospectively investigate the association between plasma urea cycle metabolites and the risk of MMD and its subcategories. We measured plasma urea cycle metabolite levels for 360 adult MMD patients and 89 matched healthy controls. Clinical and laboratory characteristics were obtained from the medical record. The study was conducted from July 2020 to December 2021. After multivariate adjustment, the risk of MMD increased with each increment in ornithine level (per natural log [ornithine] increment: OR, 3.893; 95% CI, 1.366-11.090). The risk of MMD decreased with each increment in arginine level (per natural log [arginine] increment: OR, 0.109; 95% CI, 0.028-0.427), urea level (per natural log [urea] increment: OR, 0.261; 95% CI, 0.072-0.940), and global arginine bioavailability ratio (GABR) level (per natural log [GABR] increment: OR, 0.189; 95% CI, 0.074-0.484). The addition of plasma arginine (integrated discrimination improvement: 1.76%, p = 0.021) or GABR (integrated discrimination improvement: 1.76%, p = 0.004) to conventional risk factors significantly improved the risk reclassification for MMD. Plasma ornithine levels are positively associated with the risk of MMD. By contrast, the levels of arginine, urea, and GABR are inversely related to the risk of MMD. Plasma urea cycle metabolites might be potential biomarkers for the risk of MMD.

Associations of sleep quality with the skeletal muscle strength in patients with type 2 diabetes with poor glycemic control

Patients with type 2 diabetes mellitus are reported to be at a high risk for sarcopenia, and are known to have a poorer sleep quality. However, the association between sleep quality and skeletal muscle in patients with type 2 diabetes mellitus is not yet precisely understood. A total of 110 inpatients with type 2 diabetes mellitus aged 40-90 years were enrolled. The sleep quality was assessed using the Pittsburgh sleep quality index (PSQI). Skeletal muscle mass was measured using bioelectrical impedance analysis. Muscle strength was evaluated by measuring the grip strength. We also performed dietary surveys and measurements of the plasma amino acid levels. A high total score on the PSQI was significantly associated with reduced muscle strength, and the association persisted even after adjustments for confounders. On the other hand, adjusted analysis did not reveal any significant associations between the PSQI total score and the skeletal muscle mass. In regard to the associations with subscores of the PSQI, the scores for sleep latency, sleep efficiency, and daytime dysfunction were significantly negatively associated with the muscle strength. Although poor sleep quality was associated with a high confectionery intake and low plasma arginine, citrulline, and ornithine levels, neither confectionery intake levels nor the plasma levels of these amino acids was associated with the muscle strength. Our study revealed a significant association between the sleep quality and muscle strength in patients with type 2 diabetes mellitus. These results suggest that poor sleep quality is an important risk factor for sarcopenia in patients with type 2 diabetes mellitus.

Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes.

Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours’ standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child–Turcotte–Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose‐dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%–60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE.

The Curious Case of Night Blindness: A Rare Case Report

Introduction: Gyrate Atrophy of the choroid and the retina is a rare autosomal recessive disorder caused by a mutation in ornithine aminotransferase. Case Report: We present an interesting case of a 55-year-old male who presented to us with complaints of night blindness, increase in number of minus glasses, senile cataract in both eyes, constriction of peripheral visual field and chorioretinal atrophic lesions in both eyes. Blood investigation revealed raised plasma ornithine levels at 690 micromole/L (normal range 30-90 micromole/L). There is progressive night blindness and visual field constriction due to progressive chorioretinal degeneration. It has now progressed to diminution of central visual acuity due to progressive macular and glaucomatous changes and cataract formation. Conclusion: There is history of blindness in two out of 6 more siblings which indicates a hereditary pattern.

Arginine to ornithine ratio as a diagnostic marker in patients with positive newborn screening for hyperargininemia

Arginase deficiency is a rare inborn error of metabolism that interrupts the final step of the urea cycle. Untreated individuals often present with episodic hyperammonemia, developmental delay, cognitive impairment, and spasticity in early childhood. The newborn screening (NBS) algorithms for arginase deficiency vary between individual states in the US but often include hyperargininemia and elevated arginine to ornithine (Arg/Orn) ratio. Here, we report 14 arginase deficiency cases, including two patients with positive NBS for hyperargininemia in whom the diagnosis of arginase deficiency was delayed owing to normal or near normal plasma arginine levels on follow-up testing. To improve the detection capability for arginase deficiency, we evaluated plasma Arg/Orn ratio as a secondary diagnostic marker in positive NBS cases for hyperargininemia. We found that plasma Arg/Orn ratio combined with plasma arginine was a better marker than plasma arginine alone to differentiate patients with arginase deficiency from unaffected newborns. In fact, elevated plasma arginine in combination with an Arg/Orn ratio of ≥1.4 identified all 14 arginase deficiency cases. In addition, we examined the impact of age on plasma arginine and ornithine levels. Plasma arginine increased 0.94 μmol/L/day while ornithine was essentially unchanged in the first 31 days of life, which resulted in a similar increasing trend for the Arg/Orn ratio (0.01/day). This study demonstrated that plasma Arg/Orn ratio as a secondary diagnostic marker improved the detection capability for arginase deficiency in newborns with hyperargininemia, which will allow timely detection of arginase deficiency and hence initiation of treatment before developing symptoms.

Role of Plasma Amino Acids Profiles in Pathogenesis and Prediction of Severity in Patients with Drug Resistant Epilepsy

Background: Abnormal plasma levels of free amino acids may predict the severity in patients with drug resistant epilepsy (PRE), having probability to affect their therapeutic approach. Objectives:We aimed to illuminate the effect of plasma free amino acids (PFAAs) profiles on the etiology of patients with PRE and their contribution on the frequencies of epileptic fits. Patients and Methods:We collected clinical and metabolomic data of 90 subjects; 45 of them were PRE patients, and other 45 age and sex matched healthy controls. Quantitative measurements of PFAAs profiles using SykamAutomatic Amino Acid Analyzer S433, in addition to fasting blood sugar, liver function tests, kidney function tests and lipid profile also, were determined. Results: The plasma levels of glutamate, glycine and Gamma amino butyric acid(GABA) plasma levels were significantly increased in PRE group compared to controls (p˂0.0001),their plasma levels also showed significant increase with increased frequency of epileptic fits. Plasma leucine, phenylalanine, aspartate ,ornithine, citrulline, serine and alanine levels (p˂0.0001) were significantly increased in PRE group in relation to healthy controls. Interestingly, on the other hand, histidine, isoleucine, lysine, threonine and the amino acid derivative taurine levels were significantly decreased in PRE patients compared to healthy controls. Conclusion:Few biomarkers of PRE are available to find the severity and rate of progressionof PRE. The present study showed that altered plasma amino acids and their derivatives may be candidate markers for PRE, help explaining its pathogenesis, and for further researches concerning normalization of the disturbed amino acid/s or its derivative/s (GABA and taurine) in managing PRE patients.

The importance of plasma arginine level and its downstream metabolites in diagnosing prostate cancer.

There is still no certain threshold value of prostate-specific antigen (PSA) for prostate cancer diagnosis. We aimed to investigate the predictive value of arginine and its metabolites for diagnosing prostate cancer in patients with PSA 4-10ng/ml and evaluate their usefulness as prognostic tumor markers. Seventy-eight patients with a mean age of 64.50 ± 5.49years were included in our prospective observational study between November 2016 and March 2017. They were divided into two equal groups according to the pathologic results of prostate biopsy (benign vs. malignant). Plasma arginine and ornithine levels were analyzed before biopsy by liquid chromatography-tandem mass spectrometry. ELISA was used for analyzing urinary diacetylspermine. In PSA-adjusted analysis, the malignant group had lower plasma arginine levels (p = 0.021) and arginine to ornithine ratio (AOR) (p = 0.010), but higher plasma ornithine levels (p = 0.012) and urinary diacetylspermine levels (p < 0.001) as compared with the benign group. While arginine (r = - 0.628, p < 0.001) and AOR (r = - 0.714, p < 0.001) were negatively correlated with D'Amico clinical classification (p < 0.001), ornithine (r = 0.659, p < 0.001) and diacetylspermine (r = 0.710, p < 0.001) were found to be positively correlated (p < 0.001). In multivariate analysis, ornithine [OR 3.264, 95% CI (1.045-10.196), p = 0.042] and diacetylspermine [OR 6.982, 95% CI (2.403-20.290), p < 0.001] were found to be more significant in detection of prostate cancer. Plasma arginine, ornithine, AOR and urinary diacetylspermine levels may be used as molecular markers to predict prostate biopsy outcomes in patients with PSA 4-10ng/ml. But according to our results, the use of ornithine and diacethylspermine prior to biopsy seems to be the most cost-effective diagnostic strategy.

Effects of arginine supplementation on growth performance and plasma arginine, ornithine and citrulline dynamics of rainbow trout, Oncorhynchus mykiss

This study aimed to re-evaluate the effect of excessive arginine supplementation on growth and feed efficiency of rainbow trout, and to assess the effect of dietary arginine supplementation on hepatic amino acid composition, expression of arginase Ⅱ (ARG 2), inducible nitric oxide synthase (iNOS), and heat shock protein 70 (HSP70) genes in the intestine, and plasma arginine, ornithine, citrulline and urea levels at 0, 6, 12 and 18 hr-postprandial. Rainbow trout (body weight: 60.5–65 g) were fed diets containing 1.47 (control [CTRL]), 3.89 (3.89A) and 5.64% (5.64A) arginine for nine weeks. Higher muscle protein content was observed in 3.89A than CTRL (p < 0.05). In postprandial study, plasma arginine of 5.64A kept increased until 12 hr-postprandial and reached identical value (around 150 µg/ml) until 18 hr-postprandial in 5.64A. Significant increase of plasma arginine level was only observed in arginine supplemented group. Meanwhile, plasma citrulline level in CTRL was significantly higher than in 5.64A at 18 hr-postprandial. A significantly higher hepatic citrulline level was also observed in CTRL than in 5.64A (p < 0.05). Significantly higher plasma and hepatic free ornithine level was observed in 5.64A than CTRL while significantly higher expression of intestinal ARG2 and HSP70 was found in arginine supplemented groups. These results suggest that citrulline availability seems to be stimulated by arginine deficiency in the CTRL and the presence of arginase in the intestine to regulate excess dietary arginine.

Are the Macular and Choroidal Thicknesses Exchange by the Management of Gyrate Atrophy?

This is a case report of an 11-year-old boy complaining with deteriorated vision and with multiple peripheral lesions in his fundus in the setting of gyrate atrophy. Spectral domain optical coherence tomography showed, cystoid macular edema was in his both eyes. Plasma ornithine level was found elevated.

Effects of Oral Supplementation With Nitrate-Rich Beetroot Juice in Patients With Pulmonary Arterial Hypertension—Results From BEET-PAH, an Exploratory Randomized, Double-Blind, Placebo-Controlled, Crossover Study

BackgroundThe nitrate–nitrite–nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH. Methods and ResultsWe prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate-rich beetroot juice (∼16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow–independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro–B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow-rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders). ConclusionsBRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase–independent NO production from the nitrate-nitrite-NO pathway.

Resolution of cystoid macular edema following arginine-restricted diet and vitamin B6 supplementation in a case of gyrate atrophy

We report the outcome of 3years of arginine-restricted diet and vitamin B6 supplementation in a boy who presented with gyrate atrophy of the choroid and retina and bilateral cystoid macular edema. The diagnosis of gyrate atrophy was made on the basis of clinical findings and increased plasma ornithine levels. Molecular genetic testing revealed a disease-causing homozygous mutation in the ornithine aminotransferase (OAT) gene. After 3months of dietary modification and pyridoxine supplementation, visual acuity improved, and optical coherence tomography showed resolution of cystoid macular edema in both eyes. This anatomical and functional improvement was maintained during 3years of follow-up.

Inborn Errors of Metabolism: Gyrate Atrophy.

Gyrate atrophy is an autosomal recessive dystrophy in which night blindness starts early in the first decade of life. In the early stages, large areas of retinal pigment epithelium (RPE) and choriocapillaris (CC) atrophy in the far periphery (lobular shape, Fig. 37.1). (In choroideremia, atrophy appears in the mid periphery.) Later, these areas coalesce to form a characteristic scalloped border at the junction of healthy and diseased RPE. Myopia and subcapsular cataract are common by the end of second or third decade. Unlike in choroideremia (which is X-linked), patients with gyrate atrophy show areas of hyperpigmentation of the remaining RPE (Fig. 37.2). Patients with gyrate atrophy do not show the choroidal atrophy (as seen in choroideremia) until the late stages. Treatment includes a low-protein, arginine-restricted diet for all patients. In some cases, vitamin B6 (pyridoxine) may help in lowering plasma ornithine levels.

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria

Plasmodium infection depletes arginine, the substrate for nitric oxide synthesis, and impairs endothelium-dependent vasodilation. Increased conversion of arginine to ornithine by parasites or host arginase is a proposed mechanism of arginine depletion. We used high-performance liquid chromatography to measure plasma arginine, ornithine, and citrulline levels in Malawian children with cerebral malaria and in mice infected with Plasmodium berghei ANKA with or without the arginase gene. Heavy isotope-labeled tracers measured by quadrupole time-of-flight liquid chromatography-mass spectrometry were used to quantify the in vivo rate of appearance and interconversion of plasma arginine, ornithine, and citrulline in infected mice. Children with cerebral malaria and P. berghei-infected mice demonstrated depletion of plasma arginine, ornithine, and citrulline. Knock out of Plasmodium arginase did not alter arginine depletion in infected mice. Metabolic tracer analysis demonstrated that plasma arginase flux was unchanged by P. berghei infection. Instead, infected mice exhibited decreased rates of plasma arginine, ornithine, and citrulline appearance and decreased conversion of plasma citrulline to arginine. Notably, plasma arginine use by nitric oxide synthase was decreased in infected mice. Simultaneous arginine and ornithine depletion in malaria parasite-infected children cannot be fully explained by plasma arginase activity. Our mouse model studies suggest that plasma arginine depletion is driven primarily by a decreased rate of appearance.

The retarded hair growth (rhg) mutation in mice is an allele of ornithine aminotransferase (Oat)

Because of the similar phenotypes they generate and their proximate reported locations on Chromosome 7, we tested the recessive retarded hair growth (rhg) and frizzy (fr) mouse mutations for allelism, but found instead that these defects complement. To discover the molecular basis of rhg, we analyzed a large intraspecific backcross panel that segregated for rhg and restricted this locus to a 0.9Mb region that includes fewer than ten genes, only five of which have been reported to be expressed in skin. Complementation testing between rhg and a recessive null allele of fibroblast growth factor receptor 2 eliminated Fgfr2 as the possible basis of the retarded hair growth phenotype, but DNA sequencing of another of these candidates, ornithine aminotransferase (Oat), revealed a G to C transversion specifically associated with the rhg allele that would result in a glycine to alanine substitution at residue 353 of the gene product. To test whether this missense mutation might cause the mutant phenotype, we crossed rhg/rhg mice with mice that carried a recessive, perinatal-lethal, null mutation in Oat (designated OatΔ herein). Hybrid offspring that inherited both rhg and OatΔ displayed markedly delayed postnatal growth and hair development, indicating that these two mutations are allelic, and suggesting strongly that the G to C mutation in Oat is responsible for the retarded hair growth phenotype. Comparisons among +/+, +/rhg, rhg/rhg and rhg/OatΔ mice showed plasma ornithine levels and ornithine aminotransferase activities (in liver lysates) consistent with this assignment. Because histology of 7- and 12-month-old rhg/rhg and rhg/OatΔ retinas revealed chorioretinal degeneration similar to that described previously for OatΔ/OatΔ mice, we suggest that the rhg mutant may offer an ideal model for gyrate atrophy of the choroid and retina (GACR) in humans, which is also caused by the substitution of glycine 353 in some families.

Effect of Major and Minor Surgery on Plasma Levels of Arginine, Citrulline, Nitric Oxide Metabolites, and Ornithine in Humans

To determine the effect of surgical invasiveness on plasma levels of arginine, citrulline, ornithine, and nitric oxide (NO) in humans. Surgical trauma may have a profound effect on the metabolism of NO. However, human studies reported both increased and decreased NO levels after hemorrhagic shock. Arginine, citrulline, and ornithine are key amino acids involved in NO metabolism, but studies evaluating these amino acids together with NO and during 2 types of surgery are lacking. This study tests the hypothesis that major surgery has a more profound effect on plasma levels of arginine, citrulline, NO, and ornithine than minor surgery. Fifteen patients undergoing minor surgery (vulvectomy) and 13 patients undergoing major surgery (laparotomy) were prospectively followed up for 4 days. Plasma was collected for evaluation of levels of arginine, citrulline, NO, and ornithine. Throughout the experiment, arginine levels did not significantly differ between experimental groups. Perioperative plasma citrulline levels were significantly lower in the laparotomy group than in the vulvectomy group, whereas both groups showed a decrease in citrulline levels at the end of the operation and 24 hours postoperatively. Roughly the same pattern was seen for plasma NO and ornithine levels. However, ornithine levels in the laparotomy group showed a more drastic decrease at the end of the operation and 24 hours postoperatively than citrulline and NO levels. The level of surgical invasiveness has the most profound effect on plasma levels of ornithine. In addition, heavier surgical trauma is paired with lower postoperative levels of citrulline and NO metabolites than lighter surgery. It is suggested that surgical trauma stimulates the laparotomy group to consume significantly more ornithine, possibly for use in wound healing.

Effects of dietary arginine supplementation on reproductive performance and immunity of sows

Arginine (Arg) is considered to have beneficial effects on placental development and function, as well as reproductive performance. The well-developed placenta is highly required in late gestation for rapid fetal growth, however, it is unknown if there is a crucial role of Arg in late gestation. Likewise, the immunological response of sows to Arg needs to be determined. Therefore, this study is designed to investigate the effects of dietary Arg supplementation on reproductive performance and immunity of sows. At day 30 of gestation, sixty sows (Landrace &amp;times; Large White) were allocated to 3 groups receiving corn and soybean-based control diet (control group, n = 20), control diet supplemented with 1% l-arginine HCl until day 90 of gestation (Arg90 group, n = 20), and control diet supplemented with 1% l-arginine HCl until day 114 of gestation (Arg114 group, n = 20), respectively. Litter performance was recorded at parturition. Blood samples (n = 6) collected at days 30, 90, and 110 of gestation were measured for metabolic and immunological parameters. At parturition, total litter size was not affected by dietary Arg supplementation. As a result of less pigs born dead, however, sows in Arg114 group had more pigs born alive than sows in control group (+1.6 pigs, P &amp;lt; 0.05), total and live litter weights were increased (+1.6~2.1 kg, P &amp;lt; 0.05) in Arg114 group relative to both control and Arg90 groups. Compared with control group, dietary Arg supplementation increased (+12~110%, P &amp;lt; 0.05) plasma levels of ornithine, proline, and arginine at either day 90 (Arg90 and Arg110 groups) or day 110 of gestation (Arg110 group). Moreover, immune response was enhanced in Arg-supplemented sows, as indicated by the increased levels of serum immunoglobulin and porcine reproductive and respiratory syndrome virus (PRRSV) antibody. These findings indicate dietary Arg supplementation can improve litter performance and immune response, and the beneficial effect of Arg on fetal growth is evident in late gestation.

Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis

IntroductionThe role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis.MethodsPlasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions.ResultsPlasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness.ConclusionsIn severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function.

The effect of ornithine ingestion on carbohydrate metabolism during rest after acute resistance exercise in healthy young males

The effect of oral L-ornithine hydrochloride (0.1 g/kg BW) on energy expenditure during a rest period from 120 to 180 min after resistance exercise was evaluated by indirect calorimetry. Healthy male subjects who have no habit of resistance training underwent resistance exercise (chest press, lat pulldown, leg press, shoulder press, leg extension, and leg curl), with 3 sets of each exercise and 10 repetitions in each set at 90-s intervals, 30 min after ingestion of ornithine or placebo. Plasma ornithine levels immediately after, and 120 and 180 min after, resistance exercise were significantly greater after ingestion of ornithine than of placebo (Treatment: F = 347.1, P p2 = 0.95; Interaction: F = 160.7, P p2 = 0.95), but no significant difference in serum growth hormone levels was observed between the two treatments (Treatment: F = 0.1, P = 0.751, ηp2 = 0.01; Time: F = 1.7, P = 0.229, ηp2 = 0.16; Interaction: F = 2.4, P = 0.155, ηp2 = 0.21). Although there was no between-treatment difference in energy expenditure during the rest period 120 to 180 min after resistance exercise (Treatment: F = 0.1, P = 0.718, ηp2 = 0.02; Time: F = 0.1, P = 0.767, ηp2 = 0.01; Interaction: F = 0.1, P = 0.112, ηp2 = 0.26), with ornithine ingestion carbohydrate oxidation was significantly greater than with placebo from 170 to 180 min after exercise (Treatment: F = 0.8, P = 0.383, ηp2 = 0.09; Time: F = 9.7, P = 0.013, ηp2 = 0.52; Interaction: F = 5.8, P = 0.039, ηp2 = 0.39). Moreover, 180 min after exercise, serum free fatty acid levels after ornithine ingestion were lower than after placebo (Treatment: F = 0.3, P = 0.602, ηp2 = 0.03; Time: F = 34.6, P p2 = 0.79; Interaction: F = 5.6, P = 0.042, ηp2 = 0.38). A similar trend in 3-hydroxybutylate was observed. In conclusion, ornithine ingestion before resistance exercise may enhance post-exercise carbohydrate oxidation without changing total energy expenditure.

Occipital porencephaly in a child with gyrate atrophy of the choroid and retina

A 4-year-old girl was hospitalized for psychomotor delay, low vision, and horizontal nystagmus. She was found to have bilateral chorioretinal atrophic scars and 2 large occipital porencephalic cavities. High plasma ornithine levels led to the presumed diagnosis of gyrate atrophy of the choroid and retina. After 6 months of arginine-restricted diet and high-dose pyridoxine (300 mg/d), there was no change of plasma ornithine level or ocular findings. To our knowledge, this is the first report showing an association of porencephaly with gyrate atrophy of the choroid and retina.