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Biomedical subjects

D A Kelly

Publications and source records attributed to D A Kelly.

At least 73 records · Page 4Linked to original sources
PubMed1999

Expansion of the tunica albuginea during penile inflation in the nine-banded armadillo (Dasypus novemcinctus).

Artificial inflation of corpora cavernosa from the nine-banded armadillo (Dasypus novemcinctus) showed that the expansion of the tunica albuginea during erection increases both components of flexural stiffness: the second moment of area and Young's modulus of elasticity. Folded tissue and crimped collagen fibers in the tunica albuginea permit its expansion during erection. As the tunica albuginea's radii increase in size, its second moment of area also increases. The crimped collagen fibers permit the flaccid tunica albuginea to expand to strains of 25 % longitudinally and 15 % circumferentially, after which tissue stiffness increases by 3-4 orders of magnitude. Radial expansion of the corpus cavernosum is limited by collagenous trabeculae. The trabeculae maintain the non-circular cross section of the corpus cavernosum during erection. Restricting expansion appears to protect the corpus spongiosum and urethra from occlusion, but has the side effect of reducing the potential flexural stiffness of the corpus cavernosum by reducing the second moment of area of the tunica albuginea.

Animals↗
PubMed1999

Acute liver failure.

Acute liver failure is a rare but potentially fatal disease. Adult definition of fulminant hepatic failure, which includes the development of hepatic necrosis and encephalopathy within 8 weeks of onset of liver disease does not apply to acute liver failure in children particularly if secondary to autoimmune or metabolic liver disease. The etiology of acute liver failure varies with the age of the child. In neonates, infection or an inborn error of metabolism are common, while viral hepatitis and drug induced liver failure are more likely in older children. The clinical presentation of acute liver failure includes jaundice, coagulopathy and encephalopathy. In neonates, encephalopathy may be subclinical. The management of acute liver failure includes assessment of prognosis for liver transplantation; prevention and treatment of complications while awaiting hepatic regeneration or a donor liver and hepatic support. The major complications of acute liver failure are sepsis, gastro-intestinal bleeding, cerebral edema, renal and cardiac failure. Selection for liver transplantation depends on the etiology of the disease, prognostic factors, the presence or absence of multisystem disease and/or reversible brain damage. Prognostic factors for survival are less well established in children than in adults but children with metabolic liver disease, prothrombin time > 50 seconds, rising bilirubin and falling transaminase, grade II or higher grade of hepatic coma indicate poor prognosis. Most children receive a reduced or split liver graft. Living related donations for acute liver failure are also carried out by some centres. Survival post liver transplantation for acute liver failure has improved and most recipients can expect a 70% five year survival.

Age Distribution↗
PubMed1998

A single exposure of solar simulated radiation suppresses contact hypersensitivity responses both locally and systemically in humans: quantitative studies with high-frequency ultrasound.

Ultraviolet radiation (UVR)-induced suppression of cutaneous cell-mediated immunity plays an important role in the development of photocarcinogenesis in the mouse and a similar role is suspected in humans. Cell-mediated immunity is readily tested in vivo by measuring the contact hypersensitivity (CHS) response to topically applied haptens. CHS in humans is usually determine clinically, with a subjective scoring system. However, these subjective scores cannot be statistically analysed. This paper compares four methods currently used to quantify CHS elicitation responses in humans. The data show that ultrasound images provide the most accurate and reproducible measurements of the clinically observed CHS response. We also demonstrate that assessment of the primary allergic response is a useful indicator of the magnitude of the elicitation response and can be used to avoid severe CHS reactions in volunteers. There are few human studies investigating the effects of solar simulated radiation (SSR) exposure on immunosuppression. In this study we demonstrate SSR is highly immunosuppressive in all subjects tested. Irradiating a small area of skin with a single exposure to 3MEDs of SSR completely suppressed CHS both locally (12/12 volunteers) and systemically (10/12 volunteers). Our data do not support a role for a genetic susceptibility to UVR-induced immunosuppression in humans.

Adolescent↗
PubMed1998

Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver.

The existence of progenitor (stem) cells in the human liver remains a matter of debate. In rodent models of hepatocarcinogenesis and injury, oval cells proliferate in the periportal regions of the portal tracts and are suggested to derive from a stem cell compartment, because they are capable of differentiating into hepatocytes or biliary epithelial cells. In this study, the rat oval cell marker, OV-6 has been used to investigate the hypothesis that there are stem cells present in fetal and pediatric human liver. The pattern of OV-6 expression was compared with the established adult biliary cell markers human epithelial antigen-125 (HEA-125) and cytokeratin-19 (CK-19). In normal pediatric liver (n = 7), bile ducts and ductules were immunostained with CK-19 and HEA-125, whereas OV-6 staining was consistently negative. In fetal tissue (n = 10), ductal plate cells, primitive bile ducts, and hepatoblasts were stained with CK-19 and HEA-125 although only some of the ductal plate cells and hepatoblasts were OV-6 positive. In biliary atresia (n = 6) and 1, anti-trypsin deficiency (1,AT) (n = 4), CK-19 and HEA-125 immunostained ductular proliferative cells that tended to form finely anastomosing ductules, whereas OV-6 staining was found more on discrete cells confined to portal tract margins. Additionally, in diseased liver, OV-6 was strongly positive in hepatocyte lobules with greatest intensity in the periseptal regions. This widespread hepatocyte OV-6 positivity suggests that the antibody may identify cells of a less differentiated phenotype (transitional hepatocytes) that have replaced the mature cells. Therefore, it is proposed that in human liver, OV-6 is recognizing cells with a progenitor stem cell-like phenotype with the capacity to differentiate into OV-6 positive ductular cells or lobular hepatocytes.

Adult↗
PubMed1998

Efficacy of Neoral in the immediate postoperative period in children post-liver transplantation.

Cyclosporine (Sandimmune) is an effective immunosuppressive drug but may be poorly absorbed in the early postoperative period after liver transplantation, exposing the recipient to an increased risk for rejection. Neoral is a new oral formulation of cyclosporine that uses a mixture of surfactant, lipophilic, and hydrophilic solvents to permit microemulsification that leads to potentially better absorption. This oral drug has not been evaluated in children immediately posttransplantation. The aim of this study was to evaluate the pharmacokinetics, bioavailability, and safety of Neoral during the first week post-liver transplantation in children. Twelve children, 8 boys and 4 girls, with a median age of 2.6 years (range, 1 to 8 years) were administered Neoral within 12 hours posttransplantation. Pharmacokinetic profiles were performed over a 12-hour period on each child on days 1, 3, and 5 and twice-daily trough levels were obtained on days 2, 4, 6, and 7. The maximum concentration (Cmax), time to reach Cmax (Tmax), 12-hour trough levels, and area under the curve were calculated, and rejection episodes and adverse events were documented over a 12-week period. Neoral was well absorbed, even on the first postoperative day. After the introduction of enteral feeding, the peak levels increased (Cmax, 655 ng/mL) and were achieved significantly sooner (Tmax, 2 hours). There was no significant difference in drug exposure between days 1, 3, and 5 (P > .05). The incidence of acute rejection was 25% and hypertension was reported in 4 of 12 patients during the first week. Neoral was well absorbed in the early post-liver transplantation period, provided effective immunosuppression, and was not associated with a high incidence of adverse events or toxicity. The introduction of enteral feeding improved absorption.

Area Under Curve↗
PubMed1998

Chronic hepatitis in children after liver transplantation: role of hepatitis C virus and hepatitis G virus infections.

BACKGROUND/AIMS: Chronic graft hepatitis occurs in 20-30% adults after liver transplantation but the prevalence and causes in children are not known. In adults, hepatitis C virus infection is prevalent prior to transplantation and recurrent infection is a frequent cause of graft dysfunction. The significance of the recently described hepatitis G virus infection remains unproven. The aim of this study was to examine the role of hepatitis C virus and hepatitis G virus infection in chronic graft hepatitis after paediatric liver transplantation. METHODS: The prevalence of graft hepatitis and the role of hepatitis C virus and hepatitis G virus infections in 80 children after liver transplantation have been studied, with a median follow up of 4.4 years (range 0.4 to 10.7), and the persistence of hepatitis G infection in the presence of immunosuppression has been determined. RESULTS: Chronic graft hepatitis was diagnosed in 19/80 (24%) children and was most frequently seen in children transplanted for cryptogenic cirrhosis (71%). There was no significant difference in the prevalence of chronic hepatitis in those transplanted before or after donor anti-HCV screening. Hepatitis C infection occurred in three children transplanted prior to donor screening but in only one was associated with chronic hepatitis. Hepatitis G infection was found in 22/79 (28%) transplant recipients but was not associated with graft hepatitis. In 17/21 children hepatitis G infection persisted for a median of 5.2 years after transplantation. CONCLUSION: Chronic hepatitis occurred in 24% of children after liver transplantation, a similar prevalence to that in adults. Cryptogenic liver disease predisposed to graft hepatitis, but neither hepatitis C nor hepatitis G infection was associated. Hepatitis G virus caused a frequent and usually persistent infection after transplantation.

Adolescent↗
PubMed1998

Liver complications of pediatric parenteral nutrition--epidemiology.

Total parenteral nutrition (TPN)-induced liver disease develops in 40-60% of infants who require long-term TPN for intestinal failure. The clinical spectrum includes cholestasis, cholelithiasis, hepatic fibrosis with progression to biliary cirrhosis, and the development of portal hypertension and liver failure in a significant number of children who are totally parenterally fed. The pathogenesis is multifactorial and is related to prematurity, low birth weight, and duration of TPN. The degree and severity of the liver disease is related to recurrent sepsis including catheter sepsis, bacterial translocation, and cholangitis. Lack of enteral feeding leading to reduced gut hormone secretion, reduction of bile flow, and biliary stasis may be important mechanisms in the development of cholestasis, biliary sludge, and cholelithiasis. Although it is unlikely that modern TPN solutions have a major role in the etiology of TPN liver disease, manganese toxicity recently has been recognized in children with hepatic dysfunction on TPN. Although there is a definite relationship with the degree of manganese toxicity and hepatic decompensation, it is not yet clear whether this is a primary mechanism or whether the high levels are related to reduced biliary excretion of manganese. The management strategies for the prevention of TPN-induced liver disease include early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition, and aseptic catheter techniques to reduce sepsis. The administration of ursodeoxycholic acid may improve bile flow and reduce gall bladder and intestinal stasis. As survival from isolated intestinal transplantation improves, this therapeutic option should be considered before TPN liver disease becomes irreversible and combined liver and small bowel transplantation is required.

Animals↗
PubMed1998

Cholestasis and end-stage liver disease.

Protein-energy malnutrition is an inevitable consequence of chronic liver disease, particularly in the developing infant. Severe malnutrition with loss of fat stores and muscle wasting affects between 60% and 80% of infants with liver disease (Beath, 1993a; Holt et al, 1997). Reduced energy intake secondary to anorexia, vomiting and fat malabsorption, in association with a disordered metabolism of carbohydrate and protein, increased energy requirements and vitamin and mineral deficiencies, contributes towards growth failure. Reversal of malnutrition is one of the key aims of liver transplantation and is achieved in the majority of long-term survivors. The aetiology of persistent growth failure post-transplantation is multifactorial and is related to pre-operative malnutrition, glucocorticoid administration, feeding problems and post-operative complications. Strategies to prevent pre- and post-transplant growth failure include early referral for liver transplantation and a multidisciplinary approach to nutritional support, which may increase survival and improve the quality of life and outcome of liver transplantation.

Child↗
PubMed1998

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.

Alagille Syndrome↗
PubMed1998

Current results and evolving indications for liver transplantation in children.

Liver transplantation continues to be successful and effective treatment for acute and chronic liver failure, and many important lessons have been learned. The development of innovative operative techniques has much reduced the waiting list mortality rate and has extended transplantation to younger and sicker children and to those with functionally normal livers who may benefit from auxiliary liver transplantation. The incidence and range of postoperative complications have improved with increased medical and surgical expertise. As information on long-term outcome for liver transplantation is gained, it is clear that many children will benefit from early elective liver transplantation before the development of significant growth or psychosocial retardation. Early transplantation is also indicated in children with cirrhosis and intrapulmonary shunting or cystic fibrosis with moderate lung disease. During the same period, evolving medical therapy has altered the natural history, patient selection, and timing of transplantation in children with tyrosinaemia type I, primary bile acid disorders, neonatal haemochromatosis, and potentially, cystic fibrosis. It is now clear that children with significant multisystem disease, such as mitochondrial disorders or severe systemic oxalosis, are no longer suitable candidates for liver transplantation. The successful development of liver transplantation has brought good quality life to many children and their families. There are still many lessons to learn and there are future challenges such as the ever-increasing problems of donor scarcity and the search for potent but less toxic immunosuppressive agents.

Child↗
PubMed1998

Population screening for neonatal liver disease: a feasibility study.

BACKGROUND: Extra-hepatic biliary atresia and several other causes of neonatal liver disease carry high mortality and morbidity rates, especially if not treated early in life. Despite professional recommendations, delayed referral of infants with prolonged jaundice continues to be a significant problem. One approach to reducing the age of referral and diagnosis is population screening to detect significant conjugated hyperbilirubinaemia as an index of liver dysfunction. METHODS: To investigate this possibility, and to provide reference data on bilirubin and its conjugated and unconjugated fractions in a normal newborn population, 1157 neonates were anonymously tested (median age 7 days, range 4-28 days) using surplus plasma from routinely collected neonatal screening specimens, using dry slide chemistry. RESULTS: Of 2310 specimens received, 50% were suitable for analysis. The remainder were either haemolysed or insufficient (10% and 40% of the total, respectively). Total bilirubin concentrations ranged from 9 to 428 micromol/l and conjugated bilirubin from 0 to 175 micromol/l, although the latter was rarely increased to more than 30 micromol/l (2.5th-97.5th percentile ranges 15-285 micromol/l and 0-18 micromol/l, respectively). The range of the percentage of conjugated bilirubin was 0-57% (2.5th-97.5th percentile; range 0-20%). CONCLUSION: An increased conjugated bilirubin, expressed as a concentration or as the percentage of the total bilirubin, could be used as a specific marker to screen for liver dysfunction in neonates. This approach has the potential to improve the age of referral and the prognosis of infants with neonatal liver disease.

Bilirubin↗
PubMed1998

Pediatric liver transplantation.

Liver transplantation is accepted therapy for acute or chronic liver failure. Advances in preoperative and postoperative management and surgical techniques have extended the indications for transplantation and refined selection, particularly for fulminant hepatic failure. Radiologic techniques, such as magnetic resonance imaging and placement of transjugular intrahepatic portosystemic shunts, have improved preoperative assessment and management. Successful split liver and living related transplantation may reduce waiting list deaths and relieve the organ donor shortage. Auxiliary liver transplantation, although technically difficult, is now accepted management for Crigler-Najjar type I disease but remains controversial for the treatment of organic acidemias and fulminant hepatic failure. Microsurgical techniques have reduced the incidence of postoperative hepatic thrombosis, and radiologic management of portal vein thrombosis and stenosis has decreased operative intervention and improved survival. Immunosuppressive drugs such as cyclosporine microemulsion and tacrolimus have the potential to improve rejection rates and reduce sepsis in the future. There are now good data confirming that long-term survival is achieved with nutritional rehabilitation and good quality of life.

Child↗
PubMed1998

Focal reduction of villous blood flow in early indomethacin enteropathy: a dynamic vascular study in the rat.

BACKGROUND: Oral indomethacin causes villous shortening, microvascular damage, and distortion, which might induce mucosal ischaemia and necrosis. AIMS: In order to determine the early events in indomethacin induced jejunal injury we examined the temporal relations between morphological damage and changes in villous blood flow following indomethacin. METHODS: In anaesthetised rats, mid jejunal villi were exteriorised in a chamber and observed by fluorescence microscopy. Blood flow in surface capillaries was calculated from velocities and diameters. Indomethacin was applied by both luminal and intravenous routes for 90 minutes, after which the animal was perfusion fixed and the villi were processed for histological examination. Control animals received intravenous or luminal bicarbonate (1.25%). RESULTS: Blood flow slowed in individual villi at 20 minutes, and progressed to complete stasis (in another group) by 45 minutes. Histological examination at 20 minutes revealed microvascular distortion, but no villous shortening; crypt depth:villous height ratios were 0.356 (0.02) in test and 0.386 (0.01) in surrounding villi (p > 0.05). At stasis, the villi under study showed epithelial clumping and were shortened: crypt depth:villous height ratios were 0.92 (0.2) in test and 0.42 (0.06) in surrounding villi (p < 0.02). Vehicle alone had no effect on either blood flow or histology. CONCLUSIONS: Focal slowing of villous blood flow and microvascular distortion precede villus shortening and epithelial disruption, and indicate that damage to surface microvasculature is an early event in indomethacin induced mucosal injury in this model.

Animals↗
PubMed1997

Axial orthogonal fiber reinforcement in the penis of the nine-banded armadillo (Dasypus novemcinctus).

Examination of histological sections from flaccid and artificially erected nine-banded armadillo (Dasypus novemcinctus) penises confirms that the mammalian corpus cavernosum is the first known biological hydrostat reinforced by collagen fibers arranged at 0 degree and 90 degrees to its long axis. The morphology of this axial orthogonal fiber array affects the mechanical behavior of mammalian penises during erection and copulation. Specifically, the axial orthogonal array gives the erect penis a reproducible shape, maximum size and resistance to tensile, compressive, and bending forces. These features are more appropriate for the mechanical regime associated with copulation than those found in structures reinforced by crossed-helical fibers, although the axial orthogonal array also gives the corpus cavernosum a tendency to fail by kinking. Crimped collagen fibers in the flaccid array as well as three-dimensional folding of the wall in the flaccid corpus cavernosum allow the structure to expand during erection.

Anatomy, Artistic↗
PubMed1997

Emergency transjugular intrahepatic portosystemic shunt prior to liver transplantation.

Transjugular intrahepatic portosystemic shunt (TIPSS) is a new development in the management of severe variceal haemorrhage which has been established in adult patients. We have successfully adapted this technique for children and describe our initial experience in the case of a 9-year-old boy who presented with acute and chronic liver failure and uncontrollable life-threatening bleeding from oesophageal and gastric varices, despite intensive medical management including sclerotherapy. A 10-mm TIPSS was successfully placed with immediate reduction in portal pressure and cessation of variceal bleeding. The patient's condition stabilised sufficiently for him to undergo liver transplantation 2 days later, at which time the TIPSS was patent.

Child↗