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Biomedical subjects

D A Kelly

Publications and source records attributed to D A Kelly.

At least 19 recordsLinked to original sources
PubMed2004

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.

Animals↗
PubMed2004

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.

Biliary Atresia↗
PubMed2004

Natural history of hepatitis B in perinatally infected carriers.

OBJECTIVES: To establish natural seroconversion rates and incidence of hepatic pathology in perinatally infected hepatitis B carriers. METHODS: Seventy three perinatally infected hepatitis B carriers identified through maternal screening were evaluated. Fifty three were born to parents from the Indian subcontinent, nine were Oriental, six were Afro-Caribbean, and five were white. Median follow up was 10.24 (range 2.02-20.16) years. RESULTS: Only three of the children followed up had cleared hepatitis B surface antigen during this period, and 30% of the children had seroconverted to anti-HBe. Seroconversions to anti-HBe were observed in Asian (18/50) and white (4/5) children, but not in Oriental or Afro-Caribbean children. More girls (40%) than boys (23%) had seroconverted, but the difference was not significant. All children were asymptomatic with normal physical examination, growth, and development. Almost half (48%) of the hepatitis B e antigen (HBeAg) positive children had normal hepatic transaminases and liver function. Thirty five liver biopsies were performed in children with active virus replication (HBeAg or hepatitis B virus DNA positive) who were being considered for antiviral treatment as part of a clinical trial and were scored using the Ishak method. Two thirds (62%) of the children had mild hepatitis, 60% had mild fibrosis, and 18% had moderate to severe fibrosis. There was a weak correlation between histological evidence of hepatitis and hepatic transaminase activity, implying that biochemical monitoring of hepatic disease activity may be ineffective. CONCLUSIONS: These asymptomatic hepatitis B virus carrier children remain infectious in the medium to long term with notable liver pathology. They should receive antiviral treatment to reduce infectivity and to prevent further progression of liver disease. Hepatic transaminases alone are not a reliable marker of liver pathology, and liver histology is essential before consideration for antiviral treatment.

Adolescent↗
PubMed2003

Renal function following liver transplantation for unresectable hepatoblastoma.

Combination of cyclosporine (CsA) and tacrolimus immunosuppression post-liver transplantation (LT) and the chemotherapeutic drugs used to treat hepatoblastoma (HB), are nephrotoxic. We aimed to determine the severity and duration of nephrotoxicity in children following LT for unresectable HB. We reviewed all children undergoing LT for unresectable HB at the Liver Unit, Birmingham Children's Hospital, UK, from 1991 to July 2000. Thirty-six children undergoing LT for biliary atresia, matched for age and sex, were selected as controls to compare pre- and post-LT renal function. Renal function was determined by estimation of glomerular filtration rate (eGFR) derived from plasma creatinine using Schwartz's formula. Twelve children with HB (mean age of diagnosis 33 months) who underwent LT (mean age 47 months) and 36 controls (mean age of LT 34 months) were studied. CsA was the main immunosuppressive drug used in each group. The median eGFR before, and at 3, 6, 12, 24 and 36 months after LT in HB group was significantly lower than controls (93 vs. 152, 66 vs. 79, 62 vs. 86, 66 vs. 87, 64 vs. 94, 53 vs. 90 mL/min/1.73 m2, respectively; 0.01 < p < 0.03). The reductions in the median eGFR of both the HB group and controls before and at 36 months after LT were 49 and 41%, respectively. At 36 months after LT, there was a trend for partial recovery of the eGFR in the controls but not in the HB group. Children who underwent LT for unresectable HB had renal dysfunction before transplantation that persisted for 36 months after LT.

Adolescent↗
PubMed2003

New perspective for the management of near-total or total intestinal aganglionosis in infants.

BACKGROUND/PURPOSE: Extensive intestinal aganglionosis is rare. The diagnosis and treatment are known to be difficult and it had been considered to be fatal. The aim of this study was to review our experience with children with extensive intestinal aganglionosis. METHODS: Retrospective analysis was conducted in patients referred to the intestinal transplantation unit since 1993. Presentation and outcome were analysed looking at 2 groups who had either undergone previous subtotal intestinal resection (group I) or no or limited resection (group II). RESULTS: Eight children were selected (3 patients in group I and 5 in group II). Group I was remarkable in that patients all were referred early in age with progressing liver failure. Parents of one patient refused to accept transplantation as treatment, and he died one month later. Two noncirrhotic patients were maintained in the parenteral nutrition programme and currently progress well with enteral feedings. The other 5 patients underwent transplant, and 4 of 5 are alive after transplantation with a mean follow-up of 22.2 months (range 0.4 to 63.6). CONCLUSIONS: Subtotal resection of intestine at the time of diagnosis must be avoided. Conservative management with parenteral nutrition may be associated with long-term good outcome. Small bowel transplant may open new perspective in the management of patients with end-stage liver disease.

Female↗
PubMed2003

Progress in treatment and outcome for children with neonatal haemochromatosis.

AIM: To evaluate the role of antioxidant treatment and liver transplantation in the management of neonatal haemochromatosis. METHODS: A retrospective review was performed of eight infants with acute liver failure and raised ferritin levels between 1990 and 1998. From 1994, treatment with an antioxidant cocktail (vitamin E, N-acetylcysteine, selenium, prostaglandin E1, and desferrioxamine) was begun once the diagnosis was suspected. Pathological and other findings were reviewed, and outcome before and after antioxidant treatment was evaluated. RESULTS: Median age at presentation was 4 days with median ferritin levels of 4180 micro g/l (range 1650-40 000 micro g/l; normal range 110-503 micro g/l). Three infants presented before 1994. One infant died before liver transplantation from acute liver failure and one from neurological damage after transplantation. The third patient underwent successful transplantation at day 13 and remains well on follow up 8 years later. From 1994, five patients received antioxidant treatment, of whom two responded: both responders started antioxidants earlier (by day 5) than non-responders and had lower peak ferritin levels (< 4200 micro g/l) and a milder phenotype. Treatment was continued until ferritin levels were < 500 micro g/l. Both children remain well with mean follow up of 42 months, with no recurrence of iron overload. One child showed a partial response to treatment and survived long enough for a liver transplant, but died from graft failure after the transplant. Two children did not respond to antioxidant treatment; both had multiorgan failure and were not listed for transplantation. Only three of the eight patients survived (37.5%) over this time period. CONCLUSION: Neonatal haemochromatosis can be a fatal disease with > 60% mortality. Early treatment with antioxidant cocktail is beneficial and may be curative in those who present with milder phenotype. Liver transplantation should always be considered at an early stage in non-responders and in children with more severe acute liver failure.

Antioxidants↗
PubMed2003

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.

Asphyxia↗
PubMed2003

Population screening for neonatal liver disease: potential for a community-based programme.

OBJECTIVES: To evaluate a community-based screening programme for detecting neonatal liver disease by the quantitation of conjugated bilirubin in blood. SETTINGS AND METHODS: Prospective cohort/observational study using spare plasma from routinely collected liquid neonatal screening specimens from babies born in Birmingham over a two-year period. Babies with a conjugated bilirubin above 18 mumol/l and comprising more than 20% of the total bilirubin were followed up. A total of 27654 neonates were tested in the community, with a further 2425 samples from babies hospitalised at the time of the test. RESULTS: In the community-based series, 84.7% of the specimens received were analysed, the remainder being unusable mainly because of gross haemolysis (8.6%) or insufficient sample (5.8%). In 107 neonates the results were above the cut-off limits (0.46% of the number analysed). Of these, 12 had persistently abnormal results, 11 of whom had confirmed liver disease. The liver diseases detected included neonatal hepatitis (n=6), extra-hepatic biliary atresia (n=2), hypopituitarism (n=1), alpha-1-antitrypsin deficiency (n=1) and Alagille syndrome (n=1). The sensitivity and specificity of the test for babies in the community were 100% and 99.6%, respectively. CONCLUSIONS: Conjugated bilirubin in plasma measured at 6-10 days is a reliable marker for neonatal liver disease, and a population screening programme based on this method has the potential to improve the survival and quality of life of infants born with liver disease. However, testing as part of the neonatal screening programme will prove practical only if the method can be adapted to use dried blood spots.

Bilirubin↗
PubMed2002

Concomitant basiliximab with low-dose calcineurin inhibitors in children post-liver transplantation.

Orthotopic liver transplantation (OLT) is effective therapy for end-stage liver disease but immunosuppression with calcineurin inhibitors (CNI) leads to significant nephrotoxicity, resulting in either a reduction of dosage to below the therapeutic level or omission of the drug altogether. Basiliximab (Bx) is a human/mouse chimeric monoclonal antibody that inhibits binding of interleukin-2 (IL-2) to IL-2 receptors and thus prevents proliferation of T cells, which is the main step in the development of acute cellular rejection. The aim of this study was to identify the role of Bx in the prevention of acute cellular rejection and in the reduction of nephrotoxicity in children post-liver transplantation. We evaluated three children (19 months, 22 months, and 11 yr of age; one male, two female) who were treated with Bx post-OLT on compassionate grounds. The indications were: nephrotoxicity in two children, requiring re-transplantation for hepatic artery thrombosis and recurrent giant cell hepatitis, respectively; and nephrotoxicity secondary to chemotherapy for hepatoblastoma in the third child. All patients received 10 mg of Bx, at OLT and on Day 4. Tacrolimus (0.15 mg/kg/day) was started at 48 h (n = 2) and cyclosporin (5 mg/kg/day) at 2 weeks (n = 1). Trough levels of tacrolimus were maintained at 5-8 ng/mL and trough levels of cyclosporin at 100-150 mg/L for the first 3 months. All patients received methylprednisolone (2 mg/kg) with azathioprine (1.5 mg/kg) (n = 2) and/or mycophenolate mofetil (20 mg/kg) (n = 1). The glomerular filtration rate (cGFR) was calculated using the Schwartz formula before and 10 weeks after transplant. Bx was found to be easy to administer and no major side-effects were reported. One child had two episodes of mild acute rejection at 5 and 9 weeks post-OLT and one developed chronic rejection requiring re-transplantation at 9 weeks post-OLT. One child did not develop rejection. The mean pretransplant cGFR was 58.1 (54.6-64.1) mL/min/m2. Within 10 weeks of transplantation, the cGFR had improved by 69% to a mean of 116 (88-157.6) mL/min/m2. To conclude, Bx was well tolerated in all children and had a renal sparing effect. It was effective in preventing early acute rejection, but the combination of Bx and low-dose CNI drugs did not prevent late acute or chronic rejection. Further studies to evaluate the appropriate levels of CNI immunosuppression with Bx are required.

Antibodies, Monoclonal↗
PubMed2002

Relationship between 2,4-dinitrochlorobenzene elicitation responses and individual irritant threshold.

Contact dermatitis shows significant interindividual variation. We studied the relationship between an individual's irritant threshold and the elicitation of experimentally induced allergic sensitization. The results suggest that there is an association between reactivity to an irritant and the likelihood of positive elicitation reactions to lower hapten concentrations. This novel finding would be compatible with the proposal that contact allergy is best explained using a danger model with cutaneous irritancy determining sensitization. However, the enhanced allergic reactivity of individuals with a lower irritant threshold was not apparent on visual inspection, suggesting that the determinants of skin reactivity to haptens are multifactorial.

Adult↗
PubMed2002

Immunodeficiency-related lymphoproliferative disorders: prospective data from the United Kingdom Children's Cancer Study Group Registry.

Clinical data and biological samples were prospectively collected in 42 children with lymphoproliferative disease (LPD) secondary to organ/bone marrow transplant-related immunosuppression (30: 11 liver, 10 heart/lung, 8 kidney and 1 bone marrow), other drug-induced immunosuppression (2), congenital immunodeficiency (8) or human immunodeficiency virus (HIV)-related immune dysfunction (2). Ages ranged from 10 months to 17 years and there were 15 girls. Pathology was centrally reviewed and showed polymorphic features in 5 cases, monomorphic in 23, mixed pattern in 5 patients and 9 other types. Using the Revised European-American Classification of Lymphoid Neoplasms, 5 were B lymphoblastoid, 24 were high-grade B and 14 were other subtypes. Using the Pittsburgh classification, 9 were lymphadenopathic, 10 were systemic, 25 were lymphomatous and, with the Murphy grouping for non-Hodgkin's lymphoma (NHL), 10 were localized and 32 non-localized. Twenty-four out of 38 evaluable cases were Epstein-Barr virus positive. Thirty-five patients were evaluable for clonality; 24 were monoclonal and 11 were polyclonal. Reduced immunosuppression in solid organ transplant patients resulted in resolution of disease in 14/24, which was sustained in 11. Nineteen patients received chemotherapy, 14/18 evaluable responded, which was sustained in 8 cases. Seven out of 29 solid organ transplant and 10/13 other immune-deficient patients died. In the largest group of patients, solid organ transplants, no significant clinical or biological characteristics that predicted outcome were identified. In the transplant group close monitoring of response during reduction in immunosuppression is essential and the early use of B NHL chemotherapy may be effective.

Adolescent↗
PubMed2002

Cytomegalovirus and cyclosporin-induced gingival overgrowth in children with liver grafts.

OBJECTIVE: To determine whether cytomegalovirus (CMV) is associated with gingival overgrowth in paediatric liver graft recipients treated with cyclosporin. STUDY DESIGN: Thirty-four children, 25 of whom were under 5 years of age, who had undergone liver transplantation, were examined. An Index of Severity of Gingival Overgrowth was used to measure the prevalence and severity of the gingival overgrowth. The trough cyclosporin level was recorded and the CMV status of the patient matched to the dental findings. The association between the severity of gingival overgrowth and CMV infection was examined using the contingency coefficient. An anova was used to assess the association between the circulating trough cyclosporin concentration and the severity of gingival overgrowth. Pearson's Product Moment Correlation Coefficient was used to examine the association between the duration of exposure to cyclosporin and the severity of gingival overgrowth. RESULTS: There was a significant inverse association between the duration of exposure to cyclosporin and the severity of gingival overgrowth. There was no relationship between the trough cyclosporin concentration and the severity of gingival overgrowth. There was no association between CMV and gingival overgrowth. CONCLUSION: Gingival overgrowth was related to the duration of cyclosporin therapy but was neither more prevalent nor more severe in subjects who were CMV seropositive.

Analysis of Variance↗
PubMed2002

Techniques for and outcome of liver transplantation in neonates and infants weighing up to 5 kilograms.

BACKGROUND: Neonates and small infants represent less than 5% of paediatric candidates for liver replacement. Most cases present under urgent conditions and receive grafts from large donors. Surgical techniques must be adapted for adequate graft preparation, vascular reconstruction, and abdominal closure. METHODS: Technical aspects and outcome of 15 liver transplantations in infants weighing less than 5 kg performed at our unit were analysed retrospectively. RESULTS: Liver transplantation was performed under urgent or highly urgent condition in 13 cases. Reduced or split liver grafts were used in all cases (median donor to recipient weight ratio, 9), including a monosegmental graft in 2 cases. In 10 cases, vascular reconstruction was done using a vascular conduit (5, 4, and 1 for artery, portal, and hepatic veins, respectively) and a delayed closure of the abdomen was necessary in 7 children. Postoperative complications were as follows: thrombosis of hepatic artery (n = 1) or portal vein (n = 1), gastrointestinal haemorrhage (n = 2), intraperitoneal bleeding (n = 1), biliary stricture (n = 2), septicaemia (n = 1). Two infants died of brain damage with a functioning graft. One child underwent retransplant for chronic rejection. CONCLUSIONS: Overall, survival rate is 60% (median follow-up, 34 months), which compares favourably with older patient groups when case mix is comparable.

Age Factors↗
PubMed2002

Strategy for hepatoblastoma management: Transplant versus nontransplant surgery.

BACKGROUND: Liver transplantation now is proposed for managing selected hepatoblastoma cases. Indications are not yet well defined. METHODS: The case records of 34 children with hepatoblastoma treated over a period of 10 years (1991 to 2000) were reviewed retrospectively. RESULTS: All patients benefited from preoperative chemotherapy. Twenty patients underwent major hepatic resections. Twelve patients, in absence of residual metastasis, underwent liver transplant because the tumour remained unresectable after chemotherapy. Two patients who presented with recurrence after a right hepatectomy, benefited from transplant as a second option. Two other patients did not undergo surgery because of widespread disease or resistance to chemotherapy. Disease-free survival rates were 95% after surgical resection, 100% when primary transplant was performed in patients with good response to chemotherapy, 60% after transplantation in patients with poor response to chemotherapy, 50% in patients with transplant as second option, and 0% in patients not undergoing surgery. CONCLUSIONS: Transplantation is a potentially curative option for unresectable hepatoblastoma when chemosensitive (decrease in alpha-fetoprotein and decrease in tumour size). In this context, also favourable cases with good response but difficult resections with doubtful margins of resection may best be proposed for primary transplantation. Patients with recurrent or resistant disease are not good candidates.

Antineoplastic Agents↗