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Biomedical subjects

J R Lake

Publications and source records attributed to J R Lake.

At least 19 recordsLinked to original sources
PubMed2006

Emerging issues in hepatitis C virus-positive liver and kidney transplant recipients.

Hepatitis C virus (HCV) infection is a major health care issue in liver and kidney transplantation. Besides negatively affecting both patient and graft survival, HCV is associated with a heightened risk for new onset diabetes mellitus (NODM). The mechanisms underlying the diabetogenicity of HCV are complex but are likely to involve insulin resistance caused by inhibitory actions of the virus on insulin regulatory pathways in the liver. The resultant glucose dysregulation is an important determinant of increased morbidity and mortality in liver and kidney recipients. This review highlights the concerns for outcomes in HCV-positive liver and kidney transplant patients with particular focus on the interrelationship between hepatitis C and diabetes. Data about the potential role of calcineurin inhibitors, corticosteroids and mycophenolate mofetil in HCV infection and HCV-associated NODM will also be discussed.

Diabetes Mellitus↗
PubMed2006

Mycophenolate mofetil use is associated with decreased risk of late acute rejection in adult liver transplant recipients.

Mycophenolate mofetil (MMF) used in a triple-drug regimen has been shown to decrease acute rejection rates, compared to a double-drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described. To investigate the risk of LAR (rejection > or = 6 months post-transplantation) data from the Scientific Registry of Transplant Recipients (SRTR) were used. We studied adult primary liver transplant recipients transplanted between June 1, 1995, and April 30, 2004, with hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) or a nonviral (n = 5740) primary cause of liver disease who were recorded as receiving continuous 3-(MMF + Tacro + steroids) versus 2-drug (Tacro + steroids) therapy for at least 6 months immediately post transplantation. Kaplan-Meier analysis showed significantly lower LAR rates 4 years post-transplant in 3- versus 2-drug HCV, HBV and nonviral disease patients. Multivariate regression confirmed 3- versus 2-drug therapy to be associated with a decreased risk of LAR. Late graft survival was significantly lower at 4 years post-transplant for patients with LAR 6-12 months post-transplantation versus patients with early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001). Three-drug versus 2-drug therapy for a minimum of 6 months may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.

Acute Disease↗
PubMed2005

Addition of MMF to dual immunosuppression does not increase the risk of malignant short-term death after liver transplantation.

Immunosuppression is often incriminated for the increased risk of post-transplant malignancies. To examine whether triple- (MMF+Tacro+CS) versus dual-drug therapy (Tacro+CS) is associated with an increased incidence of malignancy, or death due to malignancy, data from a large registry of liver transplant recipients were analyzed. Data from adult primary liver recipients reported to the Scientific Registry of Transplant Recipients between June 1, 1995, and April 30, 2004, and recorded at transplant on triple-drug (n = 9180) or dual-drug (n = 10 099) therapy were included. Kaplan-Meier survival analysis showed no significant differences in death due to malignancy 4 years post-transplantation between the treatment groups. Multivariable analysis using Cox proportional hazard models confirmed no differences in risk of death due to malignancy between the groups (HR: 0.83, p = 0.107). Incidence of any post-transplant malignancy was also not significantly different. Older recipient age and cause of liver disease were significantly associated with an increased risk of malignancy-related death. These data utilizing relatively short follow-up suggest the addition of MMF to Tacro+CS at transplant is not associated with death due to malignancy, at least in the short term. Individual recipient factors appear to be important risk factors for malignancy-related death; elucidating these risk factors can assist in identifying who should be monitored most aggressively for post-transplant malignancies.

Adolescent↗
PubMed2004

Successful liver transplantation in a patient with severe haemophilia A and a high-titre factor VIII inhibitor.

We present the case of a 61-year-old man with severe haemophilia A and a high-titre factor VIII inhibitor who underwent successful orthotopic liver transplantation (OLT) for hepatocellular carcinoma. Postoperatively, a modest early anamnestic response to FVIII was followed by immunological tolerance to FVIII. This case illustrates the technical feasibility of OLT in some patients with high-titre inhibitors to FVIII, and suggests that immune tolerance may be induced by endogenously produced FVIII from the transplanted organ.

Blood Loss, Surgical↗
PubMed2001

Hippocampal injections of amyloid beta-peptide 1-40 impair subsequent one-trial/day reward learning.

The injection of amyloid beta-peptide (Abeta) into rat CNS has been reported to induce cellular neuropathology. The present study investigated whether multiple intrahippocampal injections of Abeta 1-40 would impair one-trial/day reward learning 14 days later. Twenty-four male Sprague-Dawley rats, 3-4 months old, were injected with either Abeta 1-40 or distilled water into seven hippocampal sites bilaterally. Ten rats received 3 nmol Abeta 1-40 in 2 microl of distilled water per injection site, while 14 rats received distilled water alone. Following a 9-day recovery period, rats were gradually food deprived to 82% of their initial body weight. Fourteen days after the intrahippocampal injection, all rats received an initial training trial and three subsequent daily retention trials. Rats receiving Abeta 1-40 were significantly impaired on the second retention trial in terms of accuracy (number of unbaited alleys entered) and on the second and third retention trials in terms of speed (reciprocal of latency to reward). Histological analysis showed that Abeta 1-40 injections produced significant neuronal loss and gliosis. Abeta 1-40 immunoreactivity persisted locally at the injection site and in macrophages 2 weeks following the hippocampal injections. These effects appear to be sequence-specific; rats receiving Abeta 1-42 with a scrambled peptide sequence did not differ significantly from rats receiving distilled water alone in retention of the learning task or degree of histological damage.

Alzheimer Disease↗
PubMed2001

Passive immunization against nicotine prevents nicotine alleviation of nicotine abstinence syndrome.

Passive immunization against nicotine interferes with its locomotor and pressor effects. The current study determined whether immunization could prevent another nicotine action: the reversal of nicotine abstinence syndrome. IgG containing 4.4-5.6% nicotine-specific antibody was isolated from rabbits immunized with 3'-amino-methyl-nicotine conjugated to a carrier protein. Twenty rats were rendered dependent by 7 days of subcutaneous infusion of 3.15 mg/kg/day nicotine (expressed as the base). Upon termination of nicotine infusion, each rat was injected intraperitoneally with 150 mg of IgG from normal serum (n=13) or from nicotine antiserum (n=7). Twenty-two and one-half hours later, all rats were observed over 15 min for baseline nicotine abstinence signs. Two and one-half hours after baseline observations, seven of the 13 rats pretreated with control IgG and all seven rats pretreated with nicotine-specific IgG were then challenged by 0.12 mg/kg (sc) nicotine. The remaining six rats pretreated with control IgG were challenged with saline alone. All rats were then observed again for abstinence signs. Nicotine injection caused significantly less reduction of abstinence signs in the immunized rats. The nicotine effect in immunized rats was comparable to the saline effect in nonimmunized rats. Immunization also significantly reduced free serum nicotine concentration and nicotine distribution to the brain. These results raise the possibility that immunization might prevent nicotine consumption from relieving the discomforts of smoking cessation.

Analysis of Variance↗
PubMed2001

Split liver transplantation for two adult recipients: an initial experience.

The shortage of cadaver donor livers has been most severe for adult patients. Split liver transplantation is one method to expand the donor pool, but to have a significant impact on the waiting list, it needs to be applied for 2 adult recipients. We split livers from 6 cadaver donors, and transplanted 12 adult recipients. All splits were performed in situ with transection through the midplane of the liver, resulting in a right lobe and a left lobe graft. Mean donor age was 19.7 years; mean donor weight was 79.1 kg. Mean recipient age was 41.5 years. Mean weight of right lobe recipients was 89 kg; left lobe recipients, 60 kg. All donors were hemodynamically stable and had normal liver function tests. Mean operative time for the procurement was 7.4 h. Average blood loss during the transection of the liver was 490 mL. Mean GW/ RW ratio for all recipients was 0.87%; right lobe recipients, 0.86%; and left lobe recipients, 0.88%. With mean follow-up of 9.3 months, patient and graft survival rates were both 83.3%. There were 2 deaths: 1 after hepatic artery thrombosis (HAT) and subsequent multiorgan failure; the other after HAT, a liver retransplant, and subsequent gram-negative sepsis. The remaining 10 recipients are doing well. We observed no cases of primary nonfunction. Other complications included bile leak and/or stenosis (n = 3), bleeding from the Roux loop (n = 1), bleeding after percutaneous biopsy (n = 1), and incisional hernia (n = 1). In conclusion, split liver transplantation, using 1 cadaver liver for 2 adult recipients, can be performed successfully. Crucial to success is proper donor and recipient selection.

Adolescent↗
PubMed2001

Outcome of other organs recovered during in situ split-liver procurements.

Split-liver transplantation is becoming a useful technique to expand the donor pool. Whether the split should be performed in situ or ex situ is not clear. One potential disadvantage of in situ splits is that prolonged surgical time and increased blood loss may negatively affect the function of other solid organs (kidneys, pancreas, and heart) procured from the same donor. Therefore, we studied the function of other organs posttransplantation. Between September 1, 1999, and March 31, 2000, we performed six in situ splits at the University of Minnesota (Minneapolis, MN). These six splits yielded six right-lobe liver grafts and six left-lobe liver grafts, which were transplanted into 12 adult-size recipients. Other grafts obtained from these six donors were as follows: kidney (n = 11), heart (n = 4), lungs (n = 1), pancreas (n = 2), and kidney-pancreas (n = 1). We then analyzed posttransplantation function of these grafts and the postoperative course of transplant recipients. All six donors were hemodynamically stable at the time of procurement. Mean donor age was 19.7 years. Mean surgical time for the procurement was 7.4 hours, with an average blood loss of 490 mL during in situ splitting of the liver. The 12 liver grafts showed good initial function with no primary nonfunction. The other organs also showed good function. Of 11 kidney recipients, only 1 patient developed delayed graft function, which resolved within 4 days. In addition, 1 kidney was lost early because of severe acute rejection. For the 10 recipients with functioning kidneys, mean creatinine level at hospital discharge was 2.0 mg/dL, and mean creatinine level after an average 9-month follow-up was 1.3 mg/dL. Of the 4 heart transplant recipients, 3 patients had good graft function immediately posttransplantation, with an ejection fraction greater than 60%, minimal inotropic requirements, and no surgical complications. The fourth heart transplant recipient, a critically ill status 1 patient, had poor initial function and a prolonged intensive care unit stay. At hospital discharge, pancreas and pancreas-kidney transplant recipients were all insulin free, with good urine amylase levels, no surgical or infectious complications, and no evidence of significant pancreatitis posttransplantation. The kidney of the pancreas-kidney transplant recipient functioned immediately; creatinine level after 7 months of follow-up was 1.2 mg/dL. Despite increased surgical time and blood loss, in situ splitting of liver grafts can be accomplished in stable donors without significant negative effects on other organs.

Adolescent↗
PubMed2000

A nicotine conjugate vaccine reduces nicotine distribution to brain and attenuates its behavioral and cardiovascular effects in rats.

Vaccination of animals to elicit drug-specific antibodies, or the passive transfer of such antibodies from other animals, can reduce the behavioral effects of drugs such as cocaine and heroin. To study the potential application of this approach to treating nicotine dependence, IgG was isolated from rabbits immunized with a nicotine-protein conjugate vaccine. Anesthetized rats received immune IgG containing nicotine-specific antibodies (Nic-IgG) or control-IgG i.v.. Thirty minutes later, rats received nicotine at 0.03 mg/kg i.v., equivalent on an mg/kg basis to the nicotine intake from two cigarettes by a smoker. Compared to control-IgG, Nic-IgG reduced the brain nicotine concentration in a dose-related manner (65% reduction at the highest IgG dose). Pretreatment with Nic-IgG also reduced the distribution to brain of five repeated doses of nicotine (equivalent to the nicotine intake from 10 cigarettes) administered over 80 min. To study blood pressure effects, rats received control-IgG or Nic-IgG 1 day prior to administering nicotine. Nicotine-induced systolic blood pressure increases were attenuated by Nic-IgG in a dose-related manner, and were almost completely blocked by the highest Nic-IgG dose. Pretreatment with Nic-IgG also completely prevented the nicotine-induced stimulation of locomotor activity observed in rats receiving control-IgG. Nic-IgG did not prevent locomotor activation from cocaine, demonstrating its specificity for nicotine. These data demonstrate that the administration of nicotine-specific antibodies can reduce or prevent some of the pharmacokinetic, cardiovascular, and behavioral consequences of nicotine in rats. Effects were observed at nicotine doses and nicotine serum concentrations equal to or exceeding those typically associated with nicotine exposure in cigarette smokers. A potential role for immunization in the treatment of nicotine dependence is suggested.

Animals↗
PubMed2000

Nociceptin/orphanin FQ (N/OFQ) induces a quasi-morphine abstinence syndrome in the rat.

Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide that exerts antiopiate effects under some circumstances, and there is evidence that it contributes to opiate tolerance. This raises the question, might N/OFQ also contribute to opiate dependence and abstinence? Twenty-two male Sprague-Dawley rats were cannulated in the third ventricle and challenged 7 days later by third ventricle injection of 50, 200 or 1,000 ng N/OFQ or saline alone. Each rat was observed under "blind" conditions for 30 min beginning 15 min after onset of the third ventricle injection. There was a significant positive linear trend of signs as a function of N/OFQ dose. Subjects receiving saline had 18.0+/-2.0 (mean+/-SEM) overall abstinence-like signs, whereas subjects receiving 50, 200 or 1000 ng N/OFQ had 35.2+/-3.6, 49.8+/-2.6 and 63.5+/-9.7 signs, respectively. In 16 additional rats, abstinence-like signs induced by 1000 ng N/OFQ were significantly attenuated by low SC doses of morphine or clonidine. These results raise the possibility that N/OFQ might contribute to opiate dependence and subsequent abstinence syndrome. On the other hand, N/OFQ over a wide dose range induced abstinence signs with similar potency in morphine dependent and non-dependent rats.

Animals↗
PubMed2000

Posttransplantation: emerging and future therapies.

Liver transplantation in patients infected with hepatitis B virus (HBV) commonly results in reinfection that, if untreated, often compromises the viability of the allograft and negatively influences survival. Posttransplant treatment with hepatitis B immune globulin (HBIG) is now the standard of care, but patients appear to require lifelong treatment to prevent reinfection. In the past several years, new management strategies in patients with HBV have been developed, with an aim to decrease HBV-DNA replication before transplantation. Such an approach should increase the success of transplantation by decreasing the risk of reinfection and thus preventing recurrent disease posttransplantation. Nucleoside analogues, either alone or in conjunction with HBIG, are currently in use and are being studied in clinical trials as a means of preventing viral recurrence. Ganciclovir, famciclovir, and lamivudine all have demonstrated efficacy, although they vary in terms of effectiveness. Resistance may develop with the use of these agents and leads to reinfection by the mutant virus. Combination therapy may minimize the risk of viral mutation. Research continues to search for more effective ways to prevent and, if necessary, treat viral recurrence in patients undergoing liver transplantation for HBV.

2-Aminopurine↗
PubMed2000

Case studies of the hepatitis B patient: a panel discussion.

In recent years, there have been significant advances in the treatment of patients with hepatitis B who are candidates for liver transplantation. This includes the prevention and management of hepatitis B posttransplantation. However, there is no established protocol for treating these patients. Ultimately, the goal would be to have patients HBV-DNA negative pretransplantation and then to prevent HBV recurrence posttransplantation to help ensure their quality of life. Several clinical case scenarios are presented and possible treatment solutions have been suggested. The timing of a transplant is critical due to the risk of viral mutation while the patient is on a nucleoside analogue antiviral agent and waiting for an organ. One successful option might be to start therapy pretransplant and continue it posttransplant. Combination therapy appears to provide the most effective course of treatment. This should include a nucleoside analogue and patients should be covered with hepatitis B immune globulin throughout the course of therapy. Several other variations of combination therapy are discussed, but many clinical issues remain to be resolved. Guidelines for future studies designed to answer these questions are proposed.

Adult↗
PubMed1999

Resource utilization in liver transplantation: effects of patient characteristics and clinical practice. NIDDK Liver Transplantation Database Group.

CONTEXT: Liver transplantation is among the most costly of medical services, yet few studies have addressed the relationship between the resources utilized for this procedure and specific patient characteristics and clinical practices. OBJECTIVE: To assess the association of pretransplant patient characteristics and clinical practices with hospital resource utilization. DESIGN: Prospective cohort of patients who received liver transplants between January 1991 and July 1994. SETTING: University of California, San Francisco; Mayo Clinic, Rochester, Minn; and the University of Nebraska, Omaha. PATIENTS: Seven hundred eleven patients who received single-organ liver transplants, were at least 16 years old, and had nonfulminant liver disease. MAIN OUTCOME MEASURE: Standardized resource utilization derived from a database created by matching all services to a single price list. RESULTS: Higher adjusted resource utilization was associated with donor age of 60 years or older (28% [$53813] greater mean resource utilization; P=.005); recipient age of 60 years or older (17% [$32795]; P=.01); alcoholic liver disease (26% [$49596]; P=.002); Child-Pugh class C (41% [$67 658]; P<.001); care from the intensive care unit at time of transplant (42% [$77833]; P<.001); death in the hospital (35% [$67 076]; P<.001); and having multiple liver transplants during the index hospitalization (154% increase [$474 740 vs $186 726 for 1 transplant]; P<.001). Adjusted length of stay and resource utilization also differed significantly among transplant centers. CONCLUSIONS: Clinical, economic, and ethical dilemmas in liver transplantation are highlighted by these findings. Recipients who were older, had alcoholic liver disease, or were severely ill were the most expensive to treat; this suggests that organ allocation criteria may affect transplant costs. Clinical practices and resource utilization varied considerably among transplant centers; methods to reduce variation in practice patterns, such as clinical guidelines, might lower costs while maintaining quality of care.

Adult↗
PubMed1999

Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to have promise in short-term liver transplantation graft rescue studies. The purpose of this study was to evaluate the long-term efficacy and safety of MMF in liver transplant patients who had failed cyclosporine (CsA)-based conventional immunosuppression. METHODS: Nineteen orthotopic liver allograft recipients were converted from azathioprine to MMF in combination with CsA and prednisone in this prospective, open-labeled, single-center, graft rescue, pilot study. Six patients were taken off CsA when MMF was initiated. A 4-year patient follow-up is reported here. Patients were considered to have failed CsA-based immunosuppression either for refractory rejection, chronic rejection, or severe CsA neurologic toxicity. RESULTS: Twelve patients had complete histologic resolution, two had partial resolution, and three had worsening of their rejection. Thirteen patients had a complete biochemical response; one had a partial response and four had worsening of their rejection. Two patients had no histologic and one no biochemical follow-up. Of the six patients treated with MMF and prednisone alone, four had complete resolution of rejection without recurrence. The majority of adverse reactions were gastrointestinal [nausea and/or vomiting (n=5); diarrhea (n=8); gastritis, duodenitis, or esophagitis (n=4); and ulcers (n=2)] or bone marrow suppressive [leukopenia (n=9), anemia (n=6), and thrombocytopenia (n=5)]. CONCLUSIONS: MMF seems to be an effective alternative immunosuppressive in patients failing CsA-based conventional therapy. MMF may be of particular benefit in patients who do not tolerate CsA or tacrolimus. The long-term safety profile is similar to that of other immunosuppressives.

Adult↗
PubMed1999

Recurrent and new hepatitis C virus infection after liver transplantation.

Chronic infection with the hepatitis C virus (HCV) is the most common reason for liver transplantation. We examined the results of laboratory tests for HCV on a cohort of patients who received a liver transplant between 1990 and 1994 at three large centers. Seven hundred twenty-two recipients and 604 donors were tested for antibody to HCV (anti-HCV) using a second-generation enzyme-linked immunoassay (EIA-2), followed by recombinant immunoblot (RIBA-2) and HCV RNA confirmation by reverse-transcription polymerase chain reaction (RT-PCR) (with genotyping and viral quantification). Diagnosis of posttransplantation infection required detection of serum HCV RNA that could be genotyped by sequencing or was repeatedly positive despite being unsequenceable. Twenty-five percent of transplantation candidates were seropositive for anti-HCV. Approximately 86% of anti-HCV-positive, 93% of RIBA-positive, and 97% of HCV RNA-positive candidates developed infection after transplantation. Pretransplantation HCV RNA was superior to RIBA-2 for predicting posttransplantation infection. Whereas HCV genotype was identified in nearly all candidates and changed little after transplantation, serum viral levels rose markedly after transplantation. Fifteen donors were either anti-HCV- or HCV RNA-positive. Recipients of grafts from donors with HCV RNA all developed infection, whereas infection was not detected in recipients of grafts from donors with anti-HCV but without detectable HCV RNA. The rate of new infection fell significantly (P =.02) after the introduction of EIA-2 screening of blood. Donor and candidate markers for HCV predict posttransplantation infection.

Cohort Studies↗
PubMed1999

Methods to estimate and analyze medical care resource use. An example from liver transplantation.

This paper describes a method to construct a standardized health care resource use database. Billing and clinical data were analyzed for 916 patients who received liver transplantations at three medical centers over a 4-year period. Data were checked for completeness by assessing whether each patient's bill included charges covering specified dates and for specific services, and for accuracy by comparing a sample of bills to medical records. Detailed services were matched to a standardized service list from one of the centers, and a single price list was applied. For certain services, clinical data were used to estimate service use or, if a match was not possible, adjusted charges for the services were used. Twenty-three patients were eliminated from the database because of incomplete resource use data. There was very good correspondence between bills and medical records, except for blood products. Direct matches to the standardized service list accounted for 69.3% of services overall; 9.4% of services could not be matched to the standardized service list and were thus adjusted for center and/or time period. Clinical data were used to estimate resource use for blood products, operating room time, and medications; these estimations accounted for 21.3% of services overall. A database can be constructed that allows comparison of standardized resource use and avoids biases due to accounting, geographic, or temporal factors. Clinical data are essential for the creation of such a database. The methods described are particularly useful in studies of the cost-effectiveness of medical technologies.

Accounting↗