[Meta-analysis of the effects of statins on the risk of chronic liver disease and hepatocellular carcinoma].

Objective: To evaluate the relationship between the application of statins and the risk of hepatocellular carcinoma in patients with chronic liver disease. Methods: PubMed, the Cochrane Library, EMBASE, Web of science, WeiPu, Wanfang Med online, and China National Knowledge Infrastructure database were searched. The literatures about statins and the risk of hepatocellular carcinoma in patients with chronic liver disease were collected, with a search deadline of February 2020. Two researchers independently conducted literature screening, data extraction, quality evaluation and proofreading. RevMan5.3 software was used for data analysis. The I2 combined with χ (2) test was used to evaluate the heterogeneity. Funnel plots were used to evaluate the publication bias of the included literature. Results: A total of 12 articles were included. Statins application had significantly reduced the risk of hepatocellular carcinoma in patients with chronic liver disease (OR = 0.50, 95% CI: 0.43~0.58, P < 0.01). Subgroup analysis showed that statins had reduced the incidence rate of hepatocellular carcinoma in patients with chronic hepatitis B (OR = 0.56, 95% CI: 0.47~0.66, P < 0.01) and chronic hepatitis C (OR = 0.56, 95% CI: 0.45~0.71, P < 0.01). Lipophilic statins had significantly reduced the risk of chronic liver disease development to hepatocellular carcinoma (OR = 0.48, 95% CI: 0.39~0.59, P < 0.01), but hydrophilic statins did not reduce the incidence rate of chronic liver disease development to hepatocellular carcinoma, and the difference was not statistically significant (OR = 0.64, 95% CI: 0.36~1.14, P = 0.13). Conclusion: Statins can effectively reduce the risk of hepatocellular carcinoma development in patients with chronic liver disease, including chronic hepatitis B and C. Among them, the lipophilic statins have a significant preventive effect on the development of chronic liver disease to hepatocellular carcinoma, but hydrophilic statins have no obvious effect.

[Differences in the bone marrow histopathology between pediatric acquired aplastic anemia and refractory cytopenia of childhood].

Objective: To study the differences in the bone marrow histopathology between acquired aplastic anemia (AAA) in children and refractory cytopenia of childhood (RCC) to facilitate their diagnoses and differential diagnosis. Methods: The clinical data and bone marrow biopsies of the RCC and AAA cases diagnosed from January 2008 to December 2018 in Xinhua Hospital, Shanghai Jiaotong University School of Medicine and Shanghai Children's Medical Center affiliated to Shanghai Jiaotong University School of Medicine were analyzed. Results: A total of 71 AAA and 79 RCC cases were analyzed. There were 52 males and 19 females, age ranged 1.0-15.0 years (median, 8.9 years) in the AAA group, and 53 males and 26 females, age ranged 0.5-16.0 years (median, 5.0 years) in the RCC group. All the biopsy specimens of AAA patients had severe hypocellularity; the cellularity of 88.7% (63/71) specimens was under 5.0%, and 11.3%(8/71) was 5%-24%. None of the AAA specimens showed any dysplastic change. All the biopsy specimens of RCC patients had hypocellularity, including 94.9%(75/79) of the specimens with a cellularity of 5%-50%. All of the RCC specimens showed a patchy distribution of hematopoiesis. A dysplastic change of erythroid cells and micromegakaryocytes was found in 40.5% (32/79) and in 60.8% (48/79) of the RCC cases, respectively. Conclusions: The degree of hypocellularity, the distribution pattern of hematopoiesis, the cell composition and localization of erythroid cell clusters and the appearance of micromegaryocytes could help the diagnosis and differential diagnosis of AAA and RCC.

[Study on correlation between serum 25-hydroxyvitamin D3 level and esophageal variceal bleeding in cirrhotic patients].

Objective: To explore the correlation between serum 25-hydroxyvitamin D3 (25[OH]D(3)) levels and esophageal variceal bleeding (EVB) in cirrhotic patients. Methods: Eighty-three cases with liver cirrhosis hospitalized from November 2016 to January 2017 were collected. The patients were divided into bleeding group (51 cases) and non-bleeding group (32 cases) depending on the presence or absence of bleeding under gastroscopy. Serological tests were performed on both groups, including hemoglobin (Hb), albumin (ALB), alkaline phosphatase (ALP),γ-glutamyltransferase (GGT), interleukin-6 (IL-6), and 25-hydroxyvitamin D3 (25[OH]D(3)). Both groups were analyzed by univariate analysis. The differences between both groups were compared by t-test, after normality test. The other variables were compared by Mann-Whitney U test. The correlation between the relevant variables and EVB were analyzed by Spearman's rank correlation and a multivariate analysis. Cases with primary biliary cirrhosis were relatively low in number (four cases in bleeding group, accounting for 8%, 10 cases in non-bleeding group, accounting for 31%). The effects of ALP and GGT on serum 25(OH)D(3) level were analyzed by stratified analysis. Moreover, ALP and GGT levels were divided into two and three groups: < 140 U/L and >140 U/L and < 30 U/L, > 30 U/L, and ~≤60 U/L. Results: Bleeding group had low levels of hemoglobin (t= -2.827,P= 0.005), alkaline phosphatase (t= -3.097,P= 0.002), gamma-glutamyltransferase (t= -2.292,P= 0.022), and 25(OH)D(3) (t= -3.134,P= 0.002) than non-bleeding group. Both groups (P> 0.05) had similar levels of albumin, interleukin-6, AAR, and FIB-4. Logistic regression analysis showed that 25(OH)D(3), alkaline phosphatase and hemoglobin were independent risk factors for EVB. Spearman's correlation coefficient analysis showed that 25(OH)D(3)was significantly positively and negatively correlated with interleukin-6 (r= 0.306,P= 0.005) and albumin (r= -0.327,P= 0.003). Stratified analysis showed that serum 25(OH)D(3) level was lower in ALP≤140U/L group and the bleeding group, and the difference was statistically significant than non-bleeding group (P= 0.007), while the serum level of 25(OH)D(3)was decreased in both groups for alkaline phosphatase > 140 U/L group, and the difference was not statistically significant (P= 0.051). Furthermore, in the GGT > 60 U/L group, the serum level of 25(OH)D(3)was significantly lower in the bleeding group, and the difference was statistically significant in non-bleeding group (P= 0.003), while the difference between the two groups was not statistically significant (P> 0.05) in GGT≤30 U/ L, > 30 U/L, and ~≤60 U/L group. Conclusion: Serum 25(OH)D(3)level was significantly lower in EVB cirrhotic patients, and it was an independent risk factor for EVB. Serum 25(OH)D(3) low levels was more apparent with ALP normalization or GGT level > 60 U/L.

[Targeting diagnosis and treatment value of chelating anti-IL-1ß mAb-SPIONs in temporal lobe epilepsy model].

Objective: In order to study the diagnosis and treatment value of chelating anti-IL-1ß mAb-SPIONs in temporal lobe epilepsy model induced by lithium chlorid and pilocarpine. Methods: Forty-five temporal lobe epilepsy model rats were randomly and equally divided into saline group, plain-SPIONs group, anti-IL-1ß mAb-SPIONs group. Each group was injected with equal particles at day 3 and day 14 after the onset of seizures. MRI were conducteds before and 4 hours after particles injection and T2 values were measured. The distribution of iron particles in the epileptic tissue was observed and the neuronal loss, astrocyte proliferation and microglia activation were detected. The expressions of IL-1ß and NF-κBp65 in each group were detected meanwhile. Results: At day 14 after seizure, the value of T2 was 84±14 after injecting anti-IL-1ß mAb-SPIONs. Compared with the control group, the value of T2 obviously declined. These phenomena of neuron loss, astrocyte proliferation and microglia activation had been improved obviously. IL-1ßand NF-κBp65 expression also significantly reduced. Conclusion: Anti-IL-1ß mAb-SPIONs can penetrate blood brain barrier and plays an important role in targeting positioning and targeting therapy in temporal lobe epilepsy.

Association between high visceral fat area and postoperative complications in patients with Crohn's disease following primary surgery.

AIM: The aim of this study was to determine the association between visceral fat area (VFA) on CT and postoperative complications after primary surgery in patients with Crohn's disease (CD). METHOD: Inclusion criteria were patients with a confirmed diagnosis of CD who had preoperative abdominal CT scan. The areas of total fat, subcutaneous fat and visceral fat were measured using an established image-analysis method at the lumbar 3 (L3) level on CT cross-sectional images. Visceral obesity was defined as a visceral fat area (VFA) of ≥ 130 cm(2) . Clinical variables, intra-operative outcomes and postoperative courses within 30 days were analysed. RESULTS: A total of 164 patients met the inclusion criteria. Sixty-three (38.4%) patients had postoperative complications. The mean age of the patients with complications (the study group) was 40.4 ± 15.4 years and of those without complications (the control group) was 35.8 ± 12.9 years (P = 0.049). There were no differences in disease location and behaviour between patients with or without complications (P > 0.05). In multivariable analysis, VFA [odds ratio (OR) = 2.69; 95% confidence interval (CI): 1.09-6.62; P = 0.032] and corticosteroid use (OR = 2.86; 95% CI: 1.32-6.21; P = 0.008) were found to be associated with postoperative complications. Patients with visceral obesity had a significantly longer operative time (P = 0.012), more blood loss (P = 0.019), longer bowel resection length (P = 0.003), postoperative ileus (P = 0.039) and a greater number of complications overall (P < 0.001). CONCLUSION: High VFA was found to be associated with an increased risk for 30-day postoperative complications in patients with CD undergoing primary surgery.

[Changes in peripheral blood 25 - hydroxyvitamin D3, Th17 cells, and CD4+ regulatory T cells and their clinical significance in patients with primary biliary cirrhosis].

Objective: To investigate the changes in peripheral blood 25-hydroxyvitamin D3[25-(OH)D3], CD4+regulatory T (Treg) cells, and Th17 cells in patients with primary biliary cirrhosis (PBC) and their mechanism of action in PBC. Methods: A total of 22 patients with PBC were enrolled and the male/female ratio was 1:21, with a mean age of 61±12 years. There were 7 healthy volunteers matched for age in the normal control group. Electrochemiluminescence immunoassay was used to measure the peripheral blood 25-(OH)D3level in the PBC group and normal control group, and flow cytometry was used to analyze the changes in Th17 cells and CD4+Treg cells. The t-test, rank sum test, Pearson correlation analysis, or Spearman's rank correlation analysis was used for statistical analysis according to the type of the data. Results: The PBC group had a significantly lower serum 25-(OH)D3level than the normal control group (9.49±3.65 vs 27.35±2.35 ng/ml,P< 0.01). Compared with the normal control group, the PBC group had a significantly higher percentage of Th17 cells (2.05%±1.17% vs 0.99%±0.12%,P< 0.01) and a significantly lower percentage of CD4+Treg cells (2.54%±1.14% vs 3.78%±0.51%,P< 0.05); there was a significant difference in Th17/Treg ratio between the PBC group and the normal control group (1.00±0.63 vs 0.26±0.02,P< 0.01). In the PBC group, peripheral blood 25-(OH)D3 was not correlated with Th17 cells or Th17/Treg ratio (r= -0.062 and -0.328,P> 0.05), while it was positively correlated with the percentage of CD4+Treg cells (r= 0.468,P< 0.05). Conclusion: Patients with PBC have significant reductions in peripheral blood 25-(OH)D3and percentage of CD4+Treg cells, a significant increase in the percentage of Th17 cells, and immune unbalance of Th17 cells and CD4+Treg cells. 25-(OH)D3can upregulate the percentage of CD4+Treg cells and thus affect the development and progression of PBC, and exogenous vitamin D may improve immune function in PBC patients.

The impact of mesenteric tension on pouch outcome and quality of life in patients undergoing restorative proctocolectomy.

AIM: The study aimed to establish a method for the measurement of mesenteric tension after ileal pouch-anal anastomosis (IPAA) and to evaluate the impact of tension on clinical outcome and quality of life. METHODS: All consecutive patients undergoing an open IPAA from July 2008 to October 2009 were prospectively enrolled. After the creation of the anastomosis, mesenteric tension was estimated by the surgeon in the operating room on a 10-point scale (1, least tension; 10, most tension). The association was analysed between mesenteric tension defined as low (1-2), medium (3-7) and high (8-10) and postoperative complications and quality of life (Cleveland Clinic Global Scale). RESULTS: A mesenteric tension score was obtained in 134 patients (71 men, 53.0%). Median age was 38.5 (29.3-47.0) years. Fifty-six patients (41.8%) had a low, 59 (44.0%) a medium and 19 (14.2%) a high degree of mesenteric tension. Patients with a high mesenteric tension had a shorter anal transitional zone, a longer distance from the upper border of the symphysis pubis to the apex of the small bowel loop designated for the ileoanal anastomosis, a thinner abdominal wall at the stoma site and a longer distance from the pouch to the ileostomy. The proportion of patients with high mesenteric tension was less after stapled anastomosis. On long-term follow-up, patients with high mesenteric tension were more likely to suffer from anastomotic stricture and pouch failure. Pouch function was not influenced by mesenteric tension. CONCLUSION: High mesenteric tension after IPAA is adversely associated with postoperative complications and pouch survival.

Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene.

The classic murine muscular dystrophy strain, dy, was first described almost 40 years ago. We have identified the molecular basis of an allele of dy, called dy2J, by detecting a mutation in the laminin alpha 2 chain gene--the first identified mutation in laminin-2. The G to A mutation in a splice site consensus sequence causes abnormal splicing and expression of multiple mRNAs. One mRNA is translated into an alpha 2 polypeptide with a deletion in domain VI. The truncated protein apparently lacks important qualities of the wild type protein and is unable to provide sufficient muscle stability.

Neural-endocrine mechanisms of respiratory syncytial virus-associated asthma in a rat model.

We examined the underlying neural-endocrine mechanisms of asthma associated with respiratory syncytial virus infection. Thirty Sprague-Dawley rats were randomly divided into control group, respiratory syncytial virus (RSV) group, and anti-nerve growth factor (NGF) IgG group. An RSV infection model was established by nasal drip once a week. In the anti-NGF antibody intervention group, each rat was given an intraperitoneal injection of anti-NGF IgG 3 h before RSV infection. Optical microscopy and transmission electron microscopy were used to observe the structural changes in adrenal medulla cells. Changes in adrenaline and norepinephrine in serum were detected by ELISA. NGF expression was assayed by immunohistochemistry. Expression differences in synaptophysin mRNA were detected by RT-PCR. Transmission electron microscopy displayed widened adrenal medulla intercellular spaces, reduced chromaffin particle concentration, and increased mitochondria in the RSV infection group. At the same time, NGF expression was increased in the RSV infection group significantly. In addition, the adrenaline concentration was significantly decreased compared with the control and anti-NGF antibody groups. Synaptophysin mRNA expression was significantly increased in the RSV infection and anti-NGF antibody groups. However, compared with the RSV infection group, synaptophysin mRNA expression was significantly decreased in the anti-NGF antibody group. We conclude that RSV infection could induce adrenal medulla cell differentiation to nerve cells by over-expression of NGF, resulting in the decreased endocrine function found in asthma progression.

[Effects of ilioinguinal composite tissue flaps in repairing skin and soft tissue defects on hand or foot].

Objective: To explore the effects of ilioinguinal composite tissue flaps in repairing skin and soft tissue defects on hand or foot and reconstructing the flexion and extension functions of wrist, finger, ankle, and toe. Methods: From February 2012 to March 2018, 4, 5, and 3 patients (11 males and 1 female, 23-62 years old) with skin and soft tissue defects on hand or foot were admitted to Traditional Chinese Medicine Hospital of Zhongmu County of Henan Province, Henan Armed Police Corps Hospital, and the Affiliated Jiangyin Hospital of Medical College of Southeast University, respectively. Five patients had hand defects, and 7 patients had foot defects. The areas of skin and soft tissue defects after debridement were 10 cm×8 cm-15 cm×10 cm. The ilioinguinal composite tissue flaps were designed and resected according to the wound area and the length of tendon defects, and the areas of flaps were 10 cm×8 cm-15 cm×12 cm. According to the specific condition of the recipient area, the superficial iliac circumflex artery in the tissue flap was reconstructed by end-to-side anastomosis in 2 patients and end-to-end anastomosis in 1 patient with ulnar artery, end-to-side anastomosis in 4 patients with the dorsal foot artery, end-to-side anastomosis in 2 patients with the posterior tibial artery, and end-to-end anastomosis in 1 patient with the external tarsal foot artery in the recipient area, and the superficial epigastric artery in the tissue flap was reconstructed by end-to-side anastomosis in 1 patient with the radial artery and end-to-end anastomosis in 1 patient with the ulnar artery in the recipient area. The donor sites were sutured directly or repaired with medium split-thickness skin grafts. The survival of tissue flap after the operation and the appearance, texture, and the two-point discrimination distance of the tissue flaps during follow-up were observed. The hand function and foot function were evaluated by the total active movement standard of hand and the Maryland foot score standard, respectively. Results: All the tissue flaps in 12 patients survived. During follow-up of 6-36 months after operation, the tissue flaps were slightly bloated, with linear scars at the junction site in the recipient area, and the two-point discrimination distances of the tissue flaps were 15-22 mm. The hand function was excellent in 3 cases, good in 1 case, and fair in 1 case, and the foot function was excellent in 4 cases, good in 2 cases, and fair in 1 case, and all the patients were satisfied with the function and appearance of hand or foot. Conclusions: The ilioinguinal composite tissue flaps can repair the hand and foot wounds and reconstruct the flexion and extension functions of wrist, finger, ankle, and toe at the same time, which is an effective method to repair this kind of defects.

[Clinical phenotypes of epilepsy associated with GABRA1 gene variants].

Objective: To summarize the clinical phenotypes of epilepsy in patients with GABRA1 gene variants. Methods: A total of 11 epileptic patients (4 boys and 7 girls) who were treated in the Department of Pediatrics, Peking University First Hospital from March 2016 to July 2019 and detected with GABRA1 gene heterozygous pathogenic variants by targeted next-generation sequencing were enrolled. The features of clinical manifestations, electroencephalogram (EEG), and neuroimaging were analyzed retrospectively. Results: A total of 11 epileptic patients carried GABRA1 gene pathogenic variants, of whom 10 were de novo variants and the other one was inherited from the patient's mother. Two patients had the same variants. Six variants were novel. Ages at seizure onset ranged from 3 to 14 months, and the median age was 8 months. The seizure was first observed within 1 year in 10 patients and beyond 1 year of age in 1 patient. Multiple seizure types were observed, including focal seizures in 10 patients, generalized tonic clonic seizures (GTCS) in 3 patients, myoclonic seizures in 3 patients, and epileptic spasm in 2 patients. There were 5 patients with multiple seizure types. Sensitivity to fever was observed in 9 patients, among whom 6 patients had a history of status epilepticus. Two patients had photoparoxysmal response. Five patients had abnormal EEG background, and 6 patients had abnormal discharges in EEG during interictal phase. Brain magnetic resonance imaging (MRI) was normal in all patients. Developmental delay in various degrees was present in 9 patients. Among the 11 patients, Dravet syndrome was diagnosed in 5 patients, West syndrome in 2 patients, undiagnosed early-onset epileptic encephalopathy in 1 patient, and focal epilepsy in the other 3 patients. The ages at the last follow-up ranged from 8 months to 12 years. During follow-up, 8 patients were seizure-free for 6 months to 8 years, and 1 patient had discontinuation of medication. Conclusions: In epilepsy associated with GABRA1 gene variants, de novo pathogenic variants are more common than inherited. Most epilepsy caused by GABRA1 gene variants occurs in infancy. Most patients have multiple seizures and focal seizures are common. Most patients have a comparatively favorable prognosis, but they may still have varied degrees of developmental delay.

[Analysis of caries experience and the dental treatments under general anesthesia in 103 cases of children with autism spectrum disorders].

Objective: To compare the caries experience and the kinds of dental treatment between children with autism spectrum disorders (ASD) and children without systemic disease who were all treated under general anesthesia. Methods: Totally 103 children with ASD who received dental treatments under general anesthesia in 13 professional dental hospitals around China from April to November 2016 were included in the present study. A group of 97 children without systemic disease, according to the age, gender and application propensity score matching method, were chosen as controls, who received dental treatments under general anesthesia between January 2015 to November 2018 in the same hospitals as the children with ASD. Decay missing filling tooth (DMFT/dmft, DMFT for permanent teeth and dmft for primary teeth) indices of two groups of children and the contents of the dental treatments under general anesthesia were analyzed. Results: No significant difference of DMFT/dmft index ï¼»M (Q 25, Q 75)ï¼½ was found between children with ASD group ï¼»0 (0, 3)/11(8, 14)ï¼½ and control group ï¼»0 (0, 3)/9(7, 13)ï¼½ (P>0.05). The average number of dental treatments under general anesthesia and the average number of endodontic treatment in children with ASD were 13 (11, 15) and 3 (2, 6) teeth respectively, while those in the control group were 12 (9, 14) and 2 (1, 4) teeth respectively, the differences were statistically significant (P<0.01, P<0.05). Conclusions: No significant difference was found between children with ASD and the normal controls who receive dental treatments under general anesthesia in DMFT/dmft index, but the treatment needs of children with ASD is relatively higher, and their tooth decay is relatively severer.

Uroplakins Ia and Ib, two major differentiation products of bladder epithelium, belong to a family of four transmembrane domain (4TM) proteins.

The mammalian bladder epithelium elaborates, as a terminal differentiation product, a specialized plasma membrane called asymmetric unit membrane (AUM) which is believed to play a role in strengthening and stabilizing the urothelial apical surface through its interactions with an underlying cytoskeleton. Previous studies indicate that the outer leaflet of AUM is composed of crystalline patches of 12-nm protein particles, and that bovine AUMs contain three major proteins: the 27- to 28-kD uroplakin I, the 15-kD uroplakin II and the 47-kD uroplakin III. As a step towards elucidating the AUM structure and function, we have cloned the cDNAs of bovine uroplakin I (UPI). Our results established the existence of two isoforms of bovine uroplakin I: a 27-kD uroplakin Ia and a 28-kD uroplakin Ib. These two glycoproteins are closely related with 39% identity in their amino acid sequences. Hydropathy plot revealed that both have four potential transmembrane domains (TMDs) with connecting loops of similar length. Proteolytic digestion of UPIa inserted in vitro into microsomal vesicles suggested that its two main hydrophilic loops are exposed to the luminal space, possibly involved in interacting with the luminal domains of other uroplakins to form the 12-nm protein particles. The larger loop connecting TMD3 and TMD4 of both UPIa and UPIb contains six highly conserved cysteine residues; at least one centrally located cysteine doublet in UPIa is involved in forming intramolecular disulfide bridges. The sequences of UPIa and UPIb (the latter is almost identical to a hypothetical, TGF beta-inducible, TI-1 protein of mink lung epithelial cells) are homologous to members of a recently described family all possessing four transmembrane domains (the "4TM family"); members of this family include many important leukocyte differentiation markers such as CD9, CD37, CD53, and CD63. The tissue-specific and differentiation-dependent expression as well as the naturally occurring crystalline state of uroplakin I molecules make them uniquely suitable, as prototype members of the 4TM family, for studying the structure and function of these integral membrane proteins.

Uroplakin I: a 27-kD protein associated with the asymmetric unit membrane of mammalian urothelium.

The luminal surface of mammalian urothelium is covered with numerous plaques (also known as the asymmetric unit membrane or AUM) composed of semi-crystalline, hexagonal arrays of 12-nm protein particles. Despite the presumed importance of these plaques in stabilizing the urothelial surface during bladder distention, relatively little is known about their protein composition. Using a mouse mAb, AE31, we have identified a 27-kD protein that is urothelium-specific and is differentially expressed in superficial umbrella cells. This protein (pI approximately 5.8) partitions into the detergent phase during Triton X-114 phase separation. Pulse-chase experiments using cultured bovine urothelial cells showed that this protein is synthesized as a 32-kD precursor that is processed through a 30-kD intermediate, to the mature 27-kD form. In cytoplasmic vesicles containing immature AUM, the AE31 epitope is detected in patches on the cytoplasmic side, but in mature, apical AUM it is detected exclusively on the luminal side. This suggests an unusual translocation of the AE31 epitope during AUM maturation; more data are required, however, to substantiate this interpretation. Immunoaffinity purification of the 27-kD protein results in the copurification in approximately molar ratio of a 15-kD protein, as well as a small and variable amount of a 47-kD protein. Immunoblotting data indicate that these three proteins are immunologically distinguishable. This copurified 15-kD protein is relative basic (pI approximately 8.0). Like the 27-kD protein, it is urothelium-specific and is present mainly in the umbrella cells. Together, our data indicate that a 27-kD protein is urothelial plaque-associated (uroplakin I). Based on complex formation data, we provisionally name the 15-kD protein uroplakin II; additional data will be required to determine whether this and the 47-kD protein are integral parts of AUM. The identification of these AUM-associated and -related proteins, plus the availability of a culture system capable of synthesizing and processing some of these molecules, offer new opportunities for studying the detailed structure, assembly, and function of asymmetrical unit membrane.

Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux.

Urothelium synthesizes a group of integral membrane proteins called uroplakins, which form two-dimensional crystals (urothelial plaques) covering >90% of the apical urothelial surface. We show that the ablation of the mouse uroplakin III (UPIII) gene leads to overexpression, defective glycosylation, and abnormal targeting of uroplakin Ib, the presumed partner of UPIII. The UPIII-depleted urothelium features small plaques, becomes leaky, and has enlarged ureteral orifices resulting in the back flow of urine, hydronephrosis, and altered renal function indicators. Thus, UPIII is an integral subunit of the urothelial plaque and contributes to the permeability barrier function of the urothelium, and UPIII deficiency can lead to global anomalies in the urinary tract. The ablation of a single urothelial-specific gene can therefore cause primary vesicoureteral reflux (VUR), a hereditary disease affecting approximately 1% of pregnancies and representing a leading cause of renal failure in infants. The fact that VUR caused by UPIII deletion seems distinct from that caused by the deletion of angiotensin receptor II gene suggests the existence of VUR subtypes. Mutations in multiple gene, including some that are urothelial specific, may therefore cause different subtypes of primary reflux. Studies of VUR in animal models caused by well-defined genetic defects should lead to improved molecular classification, prenatal diagnosis, and therapy of this important hereditary problem.

[Pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy].

Objective: To identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy (PME). Methods: In this cross-sectional study, 26 PME children (11 boys and 15 girls) sent to neurological outpatient clinics and admitted to wards of the Department of Pediatrics, Peking University First Hospital were enrolled prospectively from January 2014 to October 2018. The pathogenic gene variants of PME children and their parents were identified by Sanger sequencing, next generation sequencing panels of epilepsy or trio-based whole exome sequencing and so on. The genotypes and phenotypes of the PME children were anaylzed. Results: The clinical features of 26 children include myoclonus, multiple types of seizures and progressive neurological regression. Their onset ages ranged from 3 months to 15 years. Several pathogenic gene variants were identified in the 15 patients, including TPP1 gene variantions in 3 patients; NEU1, GBA, TBC1D24 and KCNC1 gene variantions in 2 patients respectively; CLN6, MFSD8, ASAH1 and ATN1 gene variantions in 1 patient respectively. Several variants of uncertain significance were identified in 4 patients, including GOSR2 gene compound heterozygous variants in 2 patients, KCTD7 gene compound heterozygous variants in 1 patient, and compound heterozygous variants of an unreported TARS gene in 1 patient. No pathogenic gene variant was identified in 7 patients. In 15 children with the identified pathogenic gene variants, 5 patients were diagnosed with neuronal ceroid lipofuscinoses (NCL), 2 patients with sialidosis, 2 patients with neuronopathic Gaucher disease, 1 patient with dentatorubral-pallidoluysian atrophy (DRPLA), and 1 patient with spinal muscular atrophy-progressive myoclonic epilepsy (SMA-PME). Conclusions: PME include a group of diseases with genetic heterogeneity. Identification of the pathogenic gene variants of PME could help to predict the prognosis and guide the genetic counseling.

[Clinical features of epilepsies associated with GABRB2 variants].

Objective: To analyze the clinical phenotypes of epilepsies in children with GABRB2 variants. Methods: Data of 8 epileptic patients with heterozygous GABRB2 variants were retrospectively collected at the Department of Pediatrics, Peking University First Hospital from April 2016 to December 2018. The clinical, electroencephalographic, neuroimaging characteristics, therapeutic and follow-up were analyzed. Results: Eight patients (4 boys, 4 girls) with heterozygous GABRB2 gene pathogenic variants were enrolled. Eight patients had different GABRB2 variants, among whom 2 patients inherited the variants from either parent, and the other 6 patients had de novo variants. Seven variants were novel. Ages at seizure onset ranged from 1 day to 22 months after birth, and the median age was 6 months. The seizure was first observed within one month of age in 2 patients, 1-6 months in 2 patients, 7-12 months in 2 patients, and beyond 1 year of age in 2 patients. Multiple seizure types were observed, including focal seizures in 6 patients, generalized tonic clonic seizures (GTCS) in 4 patients, myoclonic seizures in 3 patients, and epileptic spasm in 2 patients. Developmental delay was present in 6 patients. In 8 patients, Dravet syndrome was diagnosed in 3 patients, febrile seizures plus and West syndrome in 2 patients, respectively, Ohtahara syndrome in 1 patient. Six patients had epilepsy with fever sensitivity, and status epilepticus developed in all these patients. The ages at the last follow-up ranged from 8 months to 11 years, and the follow-up data showed that 5 patients were seizure-free, and 2 patients still had seizures, and 1 patient died of recurrent status epilepticus complicated with fungal infection. Conclusions: Epilepsies associated with GABRB2 variants were characterized by an onset in infancy, and the clinical features were heterogenous in seizure types and severities. Most patients had multiple seizures with fever sensitivity, and status epilepticus was common. Their seizures were easily induced by fever or infection. Additionally, the majority of the patients had varying degrees of developmental delay.

[Clinical characteristics of PCDH19-female limited epilepsy].

Objective: To analyze the clinical characteristics of patients with PCDH19-female limited epilepsy (PCDH19-FE). Methods: The clinical data of 60 female epilepsy patients with PCDH19 gene heterozygous variations at the Department of Pediatrics, Peking University First Hospital from October 2007 to December 2018 were collected and analyzed retrospectively, their clinical manifestations, accessory examination and follow-up treatment were summarized. Results: Data of a total of 60 cases of PCDH19-FE were collected. The seizure onset occurred between 4 and 42 months of age (median: 11 months of age). Focal seizures occurred in 47 patients (78%), generalized tonic-clonic seizures (GTCS) occurred in 30 patients (50%), and other rare types of seizures included atypical absence, myoclonic, clonic, tonic, and atonic seizures. Two or more seizures types existed in 24 patients (40%), and seven patients (12%) had attacks of status epilepticus. Sensitivity to fever was observed in 47 out of them (78%) and clustering of seizures as found in all patients. During the interictal phase, focal discharges were monitored in 22 cases (22/45, 49%), multifocal discharges in 12 cases (12/45, 27%), widely discharging in 2 cases (4%), and both focal and widely discharging in 9 cases (20%). Clinical seizures were detected in 30 patients during the electroencephalogram (EEG) recording, including focal seizures in 22 cases, GTCS seizures in 8 cases, tonic seizure in three cases, myoclonic seizure followed by GTCS in one case, and two types of seizures in four cases. Before seizure onset, 57 patients had normal development and three patients had delayed language development. After seizure onset, varied degrees of intelligence disability were present in 38 cases (63%), language delay in 36 cases (60%), and gait instability in 10 cases (17%). Autistic features occurred in 17 cases (28%); and other behavioral problems like learning difficulties, personality, or emotional disorders existed in 33 cases (55%). Age at last follow-up ranged from one year and 3 months to 22 years and 3 months of age, 17 patients (28%) were seizure-free for more than 2 years (5 to 22 years at the last follow-up). The efficiency of antiepileptic drugs were 65% (33/51) in sodium valproate, 63% (27/43) in levetiracetam and 59% (20/34) in topiramate. Conclusions: The clinical features of PCDH19-FE are characterized by clustering of seizures, focal seizures in most cases, sensitivity to fever mostly, focal discharges principally in EEG, varied degrees of intellectual disability or movement disorder, combined with autism spectrum disorders in partial and high efficiency in sodium valproate or levetiracetam treatment.

Adult nasolacrimal sac mucocele.

Adult nasolacrimal sac mucocele is an uncommon mass arising in the medial canthal region of the orbit. Twenty-one cases with lacrimal sac mucocele were reviewed retrospectively. We gathered information about the clinical characteristics, natural history, mechanism for mucocele formation and optimal management of this disorder. The results show that the medial canthal mass was confirmed to be dacryo-cystocele-associated with distal nasolacrimal duct obstruction and proximal obstruction at the junction of the common canaliculus and sac. The interventional procedure of polyurethane stent placement is a practicable and simplified treatment for lacrimal sac mucocele.

[Genotype-phenotype correlation in patients with alternating hemiplegia of childhood].

Objective: To explore the correlation between ATP1A3 genotype and phenotype in children with alternating hemiplegia of childhood (AHC). Methods: This was a retrospective study. The clinical data and peripheral blood DNA of AHC patients were collected in Peking University First Hospital from August 2005 to December 2017. ATP1A3 gene mutations were screened by Sanger sequencing or next generation sequencing (NGS). AHC patients were divided into difference groups according to different hotspot mutations. SPSS 23.0 was used to analyze the correlation between genotype and phenotype. Variance analysis was used to compare the measurement data between groups. Chi square test was used to compare the categorical data between groups. Kruskal-Wallis test was used to compare the unidirectional ordered data between groups. Least-significant difference(LSD) was used to compare the data between two groups. Results: A total of 119 AHC patients were recruited, including 68 males and 51 females. The onset age of 113 (95.0%) patients was within 18 months. There were 119 cases (100.0%) with hemiplegic seizures, 109 cases (91.6%) with abnormal eyeball movements, 104 cases (87.4%) with dystonia, 31 cases (26.1%) with autonomic neurological symptoms, 31 cases (26.1%) with epileptic seizures and 117 cases (98.3%) with long-term developmental delay. In 113 patients (95.0%) with ATP1A3 gene mutations, 111 were de novo mutation and 2 were genetic mutations. A total of 39 mutation types were found, including 37 missense mutations and 2 deletion mutations. Seventeen of them were novel mutations. The three hotspot mutations were D801N (n=34, 30.1%), E815K (n=20, 17.7%) and G947R (n=13, 11.5%). The age of onset of D801N and E815K were earlier than G947R ((3.1±2.1)and (2.3±2.3)vs.(6.4±7.7) months, P=0.004 and 0.003). The age of first hemiplegic events of D801N and E815K were earlier than G947R((6.4±3.1) and (6.8±3.3) vs. (11.4±10.1) months, P=0.004 and 0.016). More patients with E815K mutations presented epilepsy than those with D801N (P=0.003) and G947R (P=0.001). More patients with E815K mutations presented greater motor and intellectual disability than the patients with D801N (P=0.001) and G947R mutations (P=0.001). Conclusions: ATP1A3 gene is the main causative gene of AHC. Three hotspot mutations, D801N, E815K and G947R, were found. Hotspot mutation E815K is associated with the most severe phenotype, which presented an earlier age at the time of the first paroxysmal manifestation and first hemiplegic event, severer developmental delay and a greater proportion of epilepsy.