Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review.

Glycogen storage disease type 1b (GSD1b) is a rare genetic disorder, resulting from mutations in the SLC37A4 gene located on chromosome 11q23.3. Although the SLC37A4 gene has been identified as the pathogenic gene for GSD1b, the complete variant spectrum of this gene remains to be fully elucidated. In this study, we present three patients diagnosed with GSD1b through genetic testing. We detected five variants of the SLC37A4 gene in these three patients, with three of these mutations (p. L382Pfs*15, p. G117fs*28, and p. T312Sfs*13) being novel variants not previously reported in the literature. We also present a literature review and general overview of the currently reported SLC37A4 gene variants. Our study expands the mutation spectrum of SLC37A4, which may help enable genetic testing to facilitate prompt diagnosis, appropriate intervention, and genetic counseling for affected families.

Neonatal Dubin-Johnson syndrome: biochemical parameters, characteristics, and genetic variants study.

BACKGROUND: The clinical characteristics and gene mutation characteristics of children with Dubin-Johnson syndrome (DJS) need in-depth study. METHODS: The clinical and genomic data of neonatal Dubin-Johnson syndrome (NDJS) and 155 cases with idiopathic cholestasis (IC) were analyzed from June 2016 to August 2020 RESULTS: ABCC2 gene variants were identified in eight patients, including one patient with homozygous variants and seven patients with compound heterozygous variants. A total of 13 different ABCC variants were detected in the NDJS patients, including three nonsense variants, six missense variants, three frameshift variants, and a splice site variant. The variant c.2443C > T (p.R815X), c.4237_4238insCT (p.H1414Lfs*17), c.960_961insGT (p.L322Cfs*3), c.4250delC (p.S1417Ffs*14), c.2224G > A (p.D742N), c.4020G > C (p.K1340N), and c.2439 + 5G > A were not reported in the Human Gene Variant Database. There was no significance in the sex, birth weight, and onset age between the NDJS and IC groups. Compared with the IC group, the NDJS group had significantly higher levels of total bilirubin (TB), but a significantly lower level of alanine transaminase and a ratio of direct bilirubin (DB) to TB. There is no significance in total bile acid, gamma-glutamyl-transpeptidase, albumin, or international normalized ratio between the two groups. CONCLUSIONS: NDJS should be considered in prolonged neonatal intrahepatic cholestasis, especially in infants with normal or slightly elevated transaminase levels. IMPACT: Explore the biochemical parameters, characteristics, and genetic profile of NDJS. By summarizing the characteristics of biochemical indicators, seven new mutation types of the ABCC2 gene were detected, which expanded the mutation spectrum of the ABCC2 gene. NDJS should be considered in prolonged neonatal intrahepatic cholestasis, especially in infants with normal or slightly elevated transaminase levels.

Characterization of novel and large fragment deletions in exon 1 of the IL10RA gene in Chinese children with very early onset inflammatory bowel diseases.

BACKGROUND: Defects in interleukin 10 (IL10) and its receptors are particularly involved in very early onset inflammatory bowel disease (VEOIBD). However, large fragment deletions of IL10 receptor A (IL10RA) are rare. METHODS: VEOIBD patients with confirmed mutations in the IL10RA gene were enrolled from January 1, 2019 to June 30, 2020. The clinical features and endoscopic-radiological findings of the patients with large fragment deletions of the IL10RA gene were determined and followed up. RESULTS: Thirty-five patients with IL10RA gene mutations, namely, 28 compound heterozygous mutations and 7 homozygote mutations, were enrolled in this study. Six patients carried the reported point mutation c.301C > T (p. R101RW) or c.537 G > A (p. T179T) in one locus and a large fragment deletion in exon 1 in another locus, which were novel mutations in this gene. A 333-bp deletion of exon 1 (117857034-11857366 del) was the main mutation in this locus in 85.7% of the patients with large fragment deletions. The time of disease onset ranged from birth to 4 years, and diarrhea was the main initial symptom. In total, 6/7 patients had perianal complications, including perianal abscess, fistula and skin tags. Six patients accepted thalidomide treatment, 5/7 accepted mesalamine, 3/7 accepted hematopoietic stem cell transplantation (HSCT), and 3/7 were waiting for HSCT. CONCLUSIONS: We identified a novel large deletion of exon 1 involving the IL10RA gene for the first time and showed the characteristics of VEOIBD patients. This study expands the spectrum of Chinese VEOIBD patients with IL0RA gene mutations.

An Efficient Topology Discovery Protocol with Node ID Assignment Based on Layered Model for Underwater Acoustic Networks.

Underwater acoustic networks are widely used in survey missions and environmental monitoring. When an underwater acoustic network (UAN) is deployed in a marine region or two UANs merge, each node hardly knows the entire network and may not have a unique node ID. Therefore, a network topology discovery protocol that can complete node discovery, link discovery, and node ID assignment are necessary and important. Considering the limited node energy and long propagation delay in UANs, it is challenging to obtain the network topology with reduced overheads and a short delay in this initial network state. In this paper, an efficient topology discovery protocol (ETDP) is proposed to achieve adaptive node ID assignment and topology discovery simultaneously. To avoiding packet collision in this initial network state, ETDP controls the transmission of topology discovery (TD) packets, based on a local timer, and divides the network into different layers to make nodes transmit TD packets orderly. Exploiting the received TD packets, each node could obtain the network topology and assign its node ID independently. Simulation results show that ETDP completes network topology discovery for all nodes in the network with significantly reduced energy consumption and short delay; meanwhile, it assigns the shortest unique IDs to all nodes with reduced overheads.

Expression of angiopoietin-like protein 2 in ovarian tissue of rat polycystic ovarian syndrome model and its correlation study.

BACKGROUND: This study investigated the expression of angiopoietin-like protein 2 (ANGPTL2) in the tissues of rat models of polycystic ovary syndrome (PCOS) and its correlation with PCOS. METHODS: Six-weeks-old female specific pathogen-free rats (n = 60) were divided into blank control, PCOS model, and metformin groups (n = 20/group). After 21 days of metformin intervention, the serum sex hormones, fasting blood glucose, fasting insulin, and insulin resistance (IR) of rats in each group were measured. The mRNA levels of ANGPTL2, Foxol, and Akt in the ovarian tissues were monitored by real-time fluorescence quantitative PCR. RESULTS: Compared with the control group, the levels of serum sex hormones, fasting blood glucose, fasting insulin, and IR in the model group showed significant increases, and the levels of ANGPTL2, Foxol, and Akt in the ovarian tissue also showed significant increases. Compared with the PCOS group, the serum sex hormones, fasting blood glucose, fasting insulin, and IR of rats in the metformin group were significantly decreased, and the levels of ANGPTL2, Foxol, and Akt in ovarian tissues also showed significant decreases. CONCLUSIONS: These findings suggest that ANGPTL2 might participate in the development of PCOS through the PI3K/Akt signaling pathway. Metformin improves IR by reducing the expression of ANGPTL2, thus improving the endocrine environment of PCOS and might change the disease outcome.

Corrigendum: Alterations of Gut Microbiota in Cholestatic Infants and Their Correlation With Hepatic Function.

[This corrects the article DOI: 10.3389/fmicb.2018.02682.].

[Value of serum gamma-glutamyl transpeptidase combined with direct bilirubin in the diagnosis of biliary atresia in infants].

OBJECTIVE: To study the value of serum gamma-glutamyl transpeptidase (GGT) combined with direct bilirubin (DB) in the diagnosis of biliary atresia. METHODS: A total of 667 infants with cholestasis who were hospitalized and treated from July 2010 to December 2018 were enrolled as subjects. According to the results of intraoperative cholangiography and follow-up, they were divided into biliary atresia group with 234 infants and cholestasis group with 433 infants. The two groups were compared in terms of age of onset, sex, and serum levels of total bilirubin (TB), DB, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA), and GGT. A receiver operating characteristic (ROC) curve analysis was performed for indices with statistical significance, and the area under the ROC curve (AUC) and the optimal cut-off value for diagnosis were calculated. RESULTS: The biliary atresia group had a significantly younger age of onset than the cholestasis group (P<0.001). There were no significant differences in sex, ALT, and AST between the two groups (P>0.05), while the biliary atresia group had significantly higher serum levels of TB, DB, TBA, and GGT than the cholestasis group (P<0.05). GGT combined with DB had the highest AUC of 0.892 (95% confidence interval: 0.868-0.916) in the diagnosis of biliary atresia. At the optimal cut-off values of 324.0 U/L for GGT and 115.1 µmmol/L for DB, GGT combined with DB had a sensitivity of 79.8% and a specificity of 83.2% in the diagnosis of biliary atresia. CONCLUSIONS: GGT combined with DB has high sensitivity and specificity in the diagnosis of biliary atresia and can be used as an effective indicator for diagnosis of biliary atresia in infants.

Hierarchy Graph Based Barrier Coverage Strategy with a Minimum Number of Sensors for Underwater Sensor Networks.

Underwater sensor networks ( UWSNs ) based barrier coverage is increasingly important for intrusion detection due to the scarcity of underwater sensor resource. To improve UWSNs' detection performance and prolong their lifetime, an efficient barrier coverage strategy is very important. In this paper, a novel concept: hierarchy graph is proposed. Hierarchy graph can make the network's topology more clarity. In accordance with the hierarchy graph, 1-barrier coverage algorithm and k-barrier coverage algorithm are presented to construct the barrier with less sensors for higher energy efficiency. Both analytical and simulation studies demonstrate that the proposed algorithms can provide high detection probability and long lifetime for UWSNs.

Persistent cholestasis resulting from duodenal papillary carcinoma in an adolescent male: A case report.

RATIONALE: Cholestasis in pediatric patients has diverse etiologies and can be broadly classified as intrahepatic or extrahepatic. The common causes of extrahepatic cholestasis are bile duct calculus, inflammation, or pancreatitis. Malignant tumor is a rare cause of bile ducts obstruction in adolescent. Here we report a 14-year-old male patient with cholestasis due to poorly differentiated adenocarcinoma. PATIENT CONCERNS: A 14-year-old male patient with cholestasis was admitted because of jaundice, weakness, weight loss, and stomach pain for 2 months. The patient had been diagnosed with epilepsy 4 years previously and was being treated with sodium valproate and oxcarbazepine. On admission, laboratory studies showed elevated levels of aspartate aminotransferase (271 IU/L), alanine aminotransferase (224 IU/l), γ-glutamyltransferase (1668.9 IU/L), total bilirubin (66.4 µmol/L), and direct bilirubin (52.6 µmol/L). Additional laboratory tests eliminated common causes of cholestasis such as bacterial/viral infection, autoimmune liver disease, Wilson disease, Alagille syndrome, or progressive familial intrahepatic cholestasis type 3. The results of laboratory investigations showed no improvement after 10 days of treatment with ursodeoxycholic acid and vitamins A, D, and K1. Enhanced magnetic resonance imaging demonstrated a tumor of 22 mm diameter in the duodenal lumen and dilatation of the common bile duct. Endoscopic retrograde cholangiopancreatography detected a tumor in the duodenal lumen. DIAGNOSIS: Considering the clinical features, imaging manifestation, endoscopic findings, and pathologic characteristic, the patient was diagnosed with poorly differentiated adenocarcinoma. INTERVENTIONS: The patient underwent pancreaticoduodenectomy and chemotherapy. OUTCOME: The patient recovered well. Elevated levels of tumor biomarkers or abnormal liver function tests have not occurred during the 2-year follow-up. CONCLUSION: Cholestasis resulting from primary duodenal papillary carcinoma is rare in pediatric patients but should be considered in the differential diagnosis.

Alterations of Gut Microbiota in Cholestatic Infants and Their Correlation With Hepatic Function.

Cholestasis is a major hepatic disease in infants, with increasing morbidity in recent years. Accumulating evidence has revealed that the gut microbiota (GM) is associated with liver diseases, such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, GM alterations in cholestatic infants and the correlation between the GM and hepatic functions remain uninvestigated. In this study, 43 cholestatic infants (IC group) and 37 healthy infants (H group) were enrolled to detect GM discrepancies using 16S rDNA analysis. The diversity in the bacterial community was significantly lower in the IC group than that in the H group (P = 0.013). After determining the top 10 abundant genera of microbes in the IC and H groups, we found that 13 of them were differentially enriched, including Bifidobacterium, Bacteroides, Streptococcus, Enterococcus, and Staphylococcus. As compared with the H group, the IC group had a more complex GM co-occurrence network featured by three core nodes: Phyllobacterium, Ruminococcus, and Anaerostipes. In addition, the positive correlation between Faecalibacterium and Erysipelatoclostridium (r = 0.689, P = 0.000, FDR = 0.009) was not observed in the IC patients. Using the GM composition, the cholestatic patients can be distinguished from healthy infants with high accuracy [areas under receiver operating curve (AUC) > 0.97], wherein Rothia, Eggerthella, Phyllobacterium, and Blautia are identified as valuable biomarkers. Using KEGG annotation, we identified 32 functional categories with significant difference in enrichment of the GM of IC patients, including IC-enriched functional categories that were related to lipid metabolism, biodegradation and metabolism of xenobiotics, and various diseases. In contrast, the number of functions associated with amino acid metabolism, nucleotide metabolism, and vitamins metabolism was reduced in the IC patients. We also identified significant correlation between GM composition and indicators of hepatic function. Megasphaera positively correlated with total bilirubin (r = 0.455, P = 0.002) and direct bilirubin (r = 0.441, P = 0.003), whereas γ-glutamyl transpeptidase was positively associated with Parasutterella (r = 0.466, P = 0.002) and negatively related to Streptococcus (r = -0.450, P = 0.003). This study describes the GM characteristics in the cholestatic infants, illustrates the association between the GM components and the hepatic function, and provides a solid theoretical basis for GM intervention for the treatment of infantile cholestasis.

Path Diversity Improved Opportunistic Routing for Underwater Sensor Networks.

The packets carried along a pre-defined route in underwater sensor networks are very vulnerble. Node mobility or intermittent channel availability easily leads to unreachable routing. Opportunistic routing has been proven to be a promising paradigm to design routing protocols for underwater sensor networks. It takes advantage of the broadcast nature of the wireless medium to combat packet losses and selects potential paths on the fly. Finding an appropriate forwarding candidate set is a key issue in opportunistic routing. Many existing solutions ignore the impact of candidates location distribution on packet forwarding. In this paper, a path diversity improved candidate selection strategy is applied in opportunistic routing to improve packet forwarding efficiency. It not only maximizes the packet forwarding advancements but also takes the candidate’s location distribution into account. Based on this strategy, we propose two effective routing protocols: position improved candidates selection (PICS) and position random candidates selection (PRCS). PICS employs two-hop neighbor information to make routing decisions. PRCS only uses one-hop neighbor information. Simulation results show that both PICS and PRCS can significantly improve network performance when compared with the previous solutions, in terms of packet delivery ratio, average energy consumption and end-to-end delay.

A Double Rate Localization Algorithm with One Anchor for Multi-Hop Underwater Acoustic Networks.

Localization is a basic issue for underwater acoustic networks (UANs). Currently, most localization algorithms only perform well in one-hop networks or need more anchors which are not suitable for the underwater environment. In this paper, we proposed a double rate localization algorithm with one anchor for multi-hop underwater acoustic networks (DRL). The algorithm firstly presents a double rate scheme which separates the localization procedure into two modes to increase the ranging accuracy in multi-hop UANs while maintaining the transmission rate. Then an optimal selection scheme of reference nodes was proposed to reduce the influence of references' topology on localization performance. The proposed DRL algorithm can be used in the multi-hop UANs to increase the localization accuracy and reduce the usage of anchor nodes. The simulation and experimental results demonstrated that the proposed DRL algorithm has a better localization performance than the previous algorithms in many aspects such as accuracy and communication cost, and is more suitable to the underwater environment.

Mutations in Interleukin-10 Receptor and Clinical Phenotypes in Patients with Very Early Onset Inflammatory Bowel Disease: A Chinese VEO-IBD Collaboration Group Survey.

BACKGROUND: Interleukin-10 (IL10) signaling plays an important role in the pathogenesis of very early onset inflammatory bowel disease (VEO-IBD) in children. However, little is known about the role of the IL10 axis in children with VEO-IBD in China. METHODS: The Chinese VEO-IBD Collaboration Group was created to collect clinical and genetic data from patients deficient in IL10 and the IL10 receptor. High-throughput sequencing was performed to identify mutations in these genes. RESULTS: We identified 32 compound heterozygous mutations and 9 homozygous mutations in IL10 receptor subunit alpha and 1 homozygous mutation in IL10 receptor subunit beta. Among these mutations, 10 novel mutations were identified, and 6 pathogenic mutations had been previously described. In patients with IL10 receptor subunit alpha mutations, c.301C>T (p.R101RW) and c.537 G>A (p.T179T) were the most common mutations. For 88.1% of the patients, the initial symptom was diarrhea, with a time of onset of 10.4 ± 8.0 days. Oral ulcers were the first symptom in 23.8% of the patients, with a time of onset of 9.7 ± 2.8 days. Extraintestinal manifestations included perianal abscesses (22/42), perianal fistulas (23/42), oral ulcers (20/42), and recurrent eczema (15/42). Twelve patients underwent enterostomy. These patients also had lower average Z scores in height-for-age and weight-for-age. Various treatment strategies were used, including fecal microbiota transplantation; however, only hematopoietic stem cell transplantation was efficacious. CONCLUSIONS: This study identified genotypes and phenotypes of Chinese VEO-IBD infants with IL10 receptor mutations. Our study expands the current knowledge on the involvement of the IL10 axis in patients with VEO-IBD.