PubMed Health⌕ Search

Biomedical subjects

Deirdre A Kelly

Publications and source records attributed to Deirdre A Kelly.

At least 19 recordsLinked to original sources
PubMed2007

Paediatric Hepatology Dependency score (PHD score): an audit tool.

BACKGROUND: The aim was to develop a tool that measures patient dependency and disease severity in children with mild to severe liver disease. METHODS: The initial pilot score was based on known markers of disease severity in acute and chronic liver disease. Between 1997 and 2001, the score was modified 4 times and reduced to comprise 10 key parameters: aspartate transaminase, prothrombin time, albumin, bilirubin, ascites, nutritional support, organ dysfunction, blood product support, sepsis and intravenous access. The score's face validity, internal consistency, interobserver agreement and construct validity were evaluated statistically and by the use of endpoints such as survival and transplant after 6 months. RESULTS: The final 10 variable score was tested on 71 children admitted over two 3-month periods. The Cronbach's alpha score (a test for internal consistency) for the total score was 0.72. Serial data paralleled clinical deterioration and response to interventions. A Paediatric Hepatology Dependency score >15 had an odds ratio of 7 (P = 0.0125) for death or transplant at 6 months. The score was also found to agree with the paediatric end-stage liver disease score for the 12 patients being listed for liver transplantation (r = 0.660, P < 0.05). CONCLUSION: The Paediatric Hepatology Dependency score is valid and internally consistent and is a convenient measure of dependency and disease severity in a heterogeneous group of patients with liver disease. It also allows admissions to be audited for comparison between eras and for monitoring the progress of patients while on the ward.

Acute Disease↗
PubMed2006

The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.

Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal malformation syndrome characterized by renal cystic dysplasia, central nervous system malformations (typically, posterior occipital encephalocele), and hepatic developmental defects. Two MKS genes, MKS1 and MKS3, have been identified recently. The present study describes the cellular, sub-cellular and functional characterization of the novel proteins, MKS1 and meckelin, encoded by these genes. In situ hybridization studies for MKS3 in early human embryos showed transcript localizations in agreement with the tissue phenotype of MKS patients. Both MKS proteins predominantly localized to epithelial cells, including proximal renal tubules and biliary epithelial cells. MKS1 localized to basal bodies, while meckelin localized both to the primary cilium and to the plasma membrane in ciliated cell-lines and primary cells. Meckelin protein with the Q376P missense mutation was unable to localize at the cell membrane. siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated epithelial cell-line blocked centriole migration to the apical membrane and consequent formation of the primary cilium. Co-immunoprecipitation experiments show that wild-type meckelin and MKS1 interact and, in three-dimensional tissue culture assays, epithelial branching morphogenesis was severely impaired. These results suggest that MKS proteins mediate a fundamental developmental stage of ciliary formation and epithelial morphogenesis.

Abnormalities, Multiple↗
PubMed2006

An economic evaluation of pediatric small bowel transplantation in the United Kingdom.

BACKGROUND: Small bowel transplantation (SBTx) offers an alternative to parenteral nutrition (PN) for the treatment of chronic intestinal failure in children: this study estimated its cost-effectiveness in the early phase of a U.K. program. METHODS: Children assessed for SBTx were categorized as: 1) requiring SBTx following PN-related complications (n=23), 2) stable at home not requiring SBTx (n=24), and 3) terminally ill and unsuitable for SBTx (n=6). Costs were estimated from detailed resource-use data. Two comparisons were used for effectiveness: actual survival following transplantation (n=14) compared to: 1) estimated survival without transplantation using a prognostic model, and 2) the waiting list experiences of all patients listed for SBTx (n=23). RESULTS: Mean costs up to 30 months were pounds sterling 207,000 for those transplanted or on the waiting list, pounds sterling 159,000 for those stable on home PN, and pounds sterling 56,000 for those terminally ill. The prognostic model estimated a mean survival gain from transplantation of 0.12 years over 30 months, and suggested that transplantation was cost-saving. The second approach suggested that transplantation reduced survival by 0.24 years at an additional cost of pounds sterling 131,000. CONCLUSIONS: Firm conclusions on cost-effectiveness of SBTx are not possible given the two different estimates. The prognostic model approach (suggesting that pediatric SBTx may provide a small survival benefit at a small reduction in costs) should be less subject to bias, but the model requires external validation. Meanwhile, children at risk of fatal PN-complications should be given the opportunity to receive a SBTx only within a continuing formal assessment of the technology.

Child↗
PubMed2006

Clinical and molecular genetic features of ARC syndrome.

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900-1,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.

Abnormalities, Multiple↗
PubMed2006

Improved outcome of referrals for intestinal transplantation in the UK.

AIM: To describe the outcome of children with intestinal failure referred to Birmingham Children's Hospital (BCH) for consideration of intestinal transplantation (ITx), to determine factors for an adverse outcome and to analyse the impact of post-1998 strategies on survival. SUBJECTS AND METHODS: A retrospective analysis was performed of children referred for ITx assessment from January 1989 to December 2003. Children were assessed by a multidisciplinary team and categorised into: (a) stable on parenteral nutrition; (b) unsuitable for transplantation (Tx); and (c) recommended for Tx. To analyse the impact of the post-1998 strategies on survival, a comparison was made between the two eras (pre-1998 and post-1998). RESULTS: 152 children with chronic intestinal failure were identified (63M:89F, median age 10 months (range 1-170)). After assessment, 69 children were considered stable on parenteral nutrition (5-year survival 95%); 28 children were unsuitable for Tx (5-year survival 4%); and 55 children were recommended for Tx (5-year survival 35%, which includes 14 children who died waiting for size-matched organs). Twenty three ITx and nine isolated liver transplants (iLTx) were performed. In a multivariate analysis, the following factors in combination had an adverse effect on survival: the presence of a primary mucosal disorder (p = 0.007, OR ratio 3.16, 95% CI 1.37 to 7.31); absence of involvement of a nutritional care team at the referring hospital (p = 0.001, OR ratio 2.55, 95% CI 1.44 to 4.52); and a serum bilirubin>100 micromol/l (p = 0.001, OR ratio 3.70, 95% CI 1.84 to 7.47). Earlier referral (median serum bilirubin 78 micromol/l in the post-1998 era compared with 237 micromol/l in the pre-1998 era, p = 0.001) may be a contributory factor to improved survival. The strategies of combined en bloc reduced liver/small bowel transplantation and iLTx resulted in fewer deaths on the waiting list in the post-1998 era (2 deaths in post-1998 era v 12 deaths in pre-1998 era). The overall 3-year survival in the post-1998 era (69%) has improved compared with the pre-1998 era (31%; p<0.001) CONCLUSION: The changing characteristics at the time of referral, including earlier referral and innovative surgical strategies have resulted in improved long-term survival of children referred for ITx.

Adolescent↗
PubMed2006

The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.

Abnormalities, Multiple↗
PubMed2006

Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B.

One year of lamivudine treatment results in increased hepatitis B e antigen (HBeAg) seroconversion and serum hepatitis B virus (HBV) DNA negativity in children with chronic hepatitis B and high serum alanine aminotransferase concentrations. Two hundred seventy-six children who participated in a 1-year randomized, placebo-controlled study of lamivudine were enrolled in a 24-month, open-label extension. Patients were stratified into two groups based on HBeAg status at week 48 of the previous study: 213 HBeAg-positive children were entered into a treatment arm, and 63 HBeAg-negative children were entered into an observation arm to evaluate durability of HBeAg loss. In the treatment arm, 28 of 133 (21%) children previously treated with lamivudine and 23 of 77 (30%) children who previously received placebo achieved the primary end point: virological response (VR) (HBeAg loss and HBV DNA negativity) at month 24. The incidence of YMDD (tyrosine, methionine, aspartate, aspartate) mutations at month 24 was 64% (66/103) in the children previously treated with lamivudine and 49% (34/70) in those previously treated with placebo. The incidence of VR at month 24 was 5% (5/100) for patients with YMDD mutant HBV and 54% (39/72) for patients without. The durability of response in the observation arm was 89% (48/54) at month 24. In conclusion, further clinical response was seen over the 24-month open-label study period in children who had not initially achieved a VR after 12 months of lamivudine treatment. However, the incidence of YMMD mutations increased over time and resulted in lower response rates. VR was maintained in most patients who had initially responded to lamivudine in the first 12 months.

Adolescent↗
PubMed2006

Progressive histological damage in liver allografts following pediatric liver transplantation.

The long-term histological outcome after pediatric liver transplantation (OLT) is not yet fully understood. De novo autoimmune hepatitis, consisting of histological chronic hepatitis associated with autoantibody formation and allograft dysfunction, is increasingly recognized as an important complication of liver transplantation, particularly in the pediatric population. In this study, 158 asymptomatic children with 5-year graft survival underwent protocol liver biopsies (113, 135, and 64 at 1, 5, and 10 years after OLT, respectively). Histological changes we re correlated with dinical,biochemical, and serological findings. All patients received cydosporine A as primary immunosuppression with withdrawal of corticosteroids at 3 months post OLT. Normal or near-normal histology was reported in 77 of 113 (68%), 61 of 135 (45%), and 20 of 64 (31%) at 1, 5, and 10 years, respectively. The commonest histological abnormality was chronic hepatitis (CH), the incidence of which increased with time [25/113 (22%), 58/135 (43%), and 41/64 (64%) at 1, 5, and 10 years, respectively) (P < .0001)]. The incidence of fibrosis associatedwith CH increasedwith time [13/25 (52%), 47/58 (81%), and 37/41 (91%) at 1, 5, and 10 years, respectively) (P < .0001)]. The severity of fibrosis associated with CH also increased with time, such that by 10 years 15% had progressed to cirrhosis. Aspartate aminotransfemse (AST) levels were slightly elevated in children with CH (median levels 52 IU/L, 63 IU/L, and 48 IU/L at 1, 5, and 10 years, respectively), but this did not reach statistical significance compared with those with normal histology. On multivariate analysis, the only factor predictive of chronic hepatitis was autoantibody positivity (present in 13% and 10% of children with normal biopsies at 5 and 10 years, respectively, and 72% and 80% of those with CH at 5 and 10 years, respectively) (P < .0001). Four children with CH and autoantibodies, who also had raised immunoglobulin G (IgG) levels and AST greater than 1.5 x normal fulfilled the diagnostic criteria for de novo autoimmune hepatitis (AIH). Another two were found to be hepatitis C positive. No definite cause for CH could be identified in the other cases. In condusion, chronic hepatitis is a common finding in children after liver transplantation and is associated with a high risk of developing progressive fibrosis, leading to cirrhosis. Standard liver biochemical tests cannot be relied on either in the diagnosis or in the monitoring of progress of chronic allograft hepatitis. In contrast, the presence ofautoantibodies is strongly associated with the presence of CH. The cause of chronic hepatitis in transplanted allografts is uncertain but may be immune mediated, representing a hepatitic form of chronic rejection.

Adolescent↗
PubMed2006

Long-term follow-up of hepatitis B carrier children treated with interferon and prednisolone.

The long-term outcome of treatment with Interferon Alpha 2B with and without Prednisolone priming in children infected perinatally with hepatitis B was reviewed. The group studied included 48 children (aged 2-16 years), who were HBe antigen and hepatitis B DNA positive between 1991 and 1993. Twenty children were randomized to a therapeutic trial at that time, and received Prednisolone in reducing doses for 6 weeks and Interferon for 16 weeks while 22 children were monitored without treatment for 12 months. Fourteen of the untreated group and 6 additional children later received treatment with Interferon alone (n = 20). Eight children for whom treatment was declined were followed long term. Median follow-up was 7.5 years (range 1.5-10.6). There was no significant effect of Interferon therapy on seroconversion with or without Prednisolone at 12 months post-treatment compared to untreated children. On longer term follow-up, the 5-year HBeAg to anti-HBe seroconversion percentages, estimated from Kaplan-Meier curves, were 54% for Prednisolone plus Interferon, 22% for Interferon alone, and 12% for untreated children. The median time to seroconversion was 3.9 years (range 0.4-8.2) and was shortest in those treated with Prednisolone plus Interferon. Children who had elevated hepatic transaminase enzymes prior to treatment or during Prednisolone priming had a better response. In contrast to many European studies, no child cleared HBsAg and produced anti-HBs. Treatment with Prednisolone priming and Interferon, improved both the time and rate of seroconversion compared to no treatment or Interferon alone, suggesting that this combination of drugs might have an immunomodulatory effect.

Adolescent↗
PubMed2006

The Budd-Chiari syndrome in children: the spectrum of management.

The Budd-Chiari syndrome (BCS), characterized by hepatic venous outflow occlusion, is rare in children. We describe the cases of 3 patients with BCS who presented at different stages of liver dysfunction that required tailored management. A 10-year-old boy who presented with a weeklong history of abdominal discomfort received an early diagnosis. Treatment with thrombolytic therapy and adjunctive percutaneous interventional radiologic management led to a favorable outcome in this patient. A 2-year-old girl referred with a 6-week illness not amenable to thrombolytic therapy was managed with a pericardial patch atriocavoplasty to restore hepatic venous outflow tract patency. The third patient, a 5-year-old girl, presented with established cirrhosis and massive ascites. After we controlled the ascites with an extracorporeal shunt system and nutritional resuscitation, we conducted an orthotopic liver transplantation on this patient. The stage of disease at diagnosis influences the management strategy, and an early diagnosis offers patients the best possible chance of cure without major surgery. However, a later presentation can still be successfully managed by more radical surgical interventions. The aims of this case report were to emphasize the importance of a high index of suspicion in the diagnosis of pediatric BCS and to highlight the importance of early referral to a specialized pediatric liver unit with the necessary facilities to deal with the medical and surgical aspects of management.

Ascites↗
PubMed2006

Intestinal failure-associated liver disease: what do we know today?

Intestinal failure-associated liver disease develops in 40% to 60% of infants who require long-term total parenteral nutrition (TPN) for intestinal failure and 15% to 40% of adults on home parenteral nutrition. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority but is more common in infants and neonates than in adults. The pathogenesis is multifactorial. In infants it is related to prematurity, low birth weight, duration of PN, short bowel syndrome requiring multiple laparotomies, and recurrent sepsis. Other important mechanisms include lack of enteral feeding, which leads to reduced gut hormone secretion; reduction of bile flow and biliary stasis, which leads to the development of cholestasis; and biliary sludge and gallstones, which exacerbate hepatic dysfunction. In adults, IFALD is less common and related to age, length of time on PN, total caloric intake, and lipid or glucose overload. In preterm infants, a deficiency of taurine or cysteine may play a role, whereas in both adults and children, choline deficiency may exacerbate IFALD. Lipid emulsions, choline deficiency, and manganese toxicity are associated with both hepatic steatosis and cholestasis in adults and children. Management strategies for the prevention of intestinal failure-induced liver disease include early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition, and aseptic catheter techniques to reduce sepsis. The addition of choline, taurine, and cysteine to PN solutions may also play a role. Oral administration of ursodeoxycholic acid may improve bile flow and reduce gallbladder stasis. Survival after either isolated small bowel or combined liver and small bowel transplantation is approximately 50% at 5 years, making this an acceptable therapeutic option in adults and children with irreversible liver and intestinal failure.

Adult↗
PubMed2006

Immunosuppression in infants with short bowel syndrome undergoing isolated liver transplantation.

BACKGROUND: Little data exist on immunosuppressive drug absorption in children with short bowel syndrome and intestinal failure associated liver disease (SBS-IFALD). AIM: To evaluate the absorption of immunosuppressive medications in children with SBS-IFALD undergoing isolated liver transplantation (iLTx). METHODS: A retrospective review was performed in children with SBS-IFALD undergoing LTx and comparison made with weight, age-matched children undergoing iLTX (extra-hepatic biliary atresia (EHBA) and normal intestinal length and function). RESULTS: Seven children with SBS-IFALD undergoing iLTx (median residual bowel length, 60 cm, range 40-80) were compared with 15 children undergoing LTx for EHBA. SBS-IFALD children had significantly lower trough tacrolimus levels at three months (5.8 vs. 7.9 ng/mL, p<0.05) and six months (5.0 vs. 8.0 ng/mL, p<0.05), but equivalent levels at 12 months after iLTx. The median calculated dose-normalized concentrations indicated that systemic availability of tacrolimus was comparable in two groups at 3, 6, 12 months (33.1 vs. 23.3; 42.4 vs. 36; 51 vs. 52.9) despite the differences in enteral function. The incidence of acute rejection was 1/7 (SBS-IFALD) and 10/15 (EHBA) group (p = 0.06). CONCLUSION: Children with SBS-IFALD demonstrated adequate absorption of oral tacrolimus without significant acute rejection rate after iLTx suggesting that modification of immunosuppression is not necessary.

Female↗
PubMed2006

Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry.

Liver Transplant (LTx) has been rarely performed in cystic fibrosis (CF) patients and indications and outcomes are not well defined. A questionnaire was sent to all European CF and LTx centers to collect data on CF transplanted patients. We obtained information regarding 57 CF patients. LTx has been performed prevalently in males and in pediatric age. The main complication of cirrhosis was portal hypertension with hypersplenism. In the majority of cases the decision to transplant was based on the contemporary presence of various factors. Post-LTx survival was high and comparable with that expected for more common pediatric LTx indications. Poor respiratory function was the main risk factor for early death. In the short-term, respiratory function significantly improved after LTx. LTx is the appropriate treatment for patients with advanced CF-related liver disease and preserved pulmonary function (Forced Expiratory Volume at 1 s, FEV(1) >50%). This poll reveals that most European liver centers perform LTx prior to the development of end-stage liver disease or overt pulmonary or other clinical decompensation.

Adolescent↗
PubMed2005

Mycophenolate mofetil for renal dysfunction after pediatric liver transplantation.

BACKGROUND: Cyclosporine A (CsA) and tacrolimus (Tac) provide effective immunosuppression after orthotopic liver transplantation (OLT) but can cause renal dysfunction that may progress to end-stage renal failure (ESRF). Mycophenolate mofetil (MMF) is a newer immunosuppressant that does not affect renal function. Its long-term use in children with renal dysfunction after OLT has not yet been fully evaluated. METHODS: A retrospective analysis was performed of all children begun on MMF for renal dysfunction and followed up for at least 1 year. Renal dysfunction was defined as calculated glomerular filtration rate (cGFR) of less than 65 mL/min/1.73 m2. cGFR and liver function were measured before and after transfer. Data were analyzed using the Wilcoxon signed rank test. RESULTS: Forty-eight children (23 males) began MMF at a median age of 11.1 (0.9-18.1) years and at a median of 4.0 (0.3-12.4) years postOLT. Median baseline cGFR was 54 (range 29-65) mL/min/1.73 m2. Immunosuppression after transfer was MMF monotherapy in 36, MMF with steroids, in 4 and MMF with low-dose CsA or Tac in 8. In 44 (92%) patients, there was a statistically significant increase to a median cGFR of 69 (28-114) mL/min/1.73 m2 by 1 month and a further increase to a median cGFR of 77 (24-105) mL/min/1.73 m2 by 2 months of MMF treatment, after which time cGFR was maintained. Children aged less than 3 years at OLT or who were less than 5 years postOLT when MMF was begun demonstrated greater increases in cGFR. Four children with a median baseline cGFR of 34 (range 31-49) mL/min/1.73 m2 did not respond and progressed to ESRF. Mild side effects occurred in seven (15%) and gastrointestinal bleeding requiring discontinuation of MMF in one (2%). Liver function abnormalities occurred in seven (15%): transient transaminitis in three, acute rejection in two, and chronic rejection in two, of whom one required retransplantation. CONCLUSIONS: In 92% children with renal dysfunction after OLT, MMF treatment provided safe and effective immunosuppression and allowed CsA or Tac to be discontinued or reduced, leading to improvement of renal function. The improvement was greatest in younger children and those who began MMF early postOLT. Side effects were uncommon. Additional steroid cover during the transfer to MMF should be considered to prevent liver-allograft rejection.

Adolescent↗
PubMed2005

Comparative evolutionary analysis of VPS33 homologues: genetic and functional insights.

VPS33B protein is a homologue of the yeast class C vacuolar protein sorting protein Vps33p that is involved in the biogenesis and function of vacuoles. Vps33p homologues contain a Sec1 domain and belong to the family of Sec1/Munc18 (SM) proteins that regulate fusion of membrane-bound organelles and interact with other vps proteins and also SNARE proteins that execute membrane fusion in all cells. We demonstrated recently that mutations in VPS33B cause ARC syndrome (MIM 208085), a lethal multisystem disease. In contrast, mutations in other Vps33p homologues result in different phenotypes, e.g. a mutation in Drosophila melanogaster car gene causes the carnation eye colour mutant and inactivation of mouse Vps33a causes buff hypopigmentation phenotype. In mammals two Vps33p homologues (e.g. VPS33A and VPS33B in humans) have been identified. As comparative genome analysis can provide novel insights into gene evolution and function, we performed nucleotide and protein sequence comparisons of Vps33 homologues in different species to define their inter-relationships and evolution. In silico analysis (a) identified two homologues of yeast Vps33p in the worm, fly, zebrafish, rodent and human genomes, (b) suggested that Carnation is an orthologue of VPS33A rather than VPS33B and (c) identified conserved candidate functional domains within VPS33B. We have shown previously that wild-type VPS33B induced perinuclear clustering of late endosomes and lysosomes in human renal cells. Consistent with the predictions of comparative analysis: (a) VPS33B induced significantly more clustering than VPS33A in a renal cell line, (b) a putative fly VPS33B homologue but not Carnation protein also induced clustering and (c) the ability to induce clustering in renal cells was linked to two evolutionary conserved domains within VPS33B. One domain was present in VPS33B but not VPS33A homologues and the other was one of three regions predicted to form a t-SNARE binding site in VPS33B. In contrast, VPS33A induced significantly more clustering of melanosomes in melanoma cells than VPS33B. These investigations are consistent with the hypothesis that there are two functional classes of Vps33p homologues in all multicellular organisms and that the two classes reflect the evolution of organelle/tissue-specific functions.

Amino Acid Sequence↗
PubMed2005

Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics.

Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa-2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa-2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent-to-treat population. Children receiving interferon alfa-2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple-dose interferon alfa-2b and ribavirin peak and trough concentrations and area-under-the-curve were similar between children and adults. In conclusion, interferon alfa-2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus.

Adolescent↗
PubMed2004

Long-term persistence of immunity to hepatitis B after vaccination during infancy in a country where endemicity is low.

BACKGROUND: The long-term response to hepatitis B vaccination during infancy has not been fully evaluated in countries where endemicity is low. METHODS: The present study was a serological investigation of immunity to hepatitis B during adolescence. In a cohort of children who were born to hepatitis B virus carrier mothers and who were vaccinated during infancy, evidence of past or current infection and the response to a single booster dose of vaccine were analyzed. Sixty-four children whose antibody levels were measured after immunization (group 1) and 52 younger siblings who did not undergo postvaccination antibody tests (group 2) were studied. RESULTS: One child in each group showed evidence of natural infection. In group 1, 32 children (50%) had undetectable antibody to hepatitis B surface antigen (anti-HBs), and only 8 (13%) had levels >100 mIU/mL. After a booster dose of vaccine, only 7 (11%) still had undetectable anti-HBs, 3 (5%) showed a primary response, and 50 (78%) had levels >100 mIU/mL. Five of the 7 vaccine nonresponders and all of the primary responders had also received hepatitis B-specific immunoglobulin (HBIG) at birth. The children in group 2 showed a similar response to the vaccine, but with slightly higher levels of anti-HBs. CONCLUSIONS: Most children vaccinated at birth retain immunological memory to hepatitis B vaccine for 15 years, but those who did not were more likely to have received HBIG at birth, suggesting that passive antibody may interfere with the induction of immunological memory.

Adolescent↗