Biomedical subjects
Publications and source records attributed to R Weil.
Plasma and serum of humans or experimental animals contain a factor which destabilizes F-actin. The factor has no DNAse or thrombin activity and after incubation with F-actin does not modify the position of the actin band on a SDS polyacrylamide gel. Hence it probably depolymerizes F-actin.
The feasibility of infection and transformation by SV40 (simian virus 40) of primary cell cultures derived from newborn-rat pancreas was investigated. As judged by the presence of intranuclear SV40 T-antigen, exposure to the virus resulted specifically in infection and transformation of epithelioid (predominantly endocrine) cells. The transformed cells were subcultured (more than 64 passages) and cloned. Culture medium and acid/ethanol extracts of the cells did not contain detectable amounts of immunoreactive insulin after the third subculture. However, inoculation of such SV40-transformed pancreatic cells into immunodeficient rats results in tumours in which insulin production was partially restored through the passage in vivo, since the tumour cells contained and synthesized small amounts of immunoreactive insulin which co-migrated with an insulin marker on gel chromatography. Interestingly, the transformed cells maintained under tissue-culture conditions produced a protein immunologically related to insulin, soluble in aqueous buffer but insoluble in acid/ethanol. This 3000-dalton protein is too large to be a translation product of the rat preproinsulin 9S mRNA. SV40-transformed pancreatic cells might prove useful in the investigation of the factors controlling and maintaining insulin biosynthesis.
Between 1970 and 1978, eight hepatic adenomas were resected. Four of the eight patients took oral contraceptive pills before the hepatic adenoma was identified; one patient was male. Four patients had evidence of bleeding at the time of presentation. The original histologic diagnosis in the first five patients was malignant hepatoma. There has been no known recurrence of tumor and all patients are well. The use of oral contraceptives in these patients has been prohibited. Formal anatomic resection is recommended for hepatic adenoma when this procedure can be done without mortality or serious morbidity; however, in the future, less drastic treatments, such as occlusion of the hepatic arterial circulation to the tumor or discontinuation of oral contraceptives, may prove as effective as tumor resection.
From 1974 to 1976, 114 kidneys transplanted to 108 patients underwent acute rejection episodes. With repeated rejections there was an increased likelihood of recovery without subsequent rejections, eg, 59% of kidneys that had three rejections regained prolonged good function. Repetitive rejections did not increase mortality. Discriminate analysis of the best serum creatinine level or creatinine clearance within 30 days of rejection and the time interval between rejection episodes correctly predicted the outcome of second rejections in 20/25 cases and correctly predicted the outcome of third rejections in 23/29 cases. Treatment of a third rejection was successful in 70% of kidneys if the best serum creatinine level was less than 2 mg/dL after the second rejection and was successful in 77% of kidneys if the time interval between second and third rejections was longer than one month.
During a 16-month period when 93 renal transplants were performed, eight kidney graft ruptures were detected within 18 days of transplantation, without evidence of venous obstruction. Six grafts were removed at the time of an exploratory operation for rupture and only one showed signs of probable irreversible rejection when examined by microscopy. Two graft ruptures were repaired and one of these grafts has had good long-term function 22 months later. These observations suggest that if bleeding at the site of grafts has had good long-term function 22 months later. These observations suggest that if bleeding at the site of graft rupture can be securely controlled and if the conditions of the patient and of the graft are favorable except for the rupture, it may be possible to save more than one of eight grafts.
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Thoracic duct drainage (TDD) was established for 21-115 days in 40 kidney recipients with an average removal per patient day of 4.7 1 lymph and 1.88 billion cells. Cellular and humoral immunity were depressed. TDD and immunosuppressive drugs were started at transplantation in 35 recipients of cross-match negative grafts. Although the results were better than in precedent non-TDD controls, eight patients rejected their grafts before a full TDD effect, and three of the eight developed predominantly anti-B lymphocyte cytotoxic antibodies which were probably responsible for positive cross-matches with their next donors. With continuing TDD, all eight patients had good initial function after early retransplantation. In five more "nontransplantable" patients with performed cytotoxic antibodies, TDD was started 30-56 days before transplantation. In these five pretreated patients, antibodies persisted with positive antidonor cross-matches. Hyperacute rejection occurred repeatedly in two patients with high anti-T (and anti-B) titers, but was surmounted in three patients with lower titers. From the clinical and immunologic data, we have concluded that TDD should be used for pretreatment of all cases with or without prior antibodies, and have suggested an adjustable management plan that takes into account new developments in antibody monitoring.
All 99mTc-DTPA studies of renal transplant patients whose grafts infarcted during a three-and-one-half-year period were reviewed. Four patients demonstrated absent renal perfusion and clearance and absent bladder activity. Three of these exhibited increased perinephric 99mTc-DTPA activity and never regained renal function. The fourth patient did not demonstrate increased perinephric activity, and some return of graft function appeared in a subsequent 99mTc-DTPA study. The pathogenesis of increased perinephric activity is unknown, but may signify renal infarction, and its absence may indicate potential renal viability.
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The development of liver transplantation has been made difficult because of the enormous technical difficulties of the procedure and because the postoperative management in early cases was defective in many instances. With surgical and medical improvements, the prospects for success have markedly increased recently. The wider use of thoracic duct fistula as an adjuvant measure during the first 1 or 2 postoperative months is being explored.
Sera from 203 recipients prior to transplantation were examined against a panel of 30 T and B lymphocytes at 5 degrees C and 37 degrees C. Those patients classified as having B-cold cytotoxins only had higher 1-year transplant survival rates from cadaver donors (82%) than patients with no antibodies (58%) or patients with antibodies reactive to T and B lymphocytes in the warm (37%). These results based on transplants from a single center confirm earlier studies derived from patients in 27 centers.
Liver transplantation in humans was first attempted more than 15 yr ago. The 1-yr survival has slowly improved until it has now reached about 50%. In our experience, 46 patients have lived for at least 1 yr, with the longest survival being 9 yr. The high acute mortality in early trials was due in many cases to technical and management errors and to the use of damaged organs. With elimination of such factors, survival increased. Further improvements will depend upon better immunosuppression. Orthotopic liver transplantation (liver replacement) is the preferred operation in most cases, but placement of an extra liver (auxiliary transplantation) may have a role under special circumstances.
Between March 1963 and January 1978, 74 patients 18 years of age or younger have had liver replacements at the University of Colorado Medical Center, Denver. The most common cause of native liver failure was biliary atresis (48/74, 65%); the second most common cause was chronic aggressive hepatitis (12/74, 16%). Twenty-nine patients (39%) lived for at least one year, and 16 are still alive one to nine years after transplantation. Technical surgical problems, rejection, and infection were the main causes of death. Improved immunosuppression is needed; nevertheless, the quality of life in the long-term survivors has encouraged continuation of this difficult work.
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The quality of life after liver transplantation ranges from poor to superior. The social and vocational outcome is dependent on the quality of homograft function and on the steroid doses necessary to maintain function. A good long-term prognosis is usually evident by 1 year postoperatively. The complete rehabilitation of so many patients has encouraged us to continue our efforts in this difficult field.
In this series of 150 orthotopic hepatic transplants, clinically significant gastrointestinal hemorrhage occurred in 34 patients (23%). Five patients (15%) survived this complication. Enteric perforations occurred in 20 patients following 198 biliary-enteric procedures. Only one patient survived. Enteric perforations unrelated to biliary procedures fared only slightly better with one survivor among eight perforations. These results clearly do not warrant complacency. Modifications advocated are an aggressive diagnostic approach and early reoperation with establishment of extensive peritoneal drainage where necessary.
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Twenty-seven consecutive recipients of cadaveric kidneys, including five with pre-existing warm cytotoxic antibodies, were treated with thoracic duct drainage before and after transplantation. Fourteen patients who had lymph drainage for 26 to 58 days before transplantation had minor cytotoxic antibody responses after grafting, even if the antibodies had been present before therapy. Only one of the 14 recipients had any rejection during the follow-up periods of one to six months. There were two deaths. The 13 patients pretreated for 17 to 23 days exhibited stronger cytotoxic antibody responsiveness, and five of these recipients had significant rejections of which four were reversible. One of the latter 13 patients died. These clinical and immunologic studies have established the value and have defined the appropriate timing of preoperative thoracic duct drainage in kidney transplantation. They have also directed attention to the rationale andthe probable value of using other immunosuppressive methods for preparatory host conditioning instead of beginning such therapy at the time of transplantation.