Soluble uric acid inhibits ß2 integrin-mediated neutrophil recruitment in innate immunity.

Neutrophils are key players during host defense and sterile inflammation. Neutrophil dysfunction is a characteristic feature of the acquired immunodeficiency during kidney disease. We speculated that the impaired renal clearance of the intrinsic purine metabolite soluble uric acid (sUA) may account for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-12 mg/dL) related or unrelated to kidney dysfunction significantly diminished neutrophil adhesion and extravasation in mice with crystal- and coronavirus-related sterile inflammation using intravital microscopy and an air pouch model. This impaired neutrophil recruitment was partially reversible by depleting UA with rasburicase. We validated these findings in vitro using either neutrophils or serum from patients with kidney dysfunction-related HU with or without UA depletion, which partially normalized the defective migration of neutrophils. Mechanistically, sUA impaired ß2 integrin activity and internalization/recycling by regulating intracellular pH and cytoskeletal dynamics, physiological processes that are known to alter the migratory and phagocytic capability of neutrophils. This effect was fully reversible by blocking intracellular uptake of sUA via urate transporters. In contrast, sUA had no effect on neutrophil extracellular trap formation in neutrophils from healthy subjects or patients with kidney dysfunction. Our results identify an unexpected immunoregulatory role of the intrinsic purine metabolite sUA, which contrasts the well-known immunostimulatory effects of crystalline UA. Specifically targeting UA may help to overcome certain forms of immunodeficiency, for example in kidney dysfunction, but may enhance sterile forms of inflammation.

Research Progress in Liquid Phase Growth of GaN Crystals.

As a wide band gap semiconductor, gallium nitride (GaN) has high breakdown voltage, excellent structural stability and mechanical properties, giving it unique advantages in applications such as high frequency, high power, and high temperature. As a result, it has broad application prospects in optoelectronics and microelectronics. However, the lack of high-quality, large-size GaN crystal substrates severely limit the improvement of electronic device performance. To solve this problem, liquid phase growth of GaN has attracted much attention because it can produce higher quality GaN crystals compared to traditional vapor phase growth methods. This review introduces two main methods of liquid phase growth of GaN: the flux method and ammonothermal method, as well as their advantages and challenges. It reviews the research history and recent advances of these two methods, including the effects of different solvents and mineralizers on the growth quality and performance of GaN crystals, as well as various technical improvements. This review aims to outline the principles, characteristics, and development trends of liquid phase growth of GaN, to provide more inspiration for future research on liquid phase growth, and to achieve further breakthroughs in its development and commercial application.

Compound heterozygous mutations in the ALDH3A2 gene cause Sjögren-Larsson syndrome: a case report.

Purpose: Sjögren-Larsson syndrome is a rare, autosomal, recessive neurocutaneous disorder caused by mutations in the ALDH3A2 gene, which encodes the fatty aldehyde dehydrogenase enzyme. Deficiency in fatty aldehyde dehydrogenase results in an abnormal accumulation of toxic fatty aldehydes in the brain and skin, which cause spasticity, intellectual disability, ichthyosis, and other clinical manifestations. We present the clinical features and mutation analyses of a case of SLS.Materials and Methods: The family history and clinical data of the patient were collected. Genomic DNA was extracted from peripheral blood samples of the patient and her parents, and next-generation sequencing was performed. The candidate mutation sites that required further validation were then sequenced by Sanger sequencing. Bioinformatics software PSIPRED and RaptorX were used to predict the secondary and tertiary structures of proteins.Results: The patient, a five-year-old girl with complaints of cough for three days and intermittent convulsions for seven hours, was admitted to the hospital. Other clinical manifestations included spastic paraplegia, mental retardation, tooth defects, and ichthyosis. Brain magnetic resonance imaging showed periventricular leukomalacia. Genetic screening revealed compound heterozygous mutations in the ALDH3A2 gene: a frameshift mutation c.779delA (p.K260Rfs*6) and a missense mutation c.1157A > G (p.N386S). Neither of the ALDH3A2 alleles in the compound heterozygote patient were able to generate normal fatty aldehyde dehydrogenase, which were likely responsible for her phenotype of Sjögren-Larsson syndrome.Conclusion: The compound heterozygous mutations found in the ALDH3A2 gene support the diagnosis of Sjögren-Larsson syndrome in the patient and expand the genotype spectrum of the gene.

Total tubeless versus standard percutaneous nephrolithotomy: a meta-analysis.

To compare the safety and efficacy of total tubeless percutaneous nephrolithotomy (PCNL) with standard PCNL for the treatment of upper urinary calculi. PubMed, EMBASE, Cochrane Library and ScienceDirect were searched for collecting related literature on the two procedures. All compared studies, including randomized controlled trials (RCT), cohort studies (CS) and case-control studies (CCS), were included. Totally, 14 studies were included. Pooled data demonstrated that patients who underwent total tubeless PCNL were associated with significantly shorter operation time [weighted mean difference (WMD): -3.41, P = 0.004], shorter hospital stay (WMD: -1.54, P < 0.00001). It seemed that significantly less postoperative analgesic requirement could be found in the total tubeless PCNL group according to subgroup analysis. However, no significant differences could be found between the two groups in stone-free rate [risk ratio (RR): 1.03, P = 0.26], hemoglobin drop (WMD: -0.03, P = 0.85), and rates of postoperative fever (RR: 0.53, P = 0.11) and transfusion (RR: 0.79, P = 0.41). Sensitivity analysis after excluding CCS revealed results similar to previous findings. Total tubeless PCNL would be superior to standard PCNL in reducing operation time, hospital stay and postoperative analgesic requirement without significantly more adverse events.

Child with cerebral malformations and epilepsy.

PURPOSE: Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is a rare autosomal dominant genetic disorder involving multiple organ systems and primarily characterized by structural brain abnormalities and a distinctive facial appearance. METHODS: To study the clinical characteristics, gene types and seizures of BWCFF. The natural history, clinical data and peripheral blood sample were collected in the child and his patients. To screen the ß-actin gene (ACTB) of a newly diagnosed child, hoping to find the gene mutation. RESULTS: The child had left ptosis, ocular hypertelorism, arched eyebrows, only 30% of the left ear hearing, a slight hypotonia, normal muscle strength, walking instability. The seizures were difficult to control with antiepileptic drugs and presented some degree of psychomotor development delay. Genetic screening showed De Novo in ACTB gene (c.484A> G, p.Thr162Ala). Parents did not detect related gene mutations. CONCLUSIONS: Patients with typical facial features and cerebral cortical malformations associated with refractory epilepsy should be highly suspected BWCFF. Patients are advised to carry out genetic screening to confirm the diagnosis.

Association of Toll-like receptor 3 gene polymorphism with the severity of enterovirus 71 infection in Chinese children.

Enterovirus 71 (EV71) infection has become one of the major threats to children globally in recent years. Toll-like receptor 3 (TLR3) plays an essential role in host defense against EV71 infection. This study was designed to assess the possible association between the TLR3c.1377C/T polymorphism and disease severity in Chinese children with EV71 infection. The TLR3c.1377C/T gene polymorphism was identified in EV71-infected patients (n = 177), including mild cases (n = 99) and severe cases (n = 78) as well as healthy controls (n = 225), using improved multiplex ligation detection reaction (iMLDR) technology. Serum levels of IFN-γ and IL-4 were measured using enzyme-linked immunosorbent assays. The presence of the TT genotype (p = 0.030) and the T allele (OR, 1.8; 95% CI, 1.2-2.8; p = 0.010) was significantly more frequent in severe cases. The plasma levels of IFN-γ and the IFN-γ/IL-4 ratio were significantly lower with the TT (102.0 ± 24.2 pg/mL, p < 0.01 and 14.2 ± 2.8, p < 0.001) and CT genotypes (114.1 ± 26.2 pg/mL, p < 0.05 and 18.0 ± 3.1, p < 0.001) than with the CC genotype (135.5 ± 36.8 pg/mL and 24.9 ± 4.7), but the plasma levels of IL-4 with the TT (7.3 ± 1.7 pg/mL, p < 0.01) and CT genotypes (6.4 ± 1.3 pg/mL, p < 0.05) were significantly higher than with the CC genotype (5.5 ±1.3 pg/mL). These findings suggest that the TLR3c.1377T allele is associated with susceptibility to severe EV71 infection in Chinese children.

Lissencephaly caused by a de novo mutation in tubulin TUBA1A: a case report and literature review.

Tubulin plays an essential role in cortical development, and TUBA1A encodes a major neuronal α-tubulin. Neonatal mutations in TUBA1A are associated with severe brain malformations, and approximately 70% of patients with reported cases of TUBA1A mutations exhibit lissencephaly. We report the case of a 1-year-old boy with the TUBA1A nascent mutation c.1204C >T, p.Arg402Cys, resulting in lissencephaly, developmental delay, and seizures, with a brain MRI showing normal cortical formation in the bilateral frontal lobes, smooth temporo-parieto-occipital gyri and shallow sulcus. This case has not been described in any previous report; thus, the present case provides new insights into the broad disease phenotype and diagnosis associated with TUBA1A mutations. In addition, we have summarized the gene mutation sites, neuroradiological findings, and clinical details of cases previously described in the literature and discussed the differences that exist between individual cases of TUBA1A mutations through a longitudinal comparative analysis of similar cases. The complexity of the disease is revealed, and the importance of confirming the genetic diagnosis from the beginning of the disease is emphasized, which can effectively shorten the diagnostic delay and help clinicians provide genetic and therapeutic counseling.

The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1.

Epilepsy, one of the most common neurological disorders, is characterized by spontaneous recurrent seizures. Temporal lobe epilepsy (TLE) is one of the most common medically intractable seizure disorders. Traf2-and NcK-interacting kinase (TNIK) has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders, but its role in epilepsy remains unclear. In this study, we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpine-induced rat model of epilepsy by western blotting, immunofluorescence, and immunohistochemistry. A pentylenetetrazole (PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy. Coimmunoprecipitation (Co-IP)/mass spectrometry (MS) was used to identify the potential mechanism. Through Co-IP, we detected and confirmed the main potential TNIK interactors. Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density (PSD) fractions. We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls. NCB-0846 delayed kindling progression and decreased seizure severity. Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi, notably CaMKII. Co-IP showed that TNIK might correlate with endogenous GRIA1, SYN2, PSD-95, CaMKIV, GABRG1, and GABRG2. In addition, the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling. Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.

IGF-1 inhibits inflammation and accelerates angiogenesis via Ras/PI3K/IKK/NF-κB signaling pathways to promote wound healing.

Exogenous insulin-like growth factor-1 (IGF-1) has been reported to promote wound healing through regulation of vascular endothelial cells (VECs). Despite the existing studies of IGF-1 on VEC and its role in angiogenesis, the mechanisms regarding anti-inflammatory and angiogenetic effects of IGF-1 remain unclear. In this study, we investigated the wound-healing process and the related signaling pathway of IGF-1 using an inflammation model induced by IFN-γ. The results demonstrated that IGF-1 can increase cell proliferation, suppress inflammation in VECs, and promote angiogenesis. In vivo studies further confirmed that IGF-1 can reduce inflammation, enhance vascular regeneration, and improve re-epithelialization and collagen deposition in acute wounds. Importantly, the Ras/PI3K/IKK/NF-κB signaling pathways was identified as the mechanisms through which IGF-1 exerts its anti-inflammatory and pro-angiogenic effects. These findings contribute to the understanding of IGF-1's role in wound healing and may have implications for the development of new wound treatment approaches.

Asymptomatic hyperuricaemia in chronic kidney disease: mechanisms and clinical implications.

Asymptomatic hyperuricaemia (HU) is considered a pathogenic factor in multiple disease contexts, but a causative role is only proven for the crystalline form of uric acid in gouty arthritis and urate nephropathy. Epidemiological studies document a robust association of HU with hypertension, cardiovascular disease (CVD) and CKD progression, but CKD-related impaired uric acid (UA) clearance and the use of diuretics that further impair UA clearance likely accounts for these associations. Interpreting the available trial evidence is further complicated by referring to xanthine oxidase inhibitors as urate-lowering treatment, although these drugs inhibit other substrates, so attributing their effects only to HU is problematic. In this review we provide new mechanistic insights into the biological effects of soluble and crystalline UA and discuss clinical evidence on the role of asymptomatic HU in CKD, CVD and sterile inflammation. We identify research areas with gaps in experimental and clinical evidence, specifically on infectious complications that represent the second common cause of death in CKD patients, referred to as secondary immunodeficiency related to kidney disease. In addition, we address potential therapeutic approaches on how and when to treat asymptomatic HU in patients with kidney disease and where further interventional studies are required.

Safety and Tolerability of COVID-19 Vaccine in Children With Epilepsy: A Prospective, Multicenter Study.

BACKGROUND: We designed this study to investigate the effects of the coronavirus disease 2019 (COVID-19) vaccine on epileptic seizures, as well as its adverse effects, in children with epilepsy (<18 years). METHODS: This anonymous questionnaire study involved a multicenter prospective survey of outpatients and inpatients with epilepsy (＜18 years) registered in epilepsy clinics in eight hospitals in six cities of Shandong Province. RESULTS: A total of 224 children with epilepsy were included in the study. Fifty of them experienced general adverse events after vaccination. The most common local adverse events were pain or tenderness at the injection site. The most common systemic adverse effects were muscle soreness and headache. No severe adverse events were reported. There were no significant differences in the number of antiseizure medications (P = 0.459), gender (P = 0.336), etiology (P = 0.449), age (P = 0.499), duration of disease (P = 0.546), or seizure type (P = 0.475) between the patients with and without general adverse events. We found that the risk of seizure after vaccination was decreased in children who were seizure free for more than six months before vaccination. There was no significant difference in the number of seizures during the first month before vaccination, the first month after the first dose, and the first month after the second dose (P = 0.091). CONCLUSION: The benefits of vaccination against COVID-19 outweighed the risks of seizures/relapses and severe adverse events after vaccination for children with epilepsy.

The Panel Spatial Econometric Analysis for Development of Green Intensive Agriculture Based on Edge Computing and Internet of Things.

To further promote the modernization of agriculture and the prosperity of green industry, the analyses are made on the intensive level of agriculture by using spatial econometric model under the Internet of Things (IoT), and the optimal defense strategy is adopted for edge network equipment to ensure the security of agricultural information. Initially, the present work introduces the related concepts of agricultural intensive development and analyzes the important role of IoT in the development process of agricultural modernization. Next, it briefly explains the spatial econometric analysis method, introduces two basic spatial analysis models-spatial lag model (SLM) and spatial error model (SEM), and explains their principles in detail. Then, it signifies the characteristics of IoT and edge computing (EC) and designs the optimal defense strategy of edge network equipment from the perspective of IoT. Finally, the simulation experiment is carried out based on the edge network defense strategy, and the spatial econometric analysis is carried out by taking the agricultural intensive development of counties in a Chinese province as an example. The experimental results show that with the increase of the number of edge network devices, the optimal strategy of edge network defense can be adopted while consuming certain computing resources. The agricultural technology input and intensive level in the jurisdiction have high spatial correlation, so it is necessary to establish a spatial econometric model for analysis. Additionally, the statistics of SLM is higher than that of SEM, which shows that SLM can better reflect the technology investment and spatial correlation than SEM does. Both industrial and agricultural division of labor and agricultural production link division of labor can promote the level of intensification, among which the promotion of industrial and agricultural division of labor is not very significant, while the promotion of agricultural production link division of labor is very significant.

MiR-200c-3p and miR-485-5p overexpression elevates cisplatin sensitivity and suppresses the malignant phenotypes of non-small cell lung cancer cells through targeting RRM2.

BACKGROUND: This study intended to investigate the potential mechanism of microRNA-200c-3p (miR-200c-3p) and miR-485-5p in mediating the cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to measure the expression of miR-200c-3p, miR-485-5p, and ribonucleotide reductase regulatory subunit M2 (RRM2) messenger RNA (mRNA). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to analyze the DDP resistance and the proliferation of NSCLC cells. Colony formation assay was used to assess cell proliferation. Transwell assays were used to evaluate cell migration and invasion. The target relationship between RRM2 and miR-200c-3p or miR-485-5p was verified using dual-luciferase reporter assay. The protein level of RRM2 was measured using Western blot assay. Animal experiments were conducted to analyze the roles of miR-200c-3p and miR-485-5p in the DDP resistance of xenograft tumors in vivo. RESULTS: MiR-200c-3p and miR-485-5p were both downregulated in DDP-resistant NSCLC tissues and cell lines. Overexpressing miR-200c-3p or miR-485-5p suppressed the DDP resistance and malignant behaviors of NSCLC cells. MiR-200c-3p played a synergistic role with miR-485-5p in regulating the chemo-resistance and biological behaviors NSCLC cells. RRM2 was confirmed as a target of miR-200c-3p and miR-485-5p. RRM2 silencing restrained the DDP resistance and progression of NSCLC. RRM2 overexpression partly reversed miR-200c-3p or miR-485-5p-induced influences in NSCLC cells. The overexpression of miR-200c-3p or miR-485-5p aggravated DDP-mediated suppressive effect on tumor growth in vivo. CONCLUSION: MiR-200c-3p or miR-485-5p enhanced the DDP sensitivity and suppressed the malignant behaviors of NSCLC cells partly through targeting RRM2.

Circ_0011292 knockdown mitigates progression and drug resistance in PTX-resistant non-small-cell lung cancer cells by regulating miR-433-3p/CHEK1 axis.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is one of the most common malignant tumors on earth. Circular RNAs have been disclosed to be vital regulators in the chemoresistance and development of diverse cancers, including NSCLC. Here, we attempted to explore the function of circ_0011292 in paclitaxel (PTX)-resistant NSCLC cells. METHODS: Quantitative real-time polymerase chain reaction or western blot was performed to detect the expression of circ_0011292, microRNA-433-3p (miR-433-3p), and checkpoint kinase 1 (CHEK1). Ribonuclease R (RNase R) assay was performed to assess the stability of circ_0011292. Cell Counting Kit-8 assay was conducted to evaluate the half maximal inhibitory concentration of PTX and cell viability. Cell proliferation was monitored by Edu incorporation and colony formation assays. Cell cycle and apoptosis were detected by flow cytometry. Transwell assay was implemented to assess cell migration and invasion. Western blot assay was utilized to determine the protein levels. Dual-luciferase reporter assay was carried out to verify the targeted interaction between miR-433-3p and circ_0011292 or CHEK1. Xenograft tumor model was constructed for determining the effect of circ_0011292 in NSCLC growth in vivo. RESULTS: Circ_0011292 was upregulated in PTX-resistant NSCLC tissues and cells. Circ_0011292 or CHEK1 knockdown enhanced PTX sensitivity and cell apoptosis, and repressed cell proliferation, migration, and invasion in PTX-resistant NSCLC cells. Mechanistically, circ_0011292 was a sponge of miR-433-3p and miR-433-3p directly targeted CHEK1. Meanwhile, silencing miR-433-3p or overexpressing CHEK1 respectively abrogated the impacts of circ_0011292 deletion or miR-433-3p introduction on PTX resistance and cell progression in PTX-resistant NSCLC cells in vitro. Moreover, circ_0011292 could positively modulate CHEK1 expression through sponging miR-433-3p. In addition, circ_0011292 knockdown retarded tumor growth of NSCLC in vivo. CONCLUSION: Circ_0011292 could accelerate PTX resistance and cell malignant progression of NSCLC cells partially through the regulation of circ_0011292/miR-433-3p/CHEK1 axis.

Plasma exchange therapy for familial chylomicronemia syndrome in infant: A case report.

INTRODUCTION: Familial chylomicronemia syndrome (FCS) is a rare genetic disease. FCS usually manifests by the age of 10 years, and 25% of cases of FCS occur during infancy. Here we present a case of FCS in a male infant and summarize our experiences on the diagnosis and therapy of this case. PATIENT CONCERNS: A male infant aged 1 month and 8 days had recurrent hematochezia and hyperchylomicronemia. DIAGNOSIS: FCS based on symptoms and genetic test. INTERVENTIONS: Plasma exchange therapy. OUTCOMES: His development was normal with a good spirit and satisfactory weight gain, and no hematochezia occurred again. CONCLUSION: Genetic test is important for accurate diagnosis of FCS, and we identified a new mutation of lipoprotein lipase gene c.88C>A which conformed to autosomal recessive inheritance. Plasma exchange therapy can be applied to infants with FCS with low risk and good outcomes.

Two siblings suffering from Angelman Syndrome with a novel c.1146T>G mutation in UBE3A: A case report.

Angelman syndrome (AS) is an autosomal dominant neurodevelopmental genetic disease with maternal imprint, which is associated with the presence of the abnormal chromosome 15q11-q13, and the loss of maternal specific expression of ubiquitin-protein ligase E3A (UBE3A). The expression levels of UBE3A depend on the parental origin and exhibit tissue specificity. In normal brain tissues, the maternal UBE3A gene is actively expressed, whereas the paternal UBE3A gene is not. In total, ~85% of pediatric patients with AS present with epilepsy within their 3rd year of life. This condition is usually difficult to control with medical treatment. An 8-year-old female visited the Affiliated Hospital of Jining Medical University due to frequent epilepsy. Her clinical manifestations included specific facial features, moderate mental retardation and frequent seizures. It was interesting to note that her 15-year-old sister exhibited similar clinical manifestations to those of AS. The results of the electroencephalogram and the imaging examinations were also in line with the characteristics of AS. In order to further clarify the diagnosis, all the suspected genes in her sister and in their parents were sequenced. The multiplex ligation-dependent probe amplification project of the Angel/chubby and copy number variation (CNV) sequencing were assessed concomitantly to identify the pathogenic genes responsible for the development of AS. The latter occurs due to the missense mutation c.1146T>G, which results in asparagine replacement by lysine at position 382 (p.Asn382Lys) in exon 7. This amino acid change affects the normal expression of UBE3A; the mutation is a novel mutation, which, to the best of our knowledge, has not been previously reported. Relevant large fragments of mutations and methylation abnormalities were not found in the associated genes. The data further revealed absence of 25-bp repeat mutations at the shear mutation site of exon 1 of the small nuclear ribonucleoprotein polypeptide N gene in the subjects examined. No suspected CNV was found following analysis.

Multimodal Neuroimaging in Rett Syndrome With MECP2 Mutation.

Rett syndrome (RTT) is a rare neurodevelopmental disorder characterized by severe cognitive, social, and physical impairments resulting from de novo mutations in the X-chromosomal methyl-CpG binding protein gene 2 (MECP2). While there is still no cure for RTT, exploring up-to date neurofunctional diagnostic markers, discovering new potential therapeutic targets, and searching for novel drug efficacy evaluation indicators are fundamental. Multiple neuroimaging studies on brain structure and function have been carried out in RTT-linked gene mutation carriers to unravel disease-specific imaging features and explore genotype-phenotype associations. Here, we reviewed the neuroimaging literature on this disorder. MRI morphologic studies have shown global atrophy of gray matter (GM) and white matter (WM) and regional variations in brain maturation. Diffusion tensor imaging (DTI) studies have demonstrated reduced fractional anisotropy (FA) in left peripheral WM areas, left major WM tracts, and cingulum bilaterally, and WM microstructural/network topology changes have been further found to be correlated with behavioral abnormalities in RTT. Cerebral blood perfusion imaging studies using single-photon emission CT (SPECT) or PET have evidenced a decreased global cerebral blood flow (CBF), particularly in prefrontal and temporoparietal areas, while magnetic resonance spectroscopy (MRS) and PET studies have contributed to unraveling metabolic alterations in patients with RTT. The results obtained from the available reports confirm that multimodal neuroimaging can provide new insights into a complex interplay between genes, neurotransmitter pathway abnormalities, disease-related behaviors, and clinical severity. However, common limitations related to the available studies include small sample sizes and hypothesis-based and region-specific approaches. We, therefore, conclude that this field is still in its early development phase and that multimodal/multisequence studies with improved post-processing technologies as well as combined PET-MRI approaches are urgently needed to further explore RTT brain alterations.

Asymptomatic Hyperuricemia Promotes Recovery from Ischemic Organ Injury by Modulating the Phenotype of Macrophages.

Acute organ injury, such as acute kidney injury (AKI) and disease (AKD), are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function but the impact of asymptomatic HU on the different phases of AKI/AKD is incompletely understood. We hypothesized that asymptomatic HU would attenuate AKD because soluble, in contrast to crystalline, uric acid (sUA) can attenuate sterile inflammation. In vitro, 10 mg/dL sUA decreased reactive oxygen species and interleukin-6 production in macrophages, while enhancing fatty acid oxidation as compared with a physiological concentration of 5 mg/dL sUA or medium. In transgenic mice, asymptomatic HU of 7-10 mg/dL did not affect post-ischemic AKI/AKD but accelerated the recovery of kidney excretory function on day 14. Improved functional outcome was associated with better tubular integrity, less peritubular inflammation, and interstitial fibrosis. Mechanistic studies suggested that HU shifted macrophage polarization towards an anti-inflammatory M2-like phenotype characterized by expression of anti-oxidative and metabolic genes as compared with post-ischemic AKI-chronic kidney disease transition in mice without HU. Our data imply that asymptomatic HU acts as anti-oxidant on macrophages and tubular epithelial cells, which endorses the recovery of kidney function and structure upon AKI.

Network meta-analysis and cost-effectiveness analysis of infliximab, cyclosporine and tacrolimus for ulcerative colitis.

BACKGROUND: Assess the efficiency and cost-effectiveness of infliximab, cyclosporine and tacrolimus for the treatment of ulcerative colitis (UC). METHODS: A literature search identified studies that investigated infliximab, cyclosporine or tacrolimus compared with placebo in UC patients. Short-term, long-term remission rates and response rates were employed to assess efficacy. Odds ratios with 95% confidence intervals were analyzed. A Markov model was constructed to simulate the progression in a cohort of patients with UC, with an over 10 years of time horizon, with a discount rate of 3%, and established threshold of €30,000/quality-adjusted life-year (QALY) or ¥82442/QALY. RESULTS: Results of network meta-analysis showed that the order was cyclosporine, tacrolimus, infliximab and placebo from high rate to low with regard to short-term clinical response. The comparison between infliximab versus cyclosporine achieved an incremental cost effectiveness ratio (ICER) of €184435/QALY and ¥531607/QALY, with a 0.34893 QALYs difference of efficacy, and an incremental cost of €64355 and ¥185494. Tacrolimus versus cyclosporine reached an ICER of €44236/QALY and ¥57494/QALY, with a difference of 0.40963 QALYs in efficacy, and a raising cost to €18120 and ¥23551. The probabilistic sensitivity analysis shows that cyclosporine would be cost-effective in the 75.8% of the simulations, tacrolimus in the 24.2%, and infliximab for the 0%. CONCLUSION: Infliximab, cyclosporine and tacrolimus as salvage therapies are efficacious. For long-term of clinical remission, the order of pharmacological agents was tacrolimus, infliximab and cyclosporine from high efficacy to low while no significant difference is seen. In cost-effectiveness analysis, the cyclosporine versus infliximab or tacrolimus is expected to be at best.