A 10-year longitudinal follow-up study of a U.K. paediatric transplant population to assess for skin cancer.

BACKGROUND: Our earlier study, published in 2004,found no skin cancer in a cohort of paediatric organ transplant recipients (POTRs) 5-16 years post-transplantation. We re-evaluated the same cohort 10 years later. OBJECTIVES: To determine the prevalence of premalignant and malignant skin lesions and identify known risk factors associated with melanocytic naevi in a U.K. paediatric transplant population. METHODS: Ninety-eight POTRs from the original 2004 study were invited to participate in this longitudinal follow-up study. History of sun exposure, demographics and transplantation details were collected using face-to-face interviews, questionnaires and case note reviews. Skin examination was performed for regional count of malignant lesions, benign and atypical naevi. RESULTS: Of the 98 patients involved in the initial study, 45 POTRs (eight kidney, 37 liver), with a median follow-up of 19 years (range 15-26 years), agreed to participate. Neither skin cancer nor premalignant lesions were detected in these patients. When compared with the 2004 cohort, 41 patients in our current cohort had increased numbers of benign naevi (P < 0·001) with 11 patients having ≥ 50 benign naevi. Seventy-one per cent of benign naevi in our 2014 cohort occurred on sun-exposed sites (13% head/neck, 35% arms and 23% legs). Patients who regularly used sunscreen had more benign naevi on their arms (P = 0·008). CONCLUSIONS: Although skin cancer was not observed in our cohort, we identified a significant increase in the number of benign naevi, particularly in those reporting frequent sunburn and sunscreen use.

Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N.

Vacuolar protein sorting 35 (VPS35) is a core component of the retromer complex, crucial to endosomal protein sorting and intracellular trafficking. We recently linked a mutation in VPS35 (p.D620N) to familial parkinsonism. Here, we characterize human VPS35 and retromer function in mature murine neuronal cultures and investigate neuron-specific consequences of the p.D620N mutation. We find VPS35 localizes to dendritic spines and is involved in the trafficking of excitatory AMPA-type glutamate receptors (AMPARs). Fundamental neuronal processes, including excitatory synaptic transmission, AMPAR surface expression and synaptic recycling are altered by VPS35 overexpression. VPS35 p.D620N acts as a loss-of-function mutation with respect to VPS35 activity regulating synaptic transmission and AMPAR recycling in mouse cortical neurons and dopamine neuron-like cells produced from induced pluripotent stem cells of human p.D620N carriers. Such perturbations to synaptic function likely produce chronic pathophysiological stress upon neuronal circuits that may contribute to neurodegeneration in this, and other, forms of parkinsonism.

Parents in transition: Experiences of parents of young people with a liver transplant transferring to adult services.

Predictors of successful transition from pediatric to adult services include ability to self-manage and engage with healthcare services. Parents have a key role in healthcare management throughout childhood and adolescence including encouraging development of self-management skills in their children. Transition to adult services can be challenging for parents and young people, yet parents' views regarding transition remain largely unexplored. Nine parents of pediatric liver transplant recipients (15.2-25.1 yr) participated in semistructured interviews. Interviews were analyzed using IPA. Analysis revealed three key themes: "emotional impact of transplantation," "protection vs. independence," and "ending relationships and changing roles." Parents expressed the dichotomous nature of the desire to promote independence in their child while still maintaining control and protection, and discussed how changing roles and relationships were difficult to navigate. Parents are important facilitators of young people's development of self-management skills for successful transfer to adult services. Parents should be supported to move from a "managerial" to a "supervisory" role during transition to help young people engage independently with the healthcare team. Findings support the development of interventions for parents to emphasize their role in transition and guide the transfer of self-management skills from parent to young person.

"Are these adult doctors gonna know me?" Experiences of transition for young people with a liver transplant.

Excellent survival rates in paediatric LTx have resulted in increasing numbers of young people transferring from paediatric to adult care. Understanding the mechanisms of successful transition is imperative for ensuring good long-term outcomes and developing services for young people. Semi-structured interviews were conducted with 17 young people (10 females; age range: 15.2-25.1 years). Eight were within 1 year of transferring to adult services; nine had transferred. Interviews were analysed using IPA. Analysis revealed two major themes in both pre- and post-transfer groups: "relationships with healthcare professionals" and "continuity of care." Young people experienced difficulty ending relationships with paediatric clinicians and forming new relationships with adult clinicians. They expressed frustrations over a perceived lack of continuity of care after transfer and a fear of the unknown nature of adult services. The importance of a holistic approach to care was emphasized. Interventions are needed to support young people in transition, particularly in ending relationships in paediatric care and forming new relationships in adult care. Young people need help to develop strategies to cope with the different approaches in adult services. Interventions to provide clinicians with skills to communicate and engage with young people are imperative.

Hepatitis B virus transmission in pre-adolescent schoolchildren in four multi-ethnic areas of England.

The aim of this study was to estimate the amount of childhood hepatitis B virus transmission in children born in the UK, a very low-prevalence country, that is preventable only by universal hepatitis B immunization of infants. Oral fluid specimens were collected from schoolchildren aged 7-11 years in four inner city multi-ethnic areas and tested for the presence of antibody to hepatitis B core antigen (anti-HBc). Those found positive or indeterminate were followed up with testing on serum to confirm their hepatitis B status. The overall prevalence of anti-HBc in children was low [0.26%, 95% confidence interval (CI) 0.14-0.44]. The estimated average annual incidence of hepatitis B was estimated to be 29.26/100 000 children (95% CI 16.00-49.08). The total incidence that is preventable only by a universal infant immunization programme in the UK was estimated to be between 5.00 and 12.49/100 000. The study demonstrates that the extent of horizontal childhood hepatitis B virus transmission is low in children born in the UK and suggests that schools in the UK are an uncommon setting for the transmission of the virus. Targeted hepatitis B testing and immunization of migrants from intermediate- and high-prevalence countries is likely to be a more effective measure to reduce childhood transmission than a universal infant immunization programme.

Durability of sustained response shown in paediatric patients with chronic hepatitis C who were treated with interferon alfa-2b plus ribavirin.

Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan-Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

Chronic hepatitis C in children--review of natural history at a National Centre.

The natural history of hepatitis C virus (HCV) infection in adults has been established, but less is known about outcome in children. We conducted a retrospective review of patients referred to Birmingham Children's Hospital Liver Unit, from 1991 till 2008, with the diagnosis of HCV was undertaken. Only children with documented positive HCV RNA and a minimum duration of follow-up of 6 months were included. One hundred and thirty-three children were identified. The route of transmission was transfusion acquired in 47%, vertically acquired in 49% and transplantation in 2%. Since 2000, most children were infected vertically. The overall rate of spontaneous viral clearance was 17.5% with higher clearance (27%) in the transfusion group compared to the vertically acquired group (9%). Seventy-six had a liver biopsy at diagnosis. There was no evidence of fibrosis in 46%, mild fibrosis in 50% and moderate to severe fibrosis in 4%. None had cirrhosis. There was a statistically significant relationship between fibrosis score and older age at the time of biopsy (P = 0.02) and longer duration of infection (P = 0.05). Eighty children received treatment for HCV. Sustained viral response (SVR) was influenced by viral genotypes, with significantly increased response rates in genotypes (G) 2 and 3 compared to G 1 and 4. Vertical infection is now the major route of HCV infection in children in the UK. Histological changes were mild at diagnosis, but the severity of fibrosis progressed with age. Consideration should be given to improve detection and diagnosis to refer children to specialist centres for management and antiviral therapy before developing fibrosis.

Sensitivity to sunburn is associated with susceptibility to ultraviolet radiation-induced suppression of cutaneous cell-mediated immunity.

Skin cancer incidence is highest in white-skinned people. Within this group, skin types I/II (sun sensitive/tan poorly) are at greater risk than skin types III/IV (sun tolerant/tan well). Studies in mice demonstrate that ultraviolet radiation (UVR)-induced suppression of cell-mediated immune function plays an important role in the development of skin cancer and induces a susceptibility to infectious disease. A similar role is suspected in humans, but we lack quantitative human data to make risk assessments of ambient solar exposure on human health. This study demonstrates that ambient levels of solar UVR, typically experienced within 1 h of exposure to noonday summer sunlight, can suppress contact hypersensitivity (CHS) responses in healthy white-skinned humans in vivo (n = 93). There was a linear relationship between increase in erythema and suppression of CHS (P < 0.001), and a moderate sunburn (two minimal erythema doses [2 MED]) was sufficient to suppress CHS in all volunteers by 93%. However, a single suberythemal exposure of either 0.25 or 0.5 MED suppressed CHS responses by 50 and 80%, respectively, in skin types I/II, whereas 1 MED only suppressed CHS by 40% in skin types III/IV. The two- to threefold greater sensitivity of skin types I/II for a given level of sunburn may play a role in their greater sensitivity to skin cancer.

The challenges and opportunities for transitional care research.

The provision of healthcare for young people with solid organ transplants as they move into adult-centered services has received increasing attention over recent years particularly as non-adherence and graft loss increase after transfer. Despite medical advances and that transitional care is now well established on national and international health agendas, progress in the research arena has unfortunately been slow. The aims of this paper are to consider why this is and discuss the particular challenges facing clinical researchers working within the area.

Liver transplantation in children using non-heart-beating donors (NHBD).

Selected livers from controlled NHBD are accepted for OLT in adults. Recent evidence has shown good medium-term outcome. The purpose of this study was to report our experience of pediatric OLT with whole and partial grafts from NHBD, analyzing complications and outcome. Retrospective review of all the recipients who underwent primary OLT between December 2005 and December 2008, using livers from NHBD. Four children (one male child) mean age was 9.5 yr (0.2-17), mean weight was 26 kg (range 2.6-48), underwent OLT using NHBD. Mean donor age was 14.2 yr, and mean WIT (systolic BP<50 mmHg to cold perfusion) 12.2 min (range 10-15). Two children received reduced grafts and two full grafts. Mean cold ischemia time was 7.18 h (range 6-8). Liver function tests one wk and nine months post-OLT confirmed a good graft function. One child was treated for two episodes of acute rejection. Post-transplant complications included two cases of mild ischemic cholangiopathy treated conservatively. Graft and patient survival was 100% with a mean follow-up of 19 months (range 8.1-43.4). Short- to medium-term follow-up suggests that liver grafts from young NHBD with short warm and cold ischemia times can be safely utilized in pediatric transplantation.

Isolated liver transplant in infants with short bowel syndrome: insights into outcomes and prognostic factors.

OBJECTIVE: Selected infants with short bowel syndrome (SBS) and progressive intestinal failure associated liver disease (IFALD) may benefit from isolated liver transplantation (iLTx). The aim of the study is to identify risk factors for unfavourable outcome in iLTx. PATIENTS AND METHODS: A retrospective review of medical records from 1998 to 2005 was undertaken. Risk factors were assessed by comparing long-term survivors with those who died after iLTx. RESULTS: Fifteen iLTx were performed in 14 infants with IFALD. All were parenteral nutrition (PN) dependent, but had tolerated enterally 54% (38-100) of energy intake before iLTx. Median residual bowel was 60 cm (30-200). Eight out of 14 had intact ileocaecal valve (ICV). Median bilirubin was 298 micromol/L (87-715) and all had portal hypertension. Eight out of 9 survivors were weaned from PN after median 15 months. In 4 out of 9 children, nontransplant surgery after iLTx facilitated intestinal adaptation. Growth velocity had improved at 3 years after iLTx (P=0.001). Five children who died had poor enteral tolerance following iLTx (P<0.002), which correlated with pretransplant dysmotility seen in 4 out of 5 children shown by contrast studies (P=0.02)and increased frequency of line infections before (>6/year P<0.04) and after (P<0.001) iLTx. CONCLUSIONS: Isolated liver transplantation is a lifesaving option for selected children with SBS and IFALD. Revised criteria are proposed: progressive IFALD; 50 cm functional bowel in absence of ICV or 30 cm with ICV; 50% daily energy intake tolerated enterally for 4 weeks with satisfactory growth; and children with dysmotile bowel should be assessed for combined liver/bowel transplant unless the dysmotility is resolved and associated with minimal line infections.

The necessity of education and hepatitis B vaccination for young people: A study of high risk behaviour for blood borne viruses in the United Kingdom.

Blood borne virus (BBV) infection in adults involved in high risk behaviour is well recognized. There are limited reported data on young people involved in high risk behaviour. A descriptive questionnaire was used to ascertain risk behaviour at the Young People's Substance Misuse Service (Birmingham). Data collection included risk behaviour and serological tests for hepatitis B, C and HIV. Sixty-five of one-hundred three (63%) young people participated; 37/65 male; age range 13.9-18.9 (median 17.4 years). Risk behaviour included 6 intravenous drug, 58 cannabis, and 61 had sexual partners, of whom 52 (85%) engaged in unprotected sex. Sixty-five participants were negative for BBV infection: 9 were HBV immune. HB vaccination was not available at the centre (for <18 year), and all refused referral to their general practitioner for vaccination due to fear of disclosure. The main risk for BBV acquisition was unprotected sex with multiple sexual partners and illicit drug use. Most were unaware of the risks related to high risk behaviour. Effective education programmes of relevant risk factors with HBV vaccination should be implemented during preadolescence. We recommend an integrated service via specialized centres, to work together to improve awareness and increase efforts to vaccinate adolescents at risk for HBV infection.

Is serum gentamicin level a good predictor of graft injury in intestinal transplantation?

INTRODUCTION: Following intestinal transplant (SBT), the early diagnosis and treatment of rejection is a major management aim. The diagnosis of rejection is based on histology of stomal biopsies. Oral gentamycin (2.5 mg/kg) was used for selective decontamination of the digestive system. Our hypothesis was that gentamycin might be absorbed in the presence of graft dysfunction. AIM: Our goal was to assess the correlation between serum gentamycin level and the health of the intestinal graft. SUBJECTS AND METHODS: Among 33 SBT performed from 1993 to 2005, serum gentamycin levels were performed once weekly or more often when there was a suspicion of rejection. All data were analyzed retrospectively. RESULTS: Adequate trough levels were achieved for only 23 patients, six of whom had histologically proven rejection and only one did not have a raised gentamycin content. Five patients with raised levels but no rejection included two with severe intestinal ischemia and three with bowel obstruction/ileus. Four of the five patients required laparotomies. CONCLUSION: We concluded that in our study raised serum gentamycin levels were a good predictor of rejection or significant injury to the graft.

Seamless management of biliary atresia in England and Wales (1999-2002).

BACKGROUND: Before 1999, infants born in the UK with suspected biliary atresia were investigated in regional centres, and, if confirmed, a Kasai operation was done there. Since 1999, all infants with suspected biliary atresia in England and Wales, UK, have been referred to one of three designated centres where both the Kasai operation and liver transplantation (if necessary) could be done. METHODS: We assessed clearance of jaundice (bilirubin <20 micromol/L) as an early outcome in all cases of biliary atresia referred from one of the three centres. We then estimated survival using the Kaplan-Meier method with endpoints of liver transplantation or death. FINDINGS: 148 infants with biliary atresia were treated between January, 1999, and June, 2002. A primary portoenterostomy was done in 142 (96%) infants and a primary liver transplant in five (3%). One child died before any intervention. Early clearance of jaundice after portoenterostomy was achieved in 81 of 142 (57%) infants. Liver transplantation was done in 52 (37%) of those undergoing portoenterostomy. 13 (9%) infants died. Of the 135 children who survived, 84 (62%) still have their native liver and 51 (38%) had transplantation. The median follow-up of survivors was 2.13 (range 0.5-4.1) years. The overall 4-year estimated actuarial survival was 89% (95% CI 82-94). The 4-year estimated actuarial survival with native liver was 51% (42-59%). INTERPRETATION: Our early results suggest that surgical outcome can be improved by centralisation of care to supra-regional centres.

Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism.

Neonatal haemochromatosis (NH) is a severe and newly recognised syndrome of uncertain aetiology, characterised by congenital cirrhosis or fulminant hepatitis and widespread tissue iron deposition. NH occurs in the context of maternal disease including viral infection, as a complication of metabolic disease in the fetus, and sporadically or recurrently, without overt cause, in sibs. Although an underlying genetic basis for NH has been suspected, no test is available for predictive analysis in at risk pregnancies. As a first step towards an understanding of the putative genetic basis for neonatal haemochromatosis, we have conducted a systematic study of the mode of transmission of this disorder in a total of 40 infants born to 27 families. We have moreover carried out a molecular analysis of candidate genes (beta(2)-microglobulin, HFE, and haem oxygenases 1 and 2) implicated in iron metabolism. No pathogenic mutations in these genes were identified that segregate consistently with the disease phenotype in multiplex pedigrees. However, excluding four pedigrees with clear evidence of maternal infection associated with NH, a pedigree showing transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and two families with possible matrilineal inheritance of disease in maternal half sibs, a large subgroup of the affected pedigrees point to the inheritance of an autosomal recessive trait. This included 14 pedigrees with affected and unaffected infants and a single pedigree where all four affected infants were the sole offspring of consanguineous but otherwise healthy parents. We thus report three distinct patterns of disease transmission in neonatal haemochromatosis. In the differentiation of a large subgroup showing transmission of disease in a manner suggesting autosomal recessive inheritance, we also provide the basis for further genome wide studies to define chromosomal determinants of iron storage disease in the newborn.

A locus for asphyxiating thoracic dystrophy, ATD, maps to chromosome 15q13.

Asphyxiating thoracic dystrophy (ATD), or Jeune syndrome, is a multisystem autosomal recessive disorder associated with a characteristic skeletal dysplasia and variable renal, hepatic, pancreatic, and retinal abnormalities. We have performed a genome wide linkage search using autozygosity mapping in a cohort of four consanguineous families with ATD, three of which originate from Pakistan, and one from southern Italy. In these families, as well as in a fifth consanguineous family from France, we localised a novel ATD locus (ATD) to chromosome 15q13, with a maximum cumulative two point lod score at D15S1031 (Zmax=3.77 at theta=0.00). Five consanguineous families shared a 1.2 cM region of homozygosity between D15S165 and D15S1010. Investigation of a further four European kindreds, with no known parental consanguinity, showed evidence of marker homozygosity across a similar interval. Families with both mild and severe forms of ATD mapped to 15q13, but mutation analysis of two candidate genes, GREMLIN and FORMIN, did not show pathogenic mutations.

Transplantation for end stage liver disease related to alpha 1 antitrypsin.

Alpha 1 antitrypsin deficiency (AT) is an autosomal recessive disease associated with chronic liver disease in adults and children and emphysema in adults. The disease is one of the most common inherited disorders of the Caucasian population of North Europe and North America and is the most common genetic reason for pediatric orthotopic liver transplantation (OLTx), although it is a rare indication in adults. The natural history of the disease is unpredictable and the pathogenesis of the liver injury unclear. Thirty-five patients with histologically apparent alpha 1 AT accumulation in the liver (22 adults, 13 children) have been transplanted in this center. Clinical features were correlated with the pretransplant phenotype, serum alpha 1 antitrypsin levels and potential precipitating factors. All children were PiZZ homozygotes, most of whom had presented with neonatal hepatitis. The majority of adult patients were heterozygotes presenting with portal hypertension and liver cirrhosis. Current one-year posttransplant survival figures are 73% for adults and 87.5% for children. Replacement of the cirrhotic liver results in acquisition of the donor phenotype, a rise in serum levels of alpha 1 antitrypsin, and apparent prevention of associated disease.

En block combined reduced-liver and small bowel transplants: from large donors to small children.

BACKGROUND: The critical shortage of size-matched donor organs for infants and small children in need of combined liver and intestinal transplantation has lead to long waiting times and a high risk of dying before transplantation. Utilizing grafts from larger donors could alleviate this problem, but using larger composite grafts in small children has been challenging and unsuccessful in the past. METHODS: We conducted a pilot study for evaluating the results of transplanting into small recipients a composite graft (reduced-size liver and whole small bowel, including duodenum and pancreas head) procured from large donors. Liver size reduction was performed ex situ using the extrahilar approach, which leaves the liver hilum untouched. Straightforward implantation of the graft was performed by simple, two-step vascular anastomoses. The preservation of the donor duodenum in continuity with the combined graft avoided the need for biliary reconstruction, thus preserving maximal bowel length for gut continuity restoration in the recipient. RESULTS: Two children, weighing 7.6 and 9.8 kg, respectively, underwent transplantation of a composite graft procured from donors weighing 35 kg. Their waiting time (68 and 97 days, respectively) was shorter compared with our previous experience with conventional techniques. Both are currently alive and well, at home and on full enteral feeds, 15 and 11 months after transplantation, respectively. CONCLUSION: This new technique has extended the range of possible donors for small candidates waiting for combined grafts and was successful in two patients. It should be considered for small recipients in the future.

Turtle and mammal penis designs are anatomically convergent.

Males in many modern amniote taxa have a hydraulic penis that inflates for copulation. Hydraulic skeletons are typically reinforced with inextensible fibres; the specific arrangement of the fibres within the skeleton determines whether it is flexible or resists bending. I show that the hydraulic skeleton in the turtle penis is reinforced by an axial orthogonal array of collagen fibres. This microanatomy is evolutionarily convergent with that of mammalian penises, and implies that there is a limited number of mechanical designs for an inflatable structure with high bending stiffness.

Metabolic liver disease in the pediatric patient.

Most metabolic liver diseases that affect pediatric patients present in the neonatal period with either cholestasis or acute liver failure. Metabolic liver disease in the older child has considerable overlap with adult patients. New diagnostic methods and therapy, including liver transplantation, has radically changed the outcome of many metabolic liver diseases.