The use of FK-506 for small intestine allotransplantation. Inhibition of acute rejection and prevention of fatal graft-versus-host disease.

Small intestine allotransplantation in humans is not yet feasible due to the failure of the current methods of immunosuppression. FK-506, a powerful new immunosuppressive agent that is synergistic with cyclosporine, allows long-term survival of recipients of cardiac, renal, and hepatic allografts. This study compares the effects of FK-506 and cyclosporine on host survival, graft rejection, and graft-versus-host-disease in a rat small intestine transplantation model. Transplants between strongly histoincompatible ACI and Lewis (LEW) strain rats, and their F1 progeny are performed so that graft rejection alone is genetically permitted (F1----LEW) or GVHD alone permitted (LEW----F1) or that both immunologic processes are allowed to occur simultaneously (ACI----LEW). Specific doses of FK-506 result in prolonged graft and host survival in all genetic combinations tested. Furthermore, graft rejection is prevented (ACI----LEW model) or inhibited (rejection only model) and lethal acute GVHD is eliminated. Even at very high doses, cyclosporine did not prevent graft rejection or lethal GVHD, nor did it allow long-term survival of the intestinal graft or the host. Animals receiving low doses of cyclosporine have outcomes similar to the untreated control groups. No toxicity specific to FK-506 is noted, but earlier studies by other investigators suggest otherwise.

Induction of stable chimerism and elimination of graft-versus-host disease by depletion of T lymphocytes from bone marrow using immunomagnetic beads.

The goal of transplantation is the induction of immunologic tolerance. At present, nonspecific immunosuppression is used to prevent graft rejection and, commonly, graft-versus-host disease (GVHD). Nevertheless, nonspecific immunosuppressive therapy is frequently complicated by infection, malignant tumors, and drug toxicity. In order to examine whether hematopoietic chimerism can be used to induce specific allograft tolerance, we have reconstituted lethally irradiated Lewis rats with ACI bone marrow that has been depleted of T cells with use of immunomagnetic beads. This technique consists of binding OX-19, a mouse anti-rat pan-T lymphocyte monoclonal antibody, to magnetic polymer beads. Mixing of bone marrow or splenocytes with the bead/OX-19 complexes, followed by magnetic separation, results in significant depletion of T cells with minimal nonspecific cell loss. Immunomagnetic T-cell depletion of bone marrow, followed by reconstitution of a lethally irradiated host, allows for the development of stable, mixed hematopoietic chimerae without evidence of GVHD. These hosts are immunocompetent by clinical criteria. Recipients of untreated donor bone marrow that did or did not receive nonspecific immunosuppression demonstrated varying degrees of GVHD and reduced survival. The ability to rapidly and simply deplete T lymphocytes from bone marrow and produce stable, immunocompetent hematopoietic chimerae without GVHD may be an important method for tolerance induction to vascularized allografts.

Long-term results of metallic stents for benign biliary strictures.

BACKGROUND: Historically, surgical correction has been the treatment of choice for benign biliary strictures (BBS). Self-expandable metallic stents (MSs) have been useful for inoperable malignant biliary strictures; however, their use for BBS is controversial and their natural history unknown. HYPOTHESIS: To test our hypothesis that MSs provide only short-term benefit, we examined the long-term outcome of MSs for the treatment of BBS. Our goal was to develop a rational approach for treating BBS. DATA EXTRACTION: Between July 1990 and December 1995, 15 patients had MSs placed for BBS and have been followed up for a mean of 86.3 months (range, 55-120 months). The mean age of the patients was 66.6 years and 12 were women. Stents were placed for surgical injury in 5 patients and underlying disease in 10 patients (lithiasis, 7; pancreatitis, 2; and primary sclerosing cholangitis, 1). One or more MSs (Gianturco-Rosch "Z" for 4 patients and Wallstents for 11 patients) were placed by percutaneous, endoscopic, or combined approaches. We considered patients to have a good clinical outcome if the stent remained patent, they required 2 or fewer invasive interventions, and they had no biliary dilation on subsequent imaging. DATA SYNTHESIS: Metallic stents were successfully placed in all 15 patients, and the mean patency rate was 30.6 months (range, 7-120 months). Five patients (33%) had a good clinical result with stent patency from 55 to 120 months. Ten patients (67%) required more than 2 radiologic and/or endoscopic procedures for recurrent cholangitis and/or obstruction (range, 7-120 months). Five of the 10 patients developed complete stent obstruction at 8, 9, 10, 15, and 120 months and underwent surgical removal of the stent and bilioenteric anastomosis. Four of these 5 patients had strictures from surgical injuries. The patient who had surgical removal 10 years after MS placement developed cholangiocarcinoma. CONCLUSIONS: Surgical repair remains the treatment of choice for BBS. Metallic stents should only be considered for poor surgical candidates, intrahepatic biliary strictures, or failed attempts at surgical repair. Most patients with MSs will develop recurrent cholangitis or stent obstruction and require intervention. Chronic inflammation and obstruction may predispose the patient to cholangiocarcinoma.

Enhanced oral cyclosporine absorption with water-soluble vitamin E early after liver transplantation.

We evaluated the effect of Liqui-E, a water-soluble vitamin E preparation, on cyclosporin A (CyA) whole blood concentration in liver transplant recipients, and its impact on the cost of CyA. Patients were 26 liver transplant recipients (19 adults, 7 children) who were unable to achieve and maintain therapeutic CyA whole blood concentrations with the standard recommended oral daily dose in the early post-transplant period. Liqui-E 6.25 IU/kg orally was administered with CyA every 12 hours (median time of starting Liqui-E day 14.5). With Liqui-E, the daily oral CyA requirements (mean +/- SD) were decreased in adults from 22.6 +/- 8.9 to 16.2 +/- 7.3 mg/kg/day (p < 0.001) and in children from 78.6 +/- 34.1 to 53.7 +/- 35.0 mg/kg/day (p < 0.02); intravenous administration of CyA was unnecessary. The CyA trough concentrations (mean +/- SD) before and after Liqui-E were 670 +/- 186 and 1012 +/- 216 ng/ml, respectively, in adults (p < 0.001) and 732 +/- 187 and 1052 +/- 166 ng/ml, respectively, in children (p < 0.01). When given with Liqui-E, the daily cost of CyA decreased by 26% in both adults and children. No clinical or biochemical evidence of Liqui-E toxicity was observed. Thus its administration in the early post-transplantation period can enhance CyA absorption in adults and children who are unable to achieve adequate whole blood concentrations with the usual recommended oral dosages. In addition, a significant cost saving can be realized by coadministration.

Transarterial chemoembolization is a safe treatment for unresectable hepatic malignancies.

Acute liver failure has been reported as a frequent complication of transarterial chemoembolization (TACE). We prospectively evaluated the adverse effects and biochemical changes of TACE. From 10/95 to 9/96, 35 patients with hepatic malignancies were evaluated for TACE. Fifteen patients (9 male and 6 female) received 23 treatments. Ten of 15 patients had hepatocellular carcinoma, and 5 had metastatic tumors. Treatment exclusion criteria included advanced liver disease, hepatic vascular thrombosis, and severe comorbidity. TACE consisted of intra-arterial infusion of a mixture of doxorubicin, cisplatin, and mitomycin followed by embolization. Clinical symptoms and laboratory studies were monitored following treatment. Technical success was achieved in all patients. Adverse symptoms were transient, and most resolved within 1 week. Changes in hepatic, renal, and hematologic function were temporary and returned to pre-TACE levels by 1 month. None developed acute liver failure. The mean hospital stay was 3 days. Ten of 13 patients had a significant decrease in baseline tumor markers. The actual survival was 93 per cent with a median follow-up of 10 months. TACE can be performed safely in patients with hepatic tumors. The adverse effects can be anticipated and easily managed.

Hepatic resection for malignancy in the elderly.

Although elderly patients are accounted for in all large series of major hepatic resections, the role of age as a determinant of outcome remains unclear. At Cedars-Sinai Medical Center, we review a series of 20 major hepatectomies for neoplasia performed in patients older than 66 years of age (4 of them > or = 80 years old) over a 5-year period. A retrospective comparison was conducted with a group of 22 hepatectomies for malignancy performed in 20 patients younger than 59 years of age during the same time period. The younger group had a significantly greater degree of liver resected (12 trisegmentectomies vs 3). Although one operative death (5% mortality) was observed in the elderly group, no statistically significant difference was noted, when compared to the younger group (Chi-square, P = 0.48). Likewise, no significant difference in the complication rate (20% vs 33%) was noticed (Chi-square, P = 0.8). Severe postoperative liver dysfunction was present in 2 cases (10%) in the elderly group and one (4%) in the younger group. These patients underwent a right trisegmentectomy (TS). Nine patients from each group were resected without red blood cell transfusion. We conclude that major hepatic resection in elderly patients without severe comorbid disease is a safe procedure that is not associated with an increased perioperative morbidity or mortality rate.

Transjugular intrahepatic portosystemic shunt: efficacy for the treatment of portal hypertension and impact on liver transplantation.

Variceal bleeding (VB) and ascites refractory to diuretics (RA) represent a significant cause of morbidity and mortality in patients with portal hypertension. Transjugular intrahepatic portosystemic shunts (TIPS) have been used effectively in patients with these complications, especially those individuals awaiting orthotopic liver transplantation (OLT). From April 1992 to July 1995, 41 adult patients underwent an attempt at TIPS placement for refractory VB or ascites at Cedars-Sinai Medical Center. Technical success was achieved in 37 of 41 cases (90.3%) with only two technical complications. Immediate control of hemorrhage and significant improvement of ascites was obtained in 91.9% and 83.5% of the patients, respectively. Six patients (16.2%) died within a week of TIPS placement due to uncontrollable ascites and multiorgan failure. Four of 31 patients (12.9%) developed mild to moderate grades of hepatic encephalopathy that was controlled with lactulose. Rebleeding from recurrent portal hypertension was noted in 5 of 31 cases (16.1%). Shunt stenosis or occlusion was seen in 7 of 31 cases (22.6%) at an average of 6.3 months following TIPS placement. Six patients underwent OLT within an average of 87 days after TIPS. These results indicate that TIPS appears to be an effective method for treatment of refractory VB and RA, especially for patients who are poor candidates for a surgical shunt or awaiting OLT. However, TIPS may not be considered a definitive solution for all patients with portal hypertension because of its current rate of shunt occlusion or stenosis.

Metastasis of hepatocellular carcinoma to the right colon manifested by gastrointestinal bleeding.

An 82-year-old black woman with a history of hepatocellular carcinoma presented with gastrointestinal bleeding. Barium enema and fibrocolonoscopy revealed a 4-cm polypoid mass at the level of the ascending colon with evidence of active bleeding. Biopsies of the lesion proved it to be metastatic hepatocellular carcinoma. Exploratory laparotomy revealed no further dissemination of the tumor, and the patient underwent an ileocolectomy. The serosal side of the colonic lesion was free from tumor, and there was no peritoneal implantation, direct extension, or lymph node involvement. This case represents an extremely rare presentation of metastatic hepatocellular carcinoma.

Following the pioneers. Addressing tobacco in chemical dependency treatment.

Traditionally, tobacco has been ignored as an issue in the treatment of addictions to alcohol and other drugs. Beginning in 1985, and especially since the publication of the 1988 Surgeon General's Report on nicotine addiction, a handful of treatment programs have worked at coming to terms with tobacco. This article explores the reasons for addressing nicotine in the course of managing other addictions and summarizes the lessons learned from the programs which have done pioneering work in this area. The reasons for addressing nicotine are compelling, and the accumulated experiences among the pioneering programs are consistently encouraging. Regional projects to help alcohol and drug treatment programs come to terms with tobacco are an appropriate next step.

Nicotine addiction counseling for chemically dependent patients.

A total of 771 professionals employed in alcohol treatment programs in Nebraska were surveyed to determine whether their personal alcohol and tobacco use status or characteristics of their treatment programs were related to whether they provided nicotine addiction counseling. About a third of respondents agreed that clients in active treatment should be urged to quit smoking. Compared with respondents who had never smoked, current smokers were one-half to one-third as likely to provide such counseling. Greater knowledge of the effects of nicotine addiction and employment in programs that provided nicotine addiction education or treatment increased the odds of counselors' providing nicotine counseling. Counselors' alcohol use status was not associated with nicotine counseling practices.

Immunomagnetic T-lymphocyte depletion (ITLD) of rat bone marrow using OX-19 monoclonal antibody.

Graft versus host disease (GVHD) may be abrogated and host survival prolonged by in vitro depletion of T lymphocytes from bone marrow (BM) prior to allotransplantation. Using a mouse anti-rat pan T-lymphocyte monoclonal antibody (OX19) bound to monosized, magnetic, polymer beads, T lymphocytes were removed in vitro from normal bone marrow. The removal of the T lymphocytes was confirmed by flow cytometry. Injection of the T-lymphocyte-depleted bone marrow into fully allogeneic rats prevents the induction of GVHD and prolongs host survival.

Quasi-quadrature interferometer for plasma density radial profile measurements.

A cw Mach Zehnder multichannel interferometer has been developed to measure time-dependent fractional fringe shifts with an accuracy of one-fortieth fringe. The design is quasi-quadrature in that known phase shifts, introduced in the reference beam, are time multiplexed with the normal reference beam. This technique requires only one detector per interferometer channel as compared to two detectors for most quadrature designs. The quadrature information makes the sense of density changes unambiguous, it automatically calibrates the instrument during the plasma event, and it makes fringe shift measurements virtually independent of fringe contrast fluctuations caused by plasma refractive and/or absorptive effects. The interferometer optical design is novel in that the electro-optic crystal used to introduce the 90 degrees phase shifts is located in the common 2-mm-diam HeNe entrance beam to the interferometer, by exploiting polarization techniques, rather than in the expanded 1-2-cm reference beam itself. This arrangement greatly reduces the size, cost, and high-voltage requirements for the phase modulating crystal.

Substance abuse education in schools of nursing: a national survey.

A concern whether the expansion of knowledge in substance abuse nursing and the contemporary prevalence of substance use disorders had influenced current educational offerings in schools of nursing provided an impetus for this national survey. The purpose of the study was to obtain information about current curricular offerings in substance abuse by schools of nursing. A total of 1,035 questionnaires were mailed to schools of nursing. Respondents included 336 schools representing a 36% return rate. The sample included 154 baccalaureate (46%), 126 associate degree (38%), and 56 diploma (17%) programs. All but one state (Alaska) of the U.S. were part of the sample. The questionnaire used for this study was adapted from one developed for a survey of alcohol and drug abuse content taught in medical schools (Pokorney & Solomon, 1983). Modifications were limited to placing questions in a nursing context. All responding schools included substance abuse in curricular offerings with the largest number (N = 192; 57%) reporting the teaching of alcohol and drug content in a combined manner. The number of required hours of instruction reported most frequently was one to five (N = 242; 72%), which did not differ significantly for the three types of programs. The relatively small number of required hours of instruction would seem disproportionate to the scope and prevalence of substance abuse problems present in patient populations.

Evidence of relaxation and spontaneous transition to a high-confinement state in high-beta steady-state plasmas sustained by rotating magnetic fields.

Evidence of relaxation has appeared, for the first time, in the extremely high-beta, steady-state field-reversed configuration plasma states driven by rotating magnetic fields (RMF) in the translation, confinement, and sustainment experiment. The plasma self-organizes into a near-force-free state in the vicinity of the magnetic axis, with significant improvement in confinement. Associated with this change in magnetic topology is the appearance of an axial RMF component; this would, in turn, generate a current drive in the poloidal direction, thus sustaining the magnetic helicity. A newly developed two-dimensional "equilibrium-lite" model is employed to analyze the magnetic properties of the final high-confinement state, and shows a large q and a significant magnetic shear in the core.

Stabilization of interchange modes by rotating magnetic fields.

Interchange modes have been a key limiting instability for many magnetic confinement fusion configurations. In previous studies intended to deal with these ubiquitous instabilities, complex, transport enhancing, minimum-B producing coils were added to the otherwise simple linear mirror plasma. Possible solutions for returning to a simple symmetric mirror configuration, such as ponderomotive fields, are weak and difficult to apply. A new method is demonstrated here for the first time, utilizing rotating magnetic fields that are simple to apply and highly effective. A simple and easily comprehensible theory has also been developed to explain the remarkable stabilizing properties. Although this work has been performed on field reversed configurations, it should have a wide application to other confinement schemes, and could become a cornerstone for high-beta plasma stability.

Observations of improved stability and confinement in a high-beta self-organized spherical-torus-like field-reversed configuration.

An extremely high-beta (over 85%) self-organized field-reversed configuration (FRC) with a spherical-torus- (ST-)like core is produced in the translation, confinement, and sustainment experiment by highly super-Alfvénic translation of a spheromaklike plasmoid. Substantial flux conversion from toroidal into poloidal occurs during the capture process, resulting in the ST-like core. This plasma state exhibits a remarkable stabilizing property for the ubiquitous centrifugally driven interchange modes present in theta-pinch formed FRCs. This is explained, for the first time, by a simple model taking into account magnetic shear and centrifugal effects. The FRC-ST configuration has up to 4 times improvement in flux confinement times over the scaling of conventional theta-pinch formed FRCs and, thus, a significant improvement in the resistivity and transport.