Quality of life and defecative function 10 years or longer after posterior sagittal anorectoplasty and laparoscopic-assisted anorectal pull-through for anorectal malformation.

PURPOSE: In our center, patients with anorectal malformation, including males with recto-vesical (RV)/recto-bladder neck (RBN)/recto-prostatic urethral (RU) fistulas, and females with recto-vaginal (RV) fistulas have been treated by posterior sagittal anorectoplasty (PSARP) before 2000, and by laparoscopic-assisted anorectal pull-through (LAARP) thereafter. We would like to compare the quality of life (QOL) and long-term defecative function between these two groups of patients 10 years after reconstructive surgery. METHODS: Patients who underwent LAARP between 2001 and 2005 were compared with historical controls treated with PSARP between 1996 and 2000. Degrees of continence were graded by the Krickenbeck classification and Kelly's score. QOL was assessed by Hirschsprung's disease/Anorectal Malformation Quality of Life (HAQL) questionnaire. Results were compared using Chi-square test and t test. RESULTS: There were 14 LAARP and 7 PSARP patients. All attained voluntary bowel movements. Moderate to severe soiling (Krickenbeck Grade 2 and 3) was found in 3/14 LAARP (21.4%) and 1/7 PSARP (14.3%) patients, p = 1.00. Constipation requiring use of laxatives was present in 3/14 LAARP (28.6%) and 1/7 PSARP (14.3%) patients, p = 0.62. Mean Kelly's scores were 3.79 ± 0.98 (LAARP) and 4.71 ± 1.25 (PSARP), p = 0.12. No patient required Malone antegrade continence enema (MACE). The QOL scores based on the HAQL questionnaire were comparable between the two groups in all areas except social functioning, in which the LAARP patients attained a significantly lower mean score (26.4 vs 71.7, p = 0.0001). CONCLUSION: The 10-year outcome between LAARP and PSARP patients in terms of QOL and defecative function is comparable. Impairment in social functioning in these patients is reflected by the self-reported lower level of functioning.

The value of the 24-h delayed abdominal radiograph of barium enema in the diagnosis of Hirschsprung's disease.

AIM OF STUDY: The objective of this study is to determine the diagnostic value of the 24-h delayed film for Hirschsprung's disease (HD). Other features of the barium enema were also examined, in particular the correlation between the radiological transition zone (TZ) and the final pathology. METHODS: All patients with suspected HD from 2003 to 2013 who had undergone barium enema and rectal biopsy were reviewed retrospectively to study the correlation between radiological features of barium enema with the final diagnosis as well as severity. RESULTS: A total of 182 patients were admitted for suspected HD during the study period, of which 82 had both investigations done. 68 patients had radiological features suggestive of the disease and ultimately, 12 patients had the disease confirmed with rectal biopsy. Among those without radiological features of HD, 2 patients were found to have the disease. Thus, the sensitivity of the 24-h delayed film was 85.7 % and the specificity was 17.6 %. The positive predictive value (PPV) of this test was 20.6 % and the negative predictive value (NPV) was 85.7 %. Regarding the level of TZ, it was not detected in the barium enema in 7 (50 %) out of the 14 patients. For those with the presence of TZ, 6 (85.7 %) of them correlated well with the intra-operative findings and 4 (57.1 %) of them correlated well with the final histology. CONCLUSION: The 24-h delayed film of barium enema has a high NPV and is useful to rule out HD. However, rectal biopsy is still suggested for disease confirmation given its low PPV. Lastly, once present, the level of radiological TZ is also a useful predictor for the actual disease involvement.

Thoracoscopic repair of congenital diaphragmatic hernia: two centres' experience with 60 patients.

INTRODUCTION: Congenital diaphragmatic hernia is a potentially life-threatening neonatal condition which required surgical intervention. With the advances in endosurgical instruments and techniques, thoracoscopic approach is gaining popularity as a standard procedure in the treatment of this condition. In this study, we reviewed our two centres' experience with thoracoscopic repair of congenital diaphragmatic hernia in recent years. METHODS: All patients who underwent thoracoscopic repair of congenital diaphragmatic hernia between 2010 and 2013 at the two tertiary referral centres were identified. Medical records were retrospectively reviewed. Data including patients' demographics, peri-operative outcomes, length of hospitalisation and post-operative complications were extracted and analysed. RESULTS: 60 patients were identified over the study period, with 46 males and 14 females. 48 patients received operation within the first 7 days of life. There were seven patients with delayed presentation and were operated after 1 month old. The average body weight was 3.03 kg. Left-sided hernia was more prevalent (n = 50). The mean operative time was 88.5 min (range 31-194 min). No conversion to open thoracotomy or laparotomy was required in any of the patients. All patients except one were intubated and paralysed in neonatal intensive care units for at least 3 days after operation. Average hospital stay was 14.6 days. There was no mortality in this series. There were five recurrences, one being the patient without post-operative paralysis, and the others with deficient posterior muscle rim. No musculoskeletal deformity was noted on follow-up examination. CONCLUSION: Thoracoscopic repair of congenital diaphragmatic hernia can be performed safely in specialised centres. The post-operative recovery and cosmesis are excellent. Diaphragmatic hernia with large defect remains a challenge for surgeons.

Fluoroquinolone-induced Achilles tendinitis.

We report a case of Achilles tendinitis after intake of ciprofloxacin for treatment of respiratory tract infection. Fluoroquinolone-induced tendinopathy is an uncommon but increasingly recognised adverse effect of this antibiotic class. Most of the cases occur in the Achilles tendon and may lead to tendon rupture. Possible predisposing risk factors include use of steroid, patients with renal impairment or renal transplant, old age, and being an athlete. The drug should be stopped once this condition is suspected. Symptomatic treatment should be given and orthopaedic referral is desirable if tendon rupture occurs.

Thoracoscopic resection of congenital cystic lung lesions is associated with better post-operative outcomes.

INTRODUCTION: The incidence of congenital cystic lung lesions has been increasing in recent years due to better antenatal detection. With the introduction and maturation of thoracoscopy, the operative management for these lesions has seen advancement in the last decade. In this study, we aimed to compare the post-operative outcomes of patients who had thoracoscopic resection with those who underwent open resection. METHODS: A retrospective review of all patients who underwent surgery for congenital cystic lung lesions between January 1996 and June 2012 in a tertiary referral center was conducted. Patients' demographics, operative procedures and post-operative outcomes were analyzed. RESULTS: Sixty-seven patients were identified over the past 15 years. Thirty-nine patients had thoracoscopic resections and 28 had open resections. Thirteen patients in the thoracoscopic group required conversion. Both groups had similar demographics in terms of age, body weight and laterality of lesions. The mean operative time and blood loss in the two groups were comparable. Patients in the thoracoscopic group had significantly shorter duration of chest tube drainage (4.3 vs. 6.9 days, p = 0.004), shorter intensive care unit stay (2.5 vs. 5.9 days, p = 0.003) and shorter hospital stay (6.9 vs. 12.0 days, p < 0.001). Post-operative complication rate was similar between the two groups. Patients with body weight less than 5 kg showed a significantly higher conversion to open surgery as compared to those with body weight more than 5 kg (62.5 vs. 25.8 %, p = 0.049). CONCLUSION: Successful thoracoscopic resection for congenital cystic lung lesions results in better post-operative outcomes. However, this technique remains technically challenging in patients with body weight less than 5 kg.

Laparoscopic inguinal hernia repair in premature neonates: is it safe?

OBJECTIVE: With advances in clinical medicine, many premature babies nowadays can have excellent survival outcomes. As the incidence of inguinal hernias in this group is high and there is scarce data in the literature regarding the optimal timing for repair, this study aims to review our experience in laparoscopic repair in premature infants. METHODS: In our centre, premature neonates with inguinal hernia noted during hospitalization were offered laparoscopic repair when the body weights reached 2.5 kg unless there is contraindication for laparoscopy. A retrospective review was carried out for all premature neonates who underwent laparoscopic inguinal hernia repair from 2001 to 2011. The operative results, complications, incarceration risk and postoperative apnea risk were recorded. RESULT: A total of 79 premature neonates received laparoscopic inguinal hernia repair during this period. The mean gestational age at birth was 31.9 weeks (27-36 weeks) and the mean gestational age at operation was 46.5 weeks (33-92 weeks). One patient had incarceration and required emergency operation while waiting for the elective repair. The mean operative time was 44.9 min (25-93 min). One patient (1.3 %) had recurrence. No postoperative apnea was noted in any patient. CONCLUSION: Laparoscopic hernia repair is safe and feasible in premature neonates when they attain reasonable body size, as long as there is excellent anaesthesia support. Low risk of incarceration was noted in this study and it is worth waiting for the body weight to build up and hence facilitate laparoscopic repair.

Association of CD247 with systemic lupus erythematosus in Asian populations.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. METHODS: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. RESULTS: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. CONCLUSION: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese.

UHRF1BP1 encodes a highly conserved protein with unknown function. Previously, a coding variant in this gene was found to be associated with systemic lupus erythematosus (SLE) in populations of European ancestry (rs11755393, R454Q, P=2.22 x 10⁻8, odds ratio=1.17). In this study, by a combination of genome-wide study and replication involving a total of 1230 patients and 3144 controls, we confirmed the association of this coding variant to SLE in Hong Kong Chinese. We also identified another coding variant in this gene that independently contributes to SLE susceptibility (rs13205210, M1098T, P=4.44 x 10⁻9, odds ratio=1.49). Cross-population confirmation establishes the involvement of this locus in SLE and indicates that distinct alleles are contributing to disease susceptibility.

The potency of allospecific Tregs cells appears to correlate with T cell receptor functional avidity.

CD4(+) CD25(+) regulatory T cells (T(reg) cells) are an attractive adoptive cell therapy in mediating transplantation tolerance. T-cell receptor (TcR) activation is critical for T(reg) function, suggesting that the TcR avidity of T(reg) cells used in therapy may affect the therapeutic outcome. To address this, we compared the regulatory capacity of T(reg) lines expressing TcRs derived from two TcR transgenic mice shown to have the same specificity but different functional avidities. T(reg) lines generated from CD4(+)CD25(+) T cells from C57BL/6 mice were transduced with one of either of these TcRs. The antigen specificity of the transduced T(reg) lines was confirmed in vitro. T(reg) lines expressing the TcR with higher functional avidity showed stronger suppressive capacity in a linked suppression model in vitro. Furthermore, the same T(reg) lines demonstrated a stronger proliferation in vivo following antigen exposure. Pretreatment of recipient BL/6 mice with these T(reg) cells, together with anti-CD8 antibody and Rapamycin therapies, prolonged survival of BALB/c skins, as compared with mice that received T(reg) lines with lower TcR avidity. Taken together, these data suggest that the TcR functional avidity may be important for T(reg) function. It highlights the fact that strategies to select T(reg) with higher functional avidity might be beneficial for immunotherapy in transplantation.

Fine mapping of the 9q31 Hirschsprung's disease locus.

Hirschsprung's disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 x 10(-6) [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system.

Performing Kasai portoenterostomy beyond 60 days of life is not necessarily associated with a worse outcome.

The introduction of Kasai portoenterostomy has dramatically improved the management and survival of children with biliary atresia. The success rate of this operation worldwide varies with different centers. In this respect, many authors have studied the correlation of a successful outcome with various factors, such as the experience and workload of the surgical center, the use of postoperative steroids, the underlying biliary anatomy, as well as the age of patients at the time of the operation. Indeed, the age of 60 days has been used by clinicians as a critical time beyond which the rate of success of the Kasai operation markedly reduces. Despite this worldwide adoption, clear evidence supporting this critical operative time is still lacking. We undertook a review of our experience in the management of children with biliary atresia and focused specifically on the issue of the timing of operation. We showed that performing the Kasai operation beyond the age of 60 days was not associated with a worse outcome and that a high percentage of patients could still achieve good bile flow with normal bilirubin postoperatively. Thus, we believe that until the age of 100 days, the age of the patients does not play a significant role in determining the success of the Kasai operation.

The first report of a single-port laparoscopic nephrectomy in a child.

There has been an exponential rise in the use of minimally invasive procedures in surgery, with obvious benefits to patients. Recently, transumbilical single-port laparoscopic surgery has been championed as the next major technical advance. In this article, we report the first case where single-port laparoscopic surgery has been used to manage a paediatric problem in the region.

Inhibition of Akt sensitises neuroblastoma cells to gold(III) porphyrin 1a, a novel antitumour drug induced apoptosis and growth inhibition.

BACKGROUND: Gold(III) porphyrin 1a is a new class of anticancer drug, which inhibits cell proliferation of wide range of human cancer cell lines and induces apoptosis in human nasopharyngeal carcinoma cells. However, the underlying signalling mechanism by which gold(III) porphyrin 1a modifies the intracellular apoptosis pathways in tumour cells has not been explained in detail in neuroblastoma cells. METHODS: Cell proliferation and apoptosis were determined by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Annexin V binding, respectively. Western blot assay was used to detect proteins involved in apoptotic and Akt pathways. In vivo tumour growth was assessed by inoculating tumour cells to nude mice subcutaneously, and gold(III) porphyrin 1a was administrated intravenously. RESULTS: This study assessed the antitumour effect and mechanism of gold(III) porphyrin 1a on neuroblastoma in vitro and in vivo. Gold(III) porphyrin 1a displayed a growth inhibition and induction of apoptosis in neuroblastoma cells effectively in vitro, which was accompanied with release of cytochrome c and Smac/DIABLO and caspases activation. Further studies indicated that gold(III) porphyrin 1a inhibited X-linked inhibitor of apoptosis (XIAP). However, we found that gold(III) porphyrin 1a can induce a survival signal, Akt activation within minutes and could last for at least 24 h. To further confirm association between activation of Akt and the effectiveness of gold(III) porphyrin 1a, neuroblastoma cells were treated with API-2, an Akt-specific inhibitor. API-2 sensitised cells to gold(III) porphyrin 1a-induced apoptosis and growth inhibition. CONCLUSION: These results suggested that Akt may be considered as a molecular 'brake' that neuroblastoma cells rely on to slow down gold(III) porphyrin 1a-induced apoptosis and antiproliferation. Gold(III) porphyrin 1a is a mitochondrial apoptotic stimulus but also activates Akt, suggesting an involvement of Akt in mediating the effectiveness to growth inhibition and apoptosis by gold(III) porphyrin 1a and that inhibition of Akt can enhance the anticancer activity of gold(III) porphyrin 1a in neuroblastoma.

Hirschsprung disease, associated syndromes and genetics: a review.

Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.

Laparoscopic hernioplasties in children: the implication on contralateral groin exploration for unilateral inguinal hernias.

BACKGROUND: Inguinal hernias are commonly seen in the paediatric population. Controversies still exist regarding the need for contralateral groin exploration when an unilateral inguinal hernia is presented, since the true incidence of contralateral patent processus vaginalis is not known. With the advent of laparoscopic hernioplasty, the status of the contralateral side can be evaluated at the same setting. Here, we describe our experience in this issue after the introduction of laparoscopic hernioplasty in our unit. METHODS: A retrospective review was carried out between October 2002 and January 2008. All patients presented with unilateral inguinal hernias were included. The demographics of the patients and the operative findings at laparoscopy were recorded. Statistics were performed using Student t-test or chi(2) test as appropriate and p < 0.05 was taken as statistically significant. RESULTS: During the study period, 363 children were included in our study, of which there were 292 males and 71 females. 212 patients presented with right-sided hernias and 151 were left-sided. The mean age of patients at presentation was 48.8 months. The incidence of contralateral PPV overall was 39.7%. There was no decrease in incidence of having a contralateral inguinal hernia in relation to age. CONCLUSION: Laparoscopy can accurately diagnose contralateral PPV in children who undergo unilateral inguinal hernia repair and thus holds an advantage over open herniotomy. Furthermore, there should not be an age criteria for contralateral exploration for surgeons who perform open herniotomy.

Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma.

Macrophage migration inhibitory factor (MIF) has been defined as a novel oncogene. Our previous results have shown that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors. The aim of this study was to test whether tumor growth could be inhibited by reduction of endogenous MIF expression in neuroblastoma and clarify the molecular mechanisms underlying MIF reduction on the control of neuroblastoma growth. We established human neuroblastoma cell lines stably expressing antisense MIF (AS-MIF) cDNA. These stable transfectants were characterized by cell proliferation, gene expression profile, tumorigenicity and metastasis in vitro and in vivo. Decreased MIF expression was observed after transfection with AS-MIF in neuroblastoma cells and downregulation of MIF expression significantly correlated with decreased expression of N-Myc, Ras, c-Met and TrkB at protein level. Affymetrix microarray analysis revealed that expression of IL-8 and c-met was inhibited and neuroblastoma-favorable genes such as EPHB6 and BLU were upregulated in MIF reduced cells. Neuroblastoma cell growth exhibited a nearly 80% reduction in AS-MIF transfectants in vitro. Furthermore, mice in which tumors formed after subcutaneous injection of AS-MIF transfectants showed a 90% reduction in tumor growth compared to control. Metastasis in mice was also suppressed dramatically. Our data demonstrate that targeting MIF expression is a promising therapeutic strategy in human neuroblastoma therapy, and also identifies the MIF target genes for further study.