Role of vitamin B12 and folic acid in treatment of Alzheimer's disease: a meta-analysis of randomized control trials.

Vitamin B12 and folic acid could reduce blood homocysteine levels, which was thought to slow down the progression of Alzheimer's disease (AD), but previous studies regarding the effect of vitamin B12 and folic acid in treatment of AD have not reached conclusive results. We searched PubMed and Embase until January 12, 2023. Only randomized control trials involving participants clearly diagnosed with AD and who received vitamin B12 and folic acid were enrolled. Five studies that met the criteria were selected for inclusion in the meta-analysis. Changes in cognitive function were measured based on either the Mini-Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Changes in daily life function and the level of blood homocysteine were also investigated. After a 6-month treatment, administration of vitamin B12 and folic acid improved the MMSE scores more than placebo did (SMD = 0.21, 95% CI = 0.01 to 0.32, p = 0.04) but did not significantly affect ADAS-Cog scores (SMD = 0.06, 95% CI = -0.22 to 0.33, p = 0.68) or measures of daily life function. Blood homocysteine levels were significantly decreased after vitamin B12 and folic acid treatment. Participants with AD who received 6 months of vitamin B12 and folic acid supplementation had better MMSE scores but had no difference in ADAS-Cog scores. Daily life function did not improve after treatment.

Risk Prediction Model for Chronic Kidney Disease in Thailand Using Artificial Intelligence and SHAP.

Chronic kidney disease (CKD) is a multifactorial, complex condition that requires proper management to slow its progression. In Thailand, 11.6 million people (17.5%) have CKD, with 5.7 million (8.6%) in the advanced stages and >100,000 requiring hemodialysis (2020 report). This study aimed to develop a risk prediction model for CKD in Thailand. Data from 17,100 patients were collected to screen for 14 independent variables selected as risk factors, using the IBK, Random Tree, Decision Table, J48, and Random Forest models to train the predictive models. In addition, we address the unbalanced category issue using the synthetic minority oversampling technique (SMOTE). The indicators of performance include classification accuracy, sensitivity, specificity, and precision. This study achieved an accuracy rate of 92.1% with the top-performing Random Forest model. Moreover, our empirical findings substantiate previous research through highlighting the significance of serum albumin, blood urea nitrogen, age, direct bilirubin, and glucose. Furthermore, this study used the SHapley Additive exPlanations approach to analyze the attributes of the top six critical factors and then extended the comparison to include dual-attribute factors. Finally, our proposed machine learning technique can be used to evaluate the effectiveness of these risk factors and assist in the development of future personalized treatment.

An activity-based functional test for identifying homologous recombination deficiencies across cancer types in real time.

Homologous recombination (HR)-mediated DNA repair is a prerequisite for maintaining genome stability. Cancer cells displaying HR deficiency (HRD) are selectively eliminated by poly(ADP-ribose) polymerase inhibitors (PARPis). To date, sequencing of HR-associated genes and analyzing genome instability have been used as clinical predictions for PARPi therapy. However, these genetic tests cannot reflect dynamic changes in the HR status. Here, we have developed a virus- and activity-based functional assay to quantify real-time HR activity directly. Instead of focusing on a few HR-associated genes, our functional assay detects endpoint HR activity and establishes an activity threshold for identifying HRD across cancer types, validated by PARPi sensitivity and BRCA status. Notably, this fluorescence-based assay can be applied to primary ovarian cancer cells from patients to reflect their level of HRD, which is associated with survival benefits. Thus, our work provides a functional test to predict the response of primary cancer cells to PARPis.

Donor lymphocyte infusion for prophylaxis and treatment of relapse in pediatric hematologic malignancies after allogeneic hematopoietic stem cell transplant.

BACKGROUND: Donor lymphocyte infusion (DLI) is effective for managing patients with hematologic malignancies after allogeneic hematopoietic stem cell transplant (HSCT). However, few studies have explored its optimal use in pediatric populations. Herein, we report our single-center experiences of DLI and factors for predicting its outcomes. METHODS: This retrospective study included pediatric patients who had received DLI (between June 1998 and December 2022) after allogeneic HSCT. Data regarding patient characteristics, preemptive DLI disease status, and DLI characteristics were collected. The primary outcomes were overall survival (OS), event-free survival (EFS), and graft-vs-host-disease (GVHD) development. RESULTS: The study cohort comprised 17 patients with acute leukemia, 3 with chronic leukemia, and 3 with lymphoma. Prophylactic, preemptive, and therapeutic DLI were used in seven, seven, and nine patients, respectively. Patients' median age and DLI dose were 9 years and 4.6 × 10 7 CD3 + cells/kg, respectively. The 5-year OS, EFS, and nonrelapse mortality were 43.5%, 38.3%, and 13.3%, respectively. Approximately 39% of the patients developed grade III or IV acute GVHD, whereas moderate/severe chronic GVHD (cGVHD) occurred in 30% of the evaluable patients. Patients' disease status before HSCT ( p = 0.009) and DLI ( p = 0.018) were the key factors influencing EFS. The implementation of a dose escalation schedule was associated with a marginal reduction in the risk of moderate/severe cGVHD ( p = 0.051). A DLI dose of ≥5 × 10 7 CD3 + cells/kg was significantly associated with a high moderate to severe cGVHD risk ( p = 0.002) and reduced OS ( p = 0.089). CONCLUSION: Patients' disease status before HSCT and DLI may help predict EFS. The use of DLI as a prophylactic and preemptive modality leads to a favorable 5-year EFS. To safely deliver DLI in children, clinicians must maintain vigilant monitoring and prepare patients in advance when escalating the dose to ≥5 × 10 7 CD3 + cells/kg.

A Customized Energy Management System for Distributed PV, Energy Storage Units, and Charging Stations on Kinmen Island of Taiwan.

Kinmen, the famous Cold War island also known as Quemoy, is a typical island with isolated power grids. It considers the promotion of renewable energy and electric charging vehicles to be two essential strategies to achieve the goal of a low-carbon island and smart grid. With this motivation in mind, the main objective of this study is to design and deploy an energy management system for hundreds of current PV sites distributed on the island, energy storage systems, and charging stations on the island. In addition, the real-time acquisition of the data for power generation, power storage, and power consumption systems will be used for future demand and response analysis. Moreover, the accumulated dataset will also be utilized for the forecast or prediction of renewable energy generated by the PV systems or power consumed by the battery units or charging stations. The results of this study are promising since a practical, robust, and workable system and database are developed and implemented with a variety of Internet of Things (IoT), data transmission technologies, and the hybrid of on-premises and cloud servers. Users of the proposed system can remotely access the visualized data through the user-friendly web-based and Line bot interfaces seamlessly.

A case series and literature review on 98 pediatric patients of germ cell tumor developing growing teratoma syndrome.

INTRODUCTION: Malignant germ cell tumors (MGCTs) can develop either extracranially or intracranially. Growing teratoma syndrome (GTS) may develop in these patients following chemotherapy. Reports on the clinical characteristics and outcomes of GTS in children with MGCTs are limited. METHODS: We retrospectively collected the data, including the clinical characteristics and outcomes of five patients in our series and 93 pediatric patients selected through a literature review of MGCTs. This study aimed to analyze survival outcomes and risk factors for subsequent events in pediatric patients with MGCTs developing GTS. RESULTS: The sex ratio was 1.09 (male/female). In total, 52 patients (53.1%) had intracranial MGCTs. Compared with patients with extracranial GCTs, those with intracranial GCTs were younger, predominantly boys, had shorter intervals between MGCT and GTS, and had GTS mostly occurring over the initial site (all p < 0.001). Ninety-five patients (96.9%) were alive. However, GTS recurrence (n = 14), GTS progression (n = 9), and MGCT recurrence (n = 19) caused a substantial decrease in event-free survival (EFS). Multivariate analyses showed that the only significant risk factors for these events were incomplete GTS resection and different locations of GCT and GTS. Patients without any risk had a 5-year EFS of 78.8% ± 7.8%, whereas those with either risk had 41.7% ± 10.2% (p < 0.001). CONCLUSION: For patients with high-risk features, every effort should be made to closely monitor, completely remove, and pathologically prove any newly developed mass to guide relevant treatment. Further studies incorporating the risk factors into treatment strategies may be required to optimize adjuvant therapy.

Deep Learning Algorithms with LIME and Similarity Distance Analysis on COVID-19 Chest X-ray Dataset.

In the last few years, many types of research have been conducted on the most harmful pandemic, COVID-19. Machine learning approaches have been applied to investigate chest X-rays of COVID-19 patients in many respects. This study focuses on the deep learning algorithm from the standpoint of feature space and similarity analysis. Firstly, we utilized Local Interpretable Model-agnostic Explanations (LIME) to justify the necessity of the region of interest (ROI) process and further prepared ROI via U-Net segmentation that masked out non-lung areas of images to prevent the classifier from being distracted by irrelevant features. The experimental results were promising, with detection performance reaching an overall accuracy of 95.5%, a sensitivity of 98.4%, a precision of 94.7%, and an F1 score of 96.5% on the COVID-19 category. Secondly, we applied similarity analysis to identify outliers and further provided an objective confidence reference specific to the similarity distance to centers or boundaries of clusters while inferring. Finally, the experimental results suggested putting more effort into enhancing the low-accuracy subspace locally, which is identified by the similarity distance to the centers. The experimental results were promising, and based on those perspectives, our approach could be more flexible to deploy dedicated classifiers specific to different subspaces instead of one rigid end-to-end black box model for all feature space.

Localization Strategy Prior to Radiofrequency Ablation for Primary and Secondary Hyperparathyroidism.

OBJECTIVE: Preoperative localization in patients with primary or secondary hyperparathyroidism before radiofrequency ablation (RFA) is crucial. There is currently a lack of consensus regarding imaging protocol. Evaluating the diagnostic performance of ultrasound, four-dimensional computed tomography (4D-CT), and technetium 99m-sestamibi single-photon-emission-computed tomography/computed tomography (SPECT/CT) is necessary for RFA of hyperparathyroidism. METHODS: This retrospective study recruited patients with primary or secondary hyperparathyroidism who underwent ultrasound, 4D-CT, and SPECT/CT before RFA at a single institution. The sensitivity, accuracy, and receiver operating characteristic curve analysis were used to evaluate the diagnostic performance of the imaging modalities. RESULTS: A total of 33 patients underwent RFA for hyperparathyroidism (8 patients with primary hyperparathyroidism, 25 patients with secondary hyperparathyroidism). Ultrasound had the highest sensitivity (0.953) and accuracy (0.943), while 4D-CT had higher sensitivity and accuracy than SPECT/CT (sensitivity/accuracy, 4D-CT vs. SPECT/CT: 0.929/0.920 vs. 0.741/0.716). Combined ultrasound with 4D-CT and the three combined modalities achieved equivalent, and the highest, diagnostic performance (sensitivity 1.000, accuracy 0.989). The lesion length and volume were important predictors of the diagnostic performance of 4D-CT and SPECT/CT (area under curve of length in 4D-CT/volume in 4D-CT/length in SPECT/volume in SPECT: 0.895/0.834/0.767/0.761). CONCLUSION: Combined ultrasound with 4D-CT provides optimal preoperative localization prior to RFA in patients with primary or secondary hyperparathyroidism. The length and volume of parathyroid lesions are determinative of the diagnostic performance of 4D-CT and SPECT/CT.

Efficacy and safety of splenic artery embolization for intractable ascites using Amplatzer vascular plug versus coil after living donor liver transplantation.

PURPOSE Intractable ascites (IA) is an uncommon but challenging complication after liver transplantation. Splenic artery embolization (SAE) modulates the splenic artery and regulates portal flow. This study aimed to evaluate the efficacy and safety of SAE using the Amplatzer vascular plug (AVP) versus coil embolization for post-living-donor liver transplantation (LDLT) IA. METHODS This retrospective study evaluated consecutive patients from 1 center who received LDLT (n=1410) between March 2006 and August 2019. The inclusion criteria for SAE were splenomegaly with IA after LDLT. RESULTS Totally 15 patients underwent SAE for post-LDLT IA. Eleven patients who received AVP embolization (age, 51.2 ± 15.1 years; range, 8-63 years; 5 men and 6 women) were compared with 4 patients receiving coil embolization (age, 30.8 ± 30.8 years; range, 1.5-63 years; 2 men and 2 women). AVP and coil embolization both significantly reduced portal vein hyperflow (plug/ coil; P <.001/.006) and decreased ascites volume (plug/coil; P <.003/.042). The benefits of AVP embolization included shorter procedure time (P =.029), significantly reduced splenic volume (P =.012), increased liver volume (P =.012), decreased spleen/liver ratio (P =.012), and improvement of pancytopenia (P =.008) due to secondary hypersplenism. No significant differences were found between the two groups in the length of hospital stay or complications such as splenic infarction, pancreatitis, or sepsis. CONCLUSION SAE using AVP and coil embolization provide effective and safe methods for managing patients with IA after LDLT. AVP embolization may be more efficient than coil embolization, providing more effective reduction of ascites volume and the advantages of shortened procedure time and improvement of hypersplenism.

Surgical treatment confers prognostic significance in pediatric malignant mediastinal germ cell tumors.

BACKGROUND: Primary malignant mediastinal germ cell tumors (GCTs) are rare pediatric tumors that have a poorer prognosis compared to GCTs occurring elsewhere in the body. The current study aimed to assess the prognostic factors and treatment outcomes of children with primary malignant mediastinal GCT in Taiwan. METHODS: The authors retrospectively reviewed children 0-18 years old who were newly diagnosed with primary malignant mediastinal GCT between January 1, 2005 and December 31, 2019 and were registered in the Taiwan Pediatric Oncology Group patient registry. The impact of presenting characteristics, including sex, age, tumor stage, histology subtype, surgical treatment, and chemotherapy regimens of the patients were analyzed. RESULTS: This study enrolled 52 children with malignant mediastinal GCT who had a median age of 16.0 (range, 6.0-17.9) years at diagnosis. The most common histological subtypes were mixed GCTs (n = 20) and yolk sac tumors (n = 15). Advanced disease stage and choriocarcinoma histology subtype were associated inferior outcomes. Children who received surgical treatment exhibited better outcomes compared to those who did not (5-year overall survival, 78% vs. 7%, p < .001). After comparing patients who received first-line cisplatin- and carboplatin-based chemotherapy, no difference in treatment outcomes was observed. Multivariate analysis showed that surgical management was the only independent predictor for superior OS. CONCLUSIONS: Surgical treatment is recommended for mediastinal GCT. Cisplatin-based chemotherapy was not superior to carboplatin-based chemotherapy as first-line treatment and may be avoided due to toxicity concerns.

Recurrent microangiopathic hemolysis after recovery from complement-mediated hemolytic uremia syndrome during chemotherapy for a CFH-mutated patient with T-lymphoblastic lymphoma.

Complement-mediated hemolytic uremic syndrome (CM-HUS) following chemotherapy for pediatric acute lymphoid neoplasms has rarely been reported. We report the case of an 8-year-old boy with T-lymphoblastic lymphoma (T-LBL) who developed CM-HUS with complement factor H (CFH) mutations (S1191L, V1197A) during induction therapy. Safe administration of chemotherapy after CM-HUS recovery was challenging. By closely monitoring hemolytic and renal parameters during the 2-year treatment period, we observed four episodes of microangiopathic hemolytic anemia (MAHA) with hypocomplementemia and low haptoglobin but no renal dysfunction or thrombocytopenia. Here, we describe the MAHA and CM-HUS episodes in the hopes of elucidating the complex pathophysiology of disorders associated with CFH mutation.

Comparison of ATP-binding pockets and discovery of homologous recombination inhibitors.

The ATP binding sites of many enzymes are structurally related, which complicates their development as therapeutic targets. In this work, we explore a diverse set of ATPases and compare their ATP binding pockets using different strategies, including direct and indirect structural methods, in search of pockets attractive for drug discovery. We pursue different direct and indirect structural strategies, as well as ligandability assessments to help guide target selection. The analyses indicate human RAD51, an enzyme crucial in homologous recombination, as a promising, tractable target. Inhibition of RAD51 has shown promise in the treatment of certain cancers but more potent inhibitors are needed. Thus, we design compounds computationally against the ATP binding pocket of RAD51 with consideration of multiple criteria, including predicted specificity, drug-likeness, and toxicity. The molecules designed are evaluated experimentally using molecular and cell-based assays. Our results provide two novel hit compounds against RAD51 and illustrate a computational pipeline to design new inhibitors against ATPases.

Betel Quid Dependence Effects on Working Memory and Remote Memory in Chewers with Concurrent Use of Cigarette and Alcohol.

OBJECTIVE: The current study asked whether BQ dependence level could affect working memory (WM) and remote memory for the chewers with concurrent use of cigarettes and alcohol, a common phenomenon in Taiwan. METHODS: The standardized neuropsychological tests (Wechsler Memory Scale III (WMS-III) and Remote Memory Test) were adopted to address the BQ chewers' verbal WM, spatial WM and remote memory. The Spatial Span Test and the Digit Span Test from WMS-III and the Remote Memory Test were adopted. The Betel Nut Dependency Scale (BNDS), the Fagerstrom Test for Nicotine Dependence (FTND), and the Alcohol Use Disorders Identification Test (AUDIT) were adopted to measure the dependence levels. RESULTS: The BQ dependence level and Last BQ did not affect spatial WM, verbal WM, and remote memory. Last Cigarette is critical in affecting WM; namely, longer interval led to worse performance. Finally, higher alcohol dependence level could lead to better remote memory. CONCLUSIONS: To our knowledge, there are no BQ studies addressing the effects of concurrent use of cigarettes and alcohol on memory. The current results suggest that cigarette smoking and alcohol drinking, rather than BQ chewing, are critical for memory performance.

Differential effects of silver nanoparticles on two types of mitochondrion-rich ionocytes in zebrafish embryos.

Silver nanoparticles (AgNPs) are increasingly used in our daily life and have become a potential environmental hazard. However, the toxic effects of AgNPs on the early stages of fish are not fully understood, and little is known about their effects on specific types of ionocytes. Using zebrafish embryos as a model, this study examined the effects (changes in cell number, morphology, NH4+ secretion and gene expression) of sublethal concentrations of AgNPs (0.1, 1, and 3 mg/L) on two major types of ionocytes: H+ pump-rich (HR) ionocytes, and Na+ pump-rich (NaR) ionocytes in the skin of embryos. After exposure to AgNPs for 96 h, the number of HR ionocytes significantly declined by 30% and 41% in the 1 and 3 mg/L AgNP groups, respectively. In addition, the apical opening of HR ionocytes became smaller, suggesting that AgNPs impaired the critical structure for ion transport. NH4+ secretion by HR ionocytes of embryos also declined significantly after AgNP exposure. In contrast, the number of NaR ionocytes increased by 29% and 43% in the 1 and 3 mg/L AgNP groups, respectively, while these cells deformed their shape. AgNPs altered mRNA levels of several ion channel and transporter genes involved in the functions of HR ionocytes and NaR ionocytes, and influenced hormone genes involved in regulating calcium homeostasis. This study shows that AgNPs can cause differential adverse effects on two types of ionocytes and the effects can threaten fish survival.

Elp1 facilitates RAD51-mediated homologous recombination repair via translational regulation.

BACKGROUND: RAD51-dependent homologous recombination (HR) is one of the most important pathways for repairing DNA double-strand breaks (DSBs), and its regulation is crucial to maintain genome integrity. Elp1 gene encodes IKAP/ELP1, a core subunit of the Elongator complex, which has been implicated in translational regulation. However, how ELP1 contributes to genome maintenance is unclear. METHODS: To investigate the function of Elp1, Elp1-deficient mouse embryonic fibroblasts (MEFs) were generated. Metaphase chromosome spreading, immunofluorescence, and comet assays were used to access chromosome abnormalities and DSB formation. Functional roles of Elp1 in MEFs were evaluated by cell viability, colony forming capacity, and apoptosis assays. HR-dependent DNA repair was assessed by reporter assay, immunofluorescence, and western blot. Polysome profiling was used to evaluate translational efficiency. Differentially expressed proteins and signaling pathways were identified using a label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics approach. RESULTS: Here, we report that Elp1 depletion enhanced genomic instability, manifested as chromosome breakage and genotoxic stress-induced genomic DNA fragmentation upon ionizing radiation (IR) exposure. Elp1-deficient cells were hypersensitive to DNA damage and exhibited impaired cell proliferation and defective HR repair. Moreover, Elp1 depletion reduced the formation of IR-induced RAD51 foci and decreased RAD51 protein levels. Polysome profiling analysis revealed that ELP1 regulated RAD51 expression by promoting its translation in response to DNA damage. Notably, the requirement for ELP1 in DSB repair could be partially rescued in Elp1-deficient cells by reintroducing RAD51, suggesting that Elp1-mediated HR-directed repair of DSBs is RAD51-dependent. Finally, using proteome analyses, we identified several proteins involved in cancer pathways and DNA damage responses as being differentially expressed upon Elp1 depletion. CONCLUSIONS: Our study uncovered a molecular mechanism underlying Elp1-mediated regulation of HR activity and provides a novel link between translational regulation and genome stability.

Complete and durable response to immune checkpoint inhibitor in a patient with refractory and metastatic hepatoblastoma.

We herein report the case of a girl with PRETEXT III hepatoblastoma (HB) developing recurrent lung metastases despite multiple chemotherapy regimens, aggressive tumor excision, multiple lung metastasectomies, and autologous peripheral blood stem cell transplantation. High tumor mutation burden (TMB) was identified through targeted next-generation sequencing, and pembrolizumab was administered post-operatively as a last resort. A complete and sustained response to the immune checkpoint inhibitor was achieved for 22 months. Although the majority of HB have a low TMB, immune checkpoint inhibitor therapy may be useful for patients with refractory HBs with a high TMB.

The corticolimbic structural covariance network as an early predictive biosignature for cognitive impairment in Parkinson's disease.

Structural covariance assesses similarities in gray matter between brain regions and can be applied to study networks of the brain. In this study, we explored correlations between structural covariance networks (SCNs) and cognitive impairment in Parkinson's disease patients. 101 PD patients and 58 age- and sex-matched healthy controls were enrolled in the study. For each participant, comprehensive neuropsychological testing using the Wechsler Adult Intelligence Scale-III and Cognitive Ability Screening Instrument were conducted. Structural brain MR images were acquired using a 3.0T whole body GE Signa MRI system. T1 structural images were preprocessed and analyzed using Statistical Parametric Mapping software (SPM12) running on Matlab R2016a for voxel-based morphometric analysis and SCN analysis. PD patients with normal cognition received follow-up neuropsychological testing at 1-year interval. Cognitive impairment in PD is associated with degeneration of the amygdala/hippocampus SCN. PD patients with dementia exhibited increased covariance over the prefrontal cortex compared to PD patients with normal cognition (PDN). PDN patients who had developed cognitive impairment at follow-up exhibited decreased gray matter volume of the amygdala/hippocampus SCN in the initial MRI. Our results support a neural network-based mechanism for cognitive impairment in PD patients. SCN analysis may reveal vulnerable networks that can be used to early predict cognitive decline in PD patients.

Allogeneic hematopoietic stem cell transplantation for treating severe lung involvement in Gaucher disease.

OBJECTIVE: To provide strategies for monitoring and treating severe lung involvement in Gaucher disease. STUDY DESIGN: We reviewed the chart of a 5-year-old boy who developed rapidly progressive, severe infiltrative lung involvement of Gaucher disease (GD) and improved after allogeneic hematopoietic stem cell transplant (HSCT), along with other case studies reported before December 2019. He was diagnosed with GD (homozygous mutation at c.1448 T > C, p.L483P), and started receiving enzyme replacement therapy (ERT) at 17 months old. He developed respiratory distress symptoms after 45 months of ERT; chest imaging reported diffuse interstitial infiltration of the bilateral lungs and consolidations at the right lungs. Allogeneic HSCT using cells from a matched unrelated donor was performed four months upon progressive respiratory symptoms. RESULTS: His respiratory symptoms subsided in one month; chest imaging improvement, pulmonary function test improvement, and normalized activity of ß-glucocerebrosidase were reported in three months. CONCLUSION: This is the first report of a patient who received early and regular ERT but developed severe infiltrative lung involvement and recovered after allogeneic HSCT. Based on study results, we suggest regular chest imaging, even for asymptomatic patients. For patients with severe lung involvement, rapid deterioration, and unresponsive to higher ERT dosages, allogeneic HSCT should be considered.

Exposure to copper nanoparticles impairs ion uptake, and acid and ammonia excretion by ionocytes in zebrafish embryos.

The potential toxicity of copper nanoparticles (CuNPs) to early stages of fishes is not fully understood, and little is known about their effects on ionocytes and associated functions. This study used zebrafish embryos as a model to investigate the toxic effects of CuNPs on two subtypes of ionocytes. Zebrafish embryos were exposed to 0.1, 1, and 3 mg L-1 CuNPs for 96 h. After exposure, whole-body Na+ and Ca2+ contents were significantly reduced at ≥0.1 mg L-1, while the K+ content had decreased at ≥1 mg L-1. H+ and NH4+ excretion by the skin significantly decreased at ≥1 mg L-1. The number of living ionocytes labeled with rhodamine-123 had significantly decreased with ≥0.1 mg L-1 CuNPs. The ionocyte subtypes of H+-ATPase-rich (HR) and Na+/K+-ATPase-rich (NaR) cells were labeled by immunostaining and had decreased with ≥1 mg L-1. Shrinkage of the apical opening of ionocytes was revealed by scanning electronic microscopy. Functional impairment was also reflected by changes in gene expressions, including ion transporters/channels and Ca2+-regulatory hormones. This study shows that CuNP exposure can impair two subtypes of ionocytes and their associated functions, including Na+/Ca2+ uptake and H+/NH4+ excretion in zebrafish embryos.

Combined effect of polymorphisms of MTHFR and MTR and arsenic methylation capacity on developmental delay in preschool children in Taiwan.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are related to cognitive dysfunction and mental disability. These genes, along with folate and vitamin B12 levels, are regulators of one-carbon metabolism, which synthesizes S-adenosylmethionine (SAM) as a methyl donor for arsenic methylation. The aim of this study was to explore whether polymorphisms of MTHFR and MTR influence arsenic methylation capacity and plasma folate and vitamin B12 levels and if these influences cause developmental delay in preschool children. A total of 178 children with developmental delay and 88 without developmental delay were recruited from August 2010 to March 2014. A high-performance liquid chromatography-hydride generator and atomic absorption spectrometer were used to determine urinary arsenic species. Plasma folate and vitamin B12 concentrations were measured by SimulTRAC-SNB radioassay. Polymorphisms of MTHFR C677T, MTHFR A1298C, and MTR A2756G were examined by polymerase chain reaction and restriction fragment length variation. The results show that MTHFR C677T C/T and T/T genotypes had a lower risk of developmental delay than the C/C genotype (odds ratio [OR] = 0.47; 95% confidence interval, 0.26-0.85). Subjects with the MTHFR C677T C/C genotype had significantly lower plasma folate and vitamin B12 levels than those with the MTHFR C677T C/T and T/T genotype. The MTHFR C677T C/C genotype combined with high total urinary arsenic and poor arsenic methylation capacity indices significantly increased the OR of developmental delay in a dose-response manner. This is the first study to show the combined effect of MTHFR C677T genotype and poor arsenic methylation capacity on developmental delay.