Aflatoxin B1-induced liver pyroptosis is mediated by disturbing the gut microbial metabolites: The roles of pipecolic acid and norepinephrine.

The disturbed gut microbiota is a key factor in activating the aflatoxin B1 (AFB1)-induced liver pyroptosis by promoting inflammatory hepatic injury; however, the pathogen associated molecular pattern (PAMP) from disturbed gut microbiota and its mechanism in activating liver pyroptosis remain undefined. By transplanting AFB1-originated fecal microbiota and sterile fecal microbial metabolites filtrate, we determined the association of PAMP in AFB1-induced liver pyroptosis. Notably, AFB1-originated sterile fecal microbial metabolites filtrate were more active in triggering liver pyroptosis in mice, as compared to parental fecal microbiota. This result supported a critical role of the metabolic homeostasis of gut microbiota in AFB1-induced liver pyroptosis, rather than an injurious response to direct exposure of AFB1 in liver. Among the gut-microbial metabolites, pipecolic acid and norepinephrine were proposed to bind TLR4 and NLRP3, the upstream proteins of pyroptosis signaling pathway. Besides, the activations of TLR4 and NLRP3 were linearly correlated with the concentrations of pipecolic acid and norepinephrine in the serum of mice. In silenced expression of TLR4 and NLRP3 in HepG2 cells, pipecolic acid or norepinephrine did not able to activate hepatocyte pyroptosis. These results demonstrated the necessity of gut microbial metabolism in sustaining liver homeostasis, as well as the potential to provide new insights into targeted intervention for AFB1 hepatotoxicity.

Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

A journey through anticoagulant therapies in the treatment of left ventricular thrombus in post-COVID-19 heparin-induced thrombocytopenia: a case report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis. CASE PRESENTATION: A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date. CONCLUSION: The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.

Dabigatran Use after Argatroban for Heparin-induced Thrombocytopenia with Thrombosis: A Case Series and Literature Review.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is immune-mediated thrombotic thrombocytopenia following the use of heparin, which contributes to a high limb-amputation rate and mortality if not appropriately handled. There is growing evidence suggesting that novel oral anticoagulants (NOACs) may be effective for treating HIT. METHODS: We described five rare cases of patients with HIT associated with deep vein thrombosis treated with dabigatran, a member of NOACs. We also reviewed representative cases and literature investigating the use of NOACs to treat patients with HIT to further discuss the efficacy and safety. RESULTS AND CONCLUSIONS: Following the treatment of dabigatran after argatroban, the platelet count of patients with HIT gradually elevated and reached the normal range eventually. There was no incidence of new symptomatic, objectively-confirmed arteriovenous thromboembolism observed within the 90-day-period follow up. The patient in case 3 presented with gastric bleeding after dabigatran treatment and died in the end. The results suggested that dabigatran use after argatroban may be effective in the treatment of patients with HIT. However, safety should be reconsidered since severe complications were observed in case 3.

Treatment and outcomes of heparin-induced thrombocytopenia (HIT) in patients with neoplasm, a case series.

Heparin-induced thrombocytopenia (HIT) is a highly thrombogenic condition. Cancer patients are already at high risk of thrombosis. The treatment and outcomes of HIT in cancer patients are not well established. We retrospectively identified patients with active cancer who were diagnosed with HIT at our institution. Only patients with a positive HIT assay and intermediate to high 4Ts score were included. We assessed patients for baseline characteristics, HIT characteristics, non-heparin agent usage, and outcomes (recurrent thrombosis, bleeding, and death) up to 180 days after diagnosis of HIT. Between November 1, 2006 and December 31, 2016, 39 patients with active cancer received a diagnosis of HIT. Of these, 35.9% had thrombotic complications at diagnosis. Gastrointestinal cancer was the most common solid organ malignancy while myeloproliferative neoplasm (MPN) was the most common hematological malignancy. Fondaparinux was the most often used parenteral agent at any point of follow-up (87.2%), followed by argatroban (41.0%). Less than half the patients transitioned to an oral agent. The recurrent thrombosis rate was 17.9%, the bleeding rate was 20.5%, the major bleeding rate was 10.3%, and the mortality rate was 15.4% in the entire cohort. HIT in cancer patients is associated with poor outcomes.

Thrombin inhibitor argatroban modulates bone marrow stromal cells behaviors and promotes osteogenesis through canonical Wnt signaling.

AIMS: Coagulation is a common event that play a double-edged role in physiological and pathological process. Anti-coagulation methods were applied in joint surgery or scaffolds implantation to encourage new vascular formation and avoid coagulation block. However, whether anti-coagulation drug perform regulatory roles in bone structure is unknown. This study aims to explore a direct thrombin inhibitor, argatroban, effects on bone marrow stromal cells (BMSCs) and decipher the underlying mechanisms. MATERIALS AND METHODS: Argatroban effects on BMSCs were investigated in vivo and in vitro. The drug was applied in periodontal disease model mice and bone loss was evaluated by µCT and histology. BMSCs were treated with different doses argatroban or vehicle. Cellular reactions were analyzed using wound healing assay, qRT-PCR, Alizarin Red S staining and western blotting. KEY FINDINGS: We demonstrated that local injection of argatroban can rescue bone loss in periodontal disease in vivo. To explore the underlying mechanism, we examined that cell proliferation and differentiation capability. Proliferation and migration of BMSCs were both inhibited by applying lower dose of argatroban. Interestingly, without affecting osteoclastogenesis, osteogenic differentiation was significantly induced by argatroban, which were shown by extracellular mineralization and upregulation of early osteoblastic differentiation markers, alkaline phosphatase, Osteocalcin, transcription factors RUNX2 and Osterix. In addition, molecular analysis revealed that argatroban promoted ß-catenin nuclear translocation and led to an increase of osteogenesis through activating canonical Wnt signaling. SIGNIFICANCE: Taken together, our results show the novel application of the anti-coagulation compound argatroban in the commitment of BMSCs-based alveolar bone regeneration and remodeling.

A pipecolic acid-rich branched cyclic depsipeptide ulleungamide C from a Streptomyces species induces G0/G1 cell cycle arrest in promyelocytic leukemia cells.

In this study, screening by LC-MS and cytotoxicity-guided isolation led to the identification of ulleungamide C (1), a previously unknown pipecolic acid-rich branched cyclic depsipeptide, from a soil actinobacterium Streptomyces sp. KCB13F003. The structure of 1 was determined by interpretation of spectroscopic and spectrometric data from 1D and 2D NMR and HRESIMS experiments. Antiproliferative assays using mammalian cancerous cells revealed that 1 inhibits the proliferation of HL-60 human promyelocytic leukemia cells. Cell cycle analysis showed an increased accumulation of cells in the G0/G1 phase after treatment with 1. Results of immunoblotting assays revealed that 1 reduced the expression levels of cyclin-dependent kinase 4 (CDK4), CDK6, retinoblastoma protein (Rb), and phosphorylated Rb, whereas it induced cyclin-dependent kinase inhibitor 1B (p27/Kip1) expression.

Cysteine Sulfoxides Enhance Steroid Hormone Production via Activation of the Protein Kinase A Pathway in Testis-Derived I-10 Tumor Cells.

Testosterone plays an important role in male sexual characteristics and maturation, and decreased testosterone levels increase the risk of several diseases. Recently, onion extract rich in cysteine sulfoxides, which are amino acids unique to onions, has been reported to alleviate age-related symptoms resulting from decreased testosterone levels in males. However, the mechanism underlying the suppression of low testosterone levels by cysteine sulfoxides has not been elucidated. In this study, we found that onion extract containing cysteine sulfoxides enhanced progesterone, a precursor of testosterone, in mouse testis-derived I-10 tumor cells. Furthermore, cysteine sulfoxides activated protein kinase A (PKA) and cyclic adenosine monophosphate response element-binding protein, which are key factors in steroidogenesis. These results suggest that cysteine sulfoxides enhance steroid hormone production via activation of the PKA signaling pathway.

Inducible biosynthesis and immune function of the systemic acquired resistance inducer N-hydroxypipecolic acid in monocotyledonous and dicotyledonous plants.

Recent work has provided evidence for the occurrence of N-hydroxypipecolic acid (NHP) in Arabidopsis thaliana, characterized its pathogen-inducible biosynthesis by a three-step metabolic sequence from l-lysine, and established a central role for NHP in the regulation of systemic acquired resistance. Here, we show that NHP is biosynthesized in several other plant species in response to microbial attack, generally together with its direct metabolic precursor pipecolic acid and the phenolic immune signal salicylic acid. For example, NHP accumulates locally in inoculated leaves and systemically in distant leaves of cucumber in response to Pseudomonas syringae attack, in Pseudomonas-challenged tobacco and soybean leaves, in tomato inoculated with the oomycete Phytophthora infestans, in leaves of the monocot Brachypodium distachyon infected with bacterial (Xanthomonas translucens) and fungal (Magnaporthe oryzae) pathogens, and in M. oryzae-inoculated barley. Notably, resistance assays indicate that NHP acts as a potent inducer of acquired resistance to bacterial and fungal infection in distinct monocotyledonous and dicotyledonous species. Pronounced systemic accumulation of NHP in leaf phloem sap of locally inoculated cucumber supports a function for NHP as a phloem-mobile immune signal. Our study thus generalizes the existence and function of an NHP resistance pathway in plant systemic acquired resistance.

Efficiency and safety evaluation of prophylaxes for venous thrombosis after gynecological surgery.

BACKGROUND: In this study, we investigate the incidence of venous thrombosis (VT), and evaluate the effectiveness and safety of 3 major thromboprophylaxes and the potential risk factors for VT in women undergoing surgery for a gynecological malignancy. METHODS: We performed a randomized controlled trial of 307 patients undergoing laparoscopic surgery for gynecological malignancies at a single institution from January 2016 to October 2017. Patients were divided into 3 groups: one receiving a half dose of low-molecular-weight heparin sodium injection (FLUXUM, Alfa Wassermann, Italy) delivered by injection, one receiving a full dose of FLUXUM, and a third group receiving an Argatroban injection. RESULTS: None of the patients in our study developed a pulmonary embolism, bleeding, or infectious complications. There were no statistical differences in the rate of deep venous thrombosis (DVT) (0%, 0%, and 2.38%) and the superficial venous thromboembolism (SVT) (15.66%, 8.97%, and 18.6%) among the 3 groups. None of the patients developed symptomatic VT. The effect of treatment on alanine aminotransferase and aspartate aminotransferase differed between the groups, with a minimal effect in the Argatroban group, and all 3 methods resulted in minimal impairment of renal function. Decreased hemoglobin, elevated levels of D-dimer, and prothrombin time were closely related to thrombogenesis. CONCLUSION: In conclusion, the incidence of postoperative thrombosis in gynecological malignancy among these Chinese people is not as low as we had originally presumed. Argatroban is not more effective than Parnaparin as a direct thrombin inhibitor, but it has less influence on liver function, which is beneficial for patients undergoing chemotherapy. Hemoglobin, D-dimer, and prothrombin time may be used to predict or detect thrombogenesis.

[Argatroban in heparin-induced thrombocytopenia: A survey of prescribing practices and use in France]. / Argatroban et thrombopénie induite par l'héparine : observatoire des modalités de prescription et d'utilisation en France.

OBJECTIVE: A survey of prescribing practices was carried out in France to ensure that argatroban was used appropriately during the first 18months after it obtained marketing authorization for anticoagulation in adults with heparin-induced thrombocytopenia (HIT). METHODS: This observational study was proposed to public and private hospitals with at least 2 orders of argatroban. All patients who received at least one argatroban injection during the study period had to be included. Their demographic characteristics, the pathology causing heparin treatment, the indication of treatment with argatroban, as well as available real-life clinical and biological monitoring data were retrospectively collected. RESULTS: In the 23 participating centers, the drug was prescribed mainly by the following hospital units: surgery and intensive care (79.3%) (of which 18.3% cardiovascular), nephrology/hemodialysis (14.8%) and internal medicine (5.9%). Among the 169 patients included, with median age of 68 years, 118 (69.8%) had renal impairment (creatinine clearance <90mL/min). The HIT probability scoring and diagnostic tests used differed widely between the centers. The reasons for prescribing the drug were mainly suspected HIT (51.5%), declared confirmed HIT (21.3%) or a history of HIT (14.8%). Seventy-three (73) patients (43.2%) had thrombotic symptoms or a systemic reaction initially. The median initial dose prescribed was 0.5µg/kg/min (ranging from 0.05 to 4.42) and doses >2µg/kg/min were used during hemodialysis. More than half of the patients (58.6%) had no clinical complications. Most of the serious adverse reactions were hemorrhagic (11/12). CONCLUSION: This study illustrates the complexity of treatment for HIT and the need to be familiar with and follow guidelines on the management of HIT, especially for susceptible patients treated in intensive care units.

Discovery of Intake Biomarkers of Lentils, Chickpeas, and White Beans by Untargeted LC-MS Metabolomics in Serum and Urine.

SCOPE: To identify reliable biomarkers of food intake (BFIs) of pulses. METHODS AND RESULTS: A randomized crossover postprandial intervention study is conducted on 11 volunteers who consumed lentils, chickpeas, and white beans. Urine and serum samples are collected at distinct postprandial time points up to 48 h, and analyzed by LC-HR-MS untargeted metabolomics. Hypaphorine, trigonelline, several small peptides, and polyphenol-derived metabolites prove to be the most discriminating urinary metabolites. Two arginine-related compounds, dopamine sulfate and epicatechin metabolites, with their microbial derivatives, are identified only after intake of lentils, whereas protocatechuic acid is identified only after consumption of chickpeas. Urinary hydroxyjasmonic and hydroxydihydrojasmonic acids, as well as serum pipecolic acid and methylcysteine, are found after white bean consumption. Most of the metabolites identified in the postprandial study are replicated as discriminants in 24 h urine samples, demonstrating that in this case the use of a single, noninvasive sample is suitable for revealing the consumption of pulses. CONCLUSIONS: The results of the present untargeted metabolomics work reveals a broad list of metabolites that are candidates for use as biomarkers of pulse intake. Further studies are needed to validate these BFIs and to find the best combinations of them to boost their specificity.

Myocardial Infarction with Limb Arterial and Venous Thrombosis in a Patient with Enoxaparin-Induced Thrombocytopenia.

BACKGROUND Heparin, often used as an anticoagulant, acts by binding to antithrombin III. Indeed, heparin binds to a variety of proteins other than antithrombin III. Among them, platelet factor 4 can bind and neutralize the anticoagulant activity of heparin. Upon binding with heparin, platelet factor 4 undergoes a conformational change and expresses immunogenic neo-epitopes that induce the generation of antibodies of the platelet factor 4 heparin complex. This immune reaction may lead to thrombocytopenia and venous, arterial, or microvascular thrombosis. However, the risk of such complications is quite variable, as it is affected not only by the source and dose of heparin and the clinical condition (e.g., cardiovascular surgery and orthopedic surgery) of the patient, but also the molecular size of the heparin formulation. Venous, arterial, and small-vessel thrombosis can lead to leg swelling, pulmonary embolism, stroke, skin necrosis, or gangrene requiring limb amputation or intestinal resection. Myocardial infarction due to coronary thrombosis also occurs, although it is less common and can be readily recognized. CASE REPORT Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening complication of heparin therapy. We report the case of a 67-year-old woman who developed ST-segment elevation myocardial infarction and thrombocytopenia within 10 days of prophylactic enoxaparin therapy after undergoing bilateral total knee replacement surgery. She also had peripheral arterial and venous thrombosis. With thrombolysis and argatroban anticoagulation therapy, she recovered without residual sequelae. CONCLUSIONS Thrombocytopenia with coronary and other vascular thrombosis is a potentially serious complication of heparin therapy. A trend of decreased platelet count, decreased platelet count by 30% or more, and/or occurrence of any type of thrombosis should raise the suspicion of HIT. This case demonstrates that early recognition and prompt treatment of HIT can be life-saving.

Lung transplantation using argatroban in severe heparin-induced thrombocytopenia during extracorporeal membrane oxygenation: a case series.

Lung transplantation during heparin-induced thrombocytopenia (HIT) is controversial and often considered a contraindication because of the risk of increased bleeding and thrombosis in the recipient. Although lung transplantation offers the best chance for cure in end-stage lung disease, the outcome after transplantation is still controversial in patients with HIT. In our center, two patients developed HIT type II during venovenous extracorporeal membrane oxygenation (ECMO) support for acute respiratory failure. They underwent successful lung transplantation using argatroban. The subsequent clinical course was uneventful except evacuation of post-operative hematoma in 1 patient, and they were discharged. Argatroban was successfully used during lung transplant surgery in patients who developed HIT type II during ECMO support. Further studies on the feasibility and safety of lung transplantation using a direct thrombin inhibitor in patients with HIT during ECMO are required.

Sting nematodes modify metabolomic profiles of host plants.

Plant-parasitic nematodes are devastating pathogens of many important agricultural crops. They have been successful in large part due to their ability to modify host plant metabolomes to their benefit. Both root-knot and cyst nematodes are endoparasites that have co-evolved to modify host plants to create sophisticated feeding cells and suppress plant defenses. In contrast, the ability of migratory ectoparasitic nematodes to modify host plants is unknown. Based on global metabolomic profiling of sting nematodes in African bermudagrass, ectoparasites can modify the global metabolome of host plants. Specifically, sting nematodes suppress amino acids in susceptible cultivars. Upregulation of compounds linked to plant defense have negative impacts on sting nematode population densities. Pipecolic acid, linked to systemic acquired resistance induction, seems to play a large role in protecting tolerant cultivars from sting nematode feeding and could be targeted in breeding programs.

Bleeding complications after cardiac surgery, before anticoagulation start and then with argatroban or heparin in the early postoperative setting.

OBJECTIVES: After elective cardiac surgery a postoperative anticoagulation is obligatory. With critically ill patients the conventional anticoagulation standard heparin is sometimes impossible, e.g. based on HIT II. Then, argatroban is currently a possible alternative, however, due to its impaired metabolism in critically ill patients, anticoagulation effect is harder to anticipate, thus resulting in higher bleeding risk. Furthermore, to date no antidote is available. Hence, severe postoperative bleeding incidents under anticoagulation are commonly mono-causal attributed to the anticoagulation itself. This study concentrates on the number of well-defined postoperative bleeding incidents before any anticoagulation started, then actually under argatroban as well as compared to those under heparin (or switched from heparin to argatroban). MATERIAL AND METHODS: Retrospective study including 215 patients undergoing elective cardiac surgery with a postoperative stay in ICU ≥48 h. Postoperative bleeding complications before and after start of anticoagulation were evaluated. Definition of bleeding complications were: decrease of hemoglobin by more than 2 g/dl without dilution (mean value of volume balance plus one standard deviation) and/or increased need of red blood cell transfusion/day (average transfusion rate + 2 standard deviations). RESULTS: Within the study group of 215 patients, 143 were treated with heparin, 43 with argatroban, 29 switched from heparin to argatroban. Overall, 26.5% (57/215) postoperative bleeding complications occurred. In 54.4% (31/57) bleeding complications occurred before start of anticoagulation; in 43.6% (26/57) after. Of these, 14 bleeding incidents occurred under heparin 9.8% (14/143), 6 under argatroban 14% (6/43) and 6 switched 20.7% (6/29). Higher bleeding complications before start of anticoagulation was related to concomitant factors influencing the overall bleeding risk; e.g. score of severity of illness. These observations further correlate with postoperative, but not anticoagulation induced mortality rate of 2.8% of then given heparin, 20.9% then argatroban, 20.7% then switched. CONCLUSIONS: Postoperative bleeding complications cannot simply be attributed to anticoagulation since occurring often before anticoagulation was started. The risk for bleeding complications after start of anticoagulation was quite comparable for argatroban and heparin. Accordingly, the influence of argatroban on bleeding complications in the postoperative period may be less significant than previously thought.

Clinical study of argatroban for preventing vascular thrombosis in the early period after pediatric living-related donor liver transplantation.

OBJECTIVE: To evaluate the effect of heparin and argatroban on coagulation function and vascular thrombosis in the early period after pediatric LRDLT. METHOD: Eighty-four congenital biliary atresia pediatric patients who had undergone LRDLT were studied. Patients were divided into two groups according to the method of anticoagulation (heparin or argatroban). AT-Ⅲ activity, APTT, and INR of the two groups were measured in the first 5 days after LRDLT. Vascular thrombosis was investigated by Doppler ultrasound daily. RESULTS: There were no significant differences in gender, age, weight, graft-recipient weight ratio, and Kasai procedure between the two groups. The AT-Ⅲ activity of the two groups was low and increased gradually after surgery, with no significant difference between the two groups. There was no significant difference of APTT between the two groups immediately after and in the first day after surgery. After anticoagulation treatment, a significant difference in APTT between the two groups was observed. The incidences of vascular thrombosis were 4.76% (3/63) and 0% (0/21) in the heparin and argatroban groups, respectively, with no significant difference between the two groups. During the treatment, no serious complications such as active hemorrhage or drug allergy were observed in the two groups. CONCLUSION: Argatroban is a direct anticoagulant, which is independent of AT-Ⅲ activity. Argatroban might be an alternative to heparin in uncomplicated LRDLT with recovered hepatic and coagulation function.

Preoperative and intraoperative argatroban as anticoagulant for bridging a patient with heparin-induced thrombocytopaenia to lung transplantation.

A 65-year-old male was bridged to lung transplantation with veno-venous extracorporeal membrane oxygenation (ECMO). After experiencing heparin-induced thrombocytopaenia, heparin was replaced with argatroban. After 24 days, bilateral sequential lung transplantation was performed with argatroban anticoagulation. Intraoperative argatroban doses ranged between 0.4 and 0.6 µg/kg/min, resulting in activated clotting time of 169-216 s and activated partial thromboplastin time of 45-75 s. The patient was weaned from ECMO immediately after lung transplantation, and no bleeding or thrombotic complications were observed. He was discharged home on postoperative day 140.

Quantitative assessment of betainized compounds and associations with dietary and metabolic biomarkers in the randomized study of the healthy Nordic diet (SYSDIET).

BACKGROUND: Recently, a group of betainized compounds have been suggested to play a role in health effects in relation to a whole-grain-rich diet. OBJECTIVES: The aims of this study were to develop a quantitative mass spectrometric method for selected betainized compounds in human plasma, and to investigate their association with nutrient intake and measures of metabolic health in participants of the SYSDIET study. METHODS: The SYSDIET study was a controlled randomized intervention including individuals with metabolic syndrome, where the healthy Nordic diet (HND) group increased intakes of whole grains, canola oil, berries, and fish, whereas the control diet (CD) group consumed low-fiber cereal products, milk fat, and restricted amounts of fish and berries. A quantitative LC combined with triple quadrupole MS method for betainized compounds was developed and applied to fasting plasma samples from baseline (week 0) and the end of the intervention (week 18 or 24). Concentrations of betainized compounds were correlated with intakes of selected nutrients and fiber and measures of metabolic health. RESULTS: Pipecolic acid betaine (PAB) concentrations were significantly higher in the HND group than in the CD group (P = 0.00032) at the end of the intervention and correlated directly (P < 0.0001) with intakes of dietary fiber (r = 0.376) and a biomarker related to whole-grain rye intake, namely the ratio of alkylresorcinol C17:0 to C21:0 (r = 0.442). PAB was associated inversely with fasting plasma insulin consistently at the beginning and at the end of the intervention (P < 0.001, r = -0.300; P < 0.01, r = -0.250, respectively), as well as IL-1 receptor antagonist (P < 0.01, r = -0.232 at the beginning; P < 0.01, r = -0.236 at the end) and serum LDL/HDL cholesterol (P < 0.01, r = -0.239 at the beginning; P < 0.01, r = -0.241 at the end). CONCLUSIONS: Among adults with the metabolic syndrome, PAB plasma concentrations were associated with fasting insulin, inflammation, and lipids and were significantly increased with adoption of the HND. Further studies are needed to clarify the biological functions of betainized compounds. This trial was registered at clinicaltrials.gov as NCT00992641.

Simultaneous quantification of alpha-aminoadipic semialdehyde, piperideine-6-carboxylate, pipecolic acid and alpha-aminoadipic acid in pyridoxine-dependent epilepsy.

The measurements of lysine metabolites provide valuable information for the rapid diagnosis of pyridoxine-dependent epilepsy (PDE). Here, we aimed to develop a sensitive method to simultaneously quantify multiple lysine metabolites in PDE, including α-aminoadipic semialdehyde (a-AASA), piperideine-6-carboxylate (P6C), pipecolic acid (PA) and α-aminoadipic acid (α-AAA) in plasma, serum, dried blood spots (DBS), urine and dried urine spots (DUS). Fifteen patients with molecularly confirmed PDE were detected using liquid chromatography-mass spectrometry (LC-MS/MS) method. Compared to the control groups, the concentrations of a-AASA, P6C and the sum of a-AASA and P6C (AASA-P6C) in all types of samples from PDE patients were markedly elevated. The PA and a-AAA concentrations ranges overlapped partially between PDE patients and control groups. The concentrations of all the analytes in plasma and serum, as well as in urine and DUS were highly correlated. Our study provided more options for the diverse sample collection in the biochemical tests according to practical requirements. With treatment modality of newly triple therapy investigated, biomarker study might play important role not only on diagnosis but also on treatment monitoring and fine tuning the diet. The persistently elevated analytes with good correlation between plasma and DBS, as well as urine and DUS made neonatal screening using DBS and DUS possible.