Inheritance analysis and family history for microtia: A hospital-based study in China.

OBJECTIVES: Microtia is a congenital anomaly of the outer ear. Although genetic and environmental factors could play a role, no consensus has been established on the pathogenesis and cause of this condition. In this study, we surveyed the frequency and pattern of family history in patients with microtia in a Chinese specialty clinic population. METHODS: We evaluated data from 672 patients (mean age = 9.2, male-to-female ratio = 2.6:1) with microtia admitted to the Department of Auricular Reconstruction at the Plastic Surgery Hospital of Peking Union Medical College from December 2014 to February 2016. Family history of congenital ear anomalies across three generations was recorded. Pearson chi-square test or Fisher exact test was used to test the associations between the characteristics of microtia and hereditary features. RESULTS: A family history of auricle anomalies was identified in 202 patients (30.1%), of whom, 95 families showed vertical transmission, 14 families skipped a generation, and 120 families showed family aggregations. The incidence of family history varied with grades of microtia (P = 0.001). Patients with preauricular tags or pits (38.3%) had a higher familial incidence of microtia than those with simple microtia (24.1%) (P < 0.001). CONCLUSION: Patients with a lower grade of microtia demonstrated a higher incidence of family history. Patients with microtia had significantly more relatives with preauricular tags or pits. Microtia and preauricular tags or pits are different manifestations of the same defect, and their significant concurrency among relatives suggests that a considerable proportion of microtia is inherited and could recur with varying degrees of severity in other family members.

Functional Pathway and Process Enrichment Analysis of Genes Associated With Morphological Abnormalities of the Outer Ear.

Congenital anomalies of the outer ear are common birth defects, including a variety of congenital deformities or malformations ranging from mild structural anomalies to total absence of the ear. Despite its high incidence and detrimental impact on patients, the etiology of outer ear abnormalities remains poorly understood. The goal of this study was to summarize the related genes and improve our understanding of the genetic etiology of morphological abnormalities of the outer ear. Human Phenotype Ontology (HPO) database, Mouse Genome Informatics (MGI) database, and PubMed search engine were used to acquire the genes associated with abnormal human or mouse outer ear. Metascape was employed on the genes above to conduct functional annotation, pathway and process enrichment analysis, protein-protein interaction network analysis, and MCODE component analysis. After a comprehensive review of the databases and literature, we identified 394 human genes and 148 mouse genes that have been associated with abnormal phenotypes of the outer ear, and we identified several biological pathways for human and mouse respectively. Especially, the analysis of common genes shared by human and mouse emphasized the importance of certain genes ( PAX6 , PBX1 , HOXA1 , HOXA2 , TBX1 , TBX15 , PRRX1 , and HMX1 ) in the embryonic development of the external ear. Through our analysis of genes associated with morphological abnormalities of the outer ear, the authors have shown that embryonic development pathways take important roles in the morphogenesis of abnormal external ear and highlighted some potential genetic drivers.

A novel method to accurately locate the reconstructed auricle.

Background: Congenital microtia is a common congenital disease in children, the cause of which is still unclear. At present, the main treatment for congenital microtia is ear reconstruction. Accurately locating of the reconstructed ear on the affected side before ear reconstruction surgery is difficult, while it is the key of successful operation. Our ear reconstruction team has developed a novel method to accurately locate the reconstructed auricle. This novel method has achieved good results in clinical practice. Methods: Thirty patients with unilateral ear reconstruction, who underwent auricle reconstruction using our invented auricle reconstruction positioning method in the Plastic Surgery Hospital of Chinese Academy of Medical Sciences from January 2020 to July 2021, were enrolled in this study. Results: Through Wilcoxon signed rank test, we found that there was no statistical difference between the mean distance from the highest point of the patient's normal ear to the central axis of the nose and that from the highest point of the reconstructed ear to the central axis of the nose (P>0.05). Meanwhile, there was no statistical difference between the mean distance from the lowest point of the patient's normal ear to the central axis of the nose and that from the lowest point of the reconstructed ear to the central axis of the nose (P>0.05). The satisfaction rate of patients and their families to the location of the reconstructed auricle was 100%. Conclusions: The novel method of locating the reconstructed auricle employs simple materials. The implementation process is easy, and the effect is significant. To a certain extent, it solves the difficulty of locating the reconstructed auricle in ear reconstruction operation. Although this method can only be applied to patients with unilateral microtia, we recommend it for locating the reconstructed auricle by every plastic surgeon.

Classification and Surgical Strategies of Constricted Ears in a Chinese Specialty Clinic: A Retrospective Study.

BACKGROUND: The constricted ear is an auricular deformity produced by a deficiency in the circumference of the helical rim. The classification and corrective methods for constricted ears continue to be controversial. In order to identify them, the authors have reviewed and analyzed cases operated in a Chinese specialty clinic. METHODS: Correction of constricted ears from January of 2017 to June of 2021 was retrospect through medical records. Data of patients' variables (including sex, age, laterality, type of constricted ear, presence of other ear anomalies), surgical techniques, esthetic outcomes, and postoperative complications have been collected. RESULTS: The deformed ears were classified into four graded types by three criteria including deficiency of auricle cartilage, vertical height in dorsal view, and surgical outcome. A total of 68 constricted ears of 57 patients (type I, n = 6; type IIA, n = 41; type IIB, n = 19, and type III, n = 2) were enrolled in the study. Of the 66 constricted ears undergoing surgical correction, most of them were performed with helical expansion through auricular/costal cartilage graft, Mustardé-type mattress sutures, and tumbling cartilage flap. External molding using Vaseline gauze rolls was implemented on every case to assist reshaping the scapha. A triangular superficial temporal fascial flap was elevated to prevent the reoccurrence of lidding in some cases. Corrective techniques and esthetic outcomes for deformed cases of each graded type were described. Based on a four-point Likert scale, the average esthetic outcome score was 3.7. CONCLUSIONS: The classification was practical and the constricted ears were effectively corrected by simple surgical procedures without removal of deformed auricular cartilage. All corrections were performed in one stage. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Comparison of Auricle Reconstruction Using Tissue Expanders With Skin Grafting and Auricle Reconstruction Using Tissue Expanders Without Skin Grafting: A Single-Arm Meta-Analysis.

OBJECTIVE: The authors conducted this meta-analysis to compare the efficacy of auricle reconstruction using tissue expanders with skin grafting and auricle reconstruction using tissue expanders without skin grafting by comparing the 6 major evaluation indicators. METHODS: The databases such as PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP information databases were searched. RESULTS: By comparison, the authors found that, the satisfaction rate, the incidence of postoperative hematoma, the incidence of postoperative incision infection, and the incidence of cartilage framework exposure of patients with auricle reconstruction using tissue expanders with skin grafting were all lower than those with auricle reconstruction using tissue expanders without skin grafting. However, the incidence of postoperative skin necrosis, the incidence of leakage or exposure of expanders in patients with auricle reconstruction using tissue expanders with skin grafting were all higher than those with auricle reconstruction using tissue expanders without skin grafting. CONCLUSIONS: Auricle reconstruction using tissue expanders with skin grafting has advantages in reducing the incidence of postoperative hematoma, the incidence of postoperative incision infection, and the incidence of cartilage framework exposure. Auricle reconstruction using tissue expanders without skin grafting has advantages in improving the satisfaction rate, reducing the incidence of postoperative skin necrosis, and the incidence of leakage or exposure of expanders. From the comparison of specific data, there is no significant difference in the treatment effect between the 2 surgical methods.

Heterogeneity of Accompanying Phenotypes and Genomic Variants Involved in Microtia.

OBJECTIVES: The symptoms associated with microtia are ever-changing and not to stick to 1 pattern. The symptoms associated with microtia are constantly changing and are not set in stone. The aim of this article was to describe the various phenotypes from multiple systems found in microtitis patients included in the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources database, and to analyze possible pathogenic mutations. METHODS: DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources is an interactive web-based database, which incorporates a suite of tools designed to aid the interpretation of genomic variants. The term "microtia" was used as the search term, and the data extracted from the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources for this study was updated until October 2020. Pearson chi-squared test was used to test associations between types of genomic variants and the pathogenicity of variants. RESULTS: Of the 386 cases enrolled in the study, 99% (n = 382) had 1 or more associated abnormalities. The most frequently detected abnormalities were those of the face and neck (n = 362 [93.8% of all cases]); musculoskeletal system (n = 337 [87.3%]); and nervous system (n = 334 [86.5%]), followed by abnormalities of limbs (n = 252 [65.3%]); the eye (n = 212 [54.9%]); and the integument (n = 200 [51.8%]). Besides, a total of 479 genomic variants were determined, including sequence variants and copy number variants (loss and gain). The pathogenicity of loss-type variants was significantly higher among other types (P < 0.001). Twelve sharing variants had more than 5 repeats, and the repeated fragments were concentrated on chromosome 3, 7, 9, 10, 11, 15, 17, 18, and 22. CONCLUSIONS: Identification of the relation between phenotypes and genotypes will facilitate the uncovering of the mechanism of microtia and the study of potential therapeutic targets.

Utility of a Ruler for Reconstructed Auricle Positioning.

PURPOSE: This study evaluated the utility of a ruler for reconstructed article positioning. METHODS: Forty-seven patients with unilateral microtia were selected from August 2020 to September 2021. RESULTS: The linear distance from the highest point of the reconstructed auricle to the central axis of the nose was not significantly different from the distance from the highest point of the normal contralateral auricle to the central axis of the nose (P>0.05). The distance from the lowest point of the reconstructed auricle to the central axis of the nose was not significantly different from the distance from the lowest point of the normal auricle to the central axis of the nose (P>0.05). The linear distance from the highest to the lowest point of the reconstructed auricle was not significantly different from the distance from the highest to the lowest point of the normal auricle (P>0.05). These results indicate that the reconstructed auricle was symmetrical to the contralateral ear. CONCLUSION: The positioning ruler evaluated in this study is simple, easy to use, accurate, and non-invasive.

The morphological changes of thorax in pediatric microtia patients after costal cartilage harvesting.

BACKGROUND: The surgical treatment of microtia generally starts in childhood, and costal cartilage is the most widely used material for auricular reconstruction. However, multiple costal cartilage harvests lead to local cartilage defects, which may influence the growth of the hemithorax, that need close attention by doctors. In this study, morphological changes of the thorax were measured and analyzed in different follow-up groups. METHODS: Twenty-eight adolescent microtia patients underwent auricular reconstruction using 6th-8th costal cartilage. Thoracic computed tomography (CT) with three-dimensional reconstruction was performed preoperatively and during follow-up. Comparison of the hemithorax on the operated and unoperated sides was performed by measuring several thoracic parameters using Mimics software (Materialise, Belgium). The data were further analyzed by a paired-samples t-test. RESULTS: In the operated hemithorax, the costochondral junction midpoints moved medially (6th-8th), posteriorly (6th-7th) and descended less (6th-9th) with significant differences as P < 0.05 compared to the unoperated hemithorax. In addition, height differences indicated local depressions in the chest wall in the areas of cartilage defects (6th-9th, P < 0.05). Following local depression of the chest wall and migration of the ribs, the operated hemithorax also had a smaller area than the unoperated hemithorax (6th-9th, P < 0.05). The differences in the hemithorax were more significant in the midterm group (5-10 y) than in the other follow-up groups, while most parameters showed no significant differences in the long-term group (10-15 y). No significant differences were found in the modified Haller index. CONCLUSION: Multiple costal cartilage harvests caused morphological changes and asymmetry of the thorax in adolescent patients. As indicated by thoracic CT, significant changes occurred in the local area of cartilage defects, which did not affect the overall thorax. In the long term, more than 10 years after harvesting, the differences in the hemithorax between the operated and unoperated sides decreased significantly. This study provides an important reference for thoracic changes when applying auricular reconstruction in the pediatric microtia patients.

Comparison of auricle reconstruction with expanded flaps and auricle reconstruction with non-expanded flaps in patients with microtia: A meta-analysis.

OBJECTIVE: We conducted this meta-analysis to compare the efficacy of these two surgical methods by comparing the incidence of major evaluation indicators. METHODS: The databases such as PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP information databases were searched. RESULTS: The satisfaction rate of patients with auricle reconstruction using expanded flaps was 86.5%, and the satisfaction rate of patients with auricle reconstruction using non-expanded flaps was 87.9%. The incidence of postoperative hematoma was 2.5% in patients with auricle reconstruction using expanded flaps and 18.9% in patients with auricle reconstruction using non-expanded flaps. The incidence of postoperative skin necrosis was 1.2% in patients with auricle reconstruction using expanded flaps and 4.1% in patients with auricle reconstruction using non-expanded flaps. The incidence of postoperative incision infection was 2.4% in patients with auricle reconstruction using expanded flaps and 0.9% in patients with auricle reconstruction using non-expanded flaps. The incidence of cartilage framework exposure was 2.2% in patients with auricle reconstruction using expanded flaps and 1.9% in patients with auricle reconstruction using non-expanded flaps. The incidence of postoperative scar hyperplasia was 3.8% in patients with auricle reconstruction using expanded flaps and 3% in patients with auricle reconstruction using non-expanded flaps. The publication bias of included literature was evaluated by Egger test. There was no publication bias in this Meta-analysis (P > .05). CONCLUSION: The auricle reconstruction using non-expanded flaps is dominant in four of the six evaluation indexes. Therefore, we believe that the auricle reconstruction using non-expanded flaps has better therapeutic effect in patients with microtia. Due to the limitations of this meta-analysis, the conclusions of this meta-analysis still need to be further verified.

A study on the therapeutic effects of biplane skin dilator implantation in auricular reconstruction.

This study aimed to compare the therapeutic effects of biplane skin dilator implantation with those of conventional skin dilator implantation in auricular reconstruction. A total of 137 patients with microtia who met the inclusion criteria from January 2020 to April 2021 were retrospectively selected. Sixty-three patients comprised the control group and were implanted with a skin expander using the conventional method. Seventy-four patients comprised the experimental group and were implanted with a skin expander using the biplane method. Non-parametric tests were used to compare the down-moving distance of the skin dilator between the experimental group and the control group. There was a statistically significant difference in the down-moving distance of the skin dilator between the experimental group and the control group (P < 0.05). The chi-square test showed no significant difference in postoperative complications between the experimental group and the control group (P > 0.05). Moreover, there was no significant difference in the satisfaction rate of patients and their families between the experimental group and the control group (P > 0.05). In this study, the treatment effect of biplane skin dilator implantation was better than that of conventional skin dilator implantation.

Clinical Observations of a Surgical Method Comprising a Combination of Cross Flap and Autologous Auricular Cartilage Transplantation in the Treatment of Type I to III Congenital Concha-Type Microtia.

OBJECTIVES: The present study attempted to investigate the clinical efficacy of a surgical method involving a combination of cross flap with autologous auricular cartilage transplantation in the treatment of type I to III congenital concha-type microtia. METHODS: The present retrospective study was conducted on the clinical and postoperative data of 50 patients with unilateral type I to III concha-type microtia treated with a combination of cross flap and autologous auricular cartilage transplantation at the Plastic Surgery Hospital of Chinese Academy of Medical Sciences from January 2018 to December 2021. RESULTS: The postoperative perimeters of malformed ears were significantly larger than the preoperative perimeters (P < .05). Of the total, 2 patients exhibited incision dehiscence, 3 patients exhibited incision infection, 2 patients exhibited flap hematoma, and 1 patient exhibited ischemic necrosis at the flap tip. The satisfaction rate of the patients and their families was 100%. CONCLUSIONS: The surgical method involving a combination of cross flap and autogenous auricular cartilage transplantation was effective in treating patients with type I to III congenital concha-type microtia, and therefore, this surgical approach can be applied widely to correct this deformity.

Generation of an induced pluripotent stem cell line from a congenital microtia patient with 4p16.1 microduplication involving the long-range enhancer of HMX1.

Congenital microtia is a malformation of the middle and external ear. Duplications involving the ECR, an ear-specific long-range enhancer of HMX1, lead to ear malformation in different species. Use of electroporation of episomal plasmids encodes OCT4, SOX2, NANOG, LIN28, KLF4, and LMYC into peripheral blood mononuclear cells (PBMCs), we generated an induced pluripotent stem cell (iPSCs) line of a microtia patient carrying the duplication involving ECR. The iPSCs express pluripotency markers, have the potential to differentiate into three germ layers, and show the normal karyotype. This patient-specific iPSC will be used for modeling the pathophysiology of ear malformation.

Evaluation of respiratory system anomalies associated with microtia in a Chinese specialty clinic population.

BACKGROUND: Microtia is a congenital malformation of the external ear often with one or more associated congenital anomalies. The purpose of this study was to identify the characteristics and prevalence of respiratory anomalies in patients with microtia, and clarify the importance of this association in the perioperative period of patients' external ear reconstruction surgery. METHODS: Data were collected from 923 microtia patients between August 2017 and December 2020 in the Department of Auricular Reconstruction at the Plastic Surgery Hospital of Peking Union Medical College. Co-occurring respiratory anomalies were detected using chest computed tomography plus three-dimensional reconstruction and Chest X-ray. Physical examination was performed to assess the severity and type of microtia by trained clinicians. Fisher's exact test was used to analyze the relation between laterality of pulmonary underdevelopment and microtia type. RESULTS: Among the 923 participants enrolled in the study, we identified 21 cases (2.3%) having respiratory system anomalies, consisting of 6 cases with pulmonary underdevelopment (28.6% of all anomalies of respiratory system detected), 2 cases with tracheal bronchus (9.5%), 1 case with tracheal diverticula (4.8%), 11 cases with lung bullae(52.4%), and 1 case with pulmonary azygos lobe (4.8%). The laterality of pulmonary underdevelopment was related to the type of microtia (difference between types, p < 0.05), as patients with concha-type remnant ear had pulmonary underdevelopment ipsilaterally. CONCLUSIONS: This study represents the first detailed and thematic study of a association featured by microtia and respiratory anomalies. Characteristics and prevalence of respiratory anomalies was observed in a Chinese clinical microtia population. Early diagnosis of associated respiratory malformations had practical clinical significance for microtia patients, plastic surgeons and anesthesiologists. Future studies are required to improve understanding of this association and its cause.

Whole-exome sequencing analysis in 10 families of sporadic microtia with thoracic deformities.

BACKGROUND: Microtia is a congenital malformation of the external ear and may occur as an isolated deformity or as part of a syndrome. Our previous study found a high correlation between microtia and thoracic deformities, thus, we propose that external ear and thorax development may be regulated by certain genes in common. METHODS: We performed exome sequencing on 10 families of sporadic microtia with thoracic abnormalities. We identified mutated genes under different models of inheritance, and checked them through Mouse Genome Informatics and association analysis. RESULTS: We identified 45 rare mutations, including 9 de novo mutations, 20 heterozygous mutations, 3 homozygous mutations, and 13 hemizygous mutations, of which 2 are likely to be causative. They are de novo missense variant in PHF5A and compound heterozygous mutations in CYP26B1, of which CYP26B1 mutation is highly likely pathogenic. CONCLUSION: The results indicate that certain genes may affect both external ear and thorax development, and demonstrate the benefits of whole-exome sequencing in identifying candidate genes of microtia. This study provides a new way for genetic exploration in microtia.

Identification of a novel CYP26A1 mutation in a Chinese family with congenital microtia.

OBJECTIVES: Microtia is defined as a congenital malformation characterized by a small, abnormally shaped auricle, with atresia or stenosis of the auditory canal. This study investigated a mutation of the cytochrome P450, family 26, subfamily A, polypeptide 1(CYP26A1) gene, which is considered important in craniofacial development, in a family affected with microtia. METHODS: Whole-exome sequencing (WES) was performed on the proband and his family members to identify disease-associated variants. Computational predictions of the altered protein were analyzed using several bioinformatics tools. The wild-type (WT) and mutant forms of CYP26A1 cDNA were transfected into human embryonic kidney cells, and the mRNA and protein levels were compared using quantitative polymerase chain reaction (qPCR) and Western blot analyses. RESULTS: In this two-generation family, the proband and his mother were diagnosed with unilateral microtia. Unilateral microtia and ipsilateral accessory ear were observed in one of the twins, who were sisters of the proband. The father and the other twin showed no abnormal clinical features. A heterozygous mutation of a C to T in the CYP26A1 gene, which leads to truncation of the CYP26A1 protein, was identified in this family. The nonsense mutation cosegregated with patients and was absent in normal members of the family. The prediction software indicated that it was a possibly pathogenic mutation. The structure of the protein varied significantly between the WT and mutant proteins. Functional analysis showed that this mutation caused a significant decrease in both the mRNA and protein levels. CONCLUSIONS: Our findings suggest that this mutation of CYP26A1 may be a pathogenic factor leading to the phenotypes of microtia and accessory ear in this family. Further studies are needed to prove the function of this mutation and to explore the possible mechanism by which this variant is involved in the occurrence of microtia.

Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia.

HOX genes are important regulatory genes patterning head formation, including development of the ear. Microtia is a congenital ear anomaly characterized by lacking all or part of the structures of the outer ear. To date, only four HOXA2 mutations were reported in families with autosomal-recessive or dominant microtia, with or without hearing impairment. More identified mutations are needed to confirm the correlation between genotype and phenotype. Here, we collect two Chinese families with non-syndromic bilateral microtia. Next generation sequencing identified two heterozygous nonsense HOXA2 mutations, one in each family. One mutation (c.637A > T, p.Lys213*) is newly reported, while the other one (c.703C > T,p.Gln235*) is consistent with a previous report. In mouse, Hoxa2 can bind to a long-range enhancer and regulate expression of the Hmx1 gene, which is a crucial transcription factor in eye and ear development. Using dual luciferase reporter assays, we showed that both HOXA2 mutations have impaired activation of the long-range enhancer of HMX1. In the present study, we report the first two bilateral non-syndromic microtia cases with HOXA2 mutations of Chinese origin and identify a novel mutation. Our results also provide molecular insights about how these nonsense HOXA2 mutations could affect the activation of its downstream target HMX1 by interacting with the long-range enhancer.

Duplications involving the long range HMX1 enhancer are associated with human isolated bilateral concha-type microtia.

BACKGROUND: Microtia is a congenital anomaly of ear that ranges in severity from mild structural abnormalities to complete absence of the outer ears. Concha-type microtia is considered to be a mild form. The H6 family homeobox 1 transcription factor gene (HMX1) plays an important role in craniofacial structures development. Copy number variations (CNVs) of a downstream evolutionarily conserved enhancer region (ECR) of Hmx1 associated with ear and eye abnormalities have been reported in different animals, but not yet in human. To date, no genetic defects responsible for isolated human microtia has been reported except for mutations in HOXA2. Here we recruited five Chinese families with isolated bilateral concha-type microtia, and attempt to identify the underlying genetic causes. METHODS: Single Nucleotide polymorphism (SNP) array was performed to map the disease locus and detect CNVs on a genome scale primarily in the largest family (F1). Whole genome sequencing was performed to screen all SNVs and CNVs in the candidate disease locus. Array comparative genomic hybridization (aCGH) was then performed to detect CNVs in the other four families, F2-F5. Quantitative real-time polymerase chain reaction (qPCR) was used to validate and determine the extent of identified CNVs containing HMX1-ECR region. Precise breakpoints in F1 and F2 were identified by gap-PCR and sanger sequencing. Dual-luciferase assays were used to detect the enhancer function. qPCR assays were also used to detect HMX1-ECR CNVs in 61 patients with other types mictrotia. RESULTS: Linkage and haplotype analysis in F1 mapped the disease locus to a 1.9 Mb interval on 4p16.1 containing HMX1 and its downstream ECR region. Whole genome sequencing detected no potential pathogenic SNVs in coding regions of HMX1 or other genes within the candidate disease locus, but it detected a 94.6 Kb duplication in an intergenic region between HMX1 and CPZ. aCGH and qPCRs also revealed co-segregated duplications in intergenic region downstream of HMX1 in the other four families. The 21.8 Kb minimal overlapping region encompassing the core sequences consensus with mouse ECR of Hmx1. Luciferase assays confirmed the enhancer function in human sequences, and proved that HOXA2 could increase its enhancer activity. No CNVs were detected in HMX1-ECR regions in 61 patients with other type of microtia. CONCLUSION: Duplications involving long range HMX1 enhancers are associated with human isolated bilateral concha-type microtia. We add to evidences in human that copy number variations in HMX1-ECR associates with ear malformations, as in other species. This study also provides an additional example of functional conserved non-coding elements (CNEs) in humans.

Diagnostic accuracy of imaging modalities in differentiating xanthogranulomatous cholecystitis from gallbladder cancer.

BACKGROUND: The aim of this study was to assess the diagnostic performance of radiological imaging in differentiating xanthogranulomatous cholecystitis (XGC) from gallbladder cancer (GBC). METHODS: A retrospective analysis of the radiological imaging performed in patients who had pathologically confirmed XGC or GBC between December 2004 to April 2016 was performed. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each imaging modality, and combined imaging modalities were calculated. RESULTS: A total of 218 patients (XGC =109, GBC =109) were identified; 19 patients received all of abdominal ultrasound (US), contrast-enhanced ultrasound (CEUS), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT); 21 received four of these imaging examination types; 45 received three examinations; 58 received two examinations; and 75 received only one examination. The sensitivity and specificity of CEUS was 90% and 93%, respectively, higher than abdominal US (80%, 86%), CT (71%, 92%), MRI (75%, 90%), and PET/CT (55%, 90%) (all values respective). The sensitivity, specificity, NPV, and PPV of the US combined with CEUS were 91%, 90%, 94%, and 85%, respectively. Although the specificity of CEUS + CT and CEUS + MRI were 100% and 92%, respectively, the sensitivity of CEUS + CT and CEUS + MRI were both only 67%. CONCLUSIONS: The Abdominal US is not sufficiently accurate to confidently guide clinical practice, and CEUS showed better diagnostic performance than the other imaging modalities in differentiating XGC from GBC. The combination of abdominal CEUS and CT is helpful for differential diagnosis, as it indicates GBC with better specificity and PPV.

Nesfatin-1 stimulates fatty-acid oxidation by activating AMP-activated protein kinase in STZ-induced type 2 diabetic mice.

Nesfatin-1 is an anorexigenic peptide involved in energy homeostasis. Recently, nesfatin-1 was reported to decrease blood glucose level and improve insulin sensitivity in high-fat diet-fed rats. However, little information is known about the influence of nesfatin-1 on lipid metabolism either in physiological or diabetic condition. This study undertook whether nesfatin-1 was involved in the pathophysiology in Streptozotocin-induced type 2 diabetic mice (T2DM), which was induced by a combination of high-calorie diet and two low-doses Streptozotocin. We observed that plasma nesfatin-1 was significantly increased while expression of nesfatin-1 neurons were decreased in hypothalamus in diabetes group compared to only high-calorie diet control group; intravenous injection of nesfatin-1 decreased 0-1h, 0-2h, 0-3h cumulative food intake in T2DM, but 0-24h total food intake had no difference between groups. Body weight and plasma FFA were normalized after nesfatin-1(10 µg/Kg) administration for 6 days. These results suggested that nesfatin-1 improved lipid disorder in T2DM. It was found that blood glucose and insulin resistance coefficient decreased with treatment of nesfatin-1 (both in 1 µg/Kg and 10 µg/Kg doses) in diabetes mice. For further understanding the role of nesfatin-1 on lipid metabolism, we detected p-AMPK and p-ACC of skeletal muscle in T2DM using western blotting. The expression of p-AMPK and p-ACC increased when nesfatin-1 was given with doses 1 µg/Kg but not in doses 10 µg/Kg. Taken together, nesfatin-1 participated in the development of T2DM and stimulated free fatty acid utilization via AMPK-ACC pathway in skeletal muscle in T2DM.