EV71 5'UTR interacts with 3D protein affecting replication through the AKT-mTOR pathway.

BACKGROUND: EV71 is one of the important pathogens of Hand-foot-and-mouth disease (HFMD), which causes serious neurological symptoms. Several studies have speculated that there will be interaction between 5'UTR and 3D protein. However, whether 5'UTR interacts with the 3D protein in regulating virus replication has not been clarified. METHODS: Four 5'UTR mutation sites (nt88C/T, nt90-102-3C, nt157G/A and nt574T/A) and two 3D protein mutation sites (S37N and R142K) were mutated or co-mutated using virulent strains as templates. The replication of these mutant viruses and their effect on autophagy were determined. RESULTS: 5'UTR single-point mutant strains, except for EGFP-EV71(nt90-102-3C), triggered replication attenuation. The replication ability of them was weaker than that of the parent strain the virulent strain SDLY107 which is the fatal strain that can cause severe neurological complications. While the replication level of the co-mutant strains showed different characteristics. 5 co-mutant strains with interaction were screened: EGFP-EV71(S37N-nt88C/T), EGFP-EV71(S37N-nt574T/A), EGFP-EV71(R142K-nt574T/A), EGFP-EV71(R142K-nt88C/T), and EGFP-EV71(R142K-nt157G/A). The results showed that the high replicative strains significantly promoted the accumulation of autophagosomes in host cells and hindered the degradation of autolysosomes. The low replicative strains had a low ability to regulate the autophagy of host cells. In addition, the high replicative strains also significantly inhibited the phosphorylation of AKT and mTOR. CONCLUSIONS: EV71 5'UTR interacted with the 3D protein during virus replication. The co-mutation of S37N and nt88C/T, S37N and nt574T/ A, R142K and nt574T/A induced incomplete autophagy of host cells and promoted virus replication by inhibiting the autophagy pathway AKT-mTOR. The co-mutation of R142K and nt88C/T, and R142K and nt157G/A significantly reduced the inhibitory effect of EV71 on the AKT-mTOR pathway and reduced the replication ability of the virus.

Role of thrombospondin-1 in high-salt-induced mesenteric artery endothelial impairment in rats.

The matrix glycoprotein thrombospondin-1 (THBS1) modulates nitric oxide (NO) signaling in endothelial cells. A high-salt diet induces deficiencies of NO production and bioavailability, thereby leading to endothelial dysfunction. In this study we investigated the changes of THBS1 expression and its pathological role in the dysfunction of mesenteric artery endothelial cells (MAECs) induced by a high-salt diet. Wild-type rats, and wild-type and Thbs1-/- mice were fed chow containing 8% w/w NaCl for 4 weeks. We showed that a high salt diet significantly increased THBS1 expression and secretion in plasma and MAECs, and damaged endothelium-dependent vasodilation of mesenteric resistance arteries in wild-type animals, but not in Thbs1-/- mice. In rat MAECs, we demonstrated that a high salt environment (10-40 mM) dose-dependently increased THBS1 expression accompanied by suppressed endothelial nitric oxide synthase (eNOS) and phospho-eNOS S1177 production as well as NO release. Blockade of transforming growth factor-ß1 (TGF-ß1) activity by a TGF-ß1 inhibitor SB 431542 reversed THBS1 up-regulation, rescued the eNOS decrease, enhanced phospho-eNOS S1177 expression, and inhibited Smad4 translocation to the nucleus. By conducting dual-luciferase reporter experiments in HEK293T cells, we demonstrated that Smad4, a transcription promoter, upregulated Thbs1 transcription. We conclude that THBS1 contributes to endothelial dysfunction in a high-salt environment and may be a potential target for treatment of high-salt-induced endothelium dysfunction.

Serum chemokine IL-8 acts as a biomarker for identifying COVID-19-associated persistent severe acute kidney injury.

OBJECTIVES: Persistent severe acute kidney injury (PS-AKI) is associated with poor clinical outcomes. Our study attempted to evaluate the diagnostic value of chemokines for early-stage PS-AKI prediction. METHODS: According to the KDIGO criteria, 115 COVID-19 patients diagnosed with stage 2/3 AKI were recruited from the intensive care unit between December 2022 and February 2023. Primary clinical outcomes included detecting PS-AKI in the first week (≥ KDIGO stage 2 ≥ 72 h). Cytometric Bead Array was used to detect patient plasma levels (interleukin-8 (IL-8), C-C chemokine ligand 5 (CCL5), chemokine (C-X-C Motif) ligand 9 (CXCL9), and interferon-inducible protein 10 (IP-10)) of chemokines within 24 h of enrollment. RESULTS: Of the 115 COVID-19 patients with stage 2/3 AKI, 27 were diagnosed with PS-AKI. Among the four measured chemokines, only the IL-8 level was significantly elevated in the PS-AKI group than in the Non-PS-AKI group. IL-8 was more effective as a biomarker while predicting PS-AKI with an area under the curve of 0.769 (0.675-0.863). This was superior to other biomarkers related to AKI, including serum creatinine. Moreover, plasma IL-8 levels of >32.2 pg/ml on admission could predict PS-AKI risk (sensitivity = 92.6%, specificity = 51.1%). Additionally, the IL-8 level was associated with total protein and IL-6 levels. CONCLUSION: Plasma IL-8 is a promising marker for the early identification of PS-AKI among COVID-19 patients. These findings should be validated in further studies with a larger sample size.

Phylogenetic and Evolutionary Comparison of Mitogenomes Reveal Adaptive Radiation of Lampriform Fishes.

Lampriform fishes (Lampriformes), which primarily inhabit deep-sea environments, are large marine fishes varying from the whole-body endothermic opah to the world's longest bony fish-giant oarfish, with species morphologies varying from long and thin to deep and compressed, making them an ideal model for studying the adaptive radiation of teleost fishes. Moreover, this group is important from a phylogenetic perspective owing to their ancient origins among teleosts. However, knowledge about the group is limited, which is, at least partially, due to the dearth of recorded molecular data. This study is the first to analyze the mitochondrial genomes of three lampriform species (Lampris incognitus, Trachipterus ishikawae, and Regalecus russelii) and infer a time-calibrated phylogeny, including 68 species among 29 orders. Our phylomitogenomic analyses support the classification of Lampriformes as monophyletic and sister to Acanthopterygii; hence, addressing the longstanding controversy regarding the phylogenetic status of Lampriformes among teleosts. Comparative mitogenomic analyses indicate that tRNA losses existed in at least five Lampriformes species, which may reveal the mitogenomic structure variation associated with adaptive radiation. However, codon usage in Lampriformes did not change significantly, and it is hypothesized that the nucleus transported the corresponding tRNA, which led to function substitutions. The positive selection analysis revealed that atp8 and cox3 were positively selected in opah, which might have co-evolved with the endothermic trait. This study provides important insights into the systematic taxonomy and adaptive evolution studies of Lampriformes species.

Split-face comparison of the efficacy of picosecond 532 nm Nd:YAG laser and Q-switched 755 nm Alexandrite laser for treatment of freckles.

To date, there has been little study of comparison between picosecond 532 nm laser and 755 nm Q-switched Alexandrite lasers in the treatment of freckles. To evaluate the efficacy and safety of picosecond 532 nm laser (PS 532) and 755 nm Q-switched Alexandrite laser (QSAL) for treatment of freckles in a split-face manner. Eighteen patients with freckles were enrolled in the study. The right and left sides of their faces were randomly assigned to either a QSAL-treated group or PS 532-treated group. The degree of pain, satisfaction with the results, and adverse events associated with the laser treatment were evaluated using a questionnaire. All of the patients were followed up at 4 and 12 weeks after one treatment session. Among the 18 patients, PS 532 was found to be associated with less pain (3.56 ± 2.431) than QSAL (3.94 ± 1.893), but the difference was not statistically significant. The curative effect and satisfaction associated with 755 nm Q-switched Alexandrite laser was greater than that of picosecond 532 nm laser (P < .001). Both picosecond 532 nm laser and QSAL are effective in the treatment of freckles, and QSAL has a greater rate of satisfaction and curative effect.

Membrane recruitment of Atg8 by Hfl1 facilitates turnover of vacuolar membrane proteins in yeast cells approaching stationary phase.

BACKGROUND: The vacuole/lysosome is the final destination of autophagic pathways, but can also itself be degraded in whole or in part by selective macroautophagic or microautophagic processes. Diverse molecular mechanisms are involved in these processes, the characterization of which has lagged behind those of ATG-dependent macroautophagy and ESCRT-dependent endosomal multivesicular body pathways. RESULTS: Here we show that as yeast cells gradually exhaust available nutrients and approach stationary phase, multiple vacuolar integral membrane proteins with unrelated functions are degraded in the vacuolar lumen. This degradation depends on the ESCRT machinery, but does not strictly require ubiquitination of cargos or trafficking of cargos out of the vacuole. It is also temporally and mechanistically distinct from NPC-dependent microlipophagy. The turnover is facilitated by Atg8, an exception among autophagy proteins, and an Atg8-interacting vacuolar membrane protein, Hfl1. Lack of Atg8 or Hfl1 led to the accumulation of enlarged lumenal membrane structures in the vacuole. We further show that a key function of Hfl1 is the membrane recruitment of Atg8. In the presence of Hfl1, lipidation of Atg8 is not required for efficient cargo turnover. The need for Hfl1 can be partially bypassed by blocking Atg8 delipidation. CONCLUSIONS: Our data reveal a vacuolar membrane protein degradation process with a unique dependence on vacuole-associated Atg8 downstream of ESCRTs, and we identify a specific role of Hfl1, a protein conserved from yeast to plants and animals, in membrane targeting of Atg8.

Tumour draining lymph node-generated CD8 T cells play a role in controlling lung metastases after a primary tumour is removed but not when adjuvant immunotherapy is used.

Surgical resection of cancer remains the frontline therapy for millions of patients annually, but post-operative recurrence is common, with a relapse rate of around 45% for non-small cell lung cancer. The tumour draining lymph nodes (dLN) are resected at the time of surgery for staging purposes, and this cannot be a null event for patient survival and future response to immune checkpoint blockade treatment. This project investigates cancer surgery, lymphadenectomy, onset of metastatic disease, and response to immunotherapy in a novel model that closely reflects the clinical setting. In a murine metastatic lung cancer model, primary subcutaneous tumours were resected with associated dLNs remaining intact, completely resected or partially resected. Median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days (95%CI)) compared to when lymph nodes remained intact (> 88 days; p < 0.05). Survival was partially restored with incomplete lymph node resection and CD8 T cell dependent. Treatment with aCTLA4 whilst effective against the primary tumour was ineffective for metastatic lung disease. Conversely, aPD-1/aCD40 treatment was effective in both the primary and metastatic disease settings and restored the detrimental effects of complete dLN resection on survival. In this pre-clinical lung metastatic disease model that closely reflects the clinical setting, we observe decreased frequency of survival after complete lymphadenectomy, which was ameliorated with partial lymph node removal or with early administration of aPD-1/aCD40 therapy. These findings have direct relevance to surgical lymph node resection and adjuvant immunotherapy in lung cancer, and perhaps other cancer, patients.

A 5-year molecular epidemiology survey of human enterovirus 71 before vaccine application in Yunnan Province, China.

Enterovirus A71 (EV-A71) infection is known to cause hand, foot, and mouth disease (HFMD). Last year, an inactivated EV-A71 whole virus vaccine was used to prevent this disease in Yunnan, China. To obtain a viral genetic background for evaluating vaccine protection and monitor the adaptive evolution of the virus after the vaccination, a 5-year molecular epidemiology survey was performed before the vaccination. Twenty-six EV-A71 strains were separated from 561 stool specimens of patients with serious HFMD. The whole-genomic sequences of these strains were sequenced. Phylogenetic trees were constructed, and the mutation spectra were analyzed based on these viral sequences. There was no obvious mutation for the circular EV-A71 strains of the same year. Pathogenic EV-A71 strains may arise from a "subgroup" randomly each year. Whole-genomic analyses showed that a hotspot nonsynonymous substitution potentially affecting the immunogenicity of vaccines was found in the 2A gene, but not in genes of the viral capsid proteins, and the genetic diversity of whole viral genomes associated with the incidence of HFMD. Therefore, it will be valuable to monitor the genome-wide changes of EV-A71 to detect the adaptive mutations affecting immunogenicity or perform investigations using genetic diversity as a parameter.

Treatment of lidocaine on subacute thyroiditis via restraining inflammatory factor expression and inhibiting pyroptosis pathway.

BACKGROUND: To explore the role of lidocaine on subacute thyroiditis (SAT) and the molecular mechanism. METHODS: SAT models were constructed by infecting adenovirus to thyroid follicular epithelial cells. Cells were randomly divided into five groups: model group, low lidocaine, middle lidocaine, high lidocaine, and a control group. Thyroid secretion related factors TG and TPO, T3 and T4 were separately determined by reverse transcription-polymerase chain reaction (RT-PCR) and radioimmunoassay. Flow cytometry was used to determine thyroid follicular epithelial cell apoptosis situation. RT-PCR and Western blot analysis were used to determine the expression of inflammatory cytokines and pyroptosis related factors interleukin (IL)-1α, IL-6, THF-α, ELAVL1, NLR family pyrin domain containing 3 (NLRP3), caspase-1, and IL-1ß. RESULTS: Lidocaine decreased the relative level of TG, TPO, T3, and T4 in adenovirus-infected thyroid follicular epithelial cells. All levels of concentrations, including low, middle, and high, of lidocaine, significantly decreased the apoptosis rate of adenovirus-infected cells. Lidocaine dramatically reduced the protein expression of IL-1α, IL-6, THF-α, ELAVL1, NLRP3, caspase-1, and IL-1ß in adenovirus-infected thyroid follicular epithelial cells. CONCLUSION: Lidocaine can improve SAT through inhibiting expression of inflammatory factors and the pyroptosis pathway.

Prediction Model of Cardiac Risk for Dental Extraction in Elderly Patients with Cardiovascular Diseases.

BACKGROUND: With the rapidly increasing population of elderly people, dental extraction in elderly individuals with cardiovascular diseases (CVDs) has become quite common. The issue of how to assure the safety of elderly patients with CVDs undergoing dental extraction has perplexed dentists and internists for many years. And it is important to derive an appropriate risk prediction tool for this population. OBJECTIVES: The aim of this retrospective, observational study was to establish and validate a prediction model based on the random forest (RF) algorithm for the risk of cardiac complications of dental extraction in elderly patients with CVDs. METHODS: Between August 2017 and May 2018, a total of 603 patients who fulfilled the inclusion criteria were used to create a training set. An independent test set contained 230 patients between June 2018 and July 2018. Data regarding clinical parameters, laboratory tests, clinical examinations before dental extraction, and 1-week follow-up were retrieved. Predictors were identified by using logistic regression (LR) with penalized LASSO (least absolute shrinkage and selection operator) variable selection. Then, a prediction model was constructed based on the RF algorithm by using a 5-fold cross-validation method. RESULTS: The training set, based on 603 participants, including 282 men and 321 women, had an average participant age of 72.38 ± 8.31 years. Using feature selection methods, 11 predictors for risk of cardiac complications were screened out. When the RF model was constructed, its overall classification accuracy was 0.82 at the optimal cutoff value of 18.5%. In comparison to the LR model, the RF model showed a superior predictive performance. The AUROC (area under the receiver operating characteristic curve) scores of the RF and LR models were 0.83 and 0.80, respectively, in the independent test set. The AUPRC (area under the precision-recall curve) scores of the RF and LR models were 0.56 and 0.35, respectively, in the independent test set. CONCLUSION: The RF-based prediction model is expected to be applicable for preoperative clinical assessment for preventing cardiac complications in elderly patients with CVDs undergoing dental extraction. The findings may aid physicians and dentists in making more informed recommendations to prevent cardiac complications in this patient population.

Effect of Selective Thrombus Aspiration on Serum Lipoprotein-Associated Phospholipase A2 in Patients with ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention with High Thrombus Burden.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a potential therapeutic target in acute coronary syndromes. Although recent evidence does not support the routine use of manual thrombus aspiration (TA) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), the use of TA is associated with a significant improvement in myocardial reperfusion, especially in patients with high thrombus burden (HTB). We hypothesized that TA would reduce the serum Lp-PLA2 levels in STEMI patients undergoing PPCI with HTB. METHODS AND RESULTS: Our study cohort included 320 consecutive STEMI patients undergoing PPCI with HTB who were randomly assigned to receive either TA before PPCI (TA group, n = 160) or PPCI alone (standard PPCI group, n = 160). The baseline characteristics of study participants were well-matched. After 30 ± 2 days, serum Lp-PLA2 levels decreased by 53.9% in the TA group (152.9 ± 58.1 ng/mL) and decreased by 31.2% in the standard PPCI group (84.2 ± 86.6 ng/mL, p < 0.001). The TA group had a significantly lower prevalence of balloon predilatation, number of stents used, total stent length and corrected thrombolysis in myocardial infarction frame count, and a higher percentage of myocardial blush grade ≥ 2 compared with the standard PPCI group (all p < 0.001). No significant difference between the groups was observed in 30 ± 2 days for major adverse cardiovascular and cerebrovascular events (p = 0.702). CONCLUSIONS: After 30 ± 2 days of treatment, TA may significantly reduce serum levels of Lp-PLA2 in STEMI patients undergoing PPCI with HTB.

p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion.

Triple-negative breast cancer (TNBC) is highly progressive and lacks established therapeutic targets. p38γ mitogen-activated protein kinase (MAPK) (gene name: MAPK12) is overexpressed in TNBC but how overexpressed p38γ contributes to TNBC remains unknown. Here, we show that p38γ activation promotes TNBC development and progression by stimulating cancer stem-like cell (CSC) expansion and may serve as a novel therapeutic target. p38γ silencing in TNBC cells reduces mammosphere formation and decreases expression levels of CSC drivers including Nanog, Oct3/4, and Sox2. Moreover, p38γ MAPK-forced expression alone is sufficient to stimulate CSC expansion and to induce epithelial cell transformation in vitro and in vivo. Furthermore, p38γ depends on its activity to stimulate CSC expansion and breast cancer progression, indicating a therapeutic opportunity by application of its pharmacological inhibitor. Indeed, the non-toxic p38γ specific pharmacological inhibitor pirfenidone selectively inhibits TNBC growth in vitro and/or in vivo and significantly decreases the CSC population. Mechanistically, p38γ stimulates Nanog transcription through c-Jun/AP-1 via a multi-protein complex formation. These results together demonstrate that p38γ can drive TNBC development and progression and may be a novel therapeutic target for TNBC by stimulating CSC expansion. Inhibiting p38γ activity with pirfenidone may be a novel strategy for the treatment of TNBC.

Heterozygous Mutations of the DUOXA2 and DUOX2 Genes in Dizygotic Twins with Congenital Hypothyroidism.

BACKGROUND: The mutations in the dual oxidase maturation factor 2 (DUOXA2) and dual oxidase 2 (DUOX2) genes have been identified in patients with congenital hypothyroidism (CH). This study reports a set of dizygotic twins with CH due to the mutations in the DUOX2/DUOXA2 system. METHODS: The dizygotic twins, a boy and a girl, both aged 7 years, were born to euthyroid nonconsanguineous parents; they were diagnosed with CH at neonatal screening and were enrolled in this study. The DUOXA2, DUOX2, paired box 8 (PAX8), thyroid peroxidase (TPO), and thyrotropin receptor (TSHR) genes were considered for mutation screening. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen for the mutations in the exon fragments. Family members of the patients were also enrolled and evaluated. RESULTS: The fraternal twins each harbored a single heterozygous mutation, including c.738C>G (p.Y246X) in the boy inherited from the paternal DUOXA2 allele and c.2654G>A (p.R885Q) in the girl from the maternal DUOX2 allele. The two mutations have been previously reported. The boy showed enlarged thyroid lobes and a little calcification in the left lobe, while the girl's thyroid gland was severely underdeveloped and the girl had obvious complications due to irregular treatment. The germline mutations from this family were consistent with an autosomal recessive inheritance pattern. No mutations in the PAX8, TPO, and TSHR genes were detected in this study. CONCLUSIONS: The inactivating mutations in the DUOXA2 (p.Y246X) and DUOX2 (p.R885Q) genes were identified in a set of dizygotic twins with CH. The girl was more severe in several aspects than her brother. The similar genetic defect resulted in very different outcomes.

Virtual reality for improving balance in patients after stroke: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of virtual reality interventions for improving balance in people after stroke. DESIGN: Systematic review and meta-analysis of randomized controlled trials. METHODS: Studies were obtained by searching the following databases: MEDLINE, CINAHL, EMBASE, Web of Science and CENTRAL. Two reviewers assessed studies for inclusion, extracted data and assessed trial quality. RESULTS: Sixteen studies involving 428 participants were included. People who received virtual reality interventions showed marked improvements in Berg Balance Scale (mean difference: 1.46, 95% confidence interval: 0.09-2.83, P<0.05, I²=0%) and Timed Up and Go Test (mean difference: -1.62, 95% confidence interval: -3.07- -0.16, P<0.05, I²=24%) compared with controls. CONCLUSIONS: This meta-analysis of randomized controlled trials supports the use of virtual reality to improve balance after stroke.

Two novel TSHR gene mutations (p.R528C and c.392+4del4) associated with congenital hypothyroidism.

Inactivating mutations of the thyrotropin receptor (TSHR) gene are responsible for non-goitrogenic congenital hypothyroidism (CHNG). This study aimed to investigate mutations in the TSHR gene in 20 children with CHNG. Genomic DNA was extracted from peripheral blood leukocytes and was used for mutation screening by direct sequencing. Analyses of the TSHR gene revealed two novel variants in a 2-year-old boy with thyroid hypoplasia: a missense mutation c.1582C>T (p.R528C) and a splice-site deletion c.392+4del4. Bioinformatics analysis demonstrated that both variants are capable of causing disease. Family members of the patient with two mutations and normal controls were also recruited and investigated. Germline mutations from the proband's family were consistent with an autosomal recessive inheritance pattern. These findings indicate that two novel inactivating mutations (p.R528C and c.392+4del4) in the TSHR gene can cause CHNG.

Reliability and validity of center of pressure measures for balance assessment in older adults.

[Purpose] This study was conducted to assess the reliability and validity of center of pressure-based parameters for balance assessment. [Subjects and Methods] Two hundred and forty older adults were evaluated using a force platform and the Berg Balance Scale at 1-week intervals. The intra-class correlation coefficient and the Pearson correlation coefficient were used to test reliability and validity respectively. [Results] The reliability of the 12 selected center of pressure measures was satisfactory (intra-class correlation coefficient = 0.75-0.99) and the validity between the parameters and the Berg Balance Scale was moderate to good (r = -0.62 to -0.88). [Conclusion] Center of pressure-based parameters are reliable and valid measures in older adults.

Effect of Carvedilol on Serum Heart-type Fatty Acid-binding Protein, Brain Natriuretic Peptide, and Cardiac Function in Patients With Chronic Heart Failure.

OBJECTIVE: To observe the changes of serum heart-type fatty acid-binding protein (h-FABP) and brain natriuretic peptide (BNP) in children with chronic heart failure (CHF) and evaluate the effects of carvedilol. METHODS: A total of 36 patients with CHF, including 17 of endocardial fibroelastosis and 19 of dilated cardiomyopathy, were enrolled and were randomly divided into a carvedilol treatment group (group A) and a conventional treatment group (group B). Group A (n = 16) was treated with carvedilol and conventional treatment and group B (n = 20) was managed with conventional treatment only. Thirty healthy children were enrolled as controls. The concentrations of serum h-FABP and BNP were measured by enzyme-linked immunosorbent assay, and the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and cardiac index (CI) were measured by echocardiography. RESULTS: The concentrations of serum h-FABP and BNP in patients with CHF were significantly higher than in the control group (21.7 ± 4.3 ng/mL vs. 6.3 ± 1.7 ng/mL, 582.4 ± 180.6 pg/mL vs.31.2 ± 9.8 pg/mL, all P < 0.01), positively correlated with the degree of heart failure (all P < 0.01), and were both higher in groups endocardial fibroelastosis and dilated cardiomyopathy than in the control group (all P < 0.01), but there was no statistically significant difference between the 2 groups (P > 0.05). h-FABP concentration in patients with CHF was positively correlated with BNP (r = 0.78, P < 0.01) but negatively correlated with LVEF, LVFS, and CI (r = -0.65, -0.64, and -0.71, respectively; all P < 0.01). BNP concentration was also negatively correlated with LVEF, LVFS, and CI (r = -0.75, -0.61, and -0.79, respectively; all P<0.01). After treatment with carvedilol, the serum concentrations of h-FABP and BNP in group A were lower than in group B, and the magnitude of heart rate reduction, improvement of LVEF, LVFS, and CI, and reduction of left ventricular end-systolic diameter and left ventricular end-diastolic diameter in group A were all greater than in group B (all P < 0.01). Treatment with carvedilol had no adverse events. CONCLUSIONS: Serum concentrations of h-FABP and BNP can be used as biomarkers to evaluate the severity of heart failure, and carvedilol can significantly improve heart function in children with CHF.

Novel genetic variants in the TPO gene cause congenital hypothyroidism.

BACKGROUND: Mutations in the dual oxidase maturation factor 2 (DUOXA2) and thyroid peroxidase (TPO) genes have been reported to cause goitrous congenital hypothyroidism (GCH). The aim of this study was to determine the genetic basis of GCH in affected children. METHODS: Thirty children with GCH were enrolled for molecular analysis of the DUOXA2 and TPO genes. All subjects underwent clinical examination and laboratory testing. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen for DUOXA2 and TPO gene mutations in the exon fragments amplified from the extracted DNA. Family members of those patients with mutations were also enrolled and evaluated. RESULTS: Analysis of the TPO gene revealed six genetic variants, including two novel heterozygous mutations, c.1970T> C (p.I657T) and c.2665G> T (p.G889X), and four mutations that have been reported previously (c.670_672del, c.2268dup, c.2266T> C and c.2647C> T). Three patients harbored the same mutation c.2268dup. The germline mutations from four unrelated families were consistent with an autosomal recessive inheritance pattern. Conversely, no mutations in the DUOXA2 gene were detected. CONCLUSION: Two novel inactivating mutations (c.1970T> C and c.2665G> T) in the TPO gene were identified. The c.2268dup mutation occurred frequently. No mutations in the DUOXA2 gene were detected in this study.