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Mutations in PINK1 and Parkin are associated with early-onset Parkinson's disease. We recently discovered that PINK1 phosphorylates Parkin at serine65 (Ser(65)) within its Ubl domain, leading to its activation in a substrate-free activity assay. We now demonstrate the critical requirement of Ser(65) phosphorylation for substrate ubiquitylation through elaboration of a novel in vitro E3 ligase activity assay using full-length untagged Parkin and its putative substrate, the mitochondrial GTPase Miro1. We observe that Parkin efficiently ubiquitylates Miro1 at highly conserved lysine residues, 153, 230, 235, 330 and 572, upon phosphorylation by PINK1. We have further established an E2-ubiquitin discharge assay to assess Parkin activity and observe robust discharge of ubiquitin-loaded UbcH7 E2 ligase upon phosphorylation of Parkin at Ser(65) by wild-type, but not kinase-inactive PINK1 or a Parkin Ser65Ala mutant, suggesting a possible mechanism of how Ser(65) phosphorylation may activate Parkin E3 ligase activity. For the first time, to the best of our knowledge, we report the effect of Parkin disease-associated mutations in substrate-based assays using full-length untagged recombinant Parkin. Our mutation analysis indicates an essential role for the catalytic cysteine Cys431 and reveals fundamental new knowledge on how mutations may confer pathogenicity via disruption of Miro1 ubiquitylation, free ubiquitin chain formation or by impacting Parkin's ability to discharge ubiquitin from a loaded E2. This study provides further evidence that phosphorylation of Parkin at Ser(65) is critical for its activation. It also provides evidence that Miro1 is a direct Parkin substrate. The assays and reagents developed in this study will be important to uncover new insights into Parkin biology as well as aid in the development of screens to identify small molecule Parkin activators for the treatment of Parkinson's disease.

Enterovesical fistulae in Crohn's disease are relatively rare. We present the first report of a child presenting with an enterovesical fistula as the initial presentation of Crohn's disease. Management comprises of timely diagnosis, and treatment involving surgical resection with adjunctive medical management including immunomodulators. This case highlights the need to be aware of the rare but important occurrence of Crohn's enterovesical fistula as a cause for urinary symptoms in a child with inadequate weight gain.

Background: Central venous lines (CVLs) are frequently used in the management of many neonatal and pediatric conditions. Failure to remove the luminal part of the line (retained CVL) is rare. Consequently, there is lack of experience and consensus in its optimal management., Aim: To document the incidence and management of retained CVLs in a tertiary pediatric surgical centre with access to interventional cardiology services. To review the literature and report efficacy/morbidity of attempted extraction of retained CVLs., Methods: Children with retained CVLs were identified from departmental morbidity and mortality records over an 11-year period. A literature search was performed in PubMed and Scopus to identify studies reporting retained CVLs (earliest date to 1 January 2012). This was supplemented by scanning bibliographies of retrieved articles., Results: The 11-year incidence of retained CVL was 0.3% (n=10; median duration in-situ 66.5 {range 47-146} months). The underlying pathology in 8 was cystic fibrosis. Antegrade transfemoral snare retrieval was successful in 6 of 7 attempts. In the remaining 3, a conservative approach was adopted following consultation with the family. None of the 4 with retained CVL developed complications (median follow-up 7.5 {range 1-53} months). The literature describes 38 pediatric index cases (including 10 from the current series). Seventeen (49%) were managed conservatively either intentionally or by default after failed endovascular removal attempt (n=4). No complications directly attributed to retained CVLs have been reported (median follow-up 40 {range 1-120} months). Reported morbidity associated with endovascular retrieval includes: procedural failure 30%, line embolization 8%, and intra-operative thrombo-embolism 8%., Conclusion: Literature regarding management of retained CVLs is anecdotal. Although uncommon, the complication should feature in consent for removal of CVLs. Conservative management carries long-term risks of infection, thrombosis, and even migration, albeit unquantified over a child's lifetime. Endovascular retrieval is feasible with appropriate expertise., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Patients with Crohn's disease (CD) are frequently exposed to diagnostic radiation in emergency departments (EDs). We aimed to examine clinical predictors of urgent abdominopelvic computed tomography (APCT) findings in this population., Methods: A retrospective cross-sectional study was performed among adults with CD presenting to 2 emergency departments with a gastrointestinal chief complaint. The outcome, APON (abscess, perforation, obstruction, new or worsening non-CD-related findings), included APCTs with new or worsening CD-related or non-CD-related urgent findings. Variables with P < 0.05 in bivariate analyses were included in a multivariable logistic regression model, which was also used to develop a risk score for APON., Results: A total of 481 APCTs were performed and 166 (34.5%) identified APON. Variables retained in the final model were history of intestinal obstruction (odds ratio [OR]: 3.78, 95% confidence interval [CI]: 2.27-6.28), history of intraabdominal abscess (OR: 2.64, 95% CI: 1.43 to 4.88), current hematochezia (OR: 0.38, 95% CI: 0.21 to 0.68), and white blood cell count >12,000/μL (OR: 2.49, 95% CI: 1.63 to 3.84). The c-statistic was 0.72. The risk score subtracts 1 point for hematochezia, and adds 1 point for each of the other variables. Among patients with a risk score of -1, the predicted and observed risk for APON was 9% and 6%, respectively. Any score greater than -1 had a predicted and observed risk of 19.8% and higher., Conclusions: An APON risk score of -1 is associated with a low risk of urgent APCT findings in patients with CD in the emergency department. Implementation of such a tool may support clinical decision-making in the ED setting.

Aim: Excision of testicular remnants is debatable in the scenario where hypoplastic vas and vessels can be seen entering a closed internal ring during laparoscopy for impalpable testes. We aimed to establish how frequently excised remnants have identifiable testicular tissue and, hence, malignant potential., Methods: This study is a retrospective review of all excised testicular remnants in children with impalpable testis. Specimens that were excised for indications other than testicular regression syndrome were excluded. Pathology reports of excised specimens were reviewed, and the presence of multiple histologic features was noted. Histologic confirmation of testicular/paratesticular tissue required the presence of 1 or more of the following: seminiferous tubules, germ cells, Sertoli cells, Leydig cells, vas deferens, or epididymal structures. Malignancy potential was defined by the presence of germ cells or seminiferous tubules. All patients with seminiferous tubules were further examined by a single histopathologist., Results: A total of 208 testicular remnants from 206 children were excised over the 11-year period (1999-2009). Histologic evidence confirmed excision of testicular/paratesticular tissue in 180 cases (87%). Seminiferous tubules were noted in 27 (15%), and germ cells were present in 19 (11%) cases., Conclusion: Viable germ cells were found in 11% of examined remnants, which, in our opinion, justifies their removal., (Copyright © 2011. Published by Elsevier Inc.)

We describe in this report what we believe to be the first report of a rare presentation of a very rare tumor, especially in this age group. We highlight the importance of early consideration of malignancy as a cause of chylous ascites in infancy and we discuss different causes of chylous ascites.

Clinical presentation and microbiology profiles of neutropenic paediatric oncology patients presenting with ecthyma gangrenosum (EG) were studied. Surgical strategies deployed for these critically ill children are reported. Between 1994 and 2005, all children with EG were identified. Case notes were reviewed. Hospital course and long-term outcome were documented. Ten patients were identified. Eight had acute lymphoblastic leukaemia, one child had acute myeloid leukaemia and another had rhabdomyosarcoma. Lesions occurred in the perineal region (n = 5), buttocks (n = 2), thigh (n = 2) and the face (n = 1). Seven children had positive blood cultures for Pseudomonas aeruginosa. Surgery included (1) radical debridement, and (2) debridement with covering colostomy for four of those with perianal lesions. Ecthyma gangrenosum is a rapidly spreading and potentially lethal condition. Paediatric oncology patients with neutropenia are at a high risk. Surgical excision is crucial for progressive lesions to prevent mortality.

Sclerosing encapsulating peritonitis (SEP) is a rare cause of bowel obstruction, most commonly associated with chronic ambulatory peritoneal dialysis. It has not previously been reported as a complication of ventriculoperitoneal (VP) shunts. We describe the clinical features of shunt-associated SEP and the important management considerations. Two children presented with small bowel obstruction after long-standing VP shunting of hydrocephalus. Neither had a history of recent shunt infection/revision nor evidence of shunt malfunction. In each case, the bowel was "cocooned" in a fibrous sheath with a notable absence of parietal adhesions. Both children were managed by meticulous adhesiolysis accompanied by shunt exteriorization. Both had prolonged ileus and required total parenteral nutrition. One required further laparotomy at which adhesiolysis was accompanied by irrigation with icodextrin 4% and systemic high-dose methylprednisolone. Weaning of steroids was accompanied by the introduction of azathioprine. A notable feature of intestinal obstruction because of SEP was severe pain despite adequate decompression. The restrictive "cocoon" that envelops the bowel prevents bowel dilatation and accounts for atypical radiologic findings in these cases.

Anaplastic large cell lymphoma (ALCL) is a rare tumor comprising around 10-15% of childhood lymphomas. We describe the case of a female who initially presented with localized skin disease associated with an insect bite. However, she subsequently relapsed with widespread systemic ALK-positive ALCL that included lymphoma deposits in the myocardium, a very rare manifestation. Her disease responded well to chemotherapy but she later developed a fatal relapse in the CNS. We also present data on an immune response to ALK, demonstrating a fluctuation in the levels of circulating antibodies to ALK corresponding to the different phases of her illness., ((c) 2008 Wiley-Liss, Inc.)

Optimal surgical therapy for low anorectal anomalies remains controversial. We compared functional outcome after correction of perineal fistula in boys with either anoplasty (AP) or limited posterior sagittal anorectoplasty (PSARP). Thirty-nine boys from two centres treated for perineal fistula with either AP (n = 24) or PSARP (n = 15) from 1996 to 2001 underwent prospective follow-up for functional outcome. In order to minimize heterogeneity of the study groups, only boys with perineal fistula were included. Functional outcome was assessed using a validated bowel function score (maximum score 20). Day and night time wetting as well as the age at potty training were also recorded. An independent nurse specialist interviewed caregivers. AP and PSARP groups were comparable regarding age, associated malformations and frequency of sacral dysplasia. No significant differences between the groups were observed in the overall median bowel function score, AP 18 (11-20) versus PSARP 18 (11-20), or in the age at potty training, AP 32 (14-66) versus PSARP 36 (18-60). Covering colostomy was employed significantly (P < 0.05) more often with PSARP (10/15) than with AP (1/24). Surgery for local complications was carried out significantly (P < 0.05) more often after PSARP (5/15) than after AP (2/24). Two patients in both groups required a temporary salvage colostomy. Overall functional outcome is comparable after AP and PSARP for perineal fistula in boys. As a more straightforward procedure AP is safer and less prone to complications avoiding the need for covering colostomy.

Pallister-Hall and McKusick-Kaufman syndromes are developmental disorders with well defined phenotypes, distinct loci and different patterns of inheritance. The clinical features can overlap and may cause diagnostic difficulty, particularly if complex genitourinary malformations are present. A case is presented with features of both syndromes but in which a GLI3 mutation has been identified. A literature review of similar cases is presented and it is proposed that these cases probably represent the Pallister-Hall syndrome. A detailed abdominal and perineal examination should be considered in all female patients with the Pallister-Hall syndrome, looking for associated genitourinary anomalies. Conversely, all girls with features suggestive of McKusick-Kaufman syndrome require neuroimaging to look for features of the Pallister-Hall syndrome. The correct diagnosis is important so that the patient and the family may receive appropriate management. It also allows provision for an accurate recurrence risk.

Background/aim: Imperforate anus without fistula consists of a spectrum of defects with variable distance between the rectal pouch and the perineum. We have developed a novel surgical approach for individual management of these patients based on precise knowledge of the level of the anomaly., Methods: All consecutive patients with imperforate anus without fistula between 2002 and 2004 had sigmoidostomy performed after having failed to pass meconium in the first 24 hours. The upper pouch was intraluminally visualized using retrograde endoscopy through the sigmoid mucous fistula. The distal termination of the rectum was clearly identified as by convergence of the anal columns. Bright translumination of the endoscope light from the rectum to the anal dimple within the external sphincter indicated a low malformation amenable to transanal proctoplasty. The rectum was incised from below under endoscopic visual control. Poor translumination indicated a higher defect, in which case, the operation was converted to standard posterior sagittal anorectoplasty., Results: Seven patients (6 boys) were identified. Four patients (3 boys) completed transanal endoscopic-assisted proctoplasty. In all cases, the convergence of anal columns indicating rectal termination was right above the anal pit at the site of the maximal external sphincter squeeze. In 3 patients, the operation was converted to posterior sagittal anorectoplasty after verification of a higher anomaly by endoscopy. There were no operative complications. The median follow-up was 3 months (range, 1-26 months). All patients have an appropriate size anus and regular bowel actions., Conclusions: Transanal endoscopic-assisted proctoplasty allows safe and anatomical reconstruction of the anorectum, as well as contemporaneous closure of the sigmoidostomy in a significant proportion of patients with imperforate anus without fistula, avoiding the potential complications associated with the open posterior sagittal approach.

Ferrocenyl monophosphine ligands have been developed by a method based on palladium-catalyzed Suzuki-Miyaura coupling. The modular procedure creates a rapid synthesis of phosphines with diverse properties. The electron-rich phosphines have been successfully applied to the Suzuki-Miyaura coupling of activated and deactivated aryl chlorides, with low catalyst loading being feasible in the synthesis of tris-ortho-substituted biaryls.

Purpose: The aim of this study was to determine the morbidity and medium-term functional outcome of the Duhamel operation and laparotomy and transanal endorectal coloanal anastomosis (TECA) for Hirschsprung's disease (HSCR)., Methods: The study populations were 34 consecutive children who underwent the Duhamel operation (or Lester Martin modification) and 37 who had the TECA. Demographic details were obtained by case note review, and functional outcome was determined by a combination of outpatient interview, questionnaire, and telephone enquiry., Results: There was no difference between the groups with respect to age, gender, and length of aganglionic segment. Seventy percent presented as neonates (Duhamel, 24 of 34; TECA, 26 of 37). A single-stage primary pull-through was performed in 17 of 37 children in the TECA group, and in 1 of 34 from the Duhamel group. There was a single perioperative death in the Duhamel group and an unrelated, late death in the TECA group. Postoperative enterocolitis was seen in 13 of 37 TECA children and in a single child from the Duhamel group. A stricture of the pull-through segment was seen in 7 of 37 children after TECA and required temporary diversion in 2 of 9. Late division of a rectal spur was required in 6 of 33 Duhamel children. Requirement for late myectomy was the same in both groups (Duhamel 3 of 33, TECA 4 of 37). Complications requiring stoma formation occurred in 5 of 37 after TECA and 2 of 33 after the Duhamel operation. Two children from the TECA group and 1 from the Duhamel group remain diverted. One child from each group required a re-pull-through procedure. Two patients were lost to follow-up in the TECA group, leaving 34 children in this group and 33 in the Duhamel group in whom functional outcome could be assessed. Functional outcome was similar in the 2 groups., Conclusions: TECA and Duhamel procedures have similar medium-term functional outcomes. TECA has a high incidence of postoperative enterocolitis and transient stricture formation but is suitable for single-stage neonatal treatment of HSCR.

Background: Constipation is a common problem in childhood, and various radiologic methods have been advocated for investigation. Colonic transit time (CTT) has been used in adults to investigate colonic motility, but few studies evaluate this method in children. Data on CTT in the normal paediatric population are scarce., Methods: The colonic transit time was measured in 22 healthy children (median age, 10 years; range, 4 to 15 years) by Abrahamsson's method. Children took bolus ingestions of radiopaque markers on 6 consecutive days, and on day 7 a single abdominal x-ray was performed. This was evaluated for total and segmental colonic transit time., Results: The mean total CTT was 40 hours, and the upper limit of normal (95th percentile) was 84 hours. The upper limit of normal for segmental transit time was as follows: 14 hours for the ascending, 33 hours for the transverse, 21 hours for the descending, and 41 hours for the rectosigmoid colon., Conclusions: CTT provides an objective measure to assess childhood constipation. To date, 6 studies using 5 different methods have been published reporting values for healthy children. Comparing these, Abrahamson's method has low radiation exposure and is well tolerated. This study contributes additional normal values in children.

Purpose: The aim of this study was to determine medium-term outcomes of the antegrade continence enema (ACE) procedure., Methods: A retrospective casenote review plus telephone questionnaire was conducted. The study was performed at a regional paediatric surgical centre. The subjects were consecutive children undergoing the ACE procedure over a 5 year period. Main outcome measures were use of the ACE; reversal rates; complications, ease of use, effectiveness, and satisfaction scores. Data are expressed as median (range)., Results: Thirty-two (52%) of 62 children undergoing the ACE procedure were girls. The age at the time of operation was 11.5 (3.8 to 17.6) years. Underlying diagnoses included spina bifida (n = 31), anorectal malformations (n = 15), slow-transit constipation (n = 9), Hirschsprung's disease (n = 2), sacral agenesis (n = 2), and trauma/tumour (n = 2). Median follow-up was 5.4 (3.25 to 8.25) years. Eleven of 62 (18%) children were no longer using the ACE (n = 5) or had it surgically reversed (n = 6; 14.1 +/- 9.3 months postprocedure). Reasons for disuse/reversal were lack of effectiveness (n = 4), complications (n = 2), noncompliance (n = 3), independent continence (n = 1), and pain (n = 1). Five (8%) children currently have a colostomy. Gender (P =.31; Fisher's Exact), age (Pearson), and underlying diagnoses (P =.07, Chi2) were not predictors of failure. Overall, stomal stenosis was the most common complication, affecting 26 of 62 (41%) children. Of 32 questionnaire respondents to linear scores, ease of use was rated as 2 (0 to 8, 0, very easy; 10, very difficult), discomfort on use as 3 (0 to 9; 0, no pain; 10, very painful), overall satisfaction as 9 (0 to 10; 0, completely dissatisfied; 10, completely satisfied). Eighty-four percent were completely continent or had soiling less than once a month. There was a significant correlation between the level of continence and satisfaction with the procedure (P =.04; Pearson)., Conclusions: The ACE procedure offers significant benefits to some children with incontinence or intractable constipation. However, it is not universally successful, and other continence promoting strategies may need to be considered., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

A randomised trial was carried out to assess the effect of a Down syndrome screening video on test uptake, knowledge and psychological stress. A total of 2000 women referred for antenatal care were allocated to two equal groups: one to be sent a video to their home, before their hospital booking visit, and a control group. All women also received screening information in the form of a leaflet before booking and from a midwife at booking. The video had no effect on the screening uptake rate: 638/993 (64.2%) and 652/1007 (64.7%) in the video and control groups, respectively. Women were requested to return the video for reuse in other pregnancies and 612 (62%) did so. A subset of 1200 women were selected to be posted at 17-19 weeks' gestation a self-completed questionnaire to assess the psychological endpoints. Knowledge of screening was increased in the video group with a mean score of 7.3 compared with 6.7 in the controls, a statistically significant difference (t=3.24, p=0.0005). There were no significant differences between the groups in specific worries about abnormalities in the baby, and general anxiety. We conclude that a video can increase knowledge without affecting the uptake of the test, or psychological stress., (Copyright 2001 John Wiley & Sons, Ltd.)

Headache is a frequent occurrence in patients with systemic lupus erythematosus (SLE). We present two cases of young women with headache and papilledema. One patient had this as a presenting manifestation of SLE, and the other had known active SLE. The first patient had a diagnosis of cerebral venous thrombosis, and the other pseudotumor cerebri. Both of these conditions are rare but have known associations with lupus. In the lupus patient with headache, it is essential that the clinician rule out these potentially treatable conditions by carefully taking a history and performing a physical examination as well as using ancillary investigations, including lumbar puncture, computed tomograph and magnetic resonance imaging as required. These uncommon causes of headache in the lupus patient must not be missed, because there is significant potential for morbidity, such as visual loss, or even mortality.

Background/purpose: The aim of this study was to investigate long-term functional outcome and colonic motility in children who had undergone the Duhamel-type operation for Hirschsprung's disease (HSCR)., Methods: All patients (n = 91) who underwent the Duhamel or Lester Martin Modified Duhamel operation for HSCR from 1980 to 1991 were included in the study. Twenty-two healthy age-matched children were used as controls. Functional outcome was assessed by questionnaire (response rate 100%). Total and segmental colonic transit time (CTT) was determined using the saturation method (80% participation rate)., Results: Outcome scores were significantly worse in the study group for patients with rectosigmoid (RS, P < .001), long segment (LS, P < .001), and total colonic (TC) aganglionosis (P < .05), when compared with controls. The CTT was significantly prolonged in the RS group (P = .01) compared with LS, TC, and control groups; this was caused by prolonged "rectosigmoid" transit in the RS group compared with controls (P = .012). There was a positive linear correlation (P = .0002) between age and outcome score in patients with RS disease unrelated to CTT. Nine patients required a late long-term enterostomy. A satisfactory outcome (defined as outcome score > or = 10th percentile of the control group, and absence of stoma or requirement for major revisional surgery) was seen in only 42% of patients overall and in 79% of patients over 14 years of age., Conclusions: The Duhamel procedure, in common with other pull-through procedures, is associated with significant long-term morbidity, the aetiology of which is poorly understood.

The tumour vasculature is vital for the establishment, growth and metastasis of solid tumours. Its physiological properties limit the effectiveness of conventional anti-cancer strategies. Therapeutic approaches directed at the tumour vasculature are reviewed, suggesting the potential of anti-angiogenesis and the targeting of vascular proliferation antigens as cancer treatments.

In a 20-year retrospective study of 43 patients having surgery for small bowel neoplasia in a district general hospital, the commonest pathologies were lymphoma (12), carcinoid (12) and adenocarcinoma (11). Malignant neoplasms occurred in 38 patients presenting on average at 68 years of age. In 4 patients a synchronous gastrointestinal neoplasm was found. The average duration of symptoms was 11 weeks for operated patients. In 31 patients the presentation was as a surgical emergency. Only 10 had imaging investigations prior to emergency presentation from which diagnostic information was obtained in 1 patient and helpful information in a further 4. The 5-year survival figures of patients with small bowel neoplasia were carcinoid (50%), lymphoma (27%) and adenocarcinoma (15%), reflecting the poor prognosis of these patients even after 'curative resection'. Patients with carcinoid tumours were the exception, as long-term survival was not unusual even without complete resection of all macroscopic disease.

Mothers have been found to respond differently to grammatical and ungrammatical utterances in young children's language. However, parents indicate that they are conscious only of responding to communicative aspects of their children's speech, not grammar. Further, researchers have looked to the understandability of utterances to explain the effects of grammaticality on maternal responses. The present study addressed the question of whether it is actually grammatical form that mothers respond to, or whether it is ambiguity in the communicative functions of children's utterances. Three mother-child dyads were videotaped in a free play setting when the children were 2;0 and 3;0. Children's spontaneous comprehensible utterances were rated for grammaticality and ambiguity of function, and mothers' responses to them were noted. Results indicated that mothers responded differentially to both the ambiguity and grammaticality of children's utterances, and that these two factors had some degree of independence in their effects on mothers' responses.

It has been suggested that surgery for abdominal aortic aneurysm (AAA) be confined to designated centres. A prospective audit of 200 consecutive AAA repairs at a district general hospital was performed between 1981 and 1990. The 30-day mortality rates for elective, symptomatic and ruptured aneurysm repair were 1.4%, 3.5% and 30%, respectively. The major factor affecting outcome after the mode of presentation was the age of the patient, with 30-day mortality rates for emergency treatment increasing from 21% (age range 60-69 years) to 42% (age range 70-79 years). This mortality rate for ruptured aneurysms is an underestimate, with two-thirds of patients with rupture dying before reaching hospital and some patients dying in hospital undiagnosed. The major contribution to improved overall mortality would therefore be detection before rupture (usually by ultrasound) and improved diagnostic accuracy. Many patients with ruptured aneurysms had symptoms for only a short period before presentation (42% for less than 6 h) and required urgent surgery (26% reached theatre within 1 h). These two factors make long-distance transfer of these patients an unrealistic option. The concentration of this type of surgery in relatively few centres will distance the patient from their relatives and reduce the opportunity for the majority of junior doctors to acquire an understanding of the presentation, natural history and management of aortic aneurysms. This understanding when combined with a screening programme is likely to have a far greater impact on the overall mortality from AAA than restricting the centres for surgical treatment.