Rescue therapy of early neurological deterioration in lacunar stroke.

BACKGROUND: Early neurological deterioration (END) occurs in many patients with acute ischemic stroke due to a variety of causes. Although pharmacologically induced hypertension (PIH) and anticoagulants have been investigated in several clinical trials for the treatment of END, the efficacy and safety of these treatments remain unclear. Here, we investigated whether PIH or anticoagulation is better as a rescue therapy for the progression of END in patients with lacunar stroke. METHODS: This study included patients with lacunar stroke who received rescue therapy with END within 3 days of symptom onset between April 2014 and August 2021. In the PIH group, phenylephrine was administered intravenously for 24 h and slowly tapered when symptoms improved or after 5 days of PIH. In the anticoagulation group, argatroban was administered continuously intravenously for 2 days and twice daily for next 5 days. We compared END recovery, defined as improvement in NIHSS from baseline, excellent outcomes (0 or 1 mRS at 3 months), and safety profile. RESULTS: Among the 4818 patients with the lacunar stroke, END occurred in 147 patients. Seventy-nine patients with END received PIH (46.9%) and 68 patients (46.3%) received anticoagulation therapy. There was no significant difference in age (P = 0.82) and sex (P = 0.87) between the two groups. Compared to the anticoagulation group, the PIH group had a higher incidence of END recovery (77.2% vs. 51.5%, P < 0.01) and excellent outcomes (34.2% vs. 16.2%, P = 0.04). PIH was associated with END (HR 2.49; 95% CI 1.06-5.81, P = 0.04). PIH remained associated with END recovery (adjusted HR 3.91; 95% CI 1.19-12.90, P = 0.02). Safety outcomes, like hemorrhagic conversion and mortality, were not significantly different between the two groups. CONCLUSIONS: As a rescue therapy for the progression of END in lacunar stroke patients, PIH with phenylephrine was more effective with similar safety compared to anticoagulation with argatroban.

The combination of arginine and fluoride-containing bioactive glass acted synergistically in inhibiting enamel demineralization in permanent teeth.

OBJECTIVES: To evaluate the in-vitro efficacy of inhibiting enamel demineralization using arginine in combination with fluoride-containing bioactive glass (FBG). METHODS: In this study, the healthy enamel blocks were first demineralized in acetic acid for 24 h, then soaked in anti-demineralization treatment solutions containing either arginine or FBG or both for 96 h.The specimens treated in acetic acid were applied as the control group. The pH, calcium and phosphorus ion concentrations of the solutions were measured before and after treatment. Changes in enamel mineral weight, microhardness, and composition were also analyzed. RESULTS: The present of arginine facilitated fluorine release from treatment solutions with the presence of FBG. Both arginine and FBG significantly increased the pH of treatment solutions and prevented the further mineral weight loss compared to the control group. All anti-demineralization treatment groups showed significant increases in microhardness, but there was no statistical difference among the treatment groups. The SEM analysis showed enamel restoration in the arginine and FBG groups upon treatment, while the combined groups showing a superior anti-demineralization efficacy. 19F NMR showed the formation of fluorapatite in samples treated with solutions containing FBG. CONCLUSIONS: Both arginine and FBG could inhibit enamel demineralization to some extent, and their combination demonstrated an enhanced anti-demineralization efficacy. The low-concentration combination group exhibited anti-demineralization effects comparable to those of high-concentration ones. CLINICAL SIGNIFICANCE: This study introduces a new approach for caries prevention by combining the application of arginine and FBG. The release of fluorine promoted by the presented arginine along with calcium and phosphorus ions from FBG facilitated FAP formation. Additionally, the increment of pH resulting from arginine and FBG degradation further prevents enamel demineralization.

Methodological quality of research on perioperative immunomodulatory supplementation in oncological gastrointestinal tract surgery: a meta-research protocol.

INTRODUCTION: One of the topics that show differences of opinion in the scientific field of nutrition is the recommendation by clinical practice guidelines (CPGs) of an immunomodulatory diet with arginine, nucleotides and omega-3 for individuals diagnosed with cancer undergoing major surgery. The quality of the recommendations is directly related to credibility, transparency and rigour in their development, but also to the quality of the studies published and available for inclusion in the recommendation, such as systematic reviews (SRs) and randomised clinical trials. The aim of this study is to evaluate the methodological quality of the recommendation of perioperative immunomodulatory supplementation for individuals with gastrointestinal and head and neck cancer, the CPGs, and the studies that support the recommendations. METHODS AND ANALYSIS: We will conduct a systematic search for CPGs. Recommendations for nutritional supplementation with immunomodulatory substrates for individuals undergoing major oncological surgery will be analysed using the Appraisal of Guidelines Research and Evaluation-Recommendations Excellence tool. CPGs will be analysed using the Appraisal of Guidelines Research and Evaluation II tool. The SRs cited in the recommendations will be analysed using the A Measurement Tool to Assess Systematic Reviews II tool and additional questions regarding heterogeneity in reviews. The clinical trials cited in the SRs and in the guideline recommendations (when applicable) will be analysed according to questions regarding heterogeneity in trials. The results will be presented in tables or charts using descriptive analyses. ETHICS AND DISSEMINATION: The results of this study will be disseminated through relevant conferences and peer-reviewed journals. PROTOCOL REGISTRATION NUMBER: 10.17605/OSF.IO/X2GYT.

Comparative effectiveness of preemptive administration of ibuprofen and ibuprofen-arginine on the anesthetic success of inferior alveolar nerve block in teeth with symptomatic irreversible pulpitis - A double-blind randomized clinical trial.

OBJECTIVES: This study examined the impact of premedication with ibuprofen and ibuprofen-arginine and the influence of preoperative pain and anxiety on inferior alveolar nerve block (IANB) efficacy in cases of symptomatic irreversible pulpitis. MATERIALS AND METHODS: The study involved 150 SIP patients who were randomly assigned to receive ibuprofen (600 mg), ibuprofen-arginine (1,155 mg), or a placebo 30 min before IANB. Preoperative anxiety and pain levels were assessed using the Modified Dental Anxiety Scale and the Heft-Parker visual scale. IANB efficacy was determined by the absence of or mild pain during the procedure. Statistical analysis included chi-square, z-tests, Analysis of Variance, and Student's t tests. RESULTS: The ibuprofen and ibuprofen-arginine groups exhibited significantly higher IANB success rates (62% and 78%, respectively) compared to the placebo group (34%). However, no significant difference was observed between the ibuprofen and ibuprofen-arginine groups. Patients with successful IANB in the ibuprofen and ibuprofen-arginine groups displayed lower median anxiety scores (8) than those with failed blocks (15) and lower mean preoperative pain scores (118.3). CONCLUSION: In cases of symptomatic irreversible pulpitis the preemptive medication with ibuprofen-arginine effectively increased the efficacy of the inferior alveolar nerve block The inferior alveolar nerve block efficacy was influenced by preoperative anxiety levels and the intensity of pain. CLINICAL RELEVANCE: This research underscores the potential benefits of oral premedication with ibuprofen and ibuprofen-arginine in improving anesthesia outcomes in cases of symptomatic irreversible pulpitis.

Arginine, glycine, and creatine supplementation improves symptoms in a female with creatine transporter deficiency.

X-linked creatine transporter deficiency is caused by hemizygous or heterozygous pathogenic variants in SLC6A8 that cause neuropsychiatric symptoms because of impaired uptake of creatine into tissues throughout the body. Small cohorts have suggested that supplementation of creatine, arginine, and glycine can stop disease progression in males, but only six cases of supplementation in females have been published. Here, we present a female with a de-novo pathogenic SLC6A8 variant who had ongoing weight loss, mild intellectual disability, and neuropsychiatric symptoms. Magnetic resonance spectroscopy of the brain showed reduced creatine on all acquired spectra. The patient was started on creatine-monohydrate, l -arginine, and l -glycine supplementation, and she had significant symptomatic improvement within the following 3 weeks. After 8 months of supplementation, magnetic resonance spectroscopy showed improved creatine concentrations with normalizing semiquantitative ratios with other brain metabolites. Current data supports clinicians trialing creatine, arginine, and glycine supplements for female patients with creatine transporter deficiency.

Effect of l-arginine compared to placebo on sexual function in women with major depressive disorder: a randomized controlled trial.

BACKGROUND: While some evidence suggests that l-arginine may improve sexual function and alleviate depression, it has not been investigated in women with depression to assess both its effects on the depression and sexual function concurrently. METHODS: Patients who had received a diagnosis of major depressive disorder, as determined by predetermined inclusion and exclusion criteria, were enrolled in this triple-blind clinical trial. Patients were divided into two groups: group A, received L-arginine 1 gram twice daily, and group B, received a placebo for four weeks. They were evaluated at baseline, after four and eight weeks with the Hamilton Depression Rating Scale (HDRS), and Rosen's questionnaire or Female Sexual Function Index (FSFI). RESULTS: A decrease in the severity of depression was observed in all patients, which was determined due to Hamilton's questionnaire (P-value < 0.001). During the time in group A, FSFI increased. Based on the FSFI questionnaire, they had improvement in some domains, including the lubrication index and orgasm index, which significantly changed in the eighth week compared to the baseline (P-value < 0.05). However, these two indicators did not change statistically significantly compared to the placebo group. CONCLUSION: L-arginine supplementation can improve sexual function, particularly lubrication and orgasm, and mood in women with depression, with minimal side effects observed. Additional research is necessary to validate these results by examining the effects of higher dosages, extended durations, and larger populations of depressed patients. TRIAL REGISTRATION: Iranian Registry of Clinical Trial: IRCT20100127003210N26.

Evaluation and comparison of the effects of a new paste containing 8% L-Arginine and CaCO3 plus KNO3 on dentinal tubules occlusion and dental sensitivity: a randomized, triple blinded clinical trial study.

BACKGROUND: Dentin hypersensitivity, often occurring after dental treatments or from erosive lesions, is a prevalent patient complaint. This study introduces a paste combining 8% L-arginine, calcium carbonate, and potassium nitrate to evaluate its impact on dentinal tubules occlusion, dentin permeability, and tooth sensitivity. METHODS: Dentin surfaces from 24 third molars (thickness: 2 mm) were divided into two groups of 12. One received the experimental paste, while the other received a placebo without desensitizer. Permeability and sealing ability were assessed through scanning electron microscopy (SEM) and dentin permeability measurement. The pastes' effects on hypersensitivity were then examined in a triple-blind, randomized parallel-armed clinical trial with 16 eligible patients. Sensitivity to cold, touch, and spontaneous stimuli was recorded using the VAS scale at various intervals post-treatment. Statistical analysis was conducted using Shapiro-Wilk, Mann-Whitney U, Friedman, and Wilcoxon tests (α = 0.05). RESULTS: The permeability test demonstrated a significant reduction in dentin permeability in the experimental group (P = 0.002) compared to the control (P = 0.178). SEM images revealed most dentinal tubules in the intervention samples to be occluded. Clinically, both groups showed a significant decrease in the three types of evaluated sensitivity throughout the study. However, no significant difference in sensitivities between the two groups was observed, with the exception of cold sensitivity at three months post-treatment (P = 0.054). CONCLUSION: The innovative desensitizing paste featuring 8% L-arginine, calcium carbonate, and potassium nitrate effectively occluded dentinal tubules and reduced dentin permeability. It mitigated immediate and prolonged dentin hypersensitivity to various stimuli, supporting its potential role in managing dentin hypersensitivity. TRIAL REGISTRATION: http://irct.ir : IRCT20220829055822N1, September 9th, 2022.

Gyrate atrophy of the choroid and retina: Update on diagnosis and treatment.

Gyrate atrophy of the choroid and retina (GACR) is a rare autosomal recessive disease characterised by elevated plasma ornithine levels due to deficiency of the enzyme ornithine aminotransferase (OAT). The accumulation of this amino acid in plasma leads to the development of patches of chorioretinal atrophy in the peripheral retina extending into the macular area. Patients usually present with night blindness followed by constriction of the visual field and, finally, decreased central vision and blindness. The disease is diagnosed by the presence of the characteristic clinical picture, the presence of hyperornithinaemia in plasma and the detection of mutations in the OAT enzyme gene. There is currently no effective gene therapy and the most common therapeutic intervention mainly involves dietary modifications with arginine restriction. This article aims to summarise the pathogenesis, clinical and diagnostic findings and treatment options in patients with GACR.

Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?

MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.

Exploring the impact of arginine-supplemented immunonutrition on length of stay in the intensive care unit: A retrospective cross-sectional analysis.

BACKGROUND: Arginine-supplemented enteral immunonutrition has been designed to optimize outcomes in critical care patients. Existing formulas may be isocaloric and isoproteic, yet differ in L-arginine content, energy distribution, and in source and amount of many other specialized ingredients. The individual contributions of each may be difficult to pinpoint; however, all cumulate in the body's response to illness and injury. The study objective was to compare health outcomes between different immunonutrition formulas. METHODS: Real-world data from October 2015 -February 2019 in the PINC AI™ Healthcare Database (formerly the Premier Healthcare Database) was reviewed for patients with an intensive care unit (ICU) stay and ≥3 days exclusive use of either higher L-arginine formula (HAF), or lower L-arginine formula (LAF). Multivariable generalized linear model regression was used to check associations between formulas and ICU length of stay. RESULTS: 3,284 patients (74.5% surgical) were included from 21 hospitals, with 2,525 receiving HAF and 759 LAF. Inpatient mortality (19.4%) and surgical site infections (6.2%) were similar across groups. Median hospital stay of 17 days (IQR: 16) did not differ by immunonutrition formula. Median ICU stay was shorter for patients receiving HAF compared to LAF (10 vs 12 days; P<0.001). After adjusting for demographics, visit, severity of illness, and other clinical characteristics, associated regression-adjusted ICU length of stay for patients in the HAF group was 11% shorter [0.89 (95% CI: 0.84, 0.94; P<0.001)] compared to patients in the LAF group. Estimated adjusted mean ICU length of stay was 9.4 days (95% CI: 8.9, 10.0 days) for the HAF group compared to 10.6 days (95% CI: 9.9, 11.3 days) for the LAF group (P<0.001). CONCLUSIONS: Despite formulas being isocaloric and isoproteic, HAF use was associated with significantly reduced ICU length of stay, compared to LAF. Higher arginine immunonutrition formula may play a role in improving health outcomes in primarily surgical critically ill patients.

Effectiveness of glutamine and arginine in wound healing of pressure ulcers: A systematic review protocol.

INTRODUCTION: Various nutrients play a physiological role in the healing process of pressure ulcers (PUs). Nutritional interventions include the administration of enteral nutritional supplements and formulas containing arginine, glutamine, and micronutrients. The aim of this systematic review is to evaluate the effectiveness of enteral nutritional supplements and formulas containing arginine and glutamine on wound-related outcomes. These include (1) time to healing, (2) changes in wound size, (3) local wound infection, (4) PU recurrence, and (5) PU-related pain. MATERIALS AND METHODS: This protocol was developed according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). A search will be conducted in the Cochrane Library, EMBASE, PubMed (MEDLINE), CINAHL (EBSCOhost interface) and Web of Science. In addition, a manual search will be conducted to identify relevant records. Except for systematic reviews, no restrictions will be placed on the study design, the population studied or the setting. Studies that do not address PUs, in vitro studies and studies that do not report wound-related outcomes will be excluded. Study selection, risk of bias assessment and data extraction will be performed independently by three researchers. Depending on the extent of heterogeneity of interventions, follow-up time and populations, results will be summarised either by meta-analysis or narrative synthesis. CONCLUSIONS: This is the first systematic review to identify, evaluate and summarise the current evidence for enteral arginine and glutamine supplementation on wound-related outcomes in PUs. The review will provide a solid basis for deriving valid and clinically relevant conclusions in this area.

Physical properties and enamel remineralization potential of arginine-fluoride varnishes.

OBJECTIVE: The study objectives were to examine the physical properties and enamel remineralization potential of fluoride (F) varnishes incorporated with arginine (Arg). METHODS: Four commercial F varnishes: 1) Duraphat®; 2) Flúor Protector®, 3) Fluor Protector S®, and 4) Fluorimax™ were supplemented with 2% w/v. Arg. The control/experimental varnishes underwent rheometric analysis to assess varnish density (δ), velocity (ν), and associated viscosity, both quantitatively (ν/δ) and qualitatively based on determined mass, volume, distance flow, and time under experimentation. The varnish wet/dry weights (at 2 h) were also analysed. Further, sound enamel specimens (T0) with artificial incipient caries-like lesions (T1) were treated with control/experimental varnishes and subjected to remineralization assay with artificial saliva for 6 h. Thereafter (T2), the specimens were characterized to estimate precipitated Ca and net enamel F uptake. Additionally, mineral density (MD) was assessed using micro-CT at T0, T1, and T2 to derive mineral gain (MG) and % remineralization for the treatment groups. RESULTS: When Arg is incorporated, the physical properties of the F-containing varnishes undergo a significant transformation, resulting in higher density, varnish weight, dry varnish weight, and viscosity compared to their respective control varnishes (p < 0.05). Incorporating Arg-in Duraphat®, Fluor Protector S®, and Fluorimax™ significantly improved both enamel Ca precipitation and F uptake compared to the respective controls (p < 0.05). Additionally, the enamel F uptake was significantly higher with all the tested varnishes when enriched with Arg (p < 0.05). The combined data for MD, MG, and % remineralization suggests that the remineralization potential of F-varnishes significantly increased when enriched with Arg (p < 0.05). CONCLUSION: Incorporating Arg in inorganic F varnishes improves their physical properties and enhances the enamel remineralization potential of the varnishes. CLINICAL SIGNIFICANCE: This study highlights the possibility of incorporating Arg in distinct F-source varnishes. The synergism between active components (Arg-F) aids in enhanced remineralization and superior varnish physical properties, demonstrating a promising approach for high caries-risk patients.

L-arginine mitigates bleomycin-induced pulmonary fibrosis in rats through regulation of HO-1/PPAR-γ/ß-catenin axis.

Pulmonary fibrosis is a chronic and progressively deteriorating lung condition that can be replicated in laboratory animals by administering bleomycin, a chemotherapeutic antibiotic known for its lung fibrosis-inducing side effects. L-arginine, a semi-essential amino acid, is recognized for its diverse biological functions, including its potential to counteract fibrosis. This study aimed to evaluate the antifibrotic properties of L-arginine on bleomycin-induced pulmonary fibrosis in rats. The administration of a single intratracheal dose of bleomycin resulted in visible and microscopic damage to lung tissues, an uptick in oxidative stress markers, and an elevation in inflammatory, apoptotic, and fibrotic indicators. A seven-day treatment with L-arginine post-bleomycin exposure markedly improved the gross and histological architecture of the lungs, prevented the rise of malondialdehyde and carbonyl content, and enhanced total antioxidant capacity alongside the activities of antioxidant enzymes. Also, L-arginine attenuated the expression of the pro-fibrotic factors, transforming growth factor-ß and lactate dehydrogenase in bronchoalveolar lavage fluid. In the lung tissue, L-arginine reduced collagen deposition, hydroxyproline concentration, and mucus production, along with decreasing expression of α-smooth muscle actin, tumor necrosis factor-α, caspase-3, matrix metalloproteinase-9, and ß-catenin. Moreover, it boosted levels of nitric oxide and upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), heme oxygenase-1 (HO-1), and E-cadherin and downregulating the expression of ß-catenin. These findings suggest that L-arginine has preventive activities against bleomycin-induced pulmonary fibrosis. This effect can be attributed to the increased production of nitric oxide, which modulates the HO-1/PPAR-γ/ß-catenin axis.

Assessment of the treatment effectiveness of men with mild and medium degree of erectile dysfunction.

OBJECTIVE: . Aim: To assess the effectiveness of monotherapy and complex treatment of patients with erectile dysfunction depending on its severity. PATIENTS AND METHODS: Materials and Methods: Men with moderate and mild erectile dysfunction took part in the study, who, in turn, were divided into groups, depending on the treatment, with the evaluation of the results of the International Index of Erectile Function (MIEF-15), the state of cavernous hemodynamics and the function of the vascular endothelium before and after treatment. RESULTS: Results: In patients with an average degree of severity, who received complex treatment including a course of low-energy shock wave therapy, against the background of taking sildenafil and L-arginine, the best results were obtained in the quality of erection and increased cavernous blood flow, which positively affected satisfaction with sexual intercourse and overall satisfaction. It has also been proven that the function of the endothelium was improved in patients receiving L-arginine, due to which there was a probable decrease in endothelin-1. A probable improvement of erectile function was obtained in the group of patients with a mild degree who received L-arginine, and there was no statistical difference from the indicators in the group who received sildenafil, which was confirmed by the data of dopplerography. CONCLUSION: Conclusions: Patients with an average degree of erectile dysfunction require comprehensive treatment. The use of L-arginine can be an alternative to phosphodiesterase type 5 inhibitors in the treatment of mild erectile dysfunction.

Effect of topical application of ibuprofen/arginine on the in-office bleaching-induced tooth sensitivity: A randomized, triple-blind controlled trial.

OBJECTIVE: The application of anti-inflammatories as topical desensitizers before dental bleaching is an approach to reduce bleaching-induced tooth sensitivity (TS). This randomized controlled trial compared the risk and intensity of TS and the color change resulting from in-office dental bleaching after using an experimental desensitizing gel containing ibuprofen and arginine. METHODS: Sixty-two participants with upper canine shades A2 or darker were randomly assigned to either the ibuprofen-arginine desensitizing group or the placebo group. The desensitizing gel was applied for 15 min before in-office bleaching with 35 % hydrogen peroxide gel for 50 min (2 sessions). To assess the absolute risk and intensity of TS, visual (0-10) and numeric rating (0-5) scales were used, and group comparisons were made using the McNemar test, Wilcoxon test, and paired Student t-test (α = 0.05). Color change was evaluated using Vita Classical, Vita Bleachedguide (ΔSGU), and Vita EasyShade (ΔEab, ΔE00, and ΔWID) before and one month after the bleaching procedure. Group comparisons for color change were done using a paired t-test (α = 0.05). RESULTS: The odds ratio for TS was 0.14 [95 % CI 0.02 to 0.6], meaning lower odds of TS for the desensitizing gel. A lower intensity of TS was also observed for the experimental group (p < 0.005) up to 48 h after bleaching. All color evaluation tools demonstrated effective and similar whitening for both groups (p > 0.05). CONCLUSIONS: Using the experimental desensitizing gel containing ibuprofen and arginine effectively reduced the risk and intensity of TS without compromising the bleaching efficacy. CLINICAL RELEVANCE: The topical application of ibuprofen/arginine on the in-office bleaching reduced risk and intensity of bleaching-induced tooth sensitivity.

Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial.

Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.

Arginine-Nanoenzyme with Timely Angiogenesis for Promoting Diabetic Wound Healing.

The successful treatment of diabetic wounds requires strategies that promote anti-inflammation, angiogenesis, and re-epithelialization of the wound. Excessive oxidative stress in diabetic ulcers (DUs) inhibits cell proliferation and hinders timely vascular formation and macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2, resulting in a persistent inflammatory environment and a nonhealing wound. We designed arginine-nanoenzyme (FTA) with mimic-catalase and arginine-loading. 2,3,4-trihydroxy benzaldehyde and arginine (Arg) were connected by a Schiff base bond, and the nanoassembly of Arg to FTA was driven by the coordination force between a ferric ion and polyphenol and noncovalent bond force such as a hydrogen bond. FTA could remove excess reactive oxygen species at the wound site in situ and convert it to oxygen to improve hypoxia. Meanwhile, Arg was released and catalytically metabolized by NO synthase in M1 to promote vascular repair in the early phase. In the late phase, the metabolite of Arg catalyzed by arginase in M2 was mainly ornithine, which played a vital role in promoting tissue repair, which implemented angiogenesis timely and prevented hypertrophic scars. Mechanistically, FTA activated the cAMP signaling pathway combined with reducing inflammation and ameliorating angiogenesis, which resulted in excellent therapeutic effects on a DU mice model.