Multivisceral transplantation using a 2.9 kg neonatal donor.

Prematurity and very low birthweight have often been considered relative contraindications to neonatal organ donation. Organ procurement from neonatal donors is further complicated by unclear guidelines regarding neonatal brain death. We report a successful case of multivisceral transplantation using a graft from a 10-day-old, 2.9 kg, neonatal donor born at 36 6/7 wk in a 3.2 kg, three month old with intestinal and liver failure secondary to midgut volvulus. There was immediate liver graft function with correction of recipient coagulopathy, but delayed normalization of laboratory values and delayed return of bowel function. At six-yr post-transplant follow-up, the patient has normal intestine and liver function. Her last histologically confirmed rejection episode was 30 months prior to last follow-up. This case suggests that multivisceral grafts from very young or small neonatal donors may be transplanted successfully in selected cases. We propose a re-examination of the brain death guidelines for premature and young infants to potentially increase the availability of organs for infant recipients.

Reduced size liver transplantation from a donor supported by a Berlin Heart.

Patients on cardiac assist devices are often considered to be high-risk solid organ donors. We report the first case of a reduced size liver transplant performed using the left lateral segment of a pediatric donor whose cardiac function was supported by a Berlin Heart. The recipient was a 22-day-old boy with neonatal hemochromatosis who developed fulminant liver failure shortly after birth. The transplant was complicated by mild delayed graft function, which required delayed biliary reconstruction and abdominal wall closure, as well as a bile leak. However, the graft function improved quickly over the first week and the patient was discharged home with normal liver function 8 weeks after transplant. The presence of a cardiac assist device should not be considered an absolute contraindication for abdominal organ donation. Normal organ procurement procedures may require alteration due to the unusual technical obstacles that are encountered when the donor has a cardiac assist device.

Successful algorithm for selective liver biopsy in the right hepatic lobe live donor (RHLD).

Routine versus selective predonation liver biopsy (LBx) remains controversial for assuring the safety of right hepatic lobe live donor (RHLD). Between December 1999 and March 2007, 403 potential RHLD were evaluated; 142 donated. Indications for selective LBx were: abnormal liver function tests or imaging studies, body mass index (BMI) >28, history of substance abuse or family history of immune mediated liver disease. All donors had a LBx at the time of surgery. Of 403 potential RLD, 149(36.9%) were accepted as donors, 25(6.3%) had their recipient receive a deceased donor graft, 94(23.4%) were rejected, 52(12.9%) stopped the evaluation process, 76(18.8%) withdrew from the process and 7(1.7%) are currently completing evaluation. Eighty-seven (21.5%) met criteria and were biopsied. Seventy-three (83.9%) had either normal (n = 24) or macrosteatosis <10% (n = 49); 51 of these donated. Abnormal LBx eliminated 15 potential donors. No significant abnormalities were found in donation biopsies of donors not meeting algorithm criteria. Three of 87 (3.4%) had complications requiring overnight admission (2 for pain, 1 for bleeding; transfusion not required). Use of this algorithm resulted in 78% of potential donors avoiding biopsy and potential complications. No significant liver pathology was identified in donors not meeting criteria for evaluation LBx. Routine predonation LBx is unnecessary in potential RHLD.

Effects of the plant steroidal hormone, 24-epibrassinolide, on the mitotic index and growth of onion (Allium cepa) root tips.

The purpose of the present study was to determine the effects of the steroidal plant hormone, 24-epibrassinolide (BL), on the mitotic index and growth of onion (Allium cepa) root tips. The classical Allium test was used to gather and quantify data on the rate of root growth, the stages of mitosis, and the number of mitoses in control and BL-treated groups of onions. Low doses of BL (0.005 ppm) nearly doubled the mean root length and the number of mitoses over that of controls. Intermediate doses of BL (0.05 ppm) also produced mean root lengths and number of mitoses that were significantly greater than those of the controls. The highest dose of BL (0.5 ppm) produced mean root lengths and number of mitoses that were less than control values, but the differences were not statistically significant. Examination of longitudinally sectioned root tips produced relatively similar results. This study confirms the suppositions of previous authors who have claimed that exogenously applied BL can increase the number of mitoses in plants, but failed to show cytogenetic data. This is the first report detailing the effects of BL on chromosomes and the cell cycle.

Changes in AMP deaminase activities in the hearts of diabetic rats.

AMP deaminase from normal and diabetic rat hearts was separated on cellulose phosphate and quantitated by HPLC. From soluble fractions three different AMP deaminase activities, according to KCl elution from cellulose phosphate and percent of total activity were: 170 mM (85%), 250 mM (8%) and 330 mM (7%) KCl. The AMP deaminase activity which eluted with 170 mM KCl was resolved to two distinct peaks by HPLC anionic exchange. After 4 weeks of diabetes the heart enzyme profile change to: 170 mM (10%), 250 mM (75%) and 330 mM (15%). Once purified the four activities were kinetically distinct: 170 mM KCl cytosolic, AMP Km = 1.78, stimulated by ATP, GTP, NADP and strongly inhibited by NAD; 170 mM KCl mitochondria AMP Km = 17.9, stimulated by ATP, ADP; 250 mM KCl isozyme, AMP Km = 0.66, stimulated by ADP; and 330 mM KCl isozyme, AMP Km = 0.97, inhibited by ATP, NAD(P).

Dependence of the plasma triacylglycerol-lowering effect of fish oil on insulin replacement in streptozotocin diabetic rats.

Streptozotocin diabetic rats, with and without insulin replacement, and sham-injected controls were fed a high-fat (30% of energy) menhaden oil (MO) or corn oil (CO) diet for 2 weeks. After an overnight fast, plasma and livers were collected for analysis of insulin, glucose, triacylglycerol, cholesterol and glucose-6-phosphate dehydrogenase activity. Streptozotocin treatment resulted in decreased plasma insulin and elevated glucose. MO-feeding to insulin-replaced diabetic rats resulted in higher insulin and lower glucose levels compared to the respective CO-fed rats, suggesting decreased hepatic insulin extraction and greater peripheral utilization of glucose with MO. Plasma triacylglycerol and cholesterol, and hepatic glucose-6-phosphate dehydrogenase activity were reduced in MO-fed vs. CO-fed control rats. These effects of MO were prevented in the diabetic rats but were restored by insulin replacement. We conclude from our data that the presence of insulin is required to observe at least some of the effects of fish oil (FO). To explain our observations we propose that many of the effects of FO on hepatic metabolism are mediated by an inhibition of insulin action in the liver, thus providing a possible central mechanism for the regulation of hepatic lipid metabolism by dietary FO.

Adenine nucleotide metabolism in hearts of diabetic rats. Comparison to diaphragm, liver, and kidney.

High-performance liquid chromatography analysis of acid-extracted tissues revealed decreases of high-energy nucleotides and increases in low-energy nucleotides and metabolites in heart, diaphragm, and liver but not in kidneys of diabetic rats. In comparison with nondiabetic rats, the total adenine nucleotide content of diabetic rat heart and diaphragm but not liver decreased, indicating an increase in catabolism of AMP. Maximal initial rates of the AMP catabolic enzymes 5'-nucleotidase, adenosine deaminase, and AMP deaminase were elevated in the hearts of BB/Wistar and streptozocin-induced diabetic rats. Nucleotide salvage enzymes adenylosuccinate synthetase and adenylosuccinate lyase were elevated above normal in the diabetic heart, whereas hypoxanthine-guanine phosphoribosyl transferase was not altered. Cytosolic-to-mitochondrial ratios from maximal initial rates after correction for mitochondrial breakage were increased above controls in diabetic hearts for nucleoside diphosphokinase and aspartate aminotransferase. Nucleotide levels, degradation rates, and substrate compartmentation between cytosol and mitochondria are discussed in relation to concurrent diabetes.

Juvenile delinquents revisited. Adult criminal activity.

We examined the subsequent criminal activities of delinquent boys classified as having either socialized conduct disorder, undersocialized conduct disorder, aggressive type, or undersocialized conduct disorder, unaggressive type. A follow-up study of more than ten years revealed profound differences in the likelihood of criminal convictions or incarcerations between socialized and undersocialized delinquents. The socialized delinquents have less chance of being either convicted of a crime or being imprisoned. This difference supports the previous studies that demonstrated that these classifications could be distinguished on the basis of differences in behavior, personality, psychological test results, and characteristic family backgrounds, and reinforces this method of classifying conduct disorders. Differences between the undersocialized aggressive and unaggressive groups appear qualitative and indicate that subjects in the former group are involved in more crimes of violence subjects in the latter.

Giant neural systems in the inner retina and optic nerve of small whales.

Giant neural cell systems (dendrites, cell bodies, and axons) are present among more usual structures in the retina and optic nerve of the small whale (dolphin) Tursiops truncatus retina. Giant cell body dimensions range up to 75 microns in diameter. Nuclei of the cells are frequently larger (greater than 20 microns) than nearby ganglion, bipolar, and receptor cell bodies. The presence of the giant cell system and giant elements in the nerve fiber layer agree with the unusually broad fiber spectrum of the dolphin optic nerve where more than 6% of the axons are greater than 15 microns in diameter. Smaller axons in the size distribution are typical of dimensions found in terrestrial mammals. The axon estimate totaled 157,000 per optic nerve. The giant cell-axon systems of the whale retina may be a unique expression of the large ganglion cell-axon (transient or "Y" functional unit) systems recently identified in terrestrial mammals.

Blood carnitine status after orthotopic liver transplantation in patients with end-stage liver disease.

We determined the effects of orthotopic liver transplantation on plasma and red cell carnitine concentrations in patients with end-stage liver disease. Before transplantation, plasma and red cell carnitine were significantly elevated above normal. The partitioning factor (ratio of red cell carnitine to plasma carnitine) was four times greater than that observed in our reference population. After hepatic replacement, plasma and red cell carnitine approached normal levels within 6 mo. The partitioning factor, however, remained elevated at that time. These results indicate that 1) there is no evidence for carnitine deficiency in severe liver disease on the basis of carnitine concentrations in the plasma and red compartments and 2) altered partitioning of carnitine between plasma and red cells persists for greater than or equal to 6 mo after hepatic replacement.

Gilles de la Tourette's syndrome in identical twins.

The problem we studied relates to the inheritance of Gilles de la Tourette's syndrome. The method was the investigation, including blood studies, of a pair of twins who both were affected with the syndrome. It was concluded that the twins were identical and this added to the evidence of the heritability of the disorder. The twins were affected with other but related problems of behavior; considerable similarities were found in their behavior and behavioral problems. No family history of this or tic-like disorders could be obtained. Reduction of tics occurred when haloperidol treatment began.

Ganciclovir therapy of severe cytomegalovirus infections in solid-organ transplant recipients.

The clinical and virologic efficacy of ganciclovir (9-[1,3-dihydroxy-2-propoxymethyl]guanine) in the treatment of severe CMV infections in solid organ transplant recipients was investigated. Twelve patients (9 liver and 3 kidney transplant recipients) with CMV retinitis, esophagitis, hepatitis, or pneumonia received ganciclovir at a dose of 0.75-7.5 mg/kg/day for 10-30 days (mean duration 17 days). Clinical stabilization or improvement occurred in 8 patients (67%). Serial liver biopsies in 6 liver allograft recipients with CMV hepatitis demonstrated substantial histologic improvement on treatment. Of 6 patients with CMV pneumonia, 4 (67%) recovered and survived. Cultures of blood and other sites became negative in 9 patients (75%). Three patients (25%) had recurrent viral shedding after treatment, but none of these relapsed with invasive infections. Mild neutropenia was the only side effect encountered but was frequent (67%). The overall survival rate was 50%. Ganciclovir is effective in reducing CMV shedding in solid organ transplant recipients and is well tolerated. Our experience suggests a clinical benefit as well in patients with severe, invasive CMV disease. Relapse, in contrast to patients with the acquired immunodeficiency syndrome, is infrequent.

Graft function and outcome of older (> or = 60 years) donor livers.

Livers from donors > or = 60 years of age are often considered inadequate for transplantation by many centers. With waiting times exceeding 1 year in our region, we have aggressively used livers from this donor age group. Between 1990 and 1994, 209 patients received 223 liver grafts at our institution. Of these, 29 (13%) were from donors > or = 60 years of age (group A) and 194 (87%) were from donors < 60 years of age (group B). The two groups were matched for recipient diagnosis and severity of disease. Group A and B donors had similar liver, renal, and hematologic studies prior to donation. Weight, sex, race and vasopressor requirement were also similar. Postoperative alanine aminotransferase, aspartate aminotransferase,and prothrombin time were not significantly different over the first 10 postoperative days. Group A grafts were significantly more cholestatic than group B grafts on postoperative days 6-10. The retransplantation rate for primary graft nonfunction was not significantly different from group A (6.7%) and group B (3.4%; P=0.04). Patient and graft survival rates at 1 year were 58.6 % and 44.8% for group A and 79.2% and 74.5% for group B (P<0.001 for both). Four of 12 deaths in the first year in group A were completely unrelated to graft function. If these are excluded, patient and graft survival rates were 68% and 52%, which are better but still significantly less than in group B. Initial graft function of older donor livers are similar to that of the matched younger group. However, patient and graft survival rates were significantly worse for the older donors, even when corrected for unrelated deaths. Livers should not be discarded based on age alone without inspection and/or biopsy to rule out significant steatosis. Prompt retransplantation for primary graft nonfunction of older donors are generally more cholestatic than those from the younger donor age group; however, many of them function quite well. At the present time, given the inability to identify donor variables associated with decreased recipient survival, we recommend cautious use of older liver grafts in healthier recipients.

Liver transplantation for primary hepatic cancer.

Although early survival following transplantation for primary hepatic cancer is excellent, previously reported high recurrence rates have generally discouraged liver replacement for this indication. Since the inception of the Boston Center for Liver Transplantation (BCLT) in 1983, 33 of 383 (8.6%) liver allograft recipients have undergone orthotopic transplantation as definitive treatment for otherwise unresectable cancer. Diagnoses included hepatocellular carcinoma (HCCA) in 24 patients (73%), and cholangiocarcinoma (CHCA) in 9 patients (27%). Actuarial survival rates for patients with hepatocellular carcinoma were 71%, 56%, and 42% at 1, 2, and 3 years, respectively. The actuarial survival rates for patients with cholangiocarcinoma were 89% at 6 months, and 56% at 1, 2, and 3 years. Of the nine patients with cholangiocarcinoma, 56% (5/9) developed recurrent disease. Although this recurrence rate is disheartening, because of the lack of other morbidity, long-term survival in these patients is comparable to patients with HCCA. In contrast, recurrent hepatocellular carcinoma developed in 25% of recipients (5/20) who survived longer than 3 months posttransplantation. Other causes of death in patients with hepatocellular carcinoma included perioperative complications, 16.6% (4/24); sepsis, 8.3% (2/24); coronary artery disease, 4.2% (1/24); and lymphoma, 4.2% (1/24). Favorable prognostic factors included: primary tumor less than 3 cm in size and absence of associated cirrhosis. These results emphasize that orthotopic liver transplantation can provide a long-term cure for approximately 50% of patients whose primary hepatic malignancy is unresectable by conventional procedures.

Use of magnetic resonance angiography in the pretransplant evaluation of portal vein pathology.

The assessment of portal vein patency in patients selected as candidates for orthotopic liver transplantation should be accomplished noninvasively and with great accuracy. Magnetic resonance angiography (MRA) is a new technique that is completely noninvasive and is capable of graphically assessing portal vein anatomy and blood flow. In an attempt to establish the accuracy of portal venous MRA, 74 patients with established cirrhosis underwent abdominal MRA prior to liver transplantation. MRA findings were correlated with surgical findings at the time of transplantation in all patients, and were shown to be extremely accurate. The three-dimensional images generated by MRA and computer postprocessing allowed for correct identification of portal venous anatomy in all of the patients examined. We conclude that MRA is an extremely useful method of determining portal venous anatomy in potential liver transplant patients, and potentially offers greater definition and clarify compared with other non-invasive methods.

Major infectious complications after orthotopic liver transplantation and comparison of outcomes in patients receiving cyclosporine or FK506 as primary immunosuppression.

A retrospective cohort study was conducted to determine the incidence of major infectious complications after orthotopic liver transplantation and to compare outcomes in patients receiving either cyclosporine (CsA) or FK506 (tacrolimus) as primary immunosuppression. Of 133 transplants performed in 118 patients, 124 transplant episodes were evaluated. Cytomegalovirus (CMV) infection (INF) and disease (DIS), deep fungal infection (DFI), and intraabdominal bacterial infections (IAI) were catalogued. The overall incidences of major infectious outcomes were: CMV INF = 33%; CMV DIS = 19%; DFI = 15%; and IAI = 25%. Cox proportional hazard analysis identified donor seropositivity, OKT3 as secondary immunosuppression and initial intensive care unit (ICU) duration as risk factors for CMV INF and DIS in the overall population. Fungal colonization was the dominant risk factor associated with deep fungal infection. A choledochojejunostomy anastomosis, the number of cellular blood products transfused at the time of transplantation surgery, and prior CMV INF were independent risk factors for both fungal colonization and deep infection. The single risk factor identified for intraabdominal bacterial infections was the number of cellular blood products transfused at the time of surgery. In the Cox proportional hazards model the relative risk (RR) for each category of infection was lower in the FK506 group (CMV: RR = .87, 95% confidence interval [C.I.] = [.32-2.4]; DFI: .58 [.13-2.6]; IAI: .51 [.15-1.7]), but the effect was not statistically significant. Survival was similar in patients receiving FK506 or CsA. CMV INF and DFI were independent predictors of death for all patients. Risk factors identified for CMV INF and DIS support the findings of others. Higher intraoperative blood product requirements and complicated intraoperative or postoperative courses increase the risk for IAI or DFI. The development of effective strategies to prevent CMV and fungal infections in liver transplant recipients remains a priority for future endeavors.

A randomized clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection.

A multiinstitutional randomized trial was undertaken comparing OKT3 with steroids for treatment of hepatic allograft rejection. All patients received baseline immunosuppression with Cyclosporine (CsA) and steroids. At the time of biopsy-confirmed rejection, up to 2 intravenous boluses (250-1000 mg) of methylprednisolone were initially administered. Twenty-eight patients who failed to respond were then randomly assigned to OKT3 or continued steroid therapy. Rescue therapy with the opposite treatment arm was added after 6 days if the primarily allocated protocol failed. Three of 13 patients assigned to the steroid group responded promptly, and continue with good function 7-12 months later. OKT3 rescue was required in 10 patients who failed to improve despite receiving up to 6 g of methylprednisolone (mean: 3.3 g/patient). One patient died of sepsis and hepatic failure. Rejection was reversed in 9 OKT3-rescue patients, 7 of whom are well 1-17 months later. In the OKT3 group, improved allograft function was observed within 72 hr in 11 of 15 patients. Two patients with inadequate response were successfully rescued with steroids; 1 patient underwent retransplantation; and 1 patient developed a biliary fistula that eventually resulted in sepsis and death. In summary, 23 of 28 hepatic recipients (82%) are alive with the original allograft 1-17 (mean 7.8) months after treatment for acute rejection. Another patient is alive 14 months following retransplantation. Eighteen (78%) of the survivors required OKT3 as initial (11) or rescue (7) therapy, whereas only 5 were successfully managed with steroids. OKT3 is superior to steroids for reversing liver allograft rejection and has greatly reduced the need for retransplantation even in recipients selected on the basis of having failed initial steroid therapy.

Serologic and DNA follow-up data from HBsAg-positive patients treated with orthotopic liver transplantation.

Fifteen hepatitis B surface antigen (HBsAg) positive patients treated with orthotopic liver transplantation were studied to determine whether any clinical, serologic, or histologic data were predictive for recurrent hepatitis B infection leading to graft failure. Six patients died early, one due to primary graft nonfunction and the remaining five due to septic complications. There were nine patients surviving longer than two months, eight of whom are alive at a mean follow-up of 556 days. HBsAg and hepatitis B core antibody (anti-HBc) reappeared in the sera of all survivors after a variable transient period of clearance. One patient died 3 months posttransplant of fungal sepsis and was found to have histologic evidence for recurrent hepatitis and positive immunoperoxidase staining postmortem. The remaining eight survivors are home and clinically well, with no histologic evidence of hepatitis. Seven of these eight patients have hepatitis B viral DNA in their sera. We conclude that while there is a high early mortality, usually from sepsis, none of the serologic, histologic, or DNA data analyzed can be used to predict graft loss from recurrent hepatitis. No grafts have been lost due to recurrent hepatitis B in this series, and therefore we believe that HBsAg positive patients should not be excluded from transplantation.

Effect of orthotopic liver transplantation on the progression of familial amyloidotic polyneuropathy.

BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disease associated with a mutant form of the protein transthyretin (TTR). It is characterized clinically by the systemic deposition of amyloid fibrils resulting in organ dysfunction and, ultimately, death. The majority of TTR is produced in the liver, and transplantation of the liver has been shown to ameliorate this source of mutant TTR, arresting the progression of this fatal disease. METHODS: Thirteen patients with FAP have undergone successful liver transplant surgery at our center since 1992. The impact of liver transplantation on amyloid-related polyneuropathy, cardiovascular, and gastrointestinal dysfunction is reported in this study. Three patients who died before cardiovascular and neurological follow-up are excluded from the analysis. RESULTS: Ten of 13 patients (77%) remain alive an average of 49 months (range, 17-64 months) after transplantation. Three patients suffered sudden death, with autopsy documentation of amyloid deposits involving the conduction system of the heart. Liver transplantation was performed more quickly, required less blood, and a shorter postoperative hospital stay in these patients, compared with patients with cirrhosis. Neurological and nutritional symptoms improved in the majority of affected patients. Those patients with echocardiographic evidence of ventricular wall and valve thickening before transplantation progressed postoperatively despite neurologic improvement. CONCLUSIONS: Liver transplantation offers the only cure for the genetic defect causing FAP and appears to result in subjective and objective improvement in neurological dysfunction. Patients with preexisting cardiovascular abnormalities progress despite transplantation; therefore, consideration for combined heart-liver transplantation may be warranted in this subset of patients.

Pulmonary complications of orthotopic liver transplantation.

Pulmonary complications following orthotopic liver transplantation (OLT) were prospectively evaluated in 18 individuals transplanted at the New England Deaconess Hospital. Of sixteen patients who survived the immediate postoperative period, 12 (75%) sustained a pulmonary complication. Of these complications, 64% were noninfectious--whereas 22% were infectious, and 14% probably infectious. Six of eight documented infections were caused by viruses of the herpes group. In four cases of viral pneumonitis other pulmonary pathogens were isolated (fungi-3, protozoan-1, bacteria-1). Unlike noninfectious complications, pulmonary infections were associated with a fatal outcome in five of six patients who died after OLT. Pulmonary complications are frequent and serious occurrences after OLT, and contribute to both the morbidity and mortality of this procedure. Compared with pulmonary complications seen after transplantation of other organs, OLT was associated with a higher proportion of noninfectious complications but a similar spectrum of pulmonary infections.