Low Arginine Research Articles

Expression of proliferation markers in colonic mucosa in normal volunteers with a high arginine-containing diet and effect of dietary grape ingestion.

431 Background: Resveratrol, which inhibits ODC and Wnt signaling, has colon cancer prevention activity in animal models. To assess the effects of a resveratrol-rich diet on the colon, 30 normal volunteers enrolled on a cancer prevention clinical trial (NCT00578396) involving the ingestion of 1/3, 2/3, or 1 pound of grapes per day for 14 days. Data analysis was stratified based on arginine intake because meat and dietary arginine have been linked to colon carcinogenesis. Methods: Patients were placed on a low-resveratrol diet 14 days prior to and during the grape ingestion period. Detailed dietary information and colonic biopsies were obtained before and after the grape intervention in a single-subject design. Tissue was processed for RNA for qRT- PCR analysis of genes implicated in colonic proliferation, Wnt signaling and colon carcinogenesis. The % of cells expressing Ki67 in the lower 1/3 of colonic crypts was determined by IHC. Results: Mean arginine consumption for the study population was 4.5 ± 2.27 gm/day. Participants with higher initial dietary arginine consumption (> 4.5gm) had higher levels of cyclinD1 (p = 0.022), c-myc (p = 0.0002), axin2 (p = 0.0065) and CD133 (p = 0.041) mRNA in the colonic mucosa than participants with lower initial arginine consumption. No differences in the % of base of the colonic crypt cells staining for Ki67 were seen. Grape ingestion led to a significant reduction in cyclinD1 expression in participants with higher initial arginine consumption (p = 0.0039), with levels falling to those seen in low arginine consumption participants. Conclusions: Normal volunteers with a high amount of daily arginine ingestion had elevated levels of markers indicative of cell proliferation (cyclinD1, c-myc), Wnt signaling (axin2), and colonic stem cells (CD133). Expression of each of these markers was reduced following grape ingestion, though only the reduction in cyclinD1 reached statistical significance. Significance: Dietary arginine adversely affects colonic mucosa and may predispose individuals to the development of colon cancer. The effects are reversed in part by a resveratrol-rich grape-containing diet. Clinical trial information: NCT00578396.

Nephrotic syndrome complicated by idiopathic central diabetes insipidus

There is ongoing discussion regarding the mechanisms underlying edema formation in nephrotic syndrome (NS). Many studies published in the last decade reported that primary renal sodium retention was a major factor in edema formation. However, many of the factors influencing edema formation in NS remain unclear, including the role of arginine vasopressin (AVP). We report a 12-year-old boy with steroid-dependent NS complicated by idiopathic central diabetes insipidus (CDI). He did not develop edema during his first relapse of NS after developing CDI, despite having hypoalbuminemia. He had polydipsia, polyuria, low urine osmolality, and a low serum arginine AVP level. His fractional excretion of sodium was only slightly low. Endocrinological testing and magnetic resonance imaging revealed idiopathic CDI. After starting desmopressin therapy, he developed edema when his NS relapsed. This is the first known reported case of NS in a patient with CDI. The findings suggest that appropriate AVP secretion in response to an increase in serum osmolality caused by renal sodium retention is necessary for excess extracellular fluid accumulation in NS. Further investigation is needed to more fully understand the role of AVP in edema formation in NS.

Altered Nitrogen Balance and Decreased Urea Excretion in Male Rats Fed Cafeteria Diet Are Related to Arginine Availability

Hyperlipidic diets limit glucose oxidation and favor amino acid preservation, hampering the elimination of excess dietary nitrogen and the catabolic utilization of amino acids. We analyzed whether reduced urea excretion was a consequence of higher NOx; (nitrite, nitrate, and other derivatives) availability caused by increased nitric oxide production in metabolic syndrome. Rats fed a cafeteria diet for 30 days had a higher intake and accumulation of amino acid nitrogen and lower urea excretion. There were no differences in plasma nitrate or nitrite. NOx and creatinine excretion accounted for only a small part of total nitrogen excretion. Rats fed a cafeteria diet had higher plasma levels of glutamine, serine, threonine, glycine, and ornithine when compared with controls, whereas arginine was lower. Liver carbamoyl-phosphate synthetase I activity was higher in cafeteria diet-fed rats, but arginase I was lower. The high carbamoyl-phosphate synthetase activity and ornithine levels suggest activation of the urea cycle in cafeteria diet-fed rats, but low arginine levels point to a block in the urea cycle between ornithine and arginine, thereby preventing the elimination of excess nitrogen as urea. The ultimate consequence of this paradoxical block in the urea cycle seems to be the limitation of arginine production and/or availability.

Supplementation of patients with sickle cell disease with astaxanthin increases plasma- and erythrocyte-astaxanthin and may improve the hemolytic component of the disease

Aim & background: Sickle cell disease (SCD) is characterized by hemolytic and vaso-occlusive components. Astaxanthin is a carotenoid of marine origin, without pro-oxidant properties. Methods: In this open label pilot study, we investigated whether orally administered astaxanthin incorporates into erythrocytes (RBC) of SCD patients and studied the effect on hematological and clinical chemical parameters. Ten SCD patients (6e52 years) in Sint Maarten received 8e12 mg astaxanthin during 3 months. Results: Baseline plasma- (33 nmol/L) and RBC- (11 nmol/L packed RBC) astaxanthin increased to 225, 174, 167 nmol/L (plasma) and 149, 100, 71 nmol/L packed RBC at 1e3 months, respectively. Reticulocytes decreased from baseline and 2 months (9.5 and 8.8%) to 3 months (5.6%), MCV from 2 to 3 months (88 e86 fL), MCH from baseline to 3 months (30e28 pg) and RDW from baseline and 2 months (19.2 and 19.0%) to 3 months (16.7%). Plasma arginine decreased from 2 to 3 months (46.6e39.4 mmol/L). Asymmetric dimethylarginine (ADMA) did not change. Reticulocytes at baseline correlated with relative changes in reticulocytes from baseline to 3 months. Relative changes in reticulocytes correlated with relative changes in RBC, RDW, LDH, ALAT, but not hematocrit, within the same period. Conclusion: Astaxanthin incorporates into SCD RBC and may favorably affect the hemolytic component. A larger randomized controlled trial is indicated, using similar or higher dose, preferably during more than 3 months, concomitant with (other) low dose antioxidants (vitamin E, beta-carotene, vitamin C, folic acid), minerals (zinc, if necessary, selenium), arginine, fish oil and vitamin D.

Enteral Arginine Partially Ameliorates Parenteral Nutrition–Induced Small Intestinal Atrophy and Stimulates Hepatic Protein Synthesis in Neonatal Piglets

Arginine is an indispensable amino acid in neonates; de novo synthesis of arginine occurs in the small intestine (SI) but is reduced during parenteral nutrition (PN), limiting the arginine available to the mucosa. We assessed the effects of route of intake and dietary concentration of arginine on protein synthesis, superior mesenteric artery (SMA) blood flow, and SI morphology. Piglets (n = 18, 14-17 days old) were given complete PN for 3 days to induce SI atrophy, then switched to 1 of 3 treatments: arginine-free PN plus an intragastric (IG) infusion of high arginine (1.6 g · kg(-1)· d(-1), IG-H Arg) or low arginine (0.6 g · kg(-1)· d(-1), IG-L Arg) or complete high-arginine PN (1.6 g · kg(-1)· d(-1), IV-H Arg). Enteral arginine, irrespective of amount provided, stimulated hepatic protein synthesis compared with intravenous delivery of arginine (P = .01). SMA blood flow declined for all groups following the initiation of PN. After 48 hours on the test diets, all groups reached low constant levels, but the IV-H group was significantly higher than both IG groups (P < .05). Despite greater blood flow, the SI morphological characteristics in IV-H Arg pigs were not significantly improved over the other groups. IV-H Arg pigs had higher plasma concentrations of indispensable amino acids (tyrosine, isoleucine, and valine) compared with IG-H Arg, despite identical amino acid intakes. Intravenous delivery of arginine sustained the best SMA blood flow, whereas even a moderate amount of enteral arginine stimulated liver protein synthesis and maintained SI growth, independent of blood flow.

Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta

Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in nonmetabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivo microbial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.

Interactive effects of dietary arginine and histidine on the performances of Japanese flounder Paralichthys olivaceus juveniles

A 60-day feeding trial was carried out to investigate the interactive effects of arginine and histidine on the performances of Japanese flounder juveniles. Fish were fed experimental diets containing six different rations of arginine (Arg) and histidine (His), 2 levels of Arg such as 1.74 (AL) and 2.75g/100g diet (AH), combined with 3 levels of His such as 1.01(HL), 1.50 (HM) and 1.88g/100g diet (HL), respectively. The results indicated that the growth performances (final body weight, body weight gain and special growth rate) were highest in fish fed AH–HM combined group. Those parameters were significantly higher than other groups except AH–HL group. On the other hand, the interactions of arginine and histidine were found on the growth parameters. In addition, the significantly better nutrient utilizations (feed conversion ratio, protein efficiency ratio and protein retention) were also observed in higher Arg supplemented groups. There were no significant effects on the hematocrit, hemoglobin, glucose, total cholesterol, total bilirubin and mucus bactericidal activity of experimental fish among treatments. Japanese flounder fed the diet containing low dietary arginine together with low dietary histidine showed higher oxidative stress and lower lysozyme activities. The dietary arginine and histidine levels significantly affected the concentrations of fish muscle free amino acids. It would be concluded that dietary Arg and His functioned interactively, and the flounders fed the diet containing 2.70g arginine with 1.56g histidine/100g diet showed the better growth performance and physiological status than other groups.

Letter by Tsuda Regarding Article, “Low Plasma Arginine:Asymmetric Dimethyl Arginine Ratios Predict Mortality After Intracranial Aneurysm Rupture”

To the Editor: We read with great interest the article by Staalso et al1 pertaining to the relationship between asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, and survival in patients with aneurysmal subarachnoid hemorrhage. The results of their study demonstrated that a low arginine:ADMA ratio in the first week after subarachnoid hemorrhage predicted mortality rate in the first 30 days. The arginine:ADMA ratio was negatively correlated with the serum NO-metabolite levels. In addition, the arginine:ADMA ratio was higher in good grade patients, but did not change significantly overtime. The authors proposed that plasma arginine:ADMA ratio might be associated with the pathophysiology …

Response to Letter Regarding Article, “Low Plasma Arginine:Asymmetric Dimethyl Arginine Ratios Predict Mortality After Intracranial Aneurysm Rupture”

Response: We thank Dr Tsuda for his interest. Asymmetrical dimethylarginine (ADMA) and l-arginine are compounds with significant and well-known biological effects.1 Symmetrical dimethylarginine (SDMA), on the other hand, has long been regarded as a biologically inactive molecule, and as such has been under investigation as a putative marker of renal dysfunction.1 In vitro evidence provides some support for a mechanism by which SDMA through inhibition of transmembrane l-arginine transport theoretically could exert a rate-limiting effect on nitric oxide …

Genetic analysis of adiponectin variation and its association with type 2 diabetes in African Americans

ObjectiveAdiponectin is an adipocytokine that has been implicated in a variety of metabolic disorders, including T2D and cardiovascular disease. Studies evaluating genetic variants in ADIPOQ have been contradictory when testing association with T2D in different ethnic groups.Design and MethodsIn this study, 18 SNPs in ADIPOQ were tested for association with plasma adiponectin levels and diabetes status. SNPs were examined in two independent African-American cohorts (nmax=1116) from the Insulin Resistance Atherosclerosis Family Study (IRASFS) and the African American-Diabetes Heart Study (AA-DHS).ResultsFive polymorphisms were nominally associated with plasma adiponectin levels in the meta-analysis (p=0.035–1.02x10−6) including a low frequency arginine to cysteine mutation (R55C) which reduced plasma adiponectin levels to <15% of the mean. Variants were then tested for association with T2D in a meta-analysis of these and the Wake Forest T2D Case-Control study (n=3233 T2D, 2645 non-T2D). Association with T2D was not observed (p≥0.08), suggesting limited influence of ADIPOQ variants on T2D risk.ConclusionsDespite identification of variants associated with adiponectin levels, a detailed genetic analysis of ADIPOQ revealed no association with T2D risk. This puts into question the role of adiponectin in T2D pathogenesis: whether low adiponectin levels are truly causal for or rather a consequence.

G198(P) Plasma Arginine Levels and Blood Glucose Control in Very Preterm Infants Receiving Two Different Parenteral Nutrition Regimens

Background and IntroductionWe have previously shown that improving early protein intake is associated with a reduction in insulin-treated hyperglycaemia in preterm infants <29 weeks gestation. The effect of amino acids...

Plasma Arginine Levels and Blood Glucose Control in Very Preterm Infants Receiving 2 Different Parenteral Nutrition Regimens

Improving parenteral nutrition (PN) amino acid (AA) intake in very preterm infants is associated with less hyperglycemia. AAs stimulate newborn insulin secretion with arginine, demonstrating a specific effect. We hypothesized that low arginine levels would be associated with increased insulin-treated hyperglycemia and higher mean daily blood glucose levels in very preterm infants. We performed a secondary analysis on previous study data comparing high-protein/calorie PN (HPC-PN) and control groups in infants <29 weeks' gestation. Infants were substratified (within original groups) according to high (highARG) and low (lowARG) plasma arginine levels on days 8-10 using a reference population-derived threshold for high/low arginine (57 µmol/L). Daily protein, arginine, carbohydrate intake, mean daily blood glucose, and insulin treatment data from the first 15 days of life were collected. Control group infants (n = 60) were stratified into lowARG (n = 41) and highARG (n = 19) groups. There were no differences in basic demographic data or carbohydrate intake. LowARG infants had higher mean daily blood glucose levels ( P .05) and a trend to more insulin treatment on days 610. HPC-PN group infants (n = 55) were stratified into lowARG (n = 33) and highARG (n = 22) GROUPS. LowARG infants had lower gestation and birth weight and were sicker than highARG infants. There were no differences in carbohydrate intake. LowARG infants had higher mean daily blood glucose levels (p .01) and more insulin treatment (p .01) on days 15 and 610. Insulin-treated hyperglycemia was also associated with low plasma glutamine levels. Low plasma arginine levels (≤57 µmol/L) in very preterm infants are associated with poorer blood glucose control.

Low Plasma Arginine:Asymmetric Dimethyl Arginine Ratios Predict Mortality After Intracranial Aneurysm Rupture

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, predicts mortality in cardiovascular disease and has been linked to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). In this prospective study, we assessed whether circulating ADMA, arginine:ADMA ratio, and nitrite/nitrate levels were associated with survival and cerebral vasospasm in SAH patients. One hundred and eleven patients were observed day 1 to 15 after SAH, with serial measurements of transcranial Doppler flow velocities (VMCA) and plasma biomarkers. Clinical status was assessed by the World Federation of Neurosurgical Societies grading scale. Overall 30-day mortality was 18%, but differed between patients grouped by low, midrange, and high arginine:ADMA ratio in the first week after SAH. Mortality rates were 14/37, 1/37, and 5/37 in the 3 groups, respectively (P-logrank=0.0003). Cox regression showed that low versus midrange or high arginine:ADMA was associated with a hazard ratio of 4.1 independent of World Federation of Neurosurgical Societies grade (95% confidence interval, 1.5-10.9; P=0.006). ADMA or arginine:ADMA had no association to VMCA, but there was an inverse relationship between VMCA and nitrite/nitrate levels (P<0.0001). The NOS3 894G/G genotype was associated with 15% lower VMCA (P=0.01). ATbG-NOS3 haplotype homozygosity was associated with up to 64% higher nitrite/nitrate levels (P=0.003). This study suggests that plasma arginine:ADMA ratios predict mortality after SAH. Both clinical and physiological measures of changes in cerebral hemodynamics are coupled to the nitric oxide system.

Blood Flow Is Increased in Wounds and Peri-Wound Area by Laser Speckle Contrast Imaging and Infrared Thermography in Adults with Sickle Cell Leg Ulcers

AbstractAbstract 1009 Background:Leg ulcerations are a serious and debilitating complication of sickle cell disease (SCD) and other hemolytic anemias, whose etiology is not completely understood. Wound healing involves an ordered progression of vasoconstriction (hemostatic phase), followed by vasodilatation (inflammatory and proliferative phase) and epithelialization. Little is known about the changes in the microcirculation of chronic wounds in patients with sickle cell disease. Endothelial function affects microcirculation and regulates blood flow. Endothelial dysfunction is a recognized pathway to end organ dysfunction in SCD. Laser speckle contrast imaging (LSCI) and Infrared Thermography (IR) are non-invasive technique used to assess dynamic changes in blood flow in response to vaso-reactive and other insults in both health and disease, while peripheral arterial tonometry is utilized for early detection of cardiovascular disease. The aim of this study was to evaluate skin's microvasculature response and endothelial function in adults with HbSS and chronic leg ulceration. Methods:Twelve adults with HbSS and chronic leg ulcers (> 1 month duration) were evaluated at steady state with a detailed medical and ulcer history, physical examination, and clinical labs. Clinical and laboratory data were compared to 269 adults with Hb SS, without active leg ulcers, enrolled in a Pulmonary Hypertension screening protocol (Clin trial no. NCT00011648). Blood flow (LCSI) and IR measurements of the ulcer bed, the peri-ulcer area and of a distant, unaffected area (baseline) were obtained and compared. Peripheral arterial tonometry (PAT) was obtained to calculate the ratio of post-occlusion dilatation to baseline reactive hyperemia index: RHI. An RHI>1.67 is indication of normal endothelial function. Results:Mean age for the 12 subjects with chronic active leg ulcer: 31 years ± 11yrs, 5 male, 5 had a history of trauma. When compared to SS patients without active leg ulcers: mean MAP 82 vs 103 mmHg (p <0.0001), Hb 7.6 vs 9.0 g/dL (p=0.001), and LDH 533 vs. 375 (p=0.023). CRP was higher, 9.4 vs 0.81(p<0.0001), Arginine/ornithine ratio was lower (0.66 vs. 1.06) in patients with active leg ulcers (p=0.005). Thrombophila w/u was negative in 11, but half of patients were on anticoagulation for previous PE/DVT’s. A third of the patients had been admitted for VOC in the previous 12 months and 11/12 were taking daily opioids. Blood flow was highest in the ulcer center: 731+421, with progressively lesser flow measurements in the periwound: 370+157 and in the distal region(or baseline) 165+89. Temperature, as measured by IR, was higher (34.9 C°) in the periwound area than in the distant, or baseline area (34.5 C°) (p <0.03). Blunted RHI on PAT was seen in 5/12 subjects, with values <1.67. Conclusions:With this study we confirm that patients with HbSS and leg ulcers represent a subgroup with severe disease, as demonstrated by the high use of HU and/or transfusion, and number of complications at a relatively young age. We report high blood flow in the ulcer bed and immediate surrounding regions, compared to unaffected areas, never prior demonstrated. It is probable that the increase in blood flow observed in the wound and peri-wound regions reflect s a high vasodilated state, resulting from severe anemia, relative hypotension, and chronic inflammation. Laboratory and clinical data supports the presence of a persistent inflammatory and hemolytic state, as well as low arginine bioavailabitlity. Laser Speckle Contrast Imaging, Infrared Thermography and Peripheral Arterial Tonometry are effective, non invasive novel techniques useful for studying microvascular and endothelial function in patients with SCD and leg ulcers. Disclosures:No relevant conflicts of interest to declare.

Arginine plus proline supplementation elicits metabolic adaptation that favors wound healing in diabetic rats

Diabetic patients with wounds are at risk of protein malnutrition, have low arginine plasma levels, and suffer from delayed wound healing. We sought to determine the efficacy of arginine plus proline supplementation on protein and amino acid metabolism and on wound repair in a model of diabetic rats. Eighteen 11-wk-old Zucker diabetic fatty fa/fa male rats underwent a 7-cm abdominal skin incision with implantation of sponges and daily excision of full-thickness round sections of dorsal skin for 5 days. They were randomized to be fed with either a standard formula (S group, Clinutren Iso), a high-protein and arginine (ARG) plus proline (PRO)-enriched formula (ARG+PRO group, Clinutren Repair), or an isonitrogenous isoenergetic control formula (IC group). Nitrogen balance was calculated daily. The rats were euthanized on day 5, and plasma glucose, insulin, amino acids, skin epithelialization, and angiogenesis were measured. In macrophages, we assessed inducible nitric oxide synthase (iNOS) and arginase expression, production of nitric oxide (NO) and amino acid metabolism. Both the ARG+PRO and IC groups showed improved nitrogen balance. ARG plus PRO supplementation increased proline and branched-chain amino acid plasma concentrations and improved angiogenesis. Arginase and iNOS expressions in macrophages were reduced, together with NO and citrulline production. In diabetic rats, ARG plus PRO supplementation improves wound angiogenesis and favors whole body protein metabolism. Low macrophage iNOS expression at day 5 may reflect a low inflammatory state in the wounds, favoring wound closure.

Enhanced Methylarginine Characterization by Post-Translational Modification-Specific Targeted Data Acquisition and Electron-Transfer Dissociation Mass Spectrometry

When localizing protein post-translational modifications (PTMs) using liquid-chromatography (LC)-tandem mass spectrometry (MS/MS), existing implementations are limited by inefficient selection of PTM-carrying peptides for MS/MS, particularly when PTM site occupancy is sub-stoichiometric. The present contribution describes a method by which peptides carrying specific PTMs of interest-in this study, methylarginines-may be selectively targeted for MS/MS: peptide features are extracted from high mass accuracy single-stage MS data, searched against theoretical PTM-carrying peptide masses, and matching features are subjected to targeted data acquisition LC-MS/MS. Using trypsin digested Saccharomyces cerevisiae Npl3, in which evidence is presented for 18 methylarginine sites-17 of which fall within a glycine-arginine-rich (GAR) domain spanning <120 amino acids-it is shown that this approach outperforms conventional data dependent acquisition (DDA): when applied to a complex protein mixture featuring in vivo methylated Npl3, 95% more (P=0.030) methylarginine-carrying peptides are selected for MS/MS than DDA, leading to an 86% increase (P=0.044) in the number of methylated peptides producing Mascot ion scores ≥20 following electron-transfer dissociation (ETD). Notably, significantly more low abundance arginine methylated peptides (maximum ion intensities <6×10(4) cps) are selected for MS/MS using this approach relative to DDA (50% more in a digest of purified in vitro methylated Npl3). It is also demonstrated that relative to collision-induced dissociation (CID), ETD facilitates a 586% increase (P=0.016) in average Mascot ion scores of methylarginine-carrying peptides. The present PTM-specific targeted data acquisition approach, though described using methylarginine, is applicable to any ionizable PTM of known mass.

Remarkable Cystic Expansion of Microprolactinoma Causing Diabetes Insipidus during Pregnancy

A 26-yr-old woman with galactorrhea had an elevated serum prolactin (PRL) level (75 ng/ml). Magnetic resonance imaging (MRI) revealed a 4-mm intrasellar tumor, suggesting a PRL-producing microadenoma. Cabergoline was prescribed and ameliorated the patient’s galactorrhea. No tumor growth was observed for 1 yr after MRI (Fig. 1), and cabergoline administration was discontinued when the patient became pregnant. At 24 wk gestation, she was admitted to the obstetrics department for intrauterine growth retardation. She developed polyuria (7700 ml/d) at 29 wk gestation and had a low serum arginine vasopressin (AVP) level (0.5 pg/ml). MRI revealed a 2-cm cystic lesion with suprasellar extension (Fig. 2). Her serum PRL level robustly increased (461 ng/ml), but visual field testing results were normal. Diabetes insipidus caused by cystic expansion of a prolactinoma was consid-

Nephrogenic Syndrome of Inappropriate Antidiuresis

Mutations in the vasopressin V2 receptor gene are responsible for two human tubular disorders: X-linked congenital nephrogenic diabetes insipidus, due to a loss of function of the mutant V2 receptor, and the nephrogenic syndrome of inappropriate antidiuresis, due to a constitutive activation of the mutant V2 receptor. This latter recently described disease may be diagnosed from infancy to adulthood, as some carriers remain asymptomatic for many years. Symptomatic children, however, typically present with clinical and biological features suggesting inappropriate antidiuretic hormone secretion with severe hyponatremia and high urine osmolality, but a low plasma arginine vasopressin level. To date, only two missense mutations in the vasopressin V2 receptor gene have been found in the reported patients. The pathophysiology of the disease requires fuller elucidation as the phenotypic variability observed in patients bearing the same mutations remains unexplained. The treatment is mainly preventive with fluid restriction, but urea may also be proposed.

Focused Review: Agmatine in Fermented Foods

Polyamines (PAs) are ubiquitous substances considered to be bioregulators of numerous cell functions; they take part in cell growth, division, and differentiation. These biogenic amines are also involved in tissue repair and in intracellular signaling; in fact, because of their polycationic character, they interact to a large extent with membrane phospholipids and may play an important role in the regulation of membrane-linked enzymes. The intracellular polyamine content derives from the simultaneous regulation of the synthesis, catabolism, uptake, and elimination of the polyamines; furthermore, PAs are present in all cell types at different concentrations, but the highest levels are found in rapid-turnover tissues. In addition to spermidine, spermine, and putrescine, also agmatine (AGM), deriving from arginine and identified in mammals in the 1990s, is a polyamine and several studies have reported its potentially positive role in the production of secretagogues, and in neuronal, vascular, metabolic, and therapeutic functions. Because of the low arginine decarboxylase (ADC) activity in mammalians, the amounts of AGM found in their tissues can be only minimally ascribed to an endogenous de novo synthesis by ADC, while a substantial quantity of AGM may be of dietary origin. Several food products contain only small amounts of polyamines, while higher concentrations can be found in fermented foods. PAs could also be considered as indicators of freshness in fish and meat products; as these moieties are produced during food storage, it would seem to confirm the main role of microorganisms in their synthesis. In particular, high levels of AGM are present in alcoholic beverages, such as wine, beer, sake, which would seem to confirm the role of yeasts in AGM production. Although many biological functions have been attributed to polyamines, high levels of these compounds in foodstuffs can have toxicological effects; however, no safe level for the intake of polyamines in a diet has yet been established. In this paper the presence of AGM in different foodstuffs is discussed, also taking into account the various factors affecting its presence and concentration.

Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis – A randomised trial

In tuberculosis (TB), the production of nitric oxide (NO) is confirmed but its importance in host defense is debated. Our aim was to investigate whether a food supplement rich in arginine could enhance clinical improvement in TB patients by increased NO production. Smear positive TB patients from Gondar, Ethiopia (n = 180) were randomized to a food supplementation rich in arginine (peanuts, equivalent to 1 g of arginine/day) or with a low arginine content (wheat crackers, locally called daboqolo) during four weeks. The primary outcome was cure rate according to the WHO classification and secondary outcomes were sputum smear conversion, weight gain, sedimentation rate, reduction of cough and chest X-ray improvement as well as levels of NO in urine (uNO) or exhaled air (eNO) at two months. There was no effect of the intervention on the primary outcome (OR 1.44, 95% CI: 0.69-3.0, p = 0.39) or secondary outcomes. In the subgroup analysis according to HIV status, peanut supplemented HIV+/TB patients showed increased cure rate (83.8% (31/37) vs 53.1% (17/32), p < 0.01). A low baseline eNO (<10 ppb) in HIV+/TB patients was associated with a decreased cure rate. We conclude that nutritional supplementation with a food supplement rich in arginine did not have any overall clinical effect. In the subgroup of HIV positive TB patients, it significantly increased the cure rate and as an additional finding in this subgroup, low initial levels of NO in exhaled air were associated with a poor clinical outcome but this needs to be confirmed in further studies.