The Impact of Gut Microbiota Changes on Methotrexate-Induced Neurotoxicity in Developing Young Rats.

Methotrexate (MTX) is an essential part of therapy in the treatment of acute lymphoblastic leukemia (ALL) in children, and inferior intellectual outcomes have been reported in children who are leukemia survivors. Although several studies have demonstrated that the interaction between gut microbiota changes and the brain plays a vital role in the pathogenesis of chemotherapy-induced brain injury, preexisting studies on the effect of MTX on gut microbiota changes focused on gastrointestinal toxicity only. Based on our previous studies, which revealed that MTX treatment resulted in inferior neurocognitive function in developing young rats, we built a young rat model mimicking MTX treatment in a child ALL protocol, trying to investigate the interactions between the gut and brain in response to MTX treatment. We found an association between gut microbiota changes and neurogenesis/repair processes in response to MTX treatment, which suggest that MTX treatment results in gut dysbiosis, which is considered to be related to MTX neurotoxicity through an alteration in gut-brain axis communication.

Increased Circulating ADMA in Young Male Rats Caused Cognitive Deficits and Increased Intestinal and Hippocampal NLRP3 Inflammasome Expression and Microbiota Composition Alterations: Effects of Resveratrol.

Endothelial dysfunction is characterized by disturbances in nitric oxide (NO) bioavailability and increased circulating asymmetric dimethylarginine (ADMA) due to the enormous release of free radicals. Increased circulating ADMA may cause endothelial dysfunction and a variety of clinical disorders, such as liver and kidney disease. Young male Sprague-Dawley rats at postnatal day 17 ± 1 received continuous ADMA infusion via an intraperitoneal pump to induce endothelial dysfunction. Four groups of rats (n = 10 per group) were allocated: control, control and resveratrol, ADMA infusion, and ADMA infusion and resveratrol groups. Spatial memory, NLR family pyrin-domain-containing 3 (NLRP3) inflammasome, cytokine expression, tight junction proteins in the ileum and dorsal hippocampus, and microbiota composition were examined. We found cognitive deficits; increased NLRP3 inflammasome in the plasma, ileum, and dorsal hippocampus; decreased ileum and dorsal hippocampal cytokine activation and tight junction proteins; and microbiota composition alterations in the ADMA-infusion young male rats. Resveratrol had beneficial effects in this context. In conclusion, we observed NLRP3 inflammasome activation in peripheral and central dysbiosis in young male rats with increased circulating ADMA, and found that resveratrol had beneficial effects. Our work adds to the mounting evidence that inhibiting systemic inflammation is a promising therapeutic avenue for cognition impairment, probably via the gut-brain axis.

Lymphocyte disturbance and functional assessment of the [Asp521Asn] ZAP70 mutation.

Activated zeta-chain-associated protein kinase 70 (ZAP70) phosphorylates the TCRαß:CD3:zeta complex to diversify and amplify TCR signaling. Patients with ZAP70 mutations can present with phenotypes of immune dysregulation as well as infection. We identified the first Taiwanese boy with the [Asp521Asn] ZAP70 mutation who presented with recurrent pneumonia, inflammatory bowel disease-like diarrhea, transient hematuria and autoimmune hepatitis. He had isolated CD8 lymphopenia, eosinophilia, hypogammaglobulinemia, and impaired lymphocyte proliferation. Downstream CD3/CD28 signaling, phosphorylation of AKT, ZAP70 and Ca2+ influx were decreased in [Asp521Asn] ZAP70 lymphocytes. Immunophenotyping analysis revealed expansion of transitional B and CD21-low B cells, Th2-skewing T follicular helper cells, but lower Treg cells. The Asp521Asn-ZAP70 hindered TCR-CD3 downstream phosphorylation and disturbed lymphocyte subgroup "profiles" leading to autoimmunity/autoinflammation. Further large-scale studies are warranted to clarify this lymphocyte disturbance. The prognosis significantly depends on hematopoietic stem cell transplantation, but not the genotype, the presence of opportunistic infections or immune dysregulation.

Prognostic factors for functional recovery in children with moderate to severe acute disseminated encephalomyelitis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an immune-mediated encephalopathy with heterogeneous disease courses. However, clinical characteristics for a prognostication of functional recovery from acute episodes of ADEM remain limited. The study aims to characterize the clinical presentations and neuroimaging findings of children with poor functional recoveries from acute episodes of moderate to severe ADEM. METHODS: The multicenter retrospective cohort study included children under 18 years of age who presented with moderate to severe ADEM (modified Rankin Scale [mRS] ≥ 3 at nadir) from 2002 to 2019. Children were assigned to a good recovery group (mRS ≤ 2) and a poor recovery group (mRS ≥ 3) after mean 4.3 months of follow-up. The clinical presentations and the distribution of brain lesions on magnetic resonance imaging were compared between the two groups by the t-test for numerical variables and Fisher's exact test for categorical variables. Analyses of logistic regression were conducted and significant variables in the multivariate model were examined by the receiver operating characteristic curve for the prediction of functional recovery. RESULTS: Among the 73 children with moderate to severe ADEM, 56 (77%) had good functional recoveries and 17 (23%) showed poor functional recoveries. Children with poor recoveries had a lower rate of prodromal headache (12% vs. 39%, p = 0.04), and presented with higher proportions of dystonia (29% vs. 9%, p = 0.046), myoclonus (24% vs. 2%, p = 0.009), and cerebellar lesions on neuroimages (59% vs. 23%, p = 0.01). The multivariate analyses identified that a lack of prodromal headache (OR 0.1, 95% CI 0.005 - 0.7, p = 0.06) and the presentations of myoclonus (OR 21.6, 95% CI 1.7 - 874, p = 0.04) and cerebellar lesions (OR 4.8, 95% CI 1.3 - 19.9, p = 0.02) were associated with poor functional recoveries. These three factors could prognosticate poor outcomes in children with moderate to severe ADEM (area under the receiver operating characteristic curve 0.80, 95% CI 0.68 - 0.93, p = 0.0002). CONCLUSION: Nearly one-fourth of children with moderate to severe ADEM had a poor functional recovery from acute episodes, who were characterized by a lack of prodromal headache, the presentation of myoclonus, and the neuroimaging finding of cerebellar lesions. The clinical variables associated with poor functional recoveries could assist in the planning of immunotherapies during hospitalization for a better outcome in moderate to severe ADEM.

Comparison of the predictive ability of lactate and central venous blood gas in pediatric venoarterial mode extracorporeal membrane oxygenation outcome.

BACKGROUND: This study aims to compare lactate and central venous blood gas in the prediction of outcome in pediatric venoarterial mode extracorporeal membrane oxygenation (V-A ECMO). METHOD: This was a retrospective observational study conducted on patients undergoing V-A ECMO care in the pediatric intensive care unit of a tertiary medical center in Taiwan. Patients under 18 years of age undergoing V-A ECMO from January 2009 to April 2019 were included in this study. RESULTS: This study consisted of 47 children who received V-A ECMO with an overall weaning rate of 66.0%. The mean age was 5.5 years and mean ECMO duration was 11.6 days. Successful weaning group had significantly lower lactate levels at initial (58.7 ± 47.0 mg/dL vs. 108.0 ± 55.3 mg/dL, p = 0.003), 0-12 h (37.8 ± 29.0 mg/dL vs. 83.5 ± 60.0 mg/dL, p Z 0.001), and 12-24 h (29.4 ± 26.9 mg/dL vs. 69.1 ± 59.1 mg/dL, p = 0.003) after ECMO initiation; however, the central venous blood gas including pH, HCO3, CO2, base excess (BE), and O2 saturation showed no significant difference. The favorable outcome group had significantly lower lactate levels at 0-12 h (32.8 ± 26.3 mg/dL vs. 71.3 ± 53.3 mg/dL, p = 0.005), and 12-24 h (20.7 ± 10.2 mg/dL vs. 61.9 ± 53.5 mg/dL, p = 0.002); however, the HCO3 levels (26.2 ± 4.5 mmol/L vs. 22.9 ± 6.8 mmol/L, p = 0.042) and BE (2.2 ± 5.4 vs. 2.2 ± 8.5, p = 0.047) were significantly higher at 12-24 h. In multivariate logistic regression, 12-24 h lactate value was an independent factor for unfavorable outcomes (p = 0.015, odds ratio [OR] = 1.1) with the best cut-off value of 48.6 mg/dL (sensitivity 48%, specificity 100%). CONCLUSION: Lactate has better outcome prediction than central venous blood gas in pediatric V-A ECMO. The lactate value 12-24 h after ECMO initiation was an independent factor for unfavorable outcomes.

Methotrexate Neurotoxicity Is Related to Epigenetic Modification of the Myelination Process.

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.

Resveratrol prevented spatial deficits and rescued disarrayed hippocampus asymmetric dimethylarginine and brain-derived neurotrophic factor levels in young rats with increased circulating asymmetric dimethylarginine.

Increased plasma levels of asymmetric dimethylarginine can be encountered in chronic inflammatory disease, liver damage, renal failure, and multiple organ failure. In addition, an association between circulating asymmetric dimethylarginine levels and all-cause mortality has been reported. Male Sprague-Dawley rats, postnatal day 17 ± 1, received continuous asymmetric dimethylarginine infusion via an intraperitoneal pump. Spatial performance and dorsal hippocampal asymmetric dimethylarginine and brain-derived neurotrophic factor (BDNF) levels were examined, and the effect of resveratrol was tested. A 4-week continuous asymmetric dimethylarginine infusion in young male rats caused spatial deficits, increased asymmetric dimethylarginine levels, and decreased BDNF expression in the dorsal hippocampus. Increased oxidative stress and altered molecules in the dorsal hippocampus linked to asymmetric dimethylarginine and BDNF functions were detected. Resveratrol protected against these effects, reversing spatial deficits, and reducing the changes in the dorsal hippocampal asymmetric dimethylarginine and BDNF levels.

The Utility of a Point-of-Care Transcranial Doppler Ultrasound Management Algorithm on Outcomes in Pediatric Asphyxial Out-of-Hospital Cardiac Arrest - An Exploratory Investigation.

BACKGROUND: Transcranial Doppler ultrasound is a sensitive, real time tool used for monitoring cerebral blood flow; it could provide additional information for cerebral perfusion in cerebral resuscitation during post cardiac arrest care. The aim of the current study was to evaluate the utility of a point-of-care transcranial Doppler ultrasound management algorithm on outcomes in pediatric asphyxial out-of-hospital cardiac arrest. METHODS: This retrospective cohort study was conducted in two tertiary pediatric intensive care units between January 2013 and June 2018. All children between 1 month and 18 years of age with asphyxial out-of-hospital cardiac arrest and a history of at least 3 min of chest compressions, who were treated with therapeutic hypothermia and survived for 12 h or more after the return of circulation were eligible for inclusion. RESULTS: Twenty-one patients met the eligibility criteria for the study. Sixteen (76.2%) of the 21 children were male, and the mean age was 2.8 ± 4.1 years. Seven (33.3%) of the children had underlying disorders. The overall 1-month survival rate was 52.4%. Twelve (57.1%) of the children received point-of-care transcranial Doppler ultrasound. The 1-month survival rate was significantly higher (p = 0.03) in the point-of-care transcranial Doppler ultrasound group (9/12, 75%) than in the non-point-of-care transcranial Doppler ultrasound group (2/9, 22.2%). CONCLUSIONS: Point-of-care transcranial Doppler ultrasound group was associated with a significantly better 1-month survival rate compared with no point-of-care transcranial Doppler ultrasound group in pediatric asphyxial out-of-hospital cardiac arrest.

Outcome analysis of pediatric hemophagocytic lymphohistiocytosis.

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease associated with rapid clinical deterioration and the need for intensive care; therefore, it is essential to identify clinical parameters related to mortality and establish prognostic factors correlated with unfavorable outcome in high risk patients whose treatment may fail. METHODS: Between January 2004 and December 2018, a total of 51 pediatric patients (less than 18 years old) who fulfilled the diagnostic criteria of HLH-2004 with documented results of bone marrow investigations at Kaohsiung Chang Gung Memorial Hospital were enrolled. The treatment protocol was based on hemophagocytic lymphohistiocytosis-94 (HLH-94) and HLH-2004. We retrospectively reviewed electronic medical records (EMR) including clinical features, length of intensive care unit (ICU) stay, serological tests, microscopic reports of bone marrow examination, and ultrasound examination reports at diagnosis to identify prognostic factors. The patients were divided into four groups based on etiology; these included infection associated hemophagocytic syndrome (IAHS), macrophage activation syndrome (MAS), malignancy associated hemophagocytic lymphohistiocytosis (MA-HLH), and idiopathic hemophagocytic lymphohistiocytosis (IHLH) to identify differences among the groups. RESULTS: Out of 51 patients enrolled, 27 patients had IAHS, 12 MAS, 8 MA-HLH, and 4 IHLH. The median age at diagnosis was 7 years. The overall mortality rate was 15.7% (there was no mortality in the MA-HLH group); the mean length of ICU stay was 6 ± 20.8 days. Longer activated partial thromboplastin time (aPTT) (p = 0.007), lower sodium concentration (p = 0.0007), and higher creatinine (p = 0.032) and aspartate aminotransferase (AST) (p = 0.017) were significantly related to mortality. Multivariate Cox regression analysis demonstrated that aPTT (p = 0.045, HR = 1.03, 95% CI = 1.0-1.1) was an independent risk factor for mortality. The receiver operating characteristic (ROC) curve showed that aPTT longer than 44.35 s was the cutoff value predicting mortality, with a sensitivity and specificity of 72% and 66.7%, respectively. CONCLUSION: MA-HLH had the lowest mortality rate, as most children died from the underlying malignant disease and not from HLH. Impaired liver and renal functions were related to mortality. Prolonged aPTT > 44.35 s is a strong predictive factor for mortality.

An Examination of Serum Acylcarnitine and Amino Acid Profiles at Different Time Point of Ketogenic Diet Therapy and Their Association of Ketogenic Diet Effectiveness.

BACKGROUND: This study aimed to identify metabolic parameters at different time points of ketogenic diet therapy (KDT) and investigate their association with response to KDT in pediatric drug-resistant epilepsy (DRE). METHODS: Prospectively, twenty-nine patients (0.67~20 years old) with DRE received classic ketogenic diet with non-fasting, gradual KD initiation protocol (GRAD-KD) for 1 year were enrolled. A total of 22 patients remaining in study received blood examinations at baseline, 3rd, 6th, 9th, and 12th months of KDT. ß-hydroxybutyrate, free carnitine, acylcarnitines, and amino acids were compared between responders (seizure reduction rate ≥ 50%) and non-responders (seizure reduction rate < 50%) to identify the effectiveness of KDT. RESULTS: The 12-month retention rate was 76%. The responders after 12 months of KDT were 59% (13/22). The free carnitine level decreased significantly at 9th months (p < 0.001) but increased toward baseline without symptoms. Propionyl carnitine (C3), Isovaleryl carnitine (C5), 3-Hydroxyisovalerylcarnitine (C5:OH) and methylmalonyl carnitine (C4-DC) decreased but 3-hydroxybutyrylcarnitine (C4:OH) increased significantly at 12th months of KDT. The glycine level was persistently higher than baseline after KDT. KDT responders had lower baseline C3 and long-chain acylcarnitines, C14 and C18, as well as lower C5, C18, and leucine/isoleucine. CONCLUSIONS: KDT should be avoided in patients with non-ketotic hyperglycemia. Routine carnitine supplementation is not recommended because hypocarnitinemia was transient and asymptomatic during KDT. Better mitochondrial ßoxidation function associates with greater KDT response.

Maternal Iron Deficiency Programs Offspring Cognition and Its Relationship with Gastrointestinal Microbiota and Metabolites.

Iron is an essential micronutrient for the brain development of the fetus. Altered intestinal microbiota might affect behavior and cognition through the so-called microbiota-gut-brain axis. We used a Sprague-Dawley rat model of a maternal low-iron diet to explore the changes in cognition, dorsal hippocampal brain-derived neurotrophic factor (BDNF) and related pathways, gut microbiota, and related metabolites in adult male offspring. We established maternal iron-deficient rats by feeding them a low-iron diet (2.9 mg/kg), while the control rats were fed a standard diet (52.3 mg/kg). We used a Morris water maze test to assess spatial learning and long-term memory. Western blot (WB) assays and a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to detect the BDNF concentration and related signaling pathways. We collected fecal samples for microbiota profiling and measured the concentrations of plasma short-chain fatty acids. The adult male offspring of maternal rats fed low-iron diets before pregnancy, during pregnancy and throughout the lactation period had (1) spatial deficits, (2) a decreased BDNF mRNA expression and protein concentrations, accompanied by a decreased TrkB protein abundance, (3) a decreased plasma acetate concentration, and (4) an enrichment of the Bacteroidaceae genus Bacteroides and Lachnospiraceae genus Marvinbryantia. Maternal iron deficiency leads to an offspring spatial deficit and is associated with alternations in gastrointestinal microbiota and metabolites.

Epileptiform Discharge and Electrographic Seizures during the Hypothermia Phase as Predictors of Rewarming Seizures in Children after Resuscitation.

The aim of this study was to determine the frequency, timing, and predictors of rewarming seizures in a cohort of children undergoing therapeutic hypothermia after resuscitation. We retrospectively reviewed consecutive pediatric patients undergoing therapeutic hypothermia after resuscitation admitted to our pediatric intensive care unit between January 2000 and December 2019. Continuous electroencephalographic monitoring was performed during hypothermia (24 h for cardiac aetiologies and 72 h for asphyxial aetiologies), rewarming (72 h), and then an additional 12 h of normothermia. Thirty comatose children undergoing therapeutic hypothermia after resuscitation were enrolled, of whom 10 (33.3%) had rewarming seizures. Two (20%) of these patients had their first seizure during the rewarming phase. Four (40%) patients had electroclinical seizures, and six (60%) had nonconvulsive seizures. The median time from starting rewarming to the onset of rewarming seizures was 37.3 h (range 6 to 65 h). The patients with interictal epileptiform activity and electrographic seizures during the hypothermia phase were more likely to have rewarming seizures compared to those without interictal epileptiform activity or electrographic seizures (p = 0.019 and 0.019, respectively). Therefore, in high-risk patients, continuous electroencephalographic monitoring for a longer duration may help to detect rewarming seizures and guide clinical management.

Effects of Maternal Resveratrol on Maternal High-Fat Diet/Obesity with or without Postnatal High-Fat Diet.

To examine the effects of maternal resveratrol in rats borne to dams with gestational high-fat diet (HFD)/obesity with or without postnatal high-fat diet. We first tested the effects of maternal resveratrol intake on placenta and male fetus brain in rats borne to dams with gestational HFD/obesity. Then, we assessed the possible priming effect of a subsequent insult, male offspring were weaned onto either a rat chow or a HFD. Spatial learning and memory were assessed by Morris water maze test. Blood pressure and peripheral insulin resistance were examined. Maternal HFD/obesity decreased adiponectin, phosphorylation alpha serine/threonine-protein kinase (pAKT), sirtuin 1 (SIRT1), and brain-derived neurotrophic factor (BDNF) in rat placenta, male fetal brain, and adult male offspring dorsal hippocampus. Maternal resveratrol treatment restored adiponectin, pAKT, and BDNF in fetal brain. It also reduced body weight, peripheral insulin resistance, increased blood pressure, and alleviated cognitive impairment in adult male offspring with combined maternal HFD and postnatal HFD. Maternal resveratrol treatment restored hippocampal pAKT and BDNF in rats with combined maternal HFD and postnatal HFD in adult male offspring dorsal hippocampus. Maternal resveratrol intake protects the fetal brain in the context of maternal HFD/obesity. It effectively reduced the synergistic effects of maternal HFD/obesity and postnatal HFD on metabolic disturbances and cognitive impairment in adult male offspring. Our data suggest that maternal resveratrol intake may serve as an effective therapeutic strategy in the context of maternal HFD/obesity.

Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-status epilepticus epilepsy.

BACKGROUND: To compare the clinical characteristics and outcomes of pediatric patients with refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) who received therapeutic hypothermia (TH) plus anticonvulsants or anticonvulsants alone. METHODS: Two-medical referral centers, retrospective cohort study. Pediatric Intensive Care Unit (PICU) at Taoyuan Chang Gung Children's hospital and Kaohsiung Chang Gung Memorial Hospital. We reviewed the medical records of 23 patients with RSE/SRSE who were admitted to PICU from January 2014 to December 2017. Of these, 11 patients received TH (TH group) and 12 patients did not (control group). RESULTS: The selective endpoints were RSE/SRSE duration, length of PICU stay, and Glasgow Outcome Scale (GOS) score. We applied TH using the Artic Sun® temperature management system (target temperature, 34-35 °C; duration, 48-72 h). Of the 11 patients who received TH, 7 had febrile infection-related epilepsy syndrome (FIRSE), one had Dravet syndrome, and three had traumatic brain injury. The TH group had significantly shortern seizure durations than did the control group (hrs; median (IQR) 24(40) vs. 96(90), p < 0.05). Two patients in the TH group died of pulmonary embolism and extreme brain edema. The length of PICU stay was similar between the groups (days; median (IQR) 30(42) v.s 30.5(30.25)). The TH group had significantly better long-term outcomes than did the control group (GOS score, median (IQR) 4(2) v.s 3 (0.75), p = 0.01∗). The TH group had a significantly lower incidence of later chronic refractory epilepsy than did the control group (TH v.s non-TH, 5/11 (45%) v.s. 12/12(100%), p < 0.01). CONCLUSIONS: TH effectively reduced the seizure burden in patients with RSE/SRSE. Our findings support that for patients with RSE/SRSE, TH shortens the seizure duration, ultimately reducing the occurrence of post-status epilepticus epilepsy and improving patients' long-term survival.

Maternal Obesity Programs Offspring Development and Resveratrol Potentially Reprograms the Effects of Maternal Obesity.

Maternal obesity during pregnancy is a now a public health burden that may be the culprit underlying the ever-increasing rates of adult obesity worldwide. Understanding the association between maternal obesity and adult offspring's obesity would inform policy and practice regarding offspring health through available resources and interventions. This review first summarizes the programming effects of maternal obesity and discusses the possible underlying mechanisms. We then summarize the current evidence suggesting that maternal consumption of resveratrol is helpful in maternal obesity and alleviates its consequences. In conclusion, maternal obesity can program offspring development in an adverse way. Maternal resveratrol could be considered as a potential regimen in reprogramming adverse outcomes in the context of maternal obesity.

Rats with prenatal dexamethasone exposure and postnatal high-fat diet exhibited insulin resistance, and spatial learning and memory impairment: effects of enriched environment.

This study aimed to examine the combined effects of prenatal glucocorticoid exposure and a postnatal high-fat diet (HFD) on offspring brain development and metabolic disturbance. Besides, the effects of an enriched environment were assessed. Pregnant Sprague-Dawley rats were administered vehicle or dexamethasone between gestation days 14 and 21. Male offspring was then weaned onto either a standard chow or HFD. An enriched environment was implemented between postnatal days 22 and 180 in a subset of rats with prenatal dexamethasone and a postnatal HFD. Adult male offspring with prenatal exposure to dexamethasone and a postnatal HFD showed obesity, increased systolic blood pressure, peripheral and central insulin resistance, and spatial learning and memory impairment detected by Morris water maze. An enriched environment displayed beneficial effects in reducing body weight, decreasing systolic blood pressure, reducing insulin resistance, ameliorating brain molecular alterations, and alleviating spatial deficit in rats with prenatal dexamethasone and a postnatal HFD. In conclusion, adult male offspring with prenatal dexamethasone exposure and a postnatal HFD showed obesity, increased systolic blood pressure, peripheral and central insulin resistance, and spatial learning and memory impairment. In addition, an enriched environment had beneficial effects in this context.

Melatonin rescued methotrexate-induced spatial deficit and hyperhomocysteinemia and increased asymmetric dimethylarginine in plasma and dorsal hippocampus in developing rats.

AIMS: With the improvement of the survival rates in children acute lymphoblastic leukemia (ALL), some children ALL survivors show impaired cognitive function. Methotrexate (MTX), an essential component in ALL treatment, has been reported to be related to neurologic sequelae and to increased oxidative stress through its interactions with enzymes in the folate pathway. Asymmetric dimethylarginine (ADMA) is the main endogenous inhibitor of nitric oxide synthase, and increased ADMA may result from increased oxidants. Melatonin is an antioxidant; however, its role in MTX neuropathy is not well studied. We developed a rat model mimicking child ALL treatment to explore peripheral and central homocysteine and ADMA regulation after MTX and found potential treatment choice. MAIN METHODS: Preweaning male Sprague-Dawley rats were used in this study. Experiment 1 evaluated spatial performance in rats with intrathecal (IT) MTX, intraperitoneal (IP) MTX, or combined IT and IP MTX, protocols mimicking ALL treatment in children. Experiment 2 focused on rats with combined IT and IP MTX, evaluating spatial performance and plasma and dorsal hippocampal homocysteine and ADMA levels, their regulation, and the protective effect of melatonin. KEY FINDINGS: Combined IT and IP MTX treatment caused in spatial deficits in developing rats, and melatonin restored the spatial performance. Alterations in peripheral and central homocysteine and ADMA concentrations and their regulation were found and could be alleviated by melatonin treatment. SIGNIFICANCES: Combined IP and IT MTX treatment caused spatial deficits in developing rats. Melatonin could restore spatial performance through alleviating the effects on the imbalance of oxidative stress.

Young rats with increased circulatory asymmetric dimethylarginine exhibited spatial deficit and alterations in dorsal hippocampus brain-derived neurotrophic factor and asymmetric dimethylarginine: Effects of melatonin.

Increased plasma concentration of asymmetric dimethylarginine (ADMA) can be encountered in chronic inflammatory disease, liver damage, renal failure, and multiple organ failure. In addition, an association between circulating ADMA and all-cause mortality has been reported. Male Sprague-Dawley rats, postnatal day (PND) 17 ± 1, received continuous ADMA infusion via an intraperitoneal pump. Spatial performance, as well as plasma and dorsal hippocampus ADMA and brain-derived neurotrophic factor (BDNF) concentration, were examined and the effect of melatonin was tested. We found that a 4-week continuous ADMA infusion in young rats caused spatial deficit. Furthermore, increased ADMA concentration and decreased BDNF expression were found in the plasma and dorsal hippocampus. Melatonin protected against these effects, alleviating spatial deficit and reducing the changes in plasma and dorsal hippocampus ADMA and BDNF concentration.

Left Ventricle Decompression Strategies in Pediatric Peripheral Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is widely used in patients with potentially reversible acute cardiac and/or pulmonary failure who are unresponsive to conventional treatment. Patients with profound left ventricular (LV) dysfunction under venous-arterial (V-A) ECMO may experience LV distention, pulmonary edema, and thrombus formation. It is critical to unload the left ventricle to prevent such complications. The aim of this study was to identify the risks, timing and methods of LV decompression in pediatric peripheral ECMO. METHODS: Between August 2006 and November 2017, 51 patients received peripheral ECMO support in our pediatric intensive care unit. All of them were less than 18 years of age and non-cardiotomy surgery-related. We retrospectively reviewed the patients' clinical presentations, decompression methods and outcomes. RESULTS: The overall success rate of ECMO removal was 76.5% (39/51), and the survival rate after discharge was 62.7% (32/51). The myocarditis group had the most favorable outcomes among the ECMO patients (100% survival). LV decompression was needed in 12 patients who had profound LV dysfunction under V-A ECMO. Five patients received medical treatment successfully, and the other 7 patients underwent intra-aortic balloon pump (IABP) procedures. In the IABP group, 1 patient still needed further pigtail-decompression. All of our decompression patients survived with good neurological outcomes (Glasgow Outcome Scale 5). CONCLUSIONS: The patients with profound LV dysfunction under peripheral VA ECMO were at risk of thromboembolic events and LV decompress was needed. If medical decompression fails, IABP is a feasible approach for LV decompression in pediatric peripheral ECMO.