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Biomedical subjects

J McMichael

Publications and source records attributed to J McMichael.

At least 19 recordsLinked to original sources
PubMed1995

Weaning of immunosuppression in long-term liver transplant recipients.

Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n = 4), hepatitis (n = 2), patient anxiety (n = 5), or lack of cooperation by the local physician (n = 2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n = 9), HCC (n = 1), Wilson's disease (n = 4), hepatitides (n = 15), Laennec's cirrhosis (n = 1), biliary atresia (n = 16), cystic fibrosis (n = 1), hemochromatosis (n = 1), hepatic trauma (n = 1), alpha-1-antitrypsin deficiency (n = 9), and secondary biliary cirrhosis (n = 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n = 8), squamous cell carcinoma (n = 2) or verruca vulgaris of skin (n = 9), osteoporosis and/or arthritis (n = 12), obesity (n = 3), hypertension (n = 11), and opportunistic infections (n = 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to < 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.

Adolescent↗
PubMed1995

Effect of donor age and sex on the outcome of liver transplantation.

We correlated donor and recipient factors with graft outcome in 436 adult patients who underwent 462 liver transplants. Donor variables analyzed were age, gender, ABO blood group, cause of death, length of stay in the intensive care unit, use of pressors or pitressin, need for cardiopulmonary resuscitation, terminal serum transaminases, and ischemia time. Recipient variables analyzed were age, gender, primary diagnosis, history of previous liver transplant, ABO blood group, cytotoxic antibody crossmatch, United Network for Organ Sharing (UNOS) status, and waiting time (except for the cross-match results, they were all known at the time of the operation). The endpoint of the analysis was graft failure, defined as patient death or retransplantation. Using multivariate analysis, graft failure was significantly associated with donor age, donor gender, previous liver transplantation, and UNOS 4 status of the recipient. The effect of donor age became evident only when they were older than 45 years. Livers from female donors yielded significantly poorer results, with 2-year graft survival of female to male 55% (95% CI, 45% to 67%); female to female, 64% (95% CI, 54% to 77%); male to male, 72% (95% CI, 66% to 78%); and male to female, 78% (95% CI, 70% to 88%). The only donors identified as questionable for liver procurement were old (> or = 60 years) women in whom the adverse age and gender factors were at least additive. However, rather than discard even these livers, in the face of an organ shortage crisis, their individualized use is suggested with case reporting in a special category.

Adult↗
PubMed1995

Tacrolimus (FK 506), a treatment for primary sclerosing cholangitis: results of an open-label preliminary trial.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the liver that is characterized by progressive cholestasis and the development of secondary biliary cirrhosis. There is no widely recognized therapy for this disease, although anti-inflammatory agents (steroids), immunosuppressive agents (methotrexate), anti-fibrotics (colchicine), and choleretic agents (ursodeoxycholic acid) have been used in various small series. In the present study, Tacrolimus (FK 506), a new and powerful immunosuppressive macrolide antibiotic, has been used to treat 10 patients with PSC. Each subject had a liver biopsy, ERCP with visualization of the intra- and extrahepatic biliary tree, and a panel of hematological, serological, and biochemical laboratory tests before the initiation of the FK 506 therapy. The FK 506 was administered orally at 12-h intervals and was monitored by serial plasma FK 506 trough levels. After 360 days of treatment, the median serum bilirubin level was reduced by 75%, and the serum alkaline phosphatase was reduced by 70%. Moreover, the serum ALT and AST levels were reduced by 80 and 86%, respectively. No change in the serum level of BUN and creatinine levels occurred as a consequence of the FK 506 treatment. These data demonstrate that: 1) FK 506 can be used to treat PSC; 2) the response to FK 506 by patients with PSC is rapid; and, 3) no adverse effect on the serum BUN and creatinine levels was observed. It is anticipated that FK 506 will become an important agent for the treatment of patients with PSC because of its powerful immunosuppressive activity.

Adult↗
PubMed1995

Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial.

Autoimmune chronic active hepatitis (CAH-A) is a chronic liver disease of unknown etiology that is believed to have an autoimmune pathogenesis. The disease is slowly progressive until hepatic failure and portal hypertension develop and either death or liver transplantation occur. Currently, the only widely recognized therapy is the administration of glucocorticoids, which have both anti-inflammatory and immunosuppressive actions. Many patients cannot tolerate such therapy because of the psychiatric, osteoporotic, and weight-enhancing actions of steroids. Tacrolimus (FK 506) is a new macrolide antibiotic that has an immunosuppressive activity that is estimated to be 10-200 times greater than that of cyclosporine. Because of its greater immunosuppressive activity, we have used it in the treatment of 21 patients with autoimmune chronic active hepatitis. Before each subject was treated, a liver biopsy and a panel of hematological, serological, and biochemical parameters were assessed. The Tacrolimus was administered orally at 12-h intervals, and the dose was controlled by monitoring plasma FK trough levels. After 3 months of therapy at an oral dose of 3 mg twice a day, having achieved a median blood level of 0.5 ng/ml, the serum ALT level was reduced by 80%, and the AST level was reduced by 70%. Modest change in the white blood cell count and platelet count were noted. The median BUN level increased from a level of 12 to 18 mg/dl, and the serum creatinine increased from 0.9 to 1.3 mg/dl. These preliminary data demonstrate that: 1) Tacrolimus can be used to successfully treat CAH-A; 2) the response of CAH-A to Tacrolimus treatment is rapid and sustained; and 3) a minor increase in the serum BUN and creatinine levels occurs as a consequence of Tacrolimus treatment. It is anticipated that with continued treatment for periods of 1-2 yr, the natural history of CAH-A will be changed such that hepatic failure and the requirement for liver transplantation may be averted.

Adult↗
PubMed1995

Building clinical classifiers using incomplete observations--a neural network ensemble for hepatoma detection in patients with cirrhosis.

One objective of liver transplant evaluation is to identify patients that harbor a hepatoma, but standard screening techniques are not sensitive enough. We trained neural network ensembles to predict the presence of hepatoma in patients with cirrhosis, based on information collected at the time of transplant evaluation. Network architecture and training were modified to handle missing observations. Three ensembles were trained: ensemble A using the subset with no missing observations (528 patients); ensemble B using the complete set, which included missing observations (853 patients); and ensemble C using the smaller subset, originally with complete data, but after a fixed number of observations were deleted (i.e., made "missing"). Ensemble performance on testing sets was very good. The areas under the ROC curves were 0.91, 0.89, and 0.90, for ensembles A, B, and C, respectively. Neural networks can successfully perform this classification task, and strategies can be developed that allow use of incomplete observations.

Adult↗
PubMed1993

An intelligent and cost-effective computer dosing system for individualizing FK506 therapy in transplantation and autoimmune disorders.

The accuracy and precision of an intelligent dosing system (IDS) for FK506 in predicting doses to achieve target drug levels has been prospectively evaluated in transplant and autoimmune patients. For dose individualization, the knowledge base is updated with patient-specific feedback including the current dose, drug level, and the new target level. The study population of 147 patients consisted of 97 transplant patients (liver and kidney) and 50 patients with autoimmune disorders. Patients in the transplant study group were entered sequentially and followed as a cohort. Patients in the autoimmune study group were randomly assigned to one of three predefined FK506 concentration windows (low, 0.1-.3; medium, 0.4-.7; and high, 0.8-1.3 ng/mL) as part of a concentration controlled clinical trial. Predictions of steady-state plasma drug levels were made throughout the clinical course of autoimmune patients and during the first 6 weeks post-transplant in liver and kidney recipients. FK506 concentration in plasma was measured by a monoclonal antibody based ELISA assay. Accuracy was computed as the mean prediction error (mpe). Precision was computed as the root mean squared prediction error (rmspe). The accuracy of the IDS in each study group was as follows: 0.016 ng/mL (liver), -0.034 ng/mL (kidney), and -0.022 ng/mL (autoimmune). Because the 95% confidence interval included zero in each case, the IDS showed no bias. The precision of the IDS in each study group was as follows: 0.133 ng mL (liver), 0.1903 ng/mL (kidney), and 0.1188 ng/mL (autoimmune). These results indicate that the FK506 IDS is both accurate and very precise (reproducible) in transplant and autoimmune patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Computer-guided concentration-controlled trials in autoimmune disorders.

A randomized concentration-controlled clinical trial (RCCCT) is an alternate experimental design to the standard dose-controlled study. In a RCCCT, patients are randomly assigned to predefined plasma or blood drug concentration ranges (low, medium, and high). With the caveat that concentration ranges are sufficiently separated, this design should enhance the ability to discover important concentration response relationships. FK-506, a potent and promising immunosuppressive agent for prevention and treatment of graft rejection, has shown significant clinical activity in some immune-mediated disorders. To implement the RCCCT design, a novel FK-506 intelligent dosing system (IDS) was used to guide all doses to prospectively achieve the target concentration range specific in the study protocol. Patients enrolled in these trials suffered from a variety of autoimmune disorders, including multiple sclerosis, primary biliary cirrhosis, psoriasis, autoimmune chronic active hepatitis, and nephrotic syndrome. We observed excellent predictive performance of the IDS for all patients. The accuracy (mean prediction error) of the IDS was -0.022 ng/ml and the precision (standard deviation of the prediction error) was 0.119 ng/ml. Thus, the IDS is both accurate and reproducible for autoimmune patients. We conclude that the RCCCT design, guided by an accurate and precise IDS, is an informative and cost-effective approach for evaluation of efficacy and safety of effective but highly toxic agents.

Autoimmune Diseases↗
PubMed1988

A randomised prospective comparison of cefotaxime versus netilmicin/penicillin for treatment of suspected neonatal sepsis.

In an open prospective study performed in 2 neonatal units, infants with suspected neonatal sepsis (SNS) of unknown microbial cause were randomly allocated to receive treatment with either cefotaxime (CTX) or netilmicin plus penicillin (N + P). 236 patients were entered into the trial, of whom 222 were evaluable. The number of 'definitely' and 'probably' infected babies was similar in both groups. There was no difference in clinical outcome between patients in the 2 treatment groups and no side effects were recorded for either of the antibiotic regimens. Antibiotic sensitivity testing of bacterial isolates from peripheral sites showed almost universal sensitivity of potential pathogens to both antibiotic regimens at the start of treatment in all infants. Thereafter, organisms resistant to CTX were isolated from patients in both treatment groups, possibly reflecting the antibiotic sensitivity profile of the colonising bacteria in both neonatal units. The results of this study indicate that either CTX or N + P are suitable, in our units, for the 'blind' treatment of early SNS. In units where listerial infections are prevalent, specific cover should be added to CTX. For SNS developing after admission, the choice of antibiotics will depend upon the background antibiotic sensitivity profile of the colonising bacteria.

Bacterial Infections↗
PubMed1982

History of atrial fibrillation 1628-1819 Harvey - de Senac - Laënnec.

For two centuries after Harvey the arterial pulse was often regarded as independent of the heart beat. This misunderstanding was mainly because of the frequent failure of the irregular heart to elicit a radial pulse: the "pulse deficit" of later times. Harvey observed ineffective palpitation of the atrium just before death. This was probably atrial fibrillation. He established the origin of the heart beat in the right atrium. Harvey's observations were confirmed and extended by de Senac in the mid-eighteenth century. He correlated gross irregularities (palpitation) with necropsy observation of mitral valve disease and dilatation of the left ventricle. He emphasised the origin of the heart's irregularity from the distended atrium consequent on distension or reflux of blood irritating the atrial wall. He also commented on disconcerted action and rippling of the ventricular wall before final cessation of movement in a dying heart (ventricular fibrillation). De Senac's ideas were a century and a half ahead of his time.

Atrial Fibrillation↗