The effect of insulin on bone mineral density among women with type 2 diabetes: a SWAN Pharmacoepidemiology study.

This was a longitudinal study examining the effects of insulin use on bone mineral density loss. Insulin use was found to be associated with greater bone mineral density loss at the femoral neck among women with diabetes mellitus. INTRODUCTION: Women with diabetes mellitus (DM) have higher bone mineral density (BMD) and experience slower BMD loss but have an increased risk of fracture. The data regarding the effect of insulin treatment on BMD remains conflicted. We examined the impact of insulin initiation on BMD. METHODS: We investigated the annual changes in BMD associated with the new use of insulin among women with DM in the Study of Women's Health Across the Nation (SWAN). Propensity score (PS) matching, which is a statistical method that helps balance the baseline characteristics of women who did and did not initiate insulin, was used. Covariates with a potential impact on bone health were included in all models. Mixed model regression was used to test the change in BMD between the two groups. Median follow-up time was 5.4 years. RESULTS: The cohort consisted of 110 women, mean age, 53.6 years; 49% white and 51% black. Women using insulin (n = 55) were similar on most relevant characteristics to the 55 not using insulin. Median diabetes duration for the user group was 10 vs. 5.0 years for the non-user group. There was a greater loss of BMD at the femoral neck among insulin users (- 1.1%) vs non-users (- 0.77%) (p = 0.04). There were no differences in BMD loss at the spine - 0.30% vs - 0.32% (p = 0.85) or at the total hip - 0.31% vs - 0.25 (p = 0.71), respectively. CONCLUSIONS: Women with T2DM who initiated insulin experienced a more rapid BMD loss at the femoral neck as compared to women who did use insulin.

Association between changes in oestradiol and follicle-stimulating hormone levels during the menopausal transition and risk of diabetes.

AIM: To investigate the association between changes in oestradiol and follicle-stimulating hormone levels during the menopausal transition and incident diabetes. METHODS: We followed 1407 pre-menopausal women, aged 42-52 years at baseline, who experienced natural menopause, from baseline to the 12th annual follow-up visit in the Study of Women's Health Across the Nation (SWAN). Diabetes was defined based on fasting glucose level, medication use and self-report of physician diagnosis. Cox proportional hazards regression was used to evaluate the associations of incident diabetes with three components of the rate of change in hormones: the intercept (pre-menopausal levels) and two piece-wise slopes representing change during the early and late transition, respectively. RESULTS: During 15 years of follow-up, 132 women developed diabetes. After adjusting for potential confounders, a higher oestradiol intercept, but not its rate of change, was borderline significantly associated with lower risk of diabetes [hazard ratio for an interquartile range increase (75.2 pmol/L) 0.53, 95% CI 0.27-1.06]. For follicle-stimulating hormone, a greater rate of increase in the early transition, but not the intercept or late transition, was significantly associated with lower risk of diabetes [hazard ratio for an interquartile range increase (5.9 IU/L/year) 0.31, 95% CI 0.10-0.94]. CONCLUSIONS: Lower pre-menopausal oestradiol levels and a slower rate of follicle-stimulating hormone change during the early transition were associated with higher risk of developing diabetes. Given that obesity plays an important role in diabetes risk and in the levels and changes in oestradiol and follicle-stimulating hormone over the menopausal transition, weight control in earlier mid-life is important to prevent future diabetes development.

Bone mineral density changes among women initiating blood pressure lowering drugs: a SWAN cohort study.

SUMMARY: We examined the effect of blood pressure lowering drugs on BMD using data from the Study of Women's Health Across the Nation. Thiazide users had a slower decline in BMD compared to nonusers, while decline among ACE inhibitor and beta blocker users were similar to rates in nonusers. INTRODUCTION: Several blood pressure lowering drugs may affect bone mineral density (BMD), leading to altered fracture risk. We examined the effect of blood pressure lowering drugs on BMD using data from the Study of Women's Health Across the Nation. METHODS: We conducted a propensity score matched cohort study. Women were initiators of ACE inhibitors (ACEi), beta-blockers (BB), or thiazide diuretics (THZD). Their annualized BMD changes during the 14 years of observation were compared with nonusers. RESULTS: Among the 2312 eligible women, we found 69 ACEi, 71 BB, and 74 THZD users who were matched by a propensity score with the same number of nonusers. THZD users had a slower annual percent decline in BMD compared to nonusers at the femoral neck (FN) (-0.28% vs -0.88%; p = 0.008) and the spine (-0.74% vs -1.0%; p = 0.34), albeit not statistically significant. Annual percent changes in BMD among ACEi and BB users were similar to rates in nonusers. In comparison with BB, THZD use was associated with a trend toward less annualized BMD loss at the spine (-0.35% vs -0.60%; p = 0.08) and a similar trend at the FN (-0.39% vs -0.64%; p = 0.08); in comparisons with ACEi, THZD was also associated with less loss at the FN (-0.48% vs -0.82%; p = 0.02), but not at the spine (-0.40% vs -0.56%; p = 0.23). CONCLUSIONS: Neither ACEi nor BB was associated with improvements in BMD. THZD use was associated with less annualized loss of BMD compared with nonusers, as well as compared with ACEi and BB.

Post-transplant lymphoproliferative disorder after pancreas transplantation: a United Network for Organ Sharing database analysis.

There are not a great deal of data on post-transplant lymphoproliferative disorder (PTLD) following pancreas transplantation. We analyzed the United Network for Organ Sharing national database of pancreas transplants to identify predictors of PTLD development. A univariate Cox model was generated for each potential predictor, and those at least marginally associated (p < 0.15) with PTLD were entered into a multivariable Cox model. PTLD developed in 43 patients (1.0%) of 4205 pancreas transplants. Mean follow-up time was 4.9 ± 2.2 yr. In the multivariable Cox model, recipient EBV seronegativity (HR 5.52, 95% CI: 2.99-10.19, p < 0.001), not having tacrolimus in the immunosuppressive regimen (HR 6.02, 95% CI: 2.74-13.19, p < 0.001), recipient age (HR 0.96, 95% CI: 0.92-0.99, p = 0.02), non-white ethnicity (HR 0.11, 95% CI: 0.02-0.84, p = 0.03), and HLA mismatching (HR 0.80, 95% CI: 0.67-0.97, p = 0.02) were significantly associated with the development of PTLD. Patient survival was significantly decreased in patients with PTLD, with a one-, three-, and five-yr survival of 91%, 76%, and 70%, compared with 97%, 93%, and 88% in patients without PTLD (p < 0.001). PTLD is an uncommon but potentially lethal complication following pancreas transplantation. Patients with the risk factors identified should be monitored closely for the development of PTLD.

"Plasma cell hepatitis" in liver allografts: identification and characterization of an IgG4-rich cohort.

Plasma cell hepatitis (PCH), also known as "de novo autoimmune" hepatitis, is an increasingly recognized, but suboptimally named and poorly understood, category of late allograft dysfunction strongly resembling autoimmune hepatitis (AIH): They share plasma-cell-rich necro-inflammatory activity on biopsy, autoantibodies and steroid responsiveness, but overlap with rejection is problematic. A retrospective study of clinical, serological, histopathological and IgG4 immunohistological features of PCH (n = 20) in liver allograft recipients, native liver AIH (n = 19) and plasma-cell-rich renal allograft rejection (n = 20) showed: (1) high frequency (44%) of HLA-DR15; (2) less female predominance (p = 0.03) and (3) n = 9/20 PCH recipients showed >25 IgG4+ plasma cells/high-power field (IgG4+ PCH) versus AIH (n = 1/19, p = 0.008) or plasma-cell-rich kidney rejection (n = 2/20, p = 0.03). The IgG4+ PCH (n = 9) subgroup showed lower alanine transaminase (ALT) (p < 0.01) and aspartate transaminase (AST) (p < 0.05) at index biopsy but (a) higher plasma cell number/percentage, (b) more aggressive-appearing portal/periportal and perivenular necro-inflammatory activity and (c) more severe portal/periportal fibrosis than IgG4- PCH (n = 11). Significant demographic, histopathologic and plasma cell phenotype differences between PCH and AIH suggest distinct pathogenic mechanisms for at least the IgG4+ PCH subgroup likely representing an overlap between allo- and auto-immunity. IgG4+ PCH was associated with fibrosis, but also highly responsive to increased immunosuppression.

A comparison of DXA and CT based methods for estimating the strength of the femoral neck in post-menopausal women.

UNLABELLED: The study goal was to compare simple two-dimensional (2D) analyses of bone strength using dual energy x-ray absorptiometry (DXA) data to more sophisticated three-dimensional (3D) finite element analyses using quantitative computed tomography (QCT) data. DXA- and QCT-derived femoral neck geometry, simple strength indices, and strength estimates were well correlated. INTRODUCTION: Simple 2D analyses of bone strength can be done with DXA data and applied to large data sets. We compared 2D analyses to 3D finite element analyses (FEA) based on QCT data. METHODS: Two hundred thirteen women participating in the Study of Women's Health Across the Nation (SWAN) received hip DXA and QCT scans. DXA BMD and femoral neck diameter and axis length were used to estimate geometry for composite bending (BSI) and compressive strength (CSI) indices. These and comparable indices computed by Hip Structure Analysis (HSA) on the same DXA data were compared to indices using QCT geometry. Simple 2D engineering simulations of a fall impacting on the greater trochanter were generated using HSA and QCT femoral neck geometry; these estimates were benchmarked to a 3D FEA of fall impact. RESULTS: DXA-derived CSI and BSI computed from BMD and by HSA correlated well with each other (R=0.92 and 0.70) and with QCT-derived indices (R=0.83-0.85 and 0.65-0.72). The 2D strength estimate using HSA geometry correlated well with that from QCT (R=0.76) and with the 3D FEA estimate (R=0.56). CONCLUSIONS: Femoral neck geometry computed by HSA from DXA data corresponds well enough to that from QCT for an analysis of load stress in the larger SWAN data set. Geometry derived from BMD data performed nearly as well. Proximal femur breaking strength estimated from 2D DXA data is not as well correlated with that derived by a 3D FEA using QCT data.

Re-examination of the lymphocytotoxic crossmatch in liver transplantation: can C4d stains help in monitoring?

C4d-assisted recognition of antibody-mediated rejection (AMR) in formalin-fixed paraffin-embedded tissues (FFPE) from donor-specific antibody-positive (DSA+) renal allograft recipients prompted study of DSA+ liver allograft recipients as measured by lymphocytotoxic crossmatch (XM) and/or Luminex. XM results did not influence patient or allograft survival, or cellular rejection rates, but XM+ recipients received significantly more prophylactic steroids. Endothelial C4d staining strongly correlates with XM+ (<3 weeks posttransplantation) and DSA+ status and cellular rejection, but not with worse Banff grading or treatment response. Diffuse C4d staining, XM+, DSA+ and ABO- incompatibility status, histopathology and clinical-serologic profile helped establish an isolated AMR diagnosis in 5 of 100 (5%) XM+ and one ABO-incompatible, recipients. C4d staining later after transplantation was associated with rejection and nonrejection-related causes of allograft dysfunction in DSA- and DSA+ recipients, some of whom had good outcomes without additional therapy. Liver allograft FFPE C4d staining: (a) can help classify liver allograft dysfunction; (b) substantiates antibody contribution to rejection; (c) probably represents nonalloantibody insults and/or complete absorption in DSA- recipients and (d) alone, is an imperfect AMR marker needing correlation with routine histopathology, clinical and serologic profiles. Further study in late biopsies and other tissue markers of liver AMR with simultaneous DSA measurements are needed.

longitudinal analysis of levels of immunoglobulins against BK virus capsid proteins in kidney transplant recipients.

This study sought to evaluate serology and PCR as tools for measuring BK virus (BKV) replication. Levels of immunoglobulin G (IgG), IgM, and IgA against BKV capsids were measured at five time points for 535 serial samples from 107 patients by using a virus-like particle-based enzyme-linked immunosorbent assay. Viral DNA in urine and plasma samples was quantitated. The seroconversion rate was 87.5% (14/16); 78.6% (11/14) and 14.3% (2/14) of patients who seroconverted developed viruria and viremia, respectively. Transient seroreversion was observed in 18.7% of patients at 17.4 +/- 11.9 weeks posttransplant and was not attributable to loss of antigenic stimulation, changes in immunosuppression, or antiviral treatment. Titers for anti-BK IgG, IgA, and IgM were higher in patients with BKV replication than in those without BKV replication. A rise in the optical density (OD) of anti-BK IgA (0.19), IgM (0.04), or IgG (0.38) had a sensitivity of 76.6 to 88.0% and a specificity of 71.7 to 76.1% for detection of viruria. An anti-BK IgG- and IgA-positive phenotype at week 1 was less frequent in patients who subsequently developed viremia (14.3%) than in those who subsequently developed viruria (42.2%) (P = 0.04). Anti-BK IgG OD at week 1 showed a weak negative correlation with peak urine viral load (r = -0.25; P = 0.05). In summary, serial measurements of anti-BKV immunoglobulin class (i) detect onset of viral replication, (ii) document episodes of seroreversion, and (iii) can potentially provide prognostic information.

Recurrent hepatitis C in liver allografts: prospective assessment of diagnostic accuracy, identification of pitfalls, and observations about pathogenesis.

RATIONALE AND DESIGN: The accuracy of a prospective histopathologic diagnosis of rejection and recurrent hepatitis C (HCV) was determined in 48 HCV RNA-positive liver allograft recipients enrolled in an "immunosuppression minimization protocol" between July 29, 2001 and January 24, 2003. Prospective entry of all pertinent treatment, laboratory, and histopathology results into an electronic database enabled a retrospective analysis of the accuracy of histopathologic diagnoses and the pathophysiologic relationship between recurrent HCV and rejection. RESULTS: Time to first onset of acute rejection (AR) (mean, 107 days; median, 83 days; range, 7-329 days) overlapped with the time to first onset of recurrent HCV (mean, 115 days; median, 123 days; range, 22-315 days), making distinction between the two difficult. AR and chronic rejection (CR) with and without co-existent HCV showed overlapping but significantly different liver injury test profiles. One major and two minor errors occurred (positive predictive values for AR = 91%; recurrent HCV = 100%); all involved an overdiagnosis of AR in the context of recurrent HCV. Retrospective analysis of the mistakes showed that major errors can be avoided altogether and the impact of unavoidable minor errors can be minimized by strict adherence to specific histopathologic criteria, close clinicopathologic correlation including examination of HCV RNA levels, and a conservative approach to the use of additional immunosuppression. In addition, histopathologic diagnoses of moderate and severe AR and CR were associated with relatively low HCV RNA levels, whereas relatively high HCV RNA levels were associated with a histopathologic diagnosis of hepatitis alone, particularly the cholestatic variant of HCV. CONCLUSIONS: Liver allograft biopsy interpretation can rapidly and accurately distinguish between recurrent HCV and AR/CR. In addition, the histopathologic observations suggest that the immune mechanism responsible for HCV clearance overlap with those leading to significant rejection.

Real-time monitoring of acute liver-allograft rejection using the Banff schema.

BACKGROUND: The Banff schema is the internationally accepted standard for grading acute liver-allograft rejection, but it has not been prospectively tested. METHODS: Complete Banff grading was prospectively applied to 2,038 liver-allograft biopsies from 901 adult tacrolimus-treated primary hepatic allograft recipients between August 1995 and September 2001. Histopathologic data was melded with demographic, clinical, and laboratory data into a database on an ongoing basis using locally developed software. RESULTS: Acute rejection developed in 575 of 901 (64%) patients and the worst grade was mild in 422 of 575 (73%). At least one episode of moderate or severe acute rejection developed in 153 of 901 (17%) patients and most episodes, irrespective of severity, occurred within the first year after transplantation. Patients with moderate or severe acute rejection showed higher alanine aminotransferase (P =0.007) and aspartate aminotransferase ( P=0.07) levels and were more likely to develop perivenular fibrosis on follow-up biopsies (P =0.001) and graft failure from acute or chronic rejection ( P=0.004) than those with mild rejection. Regardless of severity, 80% of patients with acute rejection did not develop significant fibrosis in follow-up biopsies, and graft failure from acute or chronic rejection occurred in only 11 of 901 (1%) allografts. CONCLUSIONS: Most acute-rejection episodes are mild and do not lead to clinically significant architectural sequelae. When tested prospectively under real-life and -time conditions, the Banff schema can be used to identify those few patients who are potentially at risk for more significant problems. Creation, capture, and integration of non-free text, or "digital," pathology data can be used to prospectively conduct outcomes-based research in transplantation.

Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence.

BACKGROUND: Alcoholic liver disease has emerged as a leading indication for hepatic transplantation, although it is a controversial use of resources. We aimed to examine all aspects of liver transplantation associated with alcohol abuse. METHODS: Retrospective cohort analysis of 123 alcoholic patients with a median of 7 years follow-up at one center. RESULTS: In addition to alcohol, 43 (35%) patients had another possible factor contributing to cirrhosis. Actuarial patient and graft survival rates were, respectively, 84% and 81% (1 year); 72% and 66% (5 years); and 63% and 59% (7 years). After transplantation, 18 patients (15%) manifested 21 noncutaneous de novo malignancies, which is significantly more than controls (P=0.0001); upper aerodigestive squamous carcinomas were overrepresented (P=0.03). Thirteen patients had definitely relapsed and three others were suspected to have relapsed. Relapse was predicted by daily ethanol consumption (P=0.0314), but not by duration of pretransplant sobriety or explant histology. No patient had alcoholic hepatitis after transplantation and neither late onset acute nor chronic rejection was significantly increased. Multiple regression analyses for predictors of graft failure identified major biliary/vascular complications (P=0.01), chronic bile duct injury on biopsy (P=0.002), and pericellular fibrosis on biopsy (P=0.05); graft viral hepatitis was marginally significant (P=0.07) on univariate analysis. CONCLUSIONS: Alcoholic liver disease is an excellent indication for liver transplantation in those without coexistent conditions. Recurrent alcoholic liver disease alone is not an important cause of graft pathology or failure. Potential recipients should be heavily screened before transplantation for coexistent conditions (e.g., hepatitis C, metabolic diseases) and other target-organ damage, especially aerodigestive malignancy, which are greater causes of morbidity and mortality than is recurrent alcohol liver disease.

Hepatocellular carcinomas in native livers from patients treated with orthotopic liver transplantation: biologic and therapeutic implications.

The gross and histopathologic characteristics of 212 nonfibrolamellar hepatocellular carcinomas (HCCs) discovered in native livers removed at the time of liver transplantation were correlated with features of invasive growth and tumor-free survival. The results show that most HCCs begin as small well-differentiated tumors that have an increased proliferation rate and induce neovascularization, compared with the surrounding liver. But at this stage, they maintain a near-normal apoptosis/mitosis ratio and uncommonly show vascular invasion. As tumors enlarge, foci of dedifferentiation appear within the neoplastic nodules, which have a higher proliferation rate and show more pleomorphism than surrounding better-differentiated areas. Vascular invasion, which is the strongest predictor of disease recurrence, correlates significantly with tumor number and size, tumor giant cells and necrosis, the predominant and worst degree of differentiation, and the apoptosis/mitosis ratio. In the absence of macroscopic or large vessel invasion, largest tumor size (P <.006), apoptosis/mitosis ratio (P <.03), and number of tumors (P <.04) were independent predictors of tumor-free survival and none of 24 patients with tumors having an apoptosis/mitosis ratio greater than 7.2 had recurrence. A minority of HCCs (<15%) quickly develop aggressive features (moderate or poor differentiation, low apoptosis/mitosis ratio, and vascular invasion) while still small, similar to flat carcinomas of the bladder and colon. In conclusion, hepatic carcinogenesis in humans is a multistep and multifocal process. As in experimental animal studies, aggressive biologic behavior (vascular invasion and recurrence) correlates significantly with profound alterations in the apoptosis/mitosis ratio and with architectural and cytologic alterations that suggest a progressive accumulation of multiple genetic abnormalities.

Does tacrolimus offer virtual freedom from chronic rejection after primary liver transplantation? Risk and prognostic factors in 1,048 liver transplantations with a mean follow-up of 6 years.

Tacrolimus has proven to be a potent immunosuppressive agent in liver transplantation (LT). Its introduction has led to significantly less frequent and severe acute rejection. Little is known about the rate of chronic rejection (CR) in primary LT using tacrolimus therapy. The aim of the present study is to examine the long-term incidence of CR, risk factors, prognostic factors, and outcome after CR. The present study evaluated the development of CR in 1,048 consecutive adult primary liver allograft recipients initiated and mostly maintained on tacrolimus-based immunosuppressive therapy. They were evaluated with a mean follow-up of 77.3 +/- 14.7 months (range, 50.7 to 100.1 months). To assess the impact of primary diagnosis on the rate and outcome of CR, the population was divided into 3 groups. Group I included patients with hepatitis C virus (HCV)- or hepatitis B virus (HBV)-induced cirrhosis (n = 312); group II included patients diagnosed with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or autoimmune hepatitis (AIH; n = 217); and group III included patients with all other diagnoses (n = 519). Overall, 32 of 1,048 patients (3.1%) developed CR. This represented 13 (4.1%), 12 (5.5%), and 7 patients (1.3%) in groups I, II, and III, respectively. The relative risk for developing CR was 3.2 times greater for group I and 4.3 times greater for group II compared with group III. This difference was statistically significant (P =.004). The incidence of acute rejection and total number of acute rejection episodes were significantly greater in patients who developed CR compared with those who did not (P <.0001). Similarly, the mean donor age for CR was significantly older than for patients without CR (43.0 v 36.2 years; P =.02). Thirteen of the 32 patients (40.6%) who developed CR retained their original grafts for a mean period of 54 +/- 25 months after diagnosis. Seven patients (21.9%) underwent re-LT, and 12 patients (38.3%) died. Serum bilirubin levels and the presence of arteriopathy, arterial loss, and duct loss on liver biopsy at the time of diagnosis of CR were significantly greater among the 3 groups of patients. In addition, patient and graft survival for group I were significantly worse compared with groups II and III. We conclude that CR occurred rarely among patients maintained long term on tacrolimus-based immunosuppressive therapy. When steroid use is controlled, the incidence of acute rejection, mean donor age, HBV- and/or HCV-induced cirrhosis, or a diagnosis of PBC, PSC, or AIH were found to be predictors of CR. Greater values for serum bilirubin level, duct loss, arteriopathy, arteriolar loss, and presence of HCV or HBV were found to be poor prognostic factors for the 3 groups; greater total serum bilirubin value (P =.05) was the only factor found to be significant between patients who had graft loss versus those who recovered.

Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs.

Early chronic liver allograft rejection (CR) is characterized by distinctive cytological changes in biliary epithelial cells (BECs) that resemble cellular senescence, in vitro, and precede bile duct loss. If patients suffering from early CR are treated aggressively, the clinical and histopathological manifestations of CR can be completely reversed and bile duct loss can be prevented. We first tested whether the senescence-related p21(WAF1/Cip1) protein is increased in BECs during early CR, and whether treatment reversed the expression. The percentage of p21+ BECs and the number of p21+ BECs per portal tract is significantly increased in early CR (26 +/- 17% and 3.6 +/- 3.1) compared to BECs in normal liver allograft biopsies or those with nonspecific changes (1 +/- 1% and 0.1 +/- 0.3; P: < 0.0001 and P: < 0.02), chronic hepatitis C (2 +/- 3% and 0.7 +/- 1; P: < 0.0001 and P: < 0.04) or obstructive cholangiopathy (7 +/- 7% and 0.7 +/- 0.6; P: < 0.006 and P: = 0.04). Successful treatment of early CR is associated with a decrease in the percentage of p21+ BECs and the number of p21+ BECs per portal tract. In vitro, nuclear p21(WAF1/Cip1) expression is increased in large and multinucleated BECs, and is induced by transforming growth factor (TGF)-beta. TGF-beta1 also increases expression of TGF-beta receptor II, causes phosphorylation of SMAD-2 and nuclear translocation of p21(WAF1/Cip1), which inhibits BEC growth. Because conversion from cyclosporine to tacrolimus is an effective treatment for early CR, we next tested whether these two immunosuppressive drugs directly influenced BEC growth in vitro. The results show that cyclosporine, but not tacrolimus, stimulates BEC TGF-beta1 production, which in turn, causes BEC mito-inhibition and up-regulation of nuclear p21(WAF1/Cip1). In conclusion, expression of the senescence-related p21(WAF1/Cip1) protein is increased in BECs during early CR and decreases with successful recovery. Replicative senescence accounts for the characteristic BEC cytological alterations used for the diagnosis of early CR and lack of a proliferative response to injury. The ability of cyclosporine to inhibit the growth of damaged BECs likely accounts for the relative duct sparing properties of tacrolimus.

Long-term survival after liver transplantation in 4,000 consecutive patients at a single center.

OBJECTIVE: To evaluate the long-term survival outcomes of a large cohort of liver transplant recipients and to identify static and changing factors that influenced these outcomes over time. SUMMARY BACKGROUND DATA: Liver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, with continual improvements in patient survival as a result of advances in immunosuppression and medical management, technical achievements, and improvements in procurement and preservation. Although many reports, including registry data, have delineated short-term factors that influence survival, few reports have examined factors that affect long-term survival after liver transplantation. METHODS: Four thousand consecutive patients who underwent liver transplantation between February 1981 and April 1998 were included in this analysis and were followed up to March 2000. The effect of donor and recipient age at the time of transplantation, recipient gender, diagnosis, and year of transplantation were compared. Rates of retransplantation, causes of retransplantation, and cause of death were also examined. RESULTS: The overall patient survival for the entire cohort was 59%; the actuarial 18-year survival was 48%. Patient survival was significantly better in children, in female recipients, and in patients who received transplants after 1990. The rates of retransplantation for acute or chronic rejection were significantly lower with tacrolimus-based immunosuppression. The risk of graft failure and death was relatively stable after the first year, with recurrence of disease, malignancies, and age-related complications being the major factors for loss. CONCLUSION: Significantly improved patient and graft survival has been observed over time, and graft loss from acute or chronic rejection has emerged as a rarity. Age-related and disease-related causes of graft loss represent the greatest threat to long-term survival.

Probing lung physiology with xenon polarization transfer contrast (XTC).

One of the major goals of hyperpolarized-gas MRI has been to obtain (129)Xe dissolved-phase images in humans. So far, this goal has remained elusive, mainly due to the low concentration of xenon that dissolves in tissue. A method is proposed and demonstrated in dogs that allows information about the dissolved phase to be obtained by imaging the gas phase following the application of a series of RF pulses that selectively destroy the longitudinal magnetization of xenon dissolved in the lung parenchyma. During the delay time between consecutive RF pulses, the depolarized xenon rapidly exchanges with the gas phase, thus lowering the gas polarization. It is demonstrated that the resulting contrast in the (129)Xe gas image provides information about the local tissue density. It is further argued that minor pulse-sequence modifications may provide information about the alveolar surface area or lung perfusion.

NMR of hyperpolarized (129)Xe in the canine chest: spectral dynamics during a breath-hold.

One of the major goals of hyperpolarized-gas MR imaging has been to obtain (129)Xe dissolved-phase images in humans. Since the dissolved-phase signal is much weaker than the gas-phase signal, highly optimized MR pulse sequences are required to obtain adequate images during a single breath-hold. In particular, a solid understanding of the temporal dynamics of xenon as it passes from the lung gas spaces into the parenchyma, the blood and other downstream compartments is absolutely essential. Spectroscopy experiments were performed in the canine chest to elucidate the behavior of xenon exchange in the lung. The experiments covered a time range from 1 ms to 9 s and therefore considerably extend the data currently available in the literature. It was found that the integrals of the dissolved-phase resonances approached plateau values within approximately 200 ms, and then increased again after approximately 1 s. This behavior suggests an early saturation of the parenchyma before xenon reaches downstream compartments. Mono-exponential recovery curves with time constants on the order of 100 ms were fit to the data. These results potentially provide information on several underlying physiological parameters of the lung, including the parenchymal and blood volumes as well as the diffusion properties of lung tissue.

Chronic liver allograft rejection in a population treated primarily with tacrolimus as baseline immunosuppression: long-term follow-up and evaluation of features for histopathological staging.

BACKGROUND: Predisposing factors, long-term occurrence, and histopathological changes associated with recovery or progression to allograft failure from chronic rejection (CR) were studied in adult patients treated primarily with tacrolimus. METHODS: CR cases were identified using stringent criteria applied to a retrospective review of computerized clinicopathological data and slides. RESULTS: After 1973 days median follow-up, 35 (3.3%) of 1049 primary liver allograft recipients first developed CR between 16 and 2532 (median 242) days. The most significant risk factors for CR were the number (P<0.001) and histological severity (P<0.005) of acute rejection episodes and donor age >40 years (P<0.03). Other demographic and matching parameters were not associated with CR in this cohort. Ten patients died with, but not of, CR. Eight required retransplantation because of CR at a median of 268 days. Ten resolved either histologically or by normalization of liver injury tests over a median of 548 days. CR persisted for 340 to 2116 days in the remaining seven patients. More extensive bile duct loss (P<0.01), smallarterial loss (P<0.03), foam cell clusters (P<0.01) and higher total bilirubin (P<0.02) and aspartate aminotransferase (P<0.03) were associated with allograft failure from CR. CONCLUSIONS: Early chronic liver allograft rejection is potentially reversible and a combination of histological, clinical, and laboratory data can be used to stage CR. Unique immunological and regenerative properties of liver allografts, which lead to a low incidence and reversibility of early CR, can provide insights into transplantation biology.

Increasing effect of ethanol on 5-HT3 receptor-mediated 14C-guanidinium influx in N1E-115 neuroblastoma cells.

N1E-115 mouse neuroblastoma cells were used to study the influence of ethanol on the 5-HT- and veratridine-induced influx of 14C-guanidinium via the 5-HT3 receptor channel and the fast sodium channel, respectively. Ethanol (10-100 mM) concentration-dependently increased the 5-HT-induced 14C-guanidinium influx, leaving the basal and veratridine (100 microM)-induced influx unaffected. The increasing effect of ethanol (100 mM) was observed at all 5-HT concentrations investigated; accordingly, ethanol increased the maximum response to 5-HT. Whereas in the absence of ethanol the concentration-response curve for 5-HT was bell-shaped, this was no longer the case when ethanol (100 mM) was present in the incubation buffer; the descending branch of the concentration-response curve for 5-HT at concentrations above 300 microM was virtually no longer observed. When, in the presence of substance P (10 microM) the 5-HT-induced 14C-guanidinium influx was already enhanced, the ability of ethanol (100 mM) to increase the 5-HT-induced influx was considerably diminished (by 72%). Preincubation of N1E-115 cells with 5-HT caused a decay of the subsequent 5-HT response ("desensitization") which was dependent on the duration of preincubation; ethanol (100 mM) did not affect the rate of this decay of the 5-HT response. The 5-HT (30 microM)-induced 14C-guanidinium influx was also increased by methanol (100 mM) and n-propanol (100 mM). The rank order of the increasing effect of the n-alkanols (at 100 mM) was: methanol < ethanol < n-propanol; i.e. the degree of enhancement increased with the lipophilicity of the alcohols.(ABSTRACT TRUNCATED AT 250 WORDS)