Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy.

Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.

The feedback loop of METTL14 and USP38 regulates cell migration, invasion and EMT as well as metastasis in bladder cancer.

BACKGROUND: Bladder cancer (BCa) is one of the most prevalent malignancies globally. Previous study has reported the inhibitory effect of methyltransferase-like 14 (METTL14) on BCa tumorigenesis, but its role in the cell migration, invasion and epithelial-mesenchymal transition (EMT) in BCa remains unknown. MATERIALS AND METHODS: Quantitative real-time PCR (RT-qPCR) and western blot were applied to measure RNA and protein expression respectively. Cell migration, invasion and EMT were evaluated by wound healing, Transwell, and immunofluorescence (IF) assays as well as western blot of EMT-related proteins. In vivo experiments were performed to analyze metastasis of BCa. Mechanism investigation was also conducted to study METTL14-mediated regulation of BCa progression. RESULTS: METTL14 overexpression prohibits BCa cell migration, invasion in vitro and tumor metastasis in vivo. METTL14 stabilizes USP38 mRNA by inducing N6-methyladenosine (m6A) modification and enhances USP38 mRNA stability in YTHDF2-dependent manner. METTL14 represses BCa cell migration, invasion and EMT via USP38. Additionally, miR-3165 inhibits METTL14 expression to promote BCa progression. CONCLUSIONS: Our study demonstrated that METTL14 suppresses BCa progression and forms a feedback loop with USP38. In addition, miR-3165 down-regulates METTL14 expression to promote BCa progression. The findings may provide novel insight into the underlying mechanism of METTL14 in BCa progression.

Prenatal MRI assessment of mediastinal shift angle as a feasible and effective risk stratification tool in isolated right-sided congenital diaphragmatic hernia.

OBJECTIVES: To develop a mediastinal shift angle (MSA) measurement method applicable to right-sided congenital diaphragmatic hernia (RCDH) in fetal MRI and to validate the predictive value of MSA in RCDH. METHODS: Twenty-seven fetuses with isolated RCDH and 53 controls were included in our study. MSA was measured on MRI axial image at the level of four-chamber view of the fetal heart. The angle between the sagittal midline landmark line and the left boundary landmark line touching tangentially the lateral wall of the left ventricle was used to quantify MSA for RCDH. Appropriate statistical analyses were performed to determine whether MSA can be regarded as a valid predictive tool for postnatal outcomes. Furthermore, predictive performance of MSA was compared with that of lung area to head circumference ratio (LHR), observed/expected LHR (O/E LHR), total fetal lung volume (TFLV), and observed/expected TFLV (O/E TFLV). RESULTS: MSA was significantly higher in the RCDH group than in the control group. MSA, LHR, O/E LHR, TFLV, and O/E TFLV were all correlated with postnatal survival, pulmonary hypertension (PH), and extracorporeal membrane oxygenation (ECMO) therapy (p < 0.05). Value of the AUC demonstrated good predictive performance of MSA for postnatal survival (0.901, 95%CI: (0.781-1.000)), PH (0.828, 95%CI: (0.661-0.994)), and ECMO therapy (0.813, 95%CI: (0.645-0.980)), which was similar to O/E TFLV but slightly better than TFLV, O/E LHR, and LHR. CONCLUSIONS: We developed a measurement method of MSA for RCDH for the first time and demonstrated that MSA could be used to predict postnatal survival, PH, and ECMO therapy in RCDH. CLINICAL RELEVANCE STATEMENT: Newly developed MRI assessment method of fetal MSA in RCDH offers a simple and effective risk stratification tool for patients with RCDH. KEY POINTS: • We developed a measurement method of mediastinal shift angle for right-sided congenital diaphragmatic hernia for the first time and demonstrated its feasibility and reproducibility. • Mediastinal shift angle can predict more prognostic information other than survival in right-sided congenital diaphragmatic hernia with good performance. • Mediastinal shift angle can be used as a simple and effective risk stratification tool in right-sided congenital diaphragmatic hernia to improve planning of postnatal management.

Establishment and identification of an animal model of Hirschsprung disease in suckling mice.

BACKGROUND: Hirschsprung disease (HSCR) is a congenital intestinal malformation. Previous HSCR animal model needs invasive operation on adult animal. The aim of this study is to establish an early-onset animal model which is consistent with the clinical manifestation of HSCR patients. METHODS: The neonatal mice were randomly divided into the benzalkonium chloride (BAC) group, treated with BAC via enema, and the control group, treated with saline. Weight changes, excretion time of carmine, CT scan, hematoxylin-eosin staining and immunofluorescence staining were used to evaluate the effect of the model. Differentially expressed genes (DEGs) in the HSCR mice were analyzed by using DAVID 6.8 database and compared with DEGs from HSCR patients. RESULTS: The weight of mice was lower and the excretion time of carmine was longer in the BAC group. Moreover, distal colon stenosis and proximal colon enlargement appeared in the BAC group. Neurons in the distal colon decreased significantly after 4 weeks of BAC treatment and almost disappeared completely after 12 weeks. Transcriptome profiling of the mouse model and HSCR patients is similar in terms of altered gene expression. CONCLUSIONS: An economical and reliable HSCR animal model which has similar clinical characteristics to HSCR patients was successfully established. IMPACT: The animal model of Hirschsprung disease was first established in BALB/c mice. This model is an animal model of early-onset HSCR that is easy to operate and consistent with clinical manifestations. Transcriptome profiling of the mouse model and HSCR patients is similar in terms of altered gene expression.

Mediastinal shift angle (MSA) measurement with MRI: a simple and effective tool for prenatal risk stratification in fetuses with congenital diaphragmatic hernia.

OBJECTIVES: To investigate the predictive value of mediastinal shift angle (MSA) in congenital diaphragmatic hernia (CDH). METHODS: A retrospective analysis was performed on 87 fetuses with prenatally diagnosed left-sided CDH (LCDH) and 88 controls. MSA was measured on magnetic resonance imaging (MRI). Lung area to head circumference ratio (LHR), ratio of the observed/expected LHR (O/E LHR), total fetal lung volume (TFLV), and observed/expected total fetal lung volume (O/E TFLV) were also measured. Correlation of MSA with pulmonary hypertension (PH), extracorporeal membrane oxygenation (ECMO) use, duration of hospitalization and survival in neonates with CDH was analyzed. Performance of MSA in prediction of postnatal outcomes was compared with LHR, O/E LHR, TFLV, and O/E TFLV. RESULTS: There were significant differences in MSA values not only between the CDH group and the control group but also in CDH patients with different survival outcomes. MSA was inversely correlated with O/E LHR, O/E TFLV, and TFLV. MSA, LHR, O/E LHR, TFLV, and O/E TFLV could all be used to predict survival of CDH patients. In addition, the receiver operating characteristic (ROC) curve showed that the test performance of MSA was similar to that of TFLV, O/E TFLV, and O/E LHR, but superior to that of LHR. MSA was also correlated with PH, need for ECMO support, and duration of hospitalization. CONCLUSION: MRI measurement of MSA can provide various prognostic information for prenatally diagnosed LCDH, in addition to postnatal survival. The test performance of MSA is similar to TFLV, O/E TFLV, and O/E LHR. KEY POINTS: • Mediastinal shift angle (MSA) can be measured quickly and reproducibly on MRI images. • MSA could provide more prognostic information other than postnatal survival for LCDH with good test performance. • MSA should be incorporated into prenatal risk stratification for LCDH to improve planning of postnatal management.

Flexible endoscopic identification and catheterization of congenital H-type tracheoesophageal fistula using a laryngeal mask.

Endoscopy for revealing the orifice of congenital H-type tracheoesophageal fistula (cTEF) is important for diagnostics and therapeutics. To facilitate the identification and catheterization of cTEF, we developed a new modified flexible endoscopy technique using a laryngeal mask with intermittent airflow. A retrospective case series study was conducted from April 2016 to July 2019 at a national regional children's medical center. Twelve infants with cTEF underwent this flexible endoscopy technique. The intermittent positive pressure airflow through laryngeal mask was able to reveal the orifice of cTEF easily in tracheal lumen. Under the visual flexible endoscope, cannulation with a 3-Fr ureteral catheter in fistula was successfully used in all cases. There were no immediate or delayed complications. This case series shows that the flexible endoscopy technique is a safe, easy, and technically efficient approach for diagnosis and cannulation of cTEF.

Associations between common genetic variants in microRNAs and Hirschsprung disease susceptibility in Southern Chinese children.

INTRODUCTION: Hirschsprung disease (HSCR), characterized by the defective migration of enteric neural crest cells, is a severe congenital tract disease in infants. Its etiology is not clear at present, although a genetic component plays an important role in its etiology. Many studies focused on the polymorphisms of microRNA (miRNA) in several disease progressions have been reported, including HSCR. However, the findings remain inconclusive. The present study aimed to explore the association of genetic variants in miRNAs and HSCR susceptibility in Southern Chinese children. METHODS: Five single nucleotide polymorphisms (SNPs) (miR-146A rs2910164, miR-4318 rs8096901, miR-3142 rs2431697, miR-3142 rs2431097 and miR-3142 rs5705329) were included to be genotyped in the stratified analysis through the Mass ARRAY iPLEX Gold system (Sequenom, San Diego, CA, USA) conducted on all the samples, comprising 1470 cases and 1473 controls. After quality control, the minor allele frequency was compared in cases and controls to analyze the association between SNPs and HSCR using PLINK 1.9 (https://www.cog-genomics.org/plink) and multiple heritability models were tested (additive, recessive and dominant models). RESULTS: Our results indicated that miR-4318 rs8096901 polymorphisms were associated with HSCR susceptibility in Southern Chinese children, especially in short-segment HSCR (S-HSCR) patients after stratified analysis. CONCLUSIONS: In summary, we report that miR-4318 rs8096901 was associated with HSCR, especially in SHSCR patients.

Prenatal diagnosis and postnatal management of congenital mesoblastic nephroma: Experience at a single center in China.

OBJECTIVE: To review the prenatal and postnatal clinical characteristics and pathological subtypes, as well as the surgical outcome for congenital mesoblastic nephroma (CMN) cases. METHOD: A retrospective review was performed in 11 cases with CMN prenatally diagnosed at a single center between 2015 and 2019. The clinical characteristics, surgical outcome, histopathology, and follow-up were retrospectively obtained and reviewed. RESULTS: The median gestational age at which the sonographic diagnosis was made was 35 weeks. Polyhydramnios was found in four (36.4%) cases, and all resulted in a preterm birth. Nine infants had hypertension. Ten cases underwent radical nephrectomy, and one underwent radical nephrectomy and partial adrenalectomy. The pathological results showed that six tumors were classical variants, four mixed variants, and one was a cellular variant. Three cases presented as a stage I, eight as stage II, and no stage III or IV cases were diagnosed. All patients are alive so far. At a median follow-up of 14 months, no local recurrence, or remote metastases were found. CONCLUSION: The prognosis of prenatal CMN cases is excellent after early surgery.

The value of saline-aided ultrasound in diagnosing congenital duodenal obstruction.

PURPOSE: The aim of the study is to assess the value of saline-aided ultrasound (US) in diagnosing congenital duodenal obstruction (CDO). METHODS: The neonates with CDO were enrolled in this study, including the neonates confirmed with annular pancreas (AP) by operation, the neonates confirmed with duodenal atresia, the neonates confirmed with duodenum web, and the neonates confirmed with malrotation. Pertinent data were recorded, including the US features, intraoperative findings, and surgical procedures. The methodology of this study is a diagnostic test study which means the US feature is the test and the intraoperative finding is the gold standard. RESULTS: A total of 95 neonates were enrolled, including 33 neonates with AP, 6 neonates with duodenal atresia, 29 neonates with duodenum web, and 27 neonates with malrotation. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the hyperechogenic band for the detection of AP were 78.8% (26/33), 90.3% (56/62), 81.2% (26/32), 88.8% (56/63), and 86.3% (82/95), respectively. The sensitivity, specificity, NPV, and accuracy for the detection of duodenal atresia were 0% (0/6), 100% (89/89), 93.6% (89/95), and 93.6% (89/95), respectively. The sensitivity, specificity, PPV, NPV, and accuracy for the detection of duodenum web were 100% (29/29), 100% (66/66), 100% (29/29), 100% (66/66), and 100% (95/95), respectively. The sensitivity, specificity, PPV, NPV, and accuracy for the detection of malrotation were 100% (27/27), 100% (68/68), 100% (27/27), 100% (68/68), and 100% (95/95), respectively. CONCLUSION: Saline-aided US is a feasible tool to diagnose CDO.

Extracorporeal membrane oxygenation for congenital diaphragmatic hernia: how to begin?

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is critical for congenital diaphragmatic hernia (CDH), who fails to achieve adequate oxygenation with conventional management. We aim to evaluate initial experiences with ECMO support in a tertiary women and children's medical center in mainland China. METHODS: We retrospectively reviewed the establishment of ECMO for CDH Program in our center and analysis of five CDH neonates, who underwent repair during ECMO between December 2016 and December 2018. RESULTS: The first ECMO for CDH Program in our institution was established and managed by a multidisciplinary team since December 2016. An alert of ECMO was prenatally created for moderate-severe pulmonary hypoplasia. Of sixteen admissions prenatally diagnosed moderate-severe CDH, eight neonates (50%) required ECMO but five (31%) received eventually. Veno-arterial ECMO was established from 3 hours to 41 hours of age (median 20 h). All the five underwent CDH repair after a stabilization period on ECMO, which ranged from 12 h to 122 h (median 58 h). There were no clotting complications, related to coagulating during CDH repair. Bleeding was the most common complication. Cannula malposition was detected in one case. Their median ECMO duration was 437 (range 85-946) hours. Neonatal survival was 80% (4/5) and 3 survived (60%) in the first three months of life. CONCLUSIONS: Multidisciplinary team work, precise prenatal evaluation and skillful cannulation assist the successful beginning of ECMO for CDH. Our preliminary results would encourage other institutions, whose ECMO is not well-established.

Diagnostic value of the acute angle between the prestenotic and poststenotic duodenum in neonatal annular pancreas.

OBJECTIVES: To analyze the ability of upper gastrointestinal (GI) saline-contrast ultrasound (US) to detect neonatal annular pancreas. METHODS: Sixty-two neonates, who presented duodenal obstruction and were examined by upper GI saline-contrast US before treatment, were retrospectively analyzed and categorized into four groups according to their final diagnosis: group A, annular pancreas (n = 28); group B, duodenal atresia (n = 2); group C, descending duodenal septum (n = 25); and group D, normal (n = 7). The ultrasonic characteristics were analyzed that especially focused on whether the angle between the prestenotic and poststenotic descending duodenum (at or below a derived cutoff) could identify neonatal annular pancreas. RESULTS: To detect annular pancreas using the concave contour of the distal prestenotic duodenum, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined at 71.4%, 100%, 100%, and 80.9%, respectively. When using the hyperechogenic band around the constricted duodenum, the sensitivity, specificity, PPV, and NPV were determined at 82.1%, 94.1%, 92%, and 86.5%, respectively. For using the 40.7° acute angle cutoff between prestenotic and poststenotic descending duodenum, the values of sensitivity, specificity, PPV, and NPV were determined at 100%, 97.1%, 96.6%, and 100%, respectively, of which the area under the receiver operating characteristic curve was 0.979. CONCLUSIONS: Upper GI saline-contrast US has a lower possibility for misdiagnosis of neonatal annular pancreas when considering the acute angle between the prestenotic and poststenotic descending duodenum. KEY POINTS: • This study includes the largest series of neonates with annular pancreas of which the characteristics were analyzed using the upper GI saline-contrast US. • Neonatal annular pancreas may be diagnosed by the characteristics-concave contour of the distal prestenotic duodenum; acute angle cutoff of 40.7° between the prestenotic and poststenotic duodenum; the "S" shape formed by the pylorus, the duodenal bulb, and the prestenotic and poststenotic descending duodenum. • The acute angle with the highest diagnostic value can be used to quantitatively diagnose neonatal annular pancreas and avoid potential misdiagnosis caused by sonographers' subjectivity.

Association between DSCAM polymorphisms and non-syndromic Hirschsprung disease in Chinese population.

BACKGROUND: Hirschsprung disease (HSCR, aganglionic megacolon) is the most frequent genetic cause of congenital intestinal obstruction. DSCAM was identified as associated to HSCR with Down Syndrome (DS-HSCR) in European population,but failed to replicate in the non-syndromic HSCR patients. We aim to further investigate the relationship of DSCAM with non-sydromic HSCR in a South Chinese cohort, the largest case-control study so far. METHOD: We analyzed 1394 HSCR patients and 973 healthy controls. Two polymorphisms (rs2837770 A > G, rs8134673 A > G) on DSCAM were genotyped using Sequenom Massarray platform. RESULTS: Both SNPs were confirmed as associated with non-syndromic HSCR in the South Chinese population (P = 1.69E-03, OR = 1.29 for SNP rs2837770 and P = 3.00E-03, OR = 1.27 for SNP rs8134637). Of note, we demonstrated the associated SNPs were more likely to affect a subgroup of patients with short-segment aganglionosis (S-HSCR) (P = 3.06E-03,OR = 1.21 for SNP rs2837770 and P = 3.33E-03,OR = 1.21 for SNP rs8134637). CONCLUSION: There is an association between DSCAM polymorphisms and non-syndromic HSCR in South Chinese population.

Trends of testis-sparing surgery for pediatric testicular tumors in South China.

BACKGROUND: Testis-sparing surgery is not popular in South China. This study aimed to investigate this procedure for pediatric testicular tumors. METHODS: Children with testicular benign tumors were retrospectively analyzed from January 2001 to June 2015 in the Sun Yat-sen University Cancer Center (SYSUCC) and the First Affiliated Hospital (SYSU-1st). Follow-up was performed until June 2016, and the proportions of TSS in the two hospitals during the different periods were compared. RESULTS: Forty-seven children with testicular benign tumors were enrolled, and 16 cases underwent testis-sparing surgery. All patients were cured and discharged, which included mature teratoma (n = 37), testicular adrenal rest tumors (n = 4), epidermal cysts (n = 3), granulomatous inflammation (n = 2) and adenomatoid tumors (n = 1). Inguinal testis-sparing surgery was performed in 16 children, and no recurrence was detected during follow-up. It was performed more frequently in SYSUCC than in SYSU-1st (P = 0.031), and the tumor size of these patients was smaller than those of patients who underwent radical orchiectomy (P = 0.044). Moreover, testis-sparing surgery has become more common in the past 5 years, although differences over time have not reached significance (P = 0.051). CONCLUSIONS: Testis-sparing surgery is reliable, and tumor size and special hospitals affect its success. Additionally, its use has become more popular in recent years. However, advocacy is still needed for the use of this technique in pediatric testicular benign tumors that are small sized.

Prenatal diagnosis and early postnatal management of pyriform sinus cyst: experience at a single medical center in mainland China.

OBJECTIVE: The aim of this study was to determine whether prenatal diagnosis of pyriform sinus cyst can improve the prognosis of this disorder. METHODS: A retrospective review was performed in 15 neonates with a pyriform sinus cyst seen at a single center between 2010 and 2014. Among the 15 cases, the diagnosis was made prenatally in eight cases (PreD), while the diagnosis was made postnatally in seven cases (PostD). Neonatal outcome was compared in the two subgroups. RESULTS: The mean gestational age at diagnosis of PreD was 27 ± 6.8 weeks, while the mean age at admission of PostD was 10.1 ± 8.8 days. Cervical mass, fever, respiratory distress, and hoarseness were common symptoms. The mean duration of postoperative mechanical ventilation was 11.5 ± 13.9 and 100.71 ± 80.0 h, respectively, in PreD and PostD (p < 0.01). The average postoperative length of stay and the length of hospital stay were 11.3 ± 3.34 and 19.6 ± 4.41 days in PreD, and 15.14 ± 8.28 and 24.14 ± 8.51 days in PostD, respectively. CONCLUSION: Prenatal diagnosis and timely postnatal sequential intervention were associated with less complications and shortened duration of postoperative mechanical ventilation. © 2016 John Wiley & Sons, Ltd.

Comparison of tubularized incised plate urethroplasty combined with a meatus-based ventral dartos flap or dorsal dartos flap in hypospadias.

PURPOSE: Tubularized incised plate urethroplasty (TIPU) is the preferred surgical option for distal and mid-shaft hypospadias repair. Neourethra dartos flap coverage is routinely used as a protective layer with good results. We modified meatus-based ventral dartos flap (MBVDF) to TIPU by dissecting the proximal mid-ventral dartos attached urethra and leaving the subcutaneous fascia connecting the meatus, and retrospectively compared the outcomes of using MBVDF with single dorsal dartos flap (DDF) on the complication rates of TIPU. METHODS: We present 2 surgeons' experiences with 356 patients with distal and mid-shaft hypospadias between January 2010 and December 2014. Patients were divided into two groups. Group DDF included 185 patients (mean age 29 months) underwent TIPU with DDF rotated laterally covering the suture lines of the neourethra. Group MBVDF included 171 patients (mean age 26 months) underwent TIPU with MBVDF covering the suture lines of the neourethra. Statistical analysis of patient basic information and complications was performed by two independent sample t test and Chi square test or Fisher's exact test. RESULTS: There were no statistical differences in age, type of hypospadias, and follow-up time between the two groups. The mean operative time in the group MBVDF (68.93 ± 8.32 min) was significantly shorter than in the group DDF (73.60 ± 9.06 min). Ventral skin necrosis (2.7%) and penile rotation (3.8%) in group DDF was significantly higher than group MBVDF which did not occur. The differences in other complication rates including fistula rate (2.7 vs 2.9%) between the groups were not statistically significant. CONCLUSION: DDF and MBVDF with TIPU are similarly effective methods for decreasing fistula in hypospadias repair. MBVDF with TIPU may be an easier method and can avoid ventral skin necrosis and penile rotation.

Chinese family with diffuse oesophageal leiomyomatosis: a new COL4A5/COL4A6 deletion and a case of gonosomal mosaicism.

BACKGROUND: Diffuse oesophageal leiomyomatosis (DOL) is a rare disorder characterized by tumorous overgrowth of the muscular wall of the oesophagus. DOL is present in 5 % of Alport syndrome (AS) patients. AS is a rare hereditary disease that involves varying degrees of hearing impairment, ocular changes and progressive glomerulonephritis leading to renal failure. In DOL-AS patients, the genetic defect consists of a deletion involving the COL4A5 and COL4A6 genes on the X chromosome. CASE PRESENTATION: We report a two-generation family (4 individuals; parents and two children, one male and one female) with two members (mother and son) affected with oesophageal leiomyomatosis. Signs of potential renal failure, which characterizes AS, were only apparent in the index patient (son) 2 years and three months after the initial diagnosis of DOL. Blood DNA from the four family members were submitted to exome sequencing and array genotyping to perform a genome wide screening for disease causal single nucleotide (SN) and copy number (CN) variations. Analyses revealed a new 40kb deletion encompassing from intron 2 of COL4A5 to intron 1 of COL4A6 at Xq22.3. The breakpoints were also identified. Possible confounding pathogenic exonic variants in genes known to be involved in other extracellular matrices disorders were also shared by the two affected individuals. Meticulous analysis of the maternal DNA revealed a case of gonosomal mosaicism. CONCLUSIONS: This is the first report of gonadosomal mosaicism associated to DOL-AS.

Thymic development of autoreactive T cells in NOD mice is regulated in an age-dependent manner.

Inefficient thymic negative selection of self-specific T cells is associated with several autoimmune diseases, including type 1 diabetes. The factors that influence the efficacy of thymic negative selection, as well as the kinetics of thymic output of autoreactive T cells remain ill-defined. We investigated thymic production of ß cell-specific T cells using a thymus-transplantation model. Thymi from different aged NOD mice, representing distinct stages of type 1 diabetes, were implanted into NOD.scid recipients, and the diabetogenicity of the resulting T cell pool was examined. Strikingly, the development of diabetes-inducing ß cell-specific CD4(+) and CD8(+) T cells was regulated in an age-dependent manner. NOD.scid recipients of newborn NOD thymi developed diabetes. However, recipients of thymi from 7- and 10-d-old NOD donor mice remained diabetes-free and exhibited a progressive decline in islet infiltration and ß cell-specific CD4(+) and CD8(+) T cells. A similar temporal decrease in autoimmune infiltration was detected in some, but not all, tissues of recipient mice implanted with thymi from NOD mice lacking expression of the autoimmune regulator transcription factor, which develop multiorgan T cell-mediated autoimmunity. In contrast, recipients of 10 d or older thymi lacked diabetogenic T cells but developed severe colitis marked by increased effector T cells reactive to intestinal microbiota. These results demonstrate that thymic development of autoreactive T cells is limited to a narrow time window and occurs in a reciprocal manner compared with colonic microbiota-responsive T cells in NOD mice.

Intussusception patients older than 1 year tend to have early recurrence after pneumatic enema reduction.

PURPOSE: To identify age risk factors of early recurrent intussusception after pneumatic enema reduction. Management opinions are proposed. METHODS: Two thousand two hundred and ninety-five intussusception patients' medical records from January 2009 to December 2011 were retrospectively reviewed and analyzed. RESULTS: Of the 2295 patients, the intussusception of 1917 of them was initially reduced by pneumatic enema, with 127 cases recurring within 72 h. The early recurrence rate is 6.62%. The early recurrence rate of patients younger than 1 year old is 2.1% (22/1032), while the rate for those older than 1 year is 11.9% (105/885). The difference is significant (P = 0.0001). There were no significant differences between age groups older than 1 year. One hundred and seventeen cases of recurrence happened within 48 h, which accounted for 92.1% of all early recurrence. Recurrence patients were treated again with pneumatic enema, with a successful reduction in 93.7%. They were followed up for 2-4 years; the long-term recurrent rate was 11.8% (14/119). No patient had poor prognosis because of delayed treatment. CONCLUSION: Intussusception patients older than 1 year tend to have greater early recurrence rate after pneumatic enema reduction; 92.1% of the early recurrent cases happened in 48 h. There is no need to hospitalize patients after pneumatic enema reduction. A repeat pneumatic enema is a good choice before surgical approach.

Communicating bronchopulmonary foregut malformation type IA: radiologic anatomy and clinical dilemmas.

BACKGROUND: Communicating bronchopulmonary foregut malformation (CBPFM) type IA is extremely rare and is associated with a high mortality rate. This malformation manifests with communication between the lung and the foregut, and this can lead to esophageal atresia and tracheoesophageal fistula (EA-TEF) to the distal pouch. PURPOSE: To detail radiographic findings of CBPFM type IA cases and to summarize an appropriate therapeutic strategy for the management of this disorder. METHODS: Medical data for two patients with CBPFM type IA were retrospectively reviewed with regard to radiographic characteristics, therapy, and outcome. RESULTS: Both cases were initially misdiagnosed due to the presence of EA-TEF. Unusual atelectasis of the lateral lung was observed in chest radiographs, while non-aerated hypoplastic right lung and agenesis of the right main bronchus were detected by computed tomography. A final diagnosis was made by esophagogram. Only one patient survived following surgery. CONCLUSION: CBPFM type IA is a rare condition and is extremely difficult to diagnose. However, CBPFM type IA should be suspected in patients manifesting EA and atelectasis of a unilateral lung on a chest radiograph. The decision to perform a pneumonectomy or bronchoplasty depends on the degree of exiting permitted due to pulmonary damage assessed by computed tomography.

Probing the protein conformation and adsorption behaviors in nanographene oxide-protein complexes.

In this report, the adsorption characteristics and conformation changes of model protein bovine serum albumin (BSA) adsorbed on nanographene oxide (NGO) are described. The adsorption isotherms obtained at pH 4.0, 4.7, 7.4 and 8.8 show that NGO has the highest affinity for BSA in the acid environment of pH 4.0, but the protein adsorption capacity decreases with the pH value increasing. The data imply that the spontaneously binding of BSA to the NGO surfaces is mainly due to the protein conformation and an electrostatic attraction mechanism. The fluorescence and synchronous fluorescence spectroscopic studies show that NGO quenches the fluorescence of BSA both statically and dynamically, and induces obvious perturbations on the conformation of BSA as well as the microenvironments around the Trp and Tyr residues. Moreover, analysis of the secondary structure of the proteins via Fourier transform infrared spectroscopy revealed that evident secondary structural changes may undergo upon adsorption. This study gives an insight into the interaction between NGO and proteins, which is critical in the design of optimal graphene nanosheets-protein conjugates.