Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression.

Hepatitis C virus (HCV) causes progressive liver fibrosis in liver transplant recipients and is the principal cause of long-term allograft failure. The antifibrotic effects of sirolimus are seen in animal models but have not been described in liver transplant recipients. We reviewed 1274 liver recipients from 2002 to 2010 and identified a cohort of HCV recipients exposed to sirolimus as primary immunosuppression (SRL Cohort) and an HCV Control Group of recipients who had never received sirolimus. Yearly protocol biopsies were done recording fibrosis stage (METAVIR score) with biopsy compliance of >80% at both year one and two. In an intent-to-treat analysis, the SRL Cohort had significantly less advanced fibrosis (stage ≥2) compared to the HCV Control Group at year one (15.3% vs. 36.2%, p < 0.0001) and year two (30.1% vs. 50.5%, p = 0.001). Because sirolimus is sometimes discontinued for side effects, the SRL Cohort was subgroup stratified for sirolimus duration, showing progressively less fibrosis with longer sirolimus duration. Multivariate analysis demonstrated sirolimus as an independent predictor of minimal fibrosis at year one, and year two. This is the first study among liver transplant recipients with recurrent HCV to describe the positive impact of sirolimus in respect of reduced fibrosis extent and rate of progression.

Pulsars: observations of spectra.

Dynamic spectrograms of two of the recently discovered pulsating radio sources have been obtained. The data provide the instantaneous spectrum and the time-frequency history of the signals over a bandwidth of 3 megahertz.

Radar observations of icarus.

Radar observations of Icarus were made in mid-June 1968, at the time of closest approach. From the data, it is estimated that the radius is between 0.3 and 0.6 kilometer and the rotation period between 1.5 and 3.3 hours. A set of round-trip Doppler shift measurements is given.

Mercury: Surface Features Observed during Radar Studies.

Radar studies of Mercury have shown the presence of several large, rough surface features and of one smooth area.

Superior conjunction of pioneer 6.

Spectrograms of the radio signals from Pioneer 6 were taken as the spacecraft was occulted by the sun. The spectral bandwidths increased slowly at first, then very rapidly at 1 degree from the sun. In addition, six solar "events" produced marked increases of bandwidth lasting for several hours. The received signal power seemed unaffected by the solar corona.

A radar snapshot of venus.

A radar brightness map of Venus has been obtain d. It reveals interesting surface features and much structure over a large area.

Ganymede: observations by radar.

Radar cross-section measurements indicate that Ganymede scatters to Earth 12 percent of the power expected from a conducting sphere of the same size and distance. This compares with 8 percent for Mars, 12 percent for Venus, 6 percent for Mercury, and about 8 percent for the asteroid Toro. Furthermore, Ganymede is considerably rougher (to the scale of the wavelength used, 12.6 centimeters) than Mars, Venus, or Mercury. Roughness is made evident in this experiment by the presence of echoes away from the center of the disk. A perfectly smooth target would reflect only a glint from the center, whereas a very rough target would reflect power from over the entire disk.

Ganymede: radar surface characteristics.

Radar observations of Ganymede, at X-band, show that the surface is unusually bright and has unusual polarization properties. A model of the surface based on large numbers of random ice facets (hence vacuum-ice interfaces) is able to account for these characteristics.

Satellite radar interferometry for monitoring ice sheet motion: application to an antarctic ice stream.

Satellite radar interferometry (SRI) provides a sensitive means of monitoring the flow velocities and grounding-line positions of ice streams, which are indicators of response of the ice sheets to climatic change or internal instability. The detection limit is about 1.5 millimeters for vertical motions and about 4 millimeters for horizontal motions in the radar beam direction. The grounding line, detected by tidal motions where the ice goes afloat, can be mapped at a resolution of approximately 0.5 kilometer. The SRI velocities and grounding line of the Rutford Ice Stream, Antarctica, agree fairly well with earlier ground-based data. The combined use of SRI and other satellite methods is expected to provide data that will enhance the understanding of ice stream mechanics and help make possible the prediction of ice sheet behavior.

Remote sensing of ocean currents.

A method of remotely measuring near-surface ocean currents with a synthetic aperture radar (SAR) is described. The apparatus consists of a single SAR transmitter and two receiving antennas. The phase difference between SAR image scenes obtained from the antennas forms an interferogram that is directly proportional to the surface current. The first field test of this technique against conventional measurements gives estimates of mean currents accurate to order 20 percent, that is, root-mean-square errors of 5 to 10 centimeters per second in mean flows of 27 to 56 centimeters per second. If the full potential of the method could be realized with spacecraft, then it might be possible to routinely monitor the surface currents of the world's oceans.

Mars radar observations, a preliminary report.

Radar observations of a narrow belt of the surface of Mars, centered at 16 degrees south latitude, show a very rugged terrain, with elevation differences greater than 13 kilometers from peak to valley. For nearby points, the relative altitude is measured to 40 meters at best; the precision is worse for points at different latitudes, or widely separated in longitude, because of orbital uncertainties. Some of the larger craters have been resolved, and their depth and, in some cases, the height of the raised rim have been measured. Where high resolution photographs, are available, the correlation is excellent.

Quasars: Millisecond-of-Arc Structure Revealed by Very-Long-Baseline Interferometry.

Observations with the Goldstone-Haystack radio interferometer of the quasars 3C 279 and 3C 273 have disclosed the presence of fine structure in their radio emissions. Although the interpretation is not unique, the fringe-amplitude data for quasar 3C 279 are quite consistent with emissions from two points, each contributing equally to the correlated flux. The separation of the two points is estimated to be (1.55 +/- 0.05) x 10(-3) arc second, or about 20 light years at the distance of 3 x 10(9) light years inferred from optical red-shift data. The formal uncertainty in the right-ascension component of the separation is about 6 x 10(-6) arc second; differential proper motion in this direction at half the speed of light could be discerned within a year. The fringe-amplitude data of quasar 3C 273 allow similar, but less definitive, interpretations.

Quasars revisited: rapid time variations observed via very-long-baseline interferometry.

Recent Goldstone-Haystack radio interferometric observations of the quasars 3C 279 and 3C 273 reveal rapid variations in their fine structure. Most notably, the data for 3C 279, interpreted in terms of a symmetric double-source model and the accepted red-shift distance, indicate differential proper motion corresponding to an apparent speed about ten times that of light. A number of possible mechanisms that might give rise to such an apparent speed are considered; although several may be plausible, no definitive choice can be made on the basis of present evidence. More interferometric observations of quasars are clearly needed to clarify their structure and internal kinematics.

MELD scores do not predict patient morbidity while on the liver transplant waiting list.

The goals of this study were to assess waitlist morbidity in terms of the frequency of health care services utilized by patients while on the liver transplant (LTX) waiting list and to determine whether that utilization can be predicted by the Model for End-Stage Liver Disease (MELD). Sixty-three noncomatose subjects were followed from waitlist placement until death, change in status, LTX, or study discontinuance. Health care events included doctor/clinic visits, labs, outpatient/inpatient tests and procedures, and hospital/intensive care unit days. Listing MELD scores and LTX MELD scores were examined against the number of health care event occurrences within 60 days of listing and 60 days of LTX, respectively, as were changes in MELD scores between listing and LTX and differences in the number of occurrences between the two time points. The only significant correlations noted were between LTX MELD scores and number of hospital days near LTX (r = .360, P = .046) and between LTX MELD scores and the sum total number of occurrences near LTX (r = .370, P = .044). These results suggest that MELD scores do not appear to predict morbidity in terms of health care utilization in patients awaiting LTX. Developing a system capable of predicting waitlist morbidity may lead to the implementation of medical interventions aimed at circumventing foreseeable complications and/or crises in patients awaiting LTX.

Sirolimus conversion after liver transplantation: improvement in measured glomerular filtration rate after 2 years.

METHODS: We reviewed our prospectively maintained database of 2005 liver transplantations. Therapy was either started de novo or converted from calcineurin inhibitors (CNIs) to sirolimus as the main immunosuppressive agent for nephrotoxicity or rejection. Glomerular filtration rate (GFR) was determined with iodine 125-labeled sodium isthalamate (Glofil-125), and serum creatinine concentration was obtained before and 3 months after transplantation, and yearly in both groups. Sirolimus levels were 10 to 15 ng/mL in patients at less than 3 months after transplantations and 5 to 10 ng/mL in the remaining patients. All patients received mycophenolate mofetil as maintenance therapy. RESULTS: Data for 29 patients in the de novo group and 35 in the conversion group were reviewed. Patients in the de novo group demonstrated an acute cellular rejection rate of 17.2%, 40% of which were steroid resistant. In this group, 48.2% discontinuation of sirolimus was necessary because of adverse effects. Patients in the conversion group demonstrated an acute cellular rejection rate of 2.8% and a 34.3% rate of sirolimus discontinuation. Seventeen (56.7%) patients at 1 year and 8 (44.4%) patients at 2 years demonstrated continued improvement in GFR. In the conversion group, case-control analysis did not demonstrate a significant difference in GFR and serum creatinine concentration (P > .05) at 1 and 2 years after conversion. At the time of review, no patients in the conversion group required hemodialysis. CONCLUSIONS: Conversion to sirolimus therapy is an effective strategy in improving renal function in patients with CNI-induced nephrotoxicity and can be done without increased rejection. Most of our patients (65.7%) tolerated sirolimus conversion. Of these, 56.7% and 44.4% demonstrated continued increase in GFR with the CNI-free regimen at 1 and 2 years, respectively. Long-term, large-population, prospective, randomized, controlled studies should further validate these results.

Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome--experience in 300 patients.

We have retrospectively reviewed the first 308 patients undergoing orthotopic liver transplantation (OLTX) at our institution to determine the following: 1) To what extent does renal function deteriorate postoperatively? 2) To what extent does renal function recover after OLTX for hepatorenal syndrome (HRS)? 3) What is the survival rate of patients with HRS compared with those without HRS? In non-HRS patients, GFR declined from 97.1 +/- 2.9 cc/min to 56.6 +/- 2.4 cc/min at 6 weeks postoperative, 62.6 +/- 2.6 cc/min at 1 year, and 58.3 +/- 3.5 cc/min at 2 years. In HRS patients, GFR increased from 19.9 +/- 3.6 cc/min to 32.5 +/- 3.1 cc/min at 6 weeks, 45.9 +/- 5.5 cc/min at 1 year, and 37.9 +/- 5.9 cc/min at 2 years. Dosages of cyclosporine were comparable in both groups. There was no difference in perioperative (90-day) mortality. One- and 2-year actuarial survival rates in the non-HRS patients were 87.2% and 82.1%, respectively. The actuarial 1- and 2-year survival rate for the HRS patients was 76.6% (P = NS). Ten percent of HRS patients developed ESRD posttransplant compared with 0.8% of non-HRS patients (P less than 0.005). We conclude that patients with HRS can safely undergo OLTX with acceptable perioperative mortality and good long-term survival. Most HRS patients have return of acceptable renal function. Patients without HRS have a severe decline in GFR posttransplant, which is stable up to 3 years posttransplant.

Late-onset acute rejection in orthotopic liver transplantation--associated risk factors and outcome.

A retrospective review of 375 consecutive orthotopic liver transplants was performed to determine the incidence and outcome of late rejection episodes ([LR] rejection occurring more than 6 months following transplant). A total of 31 episodes in 26 patients were identified. Eighteen of these episodes were associated with subtherapeutic levels of cyclosporine. Of these, 7 were due to noncompliance, 2 were due to biliary strictures, and 1 was due to malabsorption in a cystic fibrosis patient. All 31 episodes were treated initially with steroids, and 22 had a complete response, although one progressed to chronic rejection over a year later. Of the remaining 9, 1 received FK506 with a complete response, and 8 received OKT3. Of the 8 patients who received OKT3, 5 had a complete response, 1 received RS61443 following OKT3 and progressed to chronic rejection, and the remaining 2 received further steroids. Of these 2, 1 had a complete response following the steroids while the second was converted to FK506 with a complete response. Compared with 315 acute rejection episodes ([AR] occurring less than 6 months posttransplant), patients with late rejection episodes had an equivalent response to steroids (63.2% AR reversed vs. 71% LR reversed) but a lower response rate to OKT3 (91.5% AR reversed vs. 62.5% LR reversed). There was, therefore, a higher rate of persistent rejection (61% AR episodes vs. 15.4% LR episodes) but no increase in the incidence of chronic rejection (7% AR episodes vs. 7.7% LR episodes). We conclude that LR is a relatively common occurrence following liver transplant, which is most often associated with low cyclosporine levels. Many of these episodes are due to noncompliance, but biliary problems must also be investigated. The incidence of resistant rejection is higher in this group of patients but is not associated with a concurrent increase in chronic rejection.

OKT3 rescue for steroid-resistant rejection in adult liver transplantation.

The results of OKT3 use for steroid-resistant rejection rescue in adult liver transplantation were analyzed retrospectively from a single transplant center. Comparison was made with concurrent patients who had no rejection (NR) or steroid-responsive rejections (SR). The records of 290 patients who underwent 323 liver transplants from April 1985 to December 1989 were examined. The first technically successful grafts were used for this analysis (265 grafts). Follow-up was a minimum of 1 year, or until death or loss of graft. All patients received triple-drug induction immunosuppression (CsA, Aza, steroids). Initial rejection was treated with 1 g methylprednisolone bolus i.v., followed by a 5-day taper of steroids from 200 mg to 20 mg. No rejection occurred in 108 (40.8%) and SR in 86 (32.4%), and OKT3 was given for persistent rejection in 71 (26.8%). The age, sex distribution, mean follow-up, and preoperative status were similar in all three groups. The preoperative diagnoses were similar, except for fulminant liver failure, in which 19 of 20 patients experienced rejection (P < 0.0001). The median hospitalization stay was 37 days for OKT3, 27 days for SR, and 21 days for NR (P < 0.0001). The median ICU stay was similar in the three groups (OKT3, 4; SR, 4; NR, 3). Infections in the first 6 weeks, and in the period of 6 weeks to 1 year posttransplant, were of similar frequency for all three groups. By the Kaplan-Meier estimation, the graft and patient actuarial survival rates were comparable. At 1 year, the graft survival rate was 79.6% for NR, 79.8% for SR, and 67.6% for OKT3. The 1-year patient survival rate was 85.2% for NR, 83.7% for SR, and 84.5% for OKT3. Following treatment by OKT3, rejection was permanently reversed in 42 patients. A temporary response occurred in 12 patients, 16 patients failed to respond to OKT3, 2 patients died during therapy, and 6 of the nonresponders died within 12 months. Additional OKT3 treatment was attempted in 6 patients for persistent rejection within a 1-month interval from the previous OKT3 course. Of these 6, 4 developed lymphoproliferative disorder, and only 1 survived in response to drastic reduction of immunosuppression. In conclusion, OKT3 was effective as rescue therapy for adult liver transplant steroid-resistant rejection. Because of the associated morbidity and expense, OKT3 should be used in a selective fashion. Failure to respond to OKT3 is a serious complication, and should not be managed by prolonged or repeated courses, but rather by alternative means.

Impact of pretransplant renal function on survival after liver transplantation.

To determine the effect of pretransplant liver function on survival following orthotopic liver transplantation and to quantify the effects of cyclosporine administration on long-term renal function in patients undergoing liver transplant, we performed an analysis of a prospectively maintained database. Data from 569 consecutive patients undergoing liver transplantation alone who were treated with CsA for immunosuppression were used for this study. Actuarial graft and patient survival rates were calculated using Kaplan-Meier statistics. Glomerular filtration rates, serum creatinine, and the use of various immunosuppressives were analyzed for this study. The initial analysis demonstrated that patients presenting for liver transplant with hepatorenal syndrome have a significantly decreased acturial patient survival after liver transplant at 5 years compared with patients without hepatorenal syndrome (60% vs. 68%, P < 0.03). Patients with hepatorenal syndrome recovered their renal function after liver transplant. Patients who had hepatorenal syndrome were sicker and required longer stays in the intensive care unit, longer hospitalizations, and more dialysis treatments after transplantation compared with patients who did not have hepatorenal syndrome. The incidence of end-stage renal disease after liver transplantation in patients who had hepatorenal syndrome was 7%, compared with 2% in patients who did not have hepatorenal syndrome. To more fully examine the effect of pretransplant renal function on posttransplant survival, the non-hepatorenal syndrome patients were divided into quartiles depending upon their pretransplant renal function. The patients with the lowest pretransplant renal function had the same survival as the patients with the highest pretransplant renal function. In addition, there was no increased incidence of acute or chronic rejection in any of the groups. The patients with the lower pretransplant renal function were treated with more azathioprine to maintain renal function and had a negligible decrease in glomerular filtration rate following transplant. Conversely, patients with the highest level of renal function pretransplant had a 40% decline in renal function in the first year, but maintained stable renal function up to 4 years after transplant. We conclude that pretransplant renal function other than hepato-renal syndrome has no effect on patient survival after orthotopic liver transplant. Renal function after liver transplant is stable after an initial decline, despite continued administration of CsA.(ABSTRACT TRUNCATED AT 400 WORDS)

Quality of life improvements at one, two, and five years after liver transplantation.

We prospectively studied adult liver transplant (OLTX) recipients to evaluate the effect of OLTX on quality of life (QOL). Over an 8-year period, all adult patients undergoing OLTX at our institution were asked to complete a psychological questionnaire that probed broad facets of QOL. Patients seen for their 1, 2, and 5 or more-year post-OLTX visits were also asked to complete the form. Questions were then grouped by categories broadly highlighting self-image (SI), health perception (HP), ability to function (F), and ability to work (W). Questions ranged from demographic and occupational topics to symptom distress/frequency, activities of daily living, and the impact of health on daily life. Numerical scores were assigned to each question, and added to derive scores on SI, HP, and F. Higher scores reflect better QOL. Employment data (W) were also compared, though not amenable to scoring. A total of 573 forms were completed (210 pretransplant, 150 at 1 year, 131 at 2 years, 79 at 5 years). All posttransplant scores were significantly higher than pretransplant ones (P < or = .0001, ANOVA). Scores at posttransplant time points were not significantly different from each other. Subscores of SI and HP revealed less symptom frequency and distress following OLTX (P < or = .0003) continuing to beyond 5 years. Health limitations on activities decreased both at 1 year post-OLTX and again at 2 years (P < or = .0001) and were sustained to beyond 5 years. Fewer people were working for pay at 1 year post-compared with pre-OLTX, but pre-OLTX levels of employment had been regained by the second year, continuing to increase to beyond 5 years. OLTX leads to improved QOL by the end of the first posttransplant year, sustained through the 5th posttransplant year and beyond. Self-image, functioning ability, and perception of health status were significantly improved. Ill health interference in daily life continues to decrease as OLTX becomes more remote. Employment suffers early after OLTX, but recovers by the second post-OLTX year and continues to increase long-term.