Biomedical subjects
Publications and source records attributed to R Fairchild.
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BACKGROUND: We attempted to minimize the undesired side effects and maximize the benefit of OKT3 induction therapy in renal transplantation. METHODS: One hundred and one recipients of kidney-only transplants were randomized to three groups. Each received low-dose 2.5-mg OKT3 induction for 7-14 days, but different premedication on days 0, 1, and 2. Group I was given 250 mg i.v. methylprednisolone at 1 and 6 hr, and group II received another 500 mg at 1 hr before initial OKT3. Group III received Atgam 15 mg/kg on day 0 and began OKT3 on day 1. A CD3+ T-cell cut-off of 50/mm3 was used to guide therapy. Maintenance therapy included cyclosporine and steroids for each patient. However, groups I and II were also given mycophenolate mofetil, and group III received azathioprine as a third agent. All rejections were biopsy confirmed and Banff scored. RESULTS: No differences in demographic or transplant characteristics were noted between groups I, II, and III, and mean follow-up was 25.7 (1-38) months. There was no significant difference in actuarial patient (90%, 91%, 94%) or graft survival (83%, 88%, 84%) at 3 years between the respective groups. Mean creatinine values and infectious complications were similar for each group. No patient experienced acute rejection during induction, and eight patients required dose escalation to sustain suppression of CD3 counts. The incidence of acute rejection at 6 and 12 months was significantly (P=0.004) greater in group III (38.2, 44.1%) than in either group I (15.1, 18.1%) or group II (14.7, 17.6%); relative risk 1.988 (95% CI 1.012-3.906). Formation of anti-OKT3 antibody was significantly (P=0.006) greater in group III (26.5%) than in group I (6%) or group II (2.9%). Group I recipients enjoyed significantly (P=0.001) fewer (2.17) OKT3 side effects on days 0, 1, and 2 than group II (3.03) or group III (2.49), and contained the largest number (61%) of recipients who experienced no side effects. Group I also exhibited the most suppressed profile of OKT3-induced release of tumor necrosis factor-alpha (P=0.006), interferon-gamma (P=NS), and interleukin-6 (P=0.01) on days 0 and 1. CONCLUSIONS: Low-dose 2.5-mg OKT3 with pretreatment of split-dose steroids on days 0, 1, and 2 provides the most effective method for OKT3 induction, which minimizes side effects for most patients. Subsequent maintenance therapy with cyclosporine, mycophenolate mofetil, and steroids provides effective rejection prophylaxis without increased complications for up to 3 years. Predepletion of T cells before exposure to OKT3 does not prevent cytokine release.
The purpose of this study was to determine if silicon phthalocyanine 4 (Pc 4), a second-generation photosensitizer being evaluated for the photodynamic therapy (PDT) of solid tumors, was immunosuppressive. Mice treated with Pc 4 PDT 3 days before dinitrofluorobenzene sensitization showed significant suppression of their cell-mediated immune response when compared to mice that were not exposed to PDT. The response was dose dependent, required both Pc 4 and light and occurred at a skin site remote from that exposed to the laser. The immunosuppression could not be reversed by in vivo pre-treatment of mice with antibodies to tumor necrosis factor-alpha or interleukin-10. These results provide evidence that induction of cell-mediated immunity is suppressed after Pc 4 PDT. Strategies that prevent PDT-mediated immunosuppression may therefore enhance the efficacy of this therapeutic modality.
BACKGROUND: Major bile duct injury is an important therapeutic problem that can be associated with simultaneous injury to the hepatic artery. Limited information exists regarding the course of patients who have combined bile duct and arterial injuries. OBJECTIVE: To compare the management and outcome of isolated bile duct injuries with bile duct and hepatic artery injuries. PATIENTS AND METHODS: Since 1991, 13 patients have undergone reconstruction of right and left hepatic confluence or proximal bile duct injuries. At the time of bile duct injury, 4 of these patients had simultaneous occlusion or extirpation of the right hepatic or common hepatic artery. All patients underwent reconstruction of the biliary tract with hepaticojejunostomies. The immediate and long-term outcomes of the patients with and without hepatic artery injury were compared. RESULTS: In the immediate postoperative period, 3 of 4 patients with combined injuries had hepatic necrosis and/or abscesses with 2 patients requiring transcutaneous or operative drainage. This problem was not diagnosed in patients with isolated bile duct injuries. None of the biliary anastomoses have failed in the patients with isolated bile duct injuries while 50% of the anastomoses in patients with combined injuries have caused recurrent problems following reconstruction. CONCLUSION: Patients with major bile duct injuries should be evaluated for concomitant hepatic arterial injury as management and outcome may be influenced by the absence of arterial blood flow to the injured bile ducts and to the liver.
Adenovirus infection occurs in 10% of pediatric orthotopic liver transplant recipients; however, no cases have been described in adult liver transplant recipients. A retrospective review of 191 adults who underwent liver transplantation from January 1988 through October 1995 was done to describe the incidence and clinical significance of adenovirus infection in this population. There were 11 (5.8%) patients with 16 cultures positive for adenovirus. Sites of isolation were urine (9), blood (2), liver biopsy (2), colonic biopsy (1), lung biopsy (1), and stool (1). Adenovirus infection was classified as either disease or asymptomatic infection. There were 7 cases of adenovirus disease (2 definite, 1 probable, and 4 possible). Disease was disseminated in 3 patients: All had pneumonia and 2 died. Of the 3 patients with pneumonia, 2 had evidence of multiorgan involvement. Adenovirus disease occurs in adult orthotopic liver transplant recipients and may be associated with significant morbidity and occasional mortality.
2',5'-Oligoadenylate-dependent RNase L functions in the interferon-inducible, RNA decay pathway known as the 2-5A system. To determine the physiological roles of the 2-5A system, mice were generated with a targeted disruption of the RNase L gene. The antiviral effect of interferon alpha was impaired in RNase L-/- mice providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. In addition, remarkably enlarged thymuses in the RNase L-/- mice resulted from a suppression of apoptosis. There was a 2-fold decrease in apoptosis in vivo in the thymuses and spleens of RNase L-/- mice. Furthermore, apoptosis was substantially suppressed in RNase L-/- thymocytes and fibroblasts treated with different apoptotic agents. These results suggest that both interferon action and apoptosis can be controlled at the level of RNA stability by RNase L. Another implication is that the 2-5A system is likely to contribute to the antiviral activity of interferon by inducing apoptosis of infected cells.
BACKGROUND: Liver graft assessment prior to transplantation continues to be controversial. Various donor organ parameters must be evaluated to ensure that the transplanted organ will function and that the number of organs discarded will be minimized. Recent attempts to quantify liver function have utilized the metabolism of lidocaine to monoethylglycinexylidide (MEGX), and the MEGX test has been employed to evaluate the functional characteristics of donor livers prior to transplantation, with conflicting results. OBJECTIVE: To ascertain the role of quantitating the metabolic rate of lidocaine in predicting the results of liver transplantation. METHODS: Consecutive liver donors (N = 37) underwent quantitation of the amount of lidocaine converted to MEGX at 15 minutes. The donor patients were divided arbitrarily into efficient and poor lidocaine metabolizers, and the results of liver transplantation were evaluated. RESULTS: Patients who received livers that produced MEGX values of 80 ng/mL or less in 15 minutes had no definable alteration in transplantation outcome compared with patients who received livers that were more efficient lidocaine metabolizers. In a collected series, 46 patients who received livers that produced MEGX values of 80 ng/mL or less had a 1-month graft survival rate of 89% (41/46), while 74 patients who received livers that produced MEGX values greater than 80 ng/mL had a 1-month graft survival rate of 86% (64/74). CONCLUSIONS: The MEGX test had no practical utility in predicting liver graft functional status.
Biliary cystadenoma is a rare benign neoplasm usually found in the parenchyma of the right lobe of the liver. The lesions are usually septated and represent less than 5 percent of non-parasitic cysts of biliary origin. Malignant degeneration to biliary cystadenocarcinoma is well documented, and recurrence is the rule following incomplete excision.
We have shown that there is a subgroup of black recipients who lack DR3 antigen expression and have decreased graft survival in comparison to black recipients who express DR3 antigen. Overall, the 3-year renal graft survival was equivalent between white and black recipients in our series and white recipients were not affected by DR3 antigen expression. We suspect that altered immune activity in the DR3-positive black patients may afford a benefit in overcoming immunologic barriers. This needs further investigation both in light of the possible association of the linked antigens A1-Cw7-B8-DR3 which are associated with loss of suppressor cell activity, as well as the issue of DR3 subtyping. However, there clearly exists the possibility of targeting higher risk groups such as the DR3-negative black recipients for more intense immunosuppressive regimens as well as eliminating pretransplant transfusion of third-party donors. Finally, we must reconsider the question of whether HLA matching is especially punitive to blacks, since matching for broad DR specificities in black recipients does not necessarily match for subtypes unique to blacks. Modifying or de-emphasizing the UNOS point system for organ allocation based on MHC antigen should be seriously considered as a mechanism for increasing the percentage of black kidney transplant recipients.
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Boron neutron capture therapy (BNCT) is a form of radiation therapy that requires selective uptake of boron by the tumor and irradiation with thermal neutrons. Phenylalanine is an amino acid precursor of melanin and when boronated (p-boronophenylalanine [BPA]) was found to be selectively taken up by Greene melanoma cells in the anterior chamber of rabbits. This tumor model was irradiated 24 hr after oral administration of BPA and was used for biodistribution studies that compared BPA and sodium pentaborate. Three groups were irradiated: group 1 (11 rabbits) received BPA followed by thermal neutron irradiation, group 2 (9 rabbits) received thermal neutron irradiation only, and group 3 (9 rabbits) served as unirradiated, undrugged control animals. Eight of the 11 tumors in group 1 were treated successfully; all tumors in groups 2 and 3 grew. Histopathologic examination did not reveal vascular or retina damage in group 1. These preliminary experiments confirm that newer boronated compounds, such as BPA, used in BNCT and improved neutron beams can provide selective irradiation of ocular melanomas.
Peptic ulcer disease (PUD) remains a well-known sequela of renal transplantation, and, when complications occur, morbidity and mortality can be significant. For this reason, all patients at our center undergo a pretransplant upper gastrointestinal series (UGI). Patients with evidence of active ulcer disease on UGI and/or a history of PUD undergo upper gastrointestinal endoscopy and do not undergo transplantation until healing is demonstrated. Following transplantation, antiulcer prophylaxis is utilized for 6 weeks (in patients without pretransplant PUD) or 3 months (in patients with pretransplant PUD). To help define the incidence and significance of PUD in the cyclosporine era, as well as the value of pretransplant screening and posttransplant ulcer prophylaxis, a retrospective chart analysis of 254 patients who underwent renal or renal/pancreas allograft transplanted between January 1984 and December 1989 was accomplished. Twenty-six patients (10%) presented with symptomatic PUD at a mean of 7.8 months posttransplant. The incidence of PUD was 10% in patients with a negative pretransplant history and UGI, 15% in patients with a positive pretransplant history and negative UGI and endoscopy, and 0% in patients with a positive pretransplant history and UGI. Age, sex, primary disease, donor source, and number of rejection episodes were not significantly different in recipients with or without PUD. At the time of presentation, 23 patients (88%) had completed their antiulcer prophylaxis. Four patients (15%) died secondary to ulcer disease including two of three (66%) following surgical treatment and two of 23 (9%) during medical treatment. Posttransplant PUD continues to result in significant morbidity and mortality in the cyclosporine era. Pretransplant screening, including UGI and endoscopy, is not a reliable predictor of posttransplant, symptomatic PUD. Based on this study, it is concluded that all patients should receive longer periods of antiulcer prophylaxis, independent of previously defined pre- and posttransplant risk factors.
Neuroendocrine activity in normal subjects was compared to patients with chronic renal failure on maintenance hemodialysis (CRF-HD) and to cyclosporine-treated renal transplantation (RT) recipients in an effort to further define the mechanisms underlying their associated fluid, electrolyte, and hemodynamic abnormalities. To evaluate neuroendocrine function in CRF and RT patients, plasma levels of angiotensin II (A-II), vasopressin (AVP), atrial natriuretic peptide (ANP), neuropeptide Y, neuropeptide Y (NPY), epinephrine (E), and norepinephrine (NE) were measured before and after HD and RT. Plasma concentrations of A-II, AVP, ANP, and NPY were significantly elevated in patients with CRF. HD did not produce a significant change in plasma concentrations of AVP, ANP, NPY, E, or NE. NE plasma levels, but not E levels, increased pre- and post-HD. A-II plasma levels were elevated basally in CRF patients and significantly increased following HD. Following RT, plasma levels of A-II, AVP, NPY, and creatinine decreased significantly over the first week, but AVP and NPY did not normalize. Plasma levels of ANP were elevated during the first month, then decreased to normal levels in RT patients. NE levels, but not E levels, were elevated both pre- and post-RT. Despite antihypertensive treatment, the group mean arterial pressure increased post-RT from 100 +/- 4.4 to 116 +/- 3.7 mmHg by POD 6.
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If a tumor can be preferentially loaded with a suitable boron-10 compound and irradiated with thermal neutrons, malignant cells can be selectively destroyed via the alpha-particle + Li 7-nucleus from the reaction 10B(n, alpha)7Li. Neutron capture therapy with two boron-10 amino acid analogs of low toxicity has been tested in recent years: (a) trimethylamine-carboxyborane, (A3) and (b) amine-carboxyborane, (A7). Now the boron-10 glycineamide analog (A8), amineboryl-carboxamide has been synthesized; it contains 13.81% boron (90% Boron 10 + 10% Boron 11) and shows a very low toxicity in mice. The effects of this compound were tested on the syngeneic solid adenocarcinoma EO 771 on the right hind leg of male C57 BL/6J mice under standard conditions, by measuring tumor volume growth delay and cell cycle changes using flow cytometry. Boron distribution between tumor and muscle was analyzed by emission spectroscopy with inductively coupled plasma (ICP) following injection of a suspension of peanut oil emulsion. In addition, boron-10 concentration in the tumor were analyzed with prompt gamma-activation analysis and neutron capture radiography (Kodak-Pathé LR 115) at the MRR reactor in Brookhaven after i.p. injection of 0.4 mg/g A8. Application of A8 alone (0.4 mg/g i.p.) or thermal neutron irradiation of the tumor EO. 771 produced a tumor growth delay of 1-2 days for tumor volume doubling. Application of the boron 10 glycine-amide analog A8 i.p. plus 5 X 10(12)n/cm2 resulted in a growth delay of 3-6 days. In contrast intratumoral application of A8 plus 4 X 10(12)n/cm2 neutrons gave a growth delay of 7-14 days; the fraction of (G2 + M) cells rose from 35% (neutrons alone) to 52%, as evaluated from flow cytometry.
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Thallium-201 merits evaluation for myocardial visualization, kidney studies, and tumor diagnosis because of its physical and biologic properties. A method is described for preparation of this radiopharmaceutical for human use. A critical evaluation of 201Tl and other radiopharmaceuticals for myocardial visualization is given.
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