Arginine In Patients Research Articles

Ultrasound criteria for assessing the correction of metabolic-associated fatty liver disease and liver blood flow disorders using arginine in patients with coronary artery disease in combination with COVID-19

Background. Coronavirus disease 2019 (COVID-19) remains one of the most urgent global health problems today. In the conditions of its spread around the world, the global scientific community is trying to study not only respiratory, but also extrapulmonary manifestations of this infection. It is known that with COVID-19, the endothelium, the hemostasis system, and the liver are affected with the occurrence of such a complication as metabolic dysfunction-associated steatotic liver disease (MASLD). The most vulnerable group of patients in terms of coronavirus disease and its complications (including MASLD) are those with coronary heart disease (CAD), therefore the search for effective drugs and optimal ultrasound criteria to evaluate liver steatosis in the dynamics of treatment is the main task of modern medicine. Goal: to determine the ultrasound criteria for assessing the correction of MASLD and liver blood flow disorders using arginine in patients with CAD associated with COVID-19. Materials and methods. A prospective study was conducted in 52 patients with CAD combined with PCR-positive COVID-19. The study was carried out upon admission to the hospital and 6 months after discharge. Group I (n = 27) consisted of CAD + COVID-19 patients who, in addition to standard therapy for MASLD, received arginine for 6 months after discharge from the hospital; group II (comparison group, n = 25) included participants who received standard therapy wi­thout arginine. Results. Splanchnic artery duplex scanning at baseline showed that 21 (78.0 %) patients in group I and 19 (76.0 %) in group II had a decrease in peak systolic velocity (PSV) in the proper hepatic artery (PHA), an increase in portal vein blood flow at the beginning of treatment, as well as increased liver size in 20 (74.0 %) patients in group I and 17 (68.0 %) in group II. An increase in the attenuation coefficient was detected in all patients of groups I and II. There were no differences between the groups at the time of inclusion in the study in terms of splanchnic blood flow and atte­nuation coefficient. After 6 months of arginine treatment, an improvement in the portal vein blood flow and a decrease in blood flow velocity in the PHA, a decrease in the diameter of the portal vein, a decrease in the size of the right and left liver lobes were found in group I, with no improvement in group II. A repeated study revealed a decrease in the attenuation coefficient in group I and no changes in group II. At the beginning of the study, a direct correlation was found between fibrinogen and the attenuation coefficient in group I (r = 0.54; p < 0.05), as well as in group II (r = 0.51; p < 0.05). After 6 months, C-reactive protein decreased in both groups. Conclusions. In patients with CAD combined with COVID-19 in the presence of MASLD, a decrease in the portal vein blood flow and an increase in PSV in the PHA were found. When arginine was used for 6 months in combination with standard therapy, according to the European Society of Cardiology protocols, there was a significant decrease in the attenuation coefficient, PSV in the PHA, and an increase in the portal vein blood flow. This indicates the possibility of using the attenuation coefficient as the main marker, and PSV in the PHA and the portal vein blood flow as additional criteria for ultrasound assessment of MASLD correction with arginine in patients with CAD combined with COVID-19.

Metabolomic profiling of amino acids study reveals a distinct diagnostic model for diabetic kidney disease

Diabetic kidney disease (DKD), a highly prevalent complication of diabetes mellitus, is a major cause of mortality in patients. However, identifying circulatory markers to diagnose DKD requires a thorough understanding of the metabolic mechanisms of DKD. In this study, we performed ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to reveal altered metabolic profiles of amino acids (AAs) in patients with DKD. We found decreased plasma levels of histidine and valine, increased urine levels of proline, decreased urine levels of histidine and valine, and increased saliva levels of arginine in patients with DKD compared with the levels in patients with type 2 diabetes mellitus (T2DM) and in healthy controls. Our analyses of the key metabolites and metabolic enzymes involved in histidine and valine metabolism indicated that the AAs level alterations may be due to enhanced carnosine hydrolysis, decreased degradation of homocarnosine and anserine, enhanced histidine methylation, and systemic enhancement of valine metabolism in patients with DKD. Notably, we generated a distinct diagnostic model with an AUC of 0.957 and an accuracy up to 92.2% on the basis of the AA profiles in plasma, urine and saliva differing in patients with DKD using logistic regression and receiver operating characteristic analyses. In conclusion, our results suggest that altered AA metabolic profiles are associated with the progression of DKD. Our DKD diagnostic model on the basis of AA levels in plasma, urine, and saliva may provide a theoretical basis for innovative strategies to diagnose DKD that may replace cumbersome kidney biopsies.

Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase

IntroductionPegargiminase (ADI-PEG 20I) degrades arginine in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma (MPM) and NSCLC. Imaging with proliferation biomarker 3'-deoxy-3'-[18F] fluorothymidine (18F-FLT) positron emission tomography (PET)-computed tomography (CT) was performed in a phase 1 study of pegargiminase with pemetrexed and cisplatin (ADIPemCis). The aim was to determine whether FLT PET-CT predicts treatment response earlier than CT. MethodsA total of 18 patients with thoracic malignancies (10 MPM; eight NSCLC) underwent imaging. FLT PET-CT was performed at baseline (PET1), 24 hours post-pegargiminase monotherapy (PET2), post one cycle of ADIPemCis (PET3), and at end of treatment (EOT, PET4). CT was performed at baseline (CT1) and EOT (CT4). CT4 (modified) Response Evaluation Criteria in Solid Tumors (RECIST) response was compared with treatment response on PET (changes in maximum standardized uptake value [SUVmax] on European Organisation for Research and Treatment of Cancer–based criteria). Categorical responses (progression, partial response, and stable disease) for PET2, PET3, and PET4 were compared against CT using Cohen’s kappa. ResultsADIPemCis treatment response resulted in 22% mean decrease in size between CT1 and CT4 and 37% mean decrease in SUVmax between PET1 and PET4. PET2 agreed with CT4 response in 62% (8 of 13) of patients (p = 0.043), although decrease in proliferation (SUVmax) did not precede decrease in size (RECIST). Partial responses on FLT PET-CT were detected in 20% (3 of 15) of participants at PET2 and 69% (9 of 13) at PET4 with good agreement between modalities in MPM at EOT. ConclusionsEarly FLT imaging (PET2) agrees with EOT CT results in nearly two-thirds of patients. Both early and late FLT PET-CT provide evidence of response to ADIPemCis therapy in MPM and NSCLC. We provide first-in-human FLT PET-CT data in MPM, indicating it is comparable with modified RECIST.

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy.

Coronavirus disease 2019 (COVID-19) represents a major public health crisis that has caused the death of nearly six million people worldwide. Emerging data have identified a deficiency of circulating arginine in patients with COVID-19. Arginine is a semi-essential amino acid that serves as key regulator of immune and vascular cell function. Arginine is metabolized by nitric oxide (NO) synthase to NO which plays a pivotal role in host defense and vascular health, whereas the catabolism of arginine by arginase to ornithine contributes to immune suppression and vascular disease. Notably, arginase activity is upregulated in COVID-19 patients in a disease-dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO. This rewiring of arginine metabolism in COVID-19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti-organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular disease in patients with COVID-19.

EP258: Pre-analytical considerations are important in the pharmacological assessment of enzyme therapeutics

Enzyme therapeutics are distinct from other modalities as they have the potential to continue metabolizing their target analyte even after blood collection. This poorly characterized phenomenon is important as it may lead to an overestimation of the in vivo pharmacological effects of an enzyme therapeutic. With the recent development of highly effective metabolite lowering enzyme therapeutics, it is important to understand the impact of pre-analytical sample processing as a source of inaccurate metabolite measurements in pharmacological evaluation of both nonclinical and clinical studies. Pegzilarginase is a pegylated modified human arginase 1 enzyme in clinical development for Arginase 1 deficiency (ARG1-D). Given the potency of pegzilarginase, the potential for spurious measurements of plasma arginine levels was investigated. Continued metabolism of arginine was demonstrated ex vivo after blood draw leading to artefactually low arginine levels in normally processed plasma samples. These effects were ameliorated by the competitive arginase inhibitor nor-NOHA when added to the collection tube prior to blood collection. This approach has been adapted to ensure accurate measurement of plasma arginine in patients receiving pegzilarginase in clinical trials. Similarly, a recently developed engineered enzyme (AGLE-177), with novel specificity for homocysteine and homocystine has been shown to artefactually lower total homocysteine plasma levels ex vivo after blood collection. Mitigation of the effect, by adding an inhibitor to the blood collection tube, enabled accurate assessment of tHcy levels in non-clinical efficacy and toxicology studies. These studies highlight the need to consider continued enzymatic digestion of metabolites during the pre-analytical sample handling for in vivo pharmacological studies of enzyme therapeutics.

The effects of preoperative supplementation with a combination of beta\u2010hydroxy\u2010beta\u2010methylbutyrate, arginine, and glutamine on inflammatory and hematological markers of patients with heart surgery: a randomized controlled trial

BackgroundCardiac surgery is associated with a widespread inflammatory response, by an additional release of free radicals. Due to the importance of these patient’s nutritional status, the present study was designed to evaluate the effectiveness of supplementation with a combination of glutamine, β-hydroxy-β-methylbutyrate (HMB) and arginine in patients undergoing to the heart surgery.MethodsThe experiment was performed in 1 month (30 days) before cardiac surgery. patients were asked to take 2 sachets of Heallagen® (a combination of 7 g l-arginine, 7 g l-glutamine, and 1.5 g daily HMB) or placebo with identical appearance and taste (maltodextrin) with 120 cc of water. Clinical and biochemical factors were evaluated in the baseline and end of the study.ResultsTotally, 60 preoperative patients (30 interventions and 30 placeboes) with a mean age of 53.13 ± 14.35 years participated in the study. Subjects in Heallagen® group had a lower serum levels of interleukin-6 (P = 0.023), erythrocyte sedimentation rate (P < 0.01), high sensitivity C-reactive protein (P < 0.01), and lymphocyte number (P = 0.007) compared to the placebo, at end of the study.ConclusionIn the patients undergoing heart surgery, Heallagen® significantly improved some of the inflammatory factors and hematological parameters. These results need to be confirmed in a larger trial.Trial registration: The protocol of the study was registered in the IRCT.ir with registration no. IRCT20120913010826N31 at 13/10/2020.

Nitric Oxide Deficiency in Mitochondrial Disorders: The Utility of Arginine and Citrulline.

Mitochondrial diseases represent a growing list of clinically heterogeneous disorders that are associated with dysfunctional mitochondria and multisystemic manifestations. In spite of a better understanding of the underlying pathophysiological basis of mitochondrial disorders, treatment options remain limited. Over the past two decades, there is growing evidence that patients with mitochondrial disorders have nitric oxide (NO) deficiency due to the limited availability of NO substrates, arginine and citrulline; decreased activity of nitric oxide synthase (NOS); and NO sequestration. Studies evaluating the use of arginine in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) presenting with stroke-like episodes showed symptomatic improvement after acute administration as well as a reduction in the frequency and severity of stroke-like episodes following chronic use. Citrulline, another NO precursor, was shown through stable isotope studies to result in a greater increase in NO synthesis. Recent studies showed a positive response of arginine and citrulline in other mitochondrial disorders besides MELAS. Randomized-controlled studies with a larger number of patients are warranted to better understand the role of NO deficiency in mitochondrial disorders and the efficacy of NO precursors as treatment modalities in these disorders.

Serum amino acid profiles in patients with mild cognitive impairment and in patients with mild dementia or moderate dementia.

Neurodegenerative disorders are one of the greatest global challenges for social and health care in the twenty-first century. Nowadays, determination of cerebrospinal fluid biomarkers for early diagnosis is served by a complex sample preparation procedure with limited diagnostic accuracy. Furthermore, neuroimaging methods are expensive, time-consuming and are not readily available for use as a complimentary and common screening method. Recently, researchers have shown an increased interest in the identification and characterization of new blood biomarkers of dementia to minimize the limitations associated with the current methods of biomarker determination. Amino acids play many important roles in the central nervous system, acting as neuromodulators, neurotransmitters and regulators of energy metabolism. The aim of this study was to evaluate if serum amino acid levels change along the continuum from no cognitive impairment to moderate dementia, and to identify putative biomarkers for early diagnosis of neurodegenerative diseases. Serum levels of 16 amino acids were determined in 3 groups of patients-22 with mild cognitive impairment, 45 with mild dementia and 28 with moderate dementia-by high-performance liquid chromatography (HPLC) with fluorescence detection using AccQ Tag column (Waters). The most exciting result is the significantly elevated concentration of arginine in patients with both stages of dementia as compared to mild cognitive impairment individuals. Recent accumulating evidence suggests the implication of changed arginine metabolism in the pathogenesis of neurodegenerative diseases. We conclude that amino acids profiling might be helpful in searching for biomarkers of neurogenerative diseases. In the present study, we discovered that arginine in plasma may have a putative diagnostic value for dementia.

Serum level of Arginine and Symmetric dimethyl arginine in patients with prediabetes and type2 diabetes mellitus

Serum level of Arginine and Symmetric dimethyl arginine in patients with prediabetes and type2 diabetes mellitus

The pathogenetic role of the nitric oxide system and its metabolites in the development and progression of chronic heart failure

Aim: to study the activity of eNOS, the concentration of L‑arginine and stable nitric oxide metabolites, as well as the degree of endothelium dependent vasodilation with 5‑minute compression test of the brachial artery in patients with chronic heart failure (CHF) of ischemic origin depending on L‑arginine administration in the treatment scheme.Material and methods. In the present study were included 303 patients (204 men and 99 women) observed about CHF ischemic genesis. Patients of the main group A+ (101 persons), in addition to the main treatment, took L‑arginine at a dose of 1 g 3 times per day in syrup (Tivortin), the rest of the patients (202 persons) were included in the comparison group А - . As a control group were examined 20 healthy volunteers. The metabolism of NO and endothelium-dependent vasodilatation were studied by determining the activity of eNOS, and concentration of NO2/NO3, determining the level of L‑arginine in the blood, assessment of endothelial function with a compression test. The endothelial function of vessels was judged according to the dopplerography of the brachial artery using the method of Solomon et al.Results. In patients taking arginine were observed additional positive effect on the arginine concentration in the peripheral blood (51,63% against 43,53% in group A, p<0.01). The distribution of the patients according to the status of LV systolic function showed that the effect of additional application of arginine is observed only in patients with low LVEF (69,63% vs 58,32% in the group with low LVEF, p<0.01). Also it was discovered that the use of arginine promotes a significantly greater increase in eNOS activity (11,53% against 4.76 per cent, p<0.001. In comparison with patients within the groups A+ and A —, classified according to the state of LV systolic function, it was found a significantly more pronounced effect of arginine in patients with normal systolic LV function.Conclusions. Patients with chronic heart failure (CHF) of ischemic origin, with low left ventricle ejection fraction (LV EF), a violation of NO metabolism is noted. Decrease of L‑arginine concentration leads to decrease in endothelial NO-synthase activity, and increase of macrophage NO-synthase activity leads to high concentration of nitric oxide and its stable metabolites in peripheral blood. Endothelial vasomotor dysfunction is associated with decrease of vasodilatation and even paradox vasoconstriction (in our study in 10 patients (3.3%)). Inclusion of L‑arginine to standard therapy of CHF gives additional positive effect on improvement of metabolism of nitric oxide and endothelial vasomotor function.

The effectiveness of the replacement of the generic blockers of the renin-angiotensin-aldosterone system by perindopril arginine in patients with uncontrolled blood pressure: the results of the regional program “DIFFERENCE”

Taking into account the widespread use of generic drugs and insufficient rate of achieving the target blood pressure (BP), a regional program “DIFFERENCE” was initiated. The purpose of this study was to assess the chance of increasing the effectiveness of antihypertensive therapy (AHT) by replacing generic perindopril and receptor blockers to angiotensin II (BRA) by the original perindopril and generic indapamide by the original one.Design and methods. The study included 330 hypertensive patients (47,3% males; the average age of men is 53,5 ± 8,5 years, women — 54,2 ± 10,2 years, p &gt; 0,05). The mean systolic BP was 149,5 ± 5,3 mm Hg, average diastolic BP — 96,4 ± 4,9 mm Hg; 1st HTN degree was achieved in 49,1% patients, 2nd — in 41,2%; 3rd degree remained in 9,7%. Monotherapy of HTN was prescribed in 79,4% patients.Results. After the transfer from the generic perindopril to the original drug (± transfer from the generic indapamide to the original one) within 4 weeks no other changes of AHT were introduced. During these 4 weeks, the average systolic BP decreased to 139,1 ± 5,1 mm Hg, diastolic blood pressure declined to 88,2 ± 5,8 mm Hg, which allowed to achieve the target BP in 37,0% patients (p &lt; 0,01). On the Month 1 visit, taking into account indications, the frequency of combined AHT increased to 76,4%, on the Month 3 visit — to 88,2%, exceeding the original one by 4,3 times (p &lt; 0,01). On the Month 3 visit the average systolic BP was 136,5 mm Hg, diastolic BP — 85,9 mm Hg, the target BP level was achieved in 53,9% cases (p &lt; 0,01). By the study completion, the most often combination included perindopril with diuretic or calcium antagonist.Conclusions. The study “DIFFERENCE” demonstrated the effectiveness of the replacement of generic perindopril and BRA by the original perindopril combined, if necessary, with the replacement of generic indapamide by the original one in patients wth uncontrolled HTN. To date, the combined AHT has not been assigned frequently enough, which is also the reason for the insufficient efficiency. The most common were the combinations of perindopril with diuretic or calcium antagonist.

Influence of three months therapy with L-arginine on the general clinical conditions of patients with various forms of heart failure

The objective: assessing of the impact of the 3 month course of treatment with L arginine on the clinical and functional and laboratory parameters in patients with various forms of heart failure.Patients and methods. The study included 55 patients with cardiomyopathy: 22 patients with isolated right ventricular dilated cardiomyopathy (RVDCMP) and 33 patients with dilated cardiomyopathy (DCM) with bi ventricular heart failure. The average age of patients 42,1 ± 9,0 year (from 21 to 54 years). Depending on the shape of heart failure patients were divided into two groups. The first group included 22 patients with RVDCMP (average age 45,3 ± 10,2 years), the second included 33 patients with dilated cardiomyopathy (mean age 45,3 ± 13,3 years).Results. It was noted improvement in clinical and functional and laboratory parameters in both groups of patients, but in the case of RVD CMP these changes were more pronounced in comparison with a group of DCM. Different effects of L-arginine in the analyzed group of patients was caused by the presence of irreversible changes in the state of decompensated myocardium in patients with dilated cardiomyopa thy, while in patients with RVDCMP compensatory response of the heart muscle must have been higher.Conclusion. The use of arginine in patients with dilated cardiomyopathy with right ventricular or bi-ventricular lesion improves vascular endothelial function, affecting the flow-dependent vasodilatation.

97 Evaluation of predictive markers of therapeutic response to oral supplementation with l -arginine in patients with preeclampsia

Introduction Dysfunction of l -arginine/NO endothelial system is one of the factors that contribute to preeclampsia development. The supplementation with l -arginine could be used as treatment and/or prevention for this disorder. Objective To supplement pregnant women with preeclampsia and determine whether endogenous biomarkers can indicate which pregnant women will respond or not supplementation with l -arginine. Patients and methods We analyzed 56 pregnant women diagnosed with preeclampsia, divided into two groups 39 without supplementation and 17 who underwent supplementation with 3 g l -arginine orally for 10 days. Results The concentrations of the inflammation markers IL-6 and CRP were lower at the beginning of the supplementation when compared with the end of supplementation IL-6 (4.08 ± 3.74 vs. 10.67 ± 9.03, P = 0,03); PCR (5.52 ± 2.72 vs. 7.00 ± 3.37, P = 0.04). For other biomarkers analyzed we did not observe significant changes or the comparison between groups (sVCAM: P = 0.74; ADMA: P = 0.76; endoglin: P = 0 28; CD40: P = 0.22 and sFlt-1: P = .35) or between the beginning and the end of supplementation (sVCAM: P = 0.53; ADMA: P = 0.89; endoglin: P = 0.15; CD40: P = 0.53 and sFlt-1: P = 0.55). Conclusion The quantification of biomarkers showed that the participants were not responsive to supplementation with l -arginine since there was no change in the concentration thereof, or in the clinical and laboratory findings.

Trimethyl-L‑lysine, the metabolic precursor of carnitine, and methylated derivatives of arginine in patients with cardiovascular diseases

Objective of the present study was to estimate the concentrations of methylated derivatives of L‑lysine and L‑arginine in patients with blood circulation disorders. Design and methods. We examined plasma samples of 151 patients with cardiovascular diseases, including 86 patients with aortic aneurysm and 47 with aortic stenosis, as well as normal subjects divided in two age groups. The concentrations of trimethyl-L‑lysine (TML), symmetric dimethyl-L‑arginine (SDMA) and asymmetric dimethyl-L‑arginine (ADMA) were determined by liquid chromatography after solid phase extraction. Results. Decreased TML level was found in all patients, regardless of diagnosis, but there was an increase in ADMA and SDMA concentrations in comparison to healthy individuals (p < 0,001). These changes were accompanied by an increase in the concentration of lactic acid. TML decline was lower in the subgroup of patients with aortic stenosis compared to the subgroup with aortic aneurysm (p < 0,05), and there was no difference in lactate/pyruvate ratio and homocysteine level compared to healthy people. No significant correlations between TML and ADMA, TML and SDMA were found. Conclusions. Patients with different cardiovascular disorders demonstrate an altered level of markers of mitochondrial and endothelial dysfunction. Determination of blood TML level allows monitoring of protein methylation in the body. Being a precursor of carnitine, TML may characterize the changes in fatty acids transport relating to mitochondrial dysfunction development.

Case of aniridia with a heterozygous PAX6 mutation in which the glucagon response to arginine was evaluated.

Pax6 is a highly evolutionally conserved transcription factor involved in the development of the eye and pancreatic islets. In humans, a heterozygous PAX6 mutation causes aniridia and mild glucose intolerance with impaired insulin secretion1. However, there have been no reports evaluating pancreatic α-cell function in aniridia patients with heterozygous PAX6 mutations. We herein present the first case of an aniridia patient with a heterozygous PAX6 mutation in which pancreatic α-cell function was evaluated. A 40-year-old woman with aniridia and obesity (165 cm, 86 kg, body mass index 31.6 kg/m2) was admitted to the Department of Metabolic Medicine, Osaka Hospital, Suita, Japan, for an endocrine examination. In childhood, she was diagnosed with aniridia, and at 28 years-of-age, it was found that she had a heterozygous PAX6 mutation (c.969C>T) leading to a truncated protein lacking a transactivation domain. The mutant PAX6 protein in the patient did not exert any transcriptional activity1. On admission, a 75-g oral glucose tolerance test showed impaired glucose tolerance (IGT) with impaired insulin secretion (Table​(Table1).1). On an arginine stimulation test (a 10% L-arginine hydrochloride solution [300 mL] was given intravenously over 30 min), the area under the concentration–time curve for the immunoreactive glucagon (AUCIRG) between time 0 and 120 min was calculated by means of the trapezoidal rule. The serum glucagon concentration was measured by RIA (SRL, Tokyo, Japan) similar to that in non-diabetic Japanese controls2. As a result, AUCIRG in the present case was comparable with that in non-diabetic Japanese controls (25.9 pg/mL/min × 103 vs 25.20 ± 7.76 pg/mL/min × 103)2. Table 1 Results of 75-g oral glucose tolerance test in the patient Recently, the involvement of glucagon in the pathogenesis of diabetes has drawn much attention. Pax6 is a transcription factor involved in the development of pancreatic α- and β-cells. Mice with a targeted disruption of Pax6 die soon after birth with an absence of glucagon-producing α-cells and a marked reduction of insulin producing β-cells. In heterozygous Pax6 mutant mice lacking a transactivation domain similar to the present case, α- and β-cells are reduced to 25 and 40% of wild type3. In contrast, aniridia patients with heterozygous PAX6 mutations had mild glucose intolerance with impaired insulin secretion1. However, secretory properties of glucagon in those patients were unclear. The present case showed impaired insulin secretion, whereas her glucagon response to arginine was comparable with those in non-diabetic control subjects. Although we could not conclude, because we failed to assess the glucagon responses to arginine in the control subjects with obese and IGT, and the other subjects with PAX6 mutation, this result might not necessarily show that her glucagon capacity is normal. This is because it has been shown that glucagon response to arginine in patients with IGT and/or obesity, as well as the present case, is exaggerated. Therefore, the result that her glucagon secretory capacity was not exaggerated despite her obesity and IGT could suggest her impaired glucagon secretory capacity. To the best of our knowledge, the present case is the first report to evaluate pancreatic α-cell function in a patient with a heterozygous PAX6 mutation. In addition, interestingly, recent studies have shown that blocking glucagon action prevents diabetes4. Considering these results, the cause of a mild degree of glucose intolerance in patients with heterozygous PAX6 mutations might be partially because of decreased glucagon secretion. In conclusion, we presented the first case of an aniridia patient with a heterozygous PAX6 mutation in which the glucagon response to arginine was evaluated. Further human studies are required to show the association of PAX6 mutations with glucagon secretion.

Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study

Arginine plays a role in many different pathways in multiple cell types. Consequently, a shortage of arginine, caused by pathologic conditions such as cancer or injury, has the potential to disturb many cellular and organ functions. Glutamine is the ultimate source for de novo synthesis of arginine in humans via the intestinal-renal axis. Therefore, we hypothesized that parenteral glutamine supplementation may stimulate the interorgan pathway of arginine production. The objectives were to quantify arginine production from its precursor glutamine and to establish the contribution of the kidneys to de novo synthesis of arginine in patients receiving intravenous supplementation of glutamine dipeptide during major abdominal surgery. Whole-body and renal metabolism of glutamine, citrulline, and arginine was assessed by stable isotope techniques in 7 patients receiving a perioperative supplement of intravenous alanyl-glutamine (0.5 g · kg(-1) · d(-1)). Plasma glutamine, citrulline, and arginine concentrations increased significantly in patients receiving intravenous glutamine dipeptide. At whole-body level, 91% of total citrulline turnover was derived from glutamine, whereas 49% of whole-body citrulline turnover was used for de novo synthesis of arginine. The kidneys were responsible for 75% of whole-body arginine production from citrulline. Glutamine and citrulline are important sources for de novo arginine synthesis. The kidneys are the main production site for endogenous arginine. After comparison of these results with previous similar studies, our data suggest that an intravenous glutamine supplement doubles renal arginine production from citrulline. This trial was registered at www.trialregister.nl as NTR2914.

Mo1516 Effects of Preoperative Enteral Glutamine and Arginine in Patients Submitted to Surgical Treatment of Enterocutaneous Fistulas

anorexia. In addition 11 patients reported GERD, 3 had recurrent episodes of acute pancreatitis and 7 cases presented symptoms of upper GI obstruction. 5 patients had previously undergone fundoplication without symptoms relief. Mean aorto-mesenteric angle was 18° +/-1.8 and distance 4.6 +/2.1 mm. A duodenojejunostomy was performed in 7 patients, in the remainders the duodenojejunostomy was done after distal duodenum resection. There were no mortality, we observed 2 post operative complications: an abdominal bleeding and a mild acute pancreatitis. At mean follow period of 10 +/6.3 months, all patients are well and alive, 2 of them are still complaining mild epigastric pain. There is a significant improvement in patient weight (pre-operatory mean 50+/-1 kg, post-operatory mean 55+/-9 kg p= 0.003) and BMI (pre-operatory mean 18.1+/-3.4 kg, post-operatory mean 20.0+/-3.4 kg p= 0.004) and there is a significant decreased in need of PPI therapy (p=0.004). We didn't observed significant differences, in the outcome, between the two surgical procedures. Conclusions: Duodenojejunostomy can be recommended as a safe and appropriate option for SMAS. In our series there is no significant difference between distal duodenal resection with duodenojejunostomy and duodenojejunostomy bypass.

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.

The diagnosis of GH deficiency in obese patients: a reappraisal with GHRH plus arginine testing after pharmacological blockade of lipolysis

The diagnosis of GH deficiency (GHD) in obese patients is complicated by the reduced GH secretion associated with overweight. A GH response to GHRH+arginine lower than 4.2 microg/l is currently considered indicative of GHD in obesity. The aim of the study was to investigate the effect of acute pharmacological blockade of lipolysis on the GH response to GHRH+arginine in obese patients. Two groups of patients were studied: 12 obese patients with proven GHD and 14 patients with essential obesity. On separate occasions, two tests were carried out in each patient: GHRH+arginine and GHRH+arginine preceded by acipimox. The mean GH peak after GHRH+arginine was significantly lower in hypopituitary patients than in subjects with essential obesity. Acipimox significantly increased the mean GH response in patients with essential obesity, but not in hypopituitary subjects. All hypopituitary patients and 7/14 patients with essential obesity displayed GH peaks lower than 4.2 microg/l after GHRH+arginine: the GH response to the test increased after acipimox pretreatment in five of these seven essentially obese subjects. After acipimox administration, free fatty acids (FFAs) significantly fell in both groups with comparable mean absolute decreases. All IGF1 values were normal in both groups of subjects. Our study has demonstrated that the acipimox-induced acute reduction of circulating FFA levels increases mean somatotropin response to GHRH+arginine in patients with essential obesity, whereas it has no effect in hypopituitary subjects. The current criterion for the diagnosis of GHD in obese patients may be misleading. Indeed, subjects affected by third degree obesity, like most of our patients, may be erroneously classified as really GH-deficient and started on an expensive unjustified treatment. It appears therefore that the current criteria for the diagnosis of GHD in obesity should be reconsidered in the light of further studies also taking into account different body mass index groups.

The effect of acute hypercalcaemia on arginine induced growth hormone release in diabetic man.

The effect of mild hypercalcaemia on the growth hormone (GH), C-peptide and glucose responses to arginine infusion in patients with insulin-dependent idiopathic diabetes mellitus (ID) was compared with that observed in patients whose diabetes was secondary to idiopathic haemochromatosis (IH) and chronic pancreatitis (CP). The summated GH responses to arginine infusion alone were similar in all three groups. Mild hypercalcaemia significantly diminished the GH response to arginine in patients with secondary diabetes, but not in those with ID. As the blood glucose and C-peptide responses were similar in the presence of a normal or raised serum calcium, the differences in GH response could not be ascribed to changes in blood glucose levels or to alterations in endogenous insulin release. For reasons as yet unknown, hypercalcaemia appears to have more of a stabilizing effect on the pituitary somatotrophic granules of those with secondary diabetes than in those with ID.