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Biomedical subjects

S L Nyberg

Publications and source records attributed to S L Nyberg.

At least 19 recordsLinked to original sources
PubMed2006

Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus.

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus-MMF-prednisone to tacrolimus-MMF-prednisone. Eighty-one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow-up = 33 months; range 13-47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 +/- 19 mL/min vs. 63 +/- 18 mL/min, p = 0.57) or 2 years (61 +/- 17 mL/min vs. 61 +/- 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI-free regimen using sirolimus-MMF-prednisone produces similar acute rejection rates, graft survival and renal function 1-2 years after transplantation compared to tacrolimus-MMF-prednisone.

Adult↗
PubMed2004

Cathepsin B inactivation attenuates hepatocyte apoptosis and liver damage in steatotic livers after cold ischemia-warm reperfusion injury.

Hepatic steatosis predisposes the liver to cold ischemia-warm reperfusion (CI/WR) injury by unclear mechanisms. Because hepatic steatosis has recently been associated with a lysosomal pathway of apoptosis, our aim was to determine whether this cell-death pathway contributes to CI/WR injury of steatotic livers. Wild-type and cathepsin B-knockout (Ctsb(-/-)) mice were fed the methionine/choline-deficient (MCD) diet for 2 wk to induce hepatic steatosis. Mouse livers were stored in the University of Wisconsin solution for 24 h at 4 degrees C and reperfused for 1 h at 37 degrees C in vitro. Immunofluorescence analysis of the lysosomal enzymes cathepsin B and D showed a punctated intracellular pattern consistent with lysosomal localization in wild-type mice fed a standard diet after CI/WR injury. In contrast, cathepsin B and D fluorescence became diffuse in livers from wild-type mice fed MCD diet after CI/WR, indicating that lysosomal permeabilization had occurred. Hepatocyte apoptosis was rare in both normal and steatotic livers in the absence of CI/WR injury but increased in wild-type mice fed an MCD diet and subjected to CI/WR injury. In contrast, hepatocyte apoptosis and liver damage were reduced in Ctsb(-/-) and cathepsin B inhibitor-treated mice fed the MCD diet following CI/WR injury. In conclusion, these findings support a prominent role for the lysosomal pathway of apoptosis in steatotic livers following CI/WR injury.

Animals↗
PubMed2001

Thymoglobulin induction decreases rejection in solitary pancreas transplantation.

BACKGROUND: Solitary pancreas transplants, both pancreas transplant alone (PTA) and pancreas after kidney (PAK), have higher rejection rates and lower graft survivals than simultaneous pancreas-kidney transplants (SPK). The aim of this study is to compare three different antibody induction regimens in solitary pancreas transplant recipients and to assess the role of surveillance pancreas biopsies in the management of these patients. METHODS: Solitary pancreas transplant recipients between 01/98 to 02/00 (n=29) received induction with either daclizumab (1 mg/kg on day 0, 7, 14), OKT 3 (5 mg/day x0-7), or thymoglobulin (1.5 mg/kg/day x0-10). Maintenance immunosuppression was similar for the three groups. All rejections were biopsy-proven either by surveillance/protocol or when clinically indicated. RESULTS: The 1-year graft survival was 89.3% overall and 91.7% in the thymoglobulin group. Thymoglobulin significantly decreased rejection in the first 6 months when compared with OKT3 or daclizumab (7.7 vs. 60 vs. 50%). Acute rejections were seen on surveillance biopsies in the absence of biochemical abnormalities in 40% of patients. CONCLUSIONS: Thymoglobulin induction regimen led to a low incidence of acute rejection and a high rate of graft survival in solitary pancreas transplants. In addition, surveillance biopsies were useful in the detection of early acute rejection in the absence of biochemical abnormalities.

Adult↗
PubMed2001

Caspase inhibition reduces apoptotic death of cryopreserved porcine hepatocytes.

Cryopreserved porcine hepatocytes are a ready source of metabolic function for use in a bioartificial liver (BAL). However, cryopreservation is associated with a loss of hepatocyte viability. The mechanism of cell death during cryopreservation is incompletely understood, but may involve apoptosis through caspase activation. This study evaluates the cytoprotective effect of a global caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (ZVAD-fmk) during cryopreservation of porcine hepatocytes. Freshly isolated porcine hepatocytes (viability, 97.4% +/- 0.9%) were cryopreserved in 60 micromol/L ZVAD-fmk (+ZVAD group) or without ZVAD-fmk (-ZVAD group) for 24 to 72 hours. Apoptotic and necrotic death were both observed after thawing and after 24 hours of culture. Caspase 3-like activity was significantly reduced by ZVAD-fmk, and was associated with improved viability and reduced apoptotic death of porcine hepatocytes after cryopreservation. Mitochondrial membrane potential (MMP) was increased in cultures of porcine hepatocytes that were cryopreserved in ZVAD-fmk. These results demonstrate the following: 1) Caspase 3-like protease activation and apoptosis occurs in porcine hepatocytes during cryopreservation; and 2) mitochondrial injury in this process is reduced by caspase inhibition.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Donor scoring system for cadaveric renal transplantation.

We studied early renal function in 241 consecutive patients who received cadaveric renal transplants at two different transplantation centers (group 1, n = 90; group 2, n = 151). Univariate and multivariate analyses of data from group 1 showed a significant correlation between seven donor variables and early renal function after cadaveric renal transplantation. A scoring system was developed from these seven donor variables (cause of death, 0-6 points; history of hypertension, 0-6; final creatinine clearance before procurement, 0-6; age, 0-6; history of diabetes mellitus, 0-3; cold ischemia time, 0-3; and severity of renal artery plaque, 0-3). Data from group 2 were used to validate the donor scoring system and stratify cadaver kidneys on the basis of score: grade A, 0-5 points; grade B, 6-10; grade C, 11-15; and grade D, 16-32. A significant decline in early renal function was observed with increasing donor score and grade of cadaver kidney. In conclusion, a donor scoring system based on information available at the time of procurement can be used to estimate early graft function after cadaveric renal transplantation and may assist in the allocation of marginal organs.

Adolescent↗
PubMed2000

Influence of human fulminant hepatic failure sera on endogenous retroviral expression in pig hepatocytes.

A porcine endogenous retrovirus (PERV) has been shown to infect human embryonic kidney 293 (HEK293) cells in vitro. The PERV proviral sequence exists in the genome of all porcine cells, including hepatocytes used in a bioartificial liver (BAL). We examined the possibility of PERV infection in HEK293 cells during exposure to supernatant from cultured pig hepatocytes. Pig hepatocytes were cultured in media supplemented with serum from patients in fulminant hepatic failure (FHF) to simulate conditions of an extracorporeal BAL. Pig hepatocytes were cultured in serum-free media for 24 hours and then exposed to fresh medium containing serum from a patient with FHF (22 patients tested). Twenty-four hours later, supernatant was collected and analyzed by polymerase chain reaction (PCR), with and without reverse transcriptase. Primers targeting the pol gene of PERV were used for PCR. Products of amplification were detected by an enzyme-linked immunosorbent assay-based technique using an internal capture probe also targeting the pol gene. Levels of PERV sequences were estimated by serial dilution. All positive samples were tested for infectivity in HEK293 cells. Porcine kidney 15 cell supernatant and fresh culture media were studied as positive and negative controls, respectively. Pig hepatocytes were also studied in the absence of FHF sera and in the presence of mitogenic stimulation with phytohemagglutinin (PHA) and phorbol 12-myristate-13-acetate (PMA). PERV DNA and PERV RNA were detected in all supernatants of cultured pig hepatocytes. The level of PERV RNA in the supernatant of pig hepatocytes was not altered by exposure to human FHF serum or stimulation with PHA and PMA. In addition, PERV RNA was undetectable in the supernatant of HEK293 cells for up to 50 days after exposure to pig hepatocyte supernatant (with or without FHF sera). These findings show that production of PERV by cultured pig hepatocytes was unaffected by exposure to growth factors and cytokines present in human FHF sera.

Animals↗
PubMed2000

Cytoprotective influence of ZVAD-fmk and glycine on gel-entrapped rat hepatocytes in a bioartificial liver.

BACKGROUND: This study was designed to determine if an anti-necrotic compound, glycine, and/or an anti-apoptotic agent, ZVAD-fmk, improved the viability and function of hepatocytes in a bioartificial liver. METHODS: Isolated rat hepatocytes were entrapped in collagen gel (1.0-10.0 x 10(6) cells/mL) and cultured in serum-free medium (1:10 ratio of gel:media) supplemented with glycine alone, ZVAD-fmk alone, or glycine and ZVAD-fmk. The cytoprotective effects of glycine and ZVAD-fmk on gel-entrapped rat hepatocytes (GERH) were determined after anoxic exposure (0-20 hours). Cell functionality (measured by urea production), cell viability (quantitated by vital staining with fluorescein diacetate:ethidium bromide [FDA:EB]), and the mechanism of cell death (verified by electron microscopy and DNA fragmentation studies) were determined for each condition. RESULTS: The viability of GERH declined gradually and then stabilized 12 hours after hepatocyte isolation. The rate of urea production by GERH was directly proportional to the number of viable hepatocytes. Apoptotic death predominated at low cell density, and necrotic cell death became significant at high cell density. Hepatocyte necrosis became more significant after exposure to longer periods of anoxia (4, 8, 12, and 20 hours). ZVAD-fmk provided dose-dependent cytoprotection to GERH with an optimum benefit at a concentration of 60 mumol/L. After anoxic exposure or under high cell density culture, glycine demonstrated a maximum benefit of inhibiting necrosis at a concentration of 3 mmol/L. The beneficial effects of glycine and ZVAD-fmk were additive. CONCLUSIONS: The metabolic activity of a hepatocyte bioartificial liver may benefit from the use of cytoprotective agents such as ZVAD-fmk and glycine.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Pancreas transplantation for the prevention of diabetic nephropathy.

Diabetic nephropathy is the leading cause of kidney failure in the United States. Poor glycemic control, hypertension, and smoking have been implicated as risk factors for the development and progression of diabetic nephropathy in patients with type 1 diabetes mellitus. Improved medical therapy including angiotensin-converting enzyme inhibitors and tight glycemic control with use of intensive insulin therapy have been shown to reduce the progression of diabetic nephropathy substantially based on albumin excretion rates. Despite these improvements in medical management, many patients still experience progression from early diabetic nephropathy to end-stage renal disease. Successful pancreas transplantation leads to normal glycemic control in patients with type 1 diabetes, but historically it has generally been limited to patients with both kidney failure and diabetes. In this review of the current treatment of diabetic nephropathy, we examine the potential role of preemptive pancreas transplantation in patients with diabetic nephropathy.

Albuminuria↗
PubMed1999

Transfer of porcine endogenous retrovirus across hollow fiber membranes: significance to a bioartificial liver.

BACKGROUND: A porcine endogenous retrovirus (PERV) capable of infecting human cells has been identified. This study was designed to determine whether hollow fiber membranes, such as those used in a bioartificial liver, block the transfer of PERV. METHODS: Three hollow fiber cartridges (HFCs) were studied in duplicate: cellulose fibers with 70 kD nominal molecular weight cut-off (MWCO), polysulfone fibers with 400 kD MWCO, and mixed cellulose fibers with 200 nm porosity. PK15 cells (porcine kidney cell line), known to produce PERV, were grown in the intraluminal compartment of HFCs fiber cartridges. Samples of medium were collected from both intraluminal and extraluminal compartments of the HFCs fiber cartridge during 14 days of culture. Samples were screened for PERV using reverse transcription polymerase chain reaction. All positive samples were tested for PERV infectivity in human 293 cells. RESULTS: PERV was detected in all samples from the intraluminal space and all intraluminal samples seemed to infect 293 cells. All extraluminal samples from the fibers of 200 nm porosity tested positive for PERV. Detection of PERV in the extraluminal space was delayed by fibers of 400 kD MWCO and 70 kD MWCO until at least day 3 and day 7, respectively, after inoculation of PK15 cells. Positive extraluminal samples from fibers of 400 kD MWCO and 70 kD MWCO did not infect 293 cells. CONCLUSION: Pore size, membrane composition, and duration of exposure influenced the transfer of PERV across HFCs. Some HFCs decrease the risk of viral exposure to patients during bioartificial liver therapy.

Animals↗
PubMed1998

Brain lactate by magnetic resonance spectroscopy during fulminant hepatic failure in the dog.

A noninvasive test is needed to assess the severity of encephalopathy during fulminant hepatic failure. This feasibility study was designed to compare a noninvasive test, brain lactate measurement by magnetic resonance spectroscopy, with intracranial pressure monitoring in a large animal model of fulminant hepatic failure. Five dogs received an intraventricular catheter for intracranial pressure measurement. Liver injury was induced by intravenous bolus of D-galactosamine. Brain lactate concentrations were determined by magnetic resonance spectroscopy for up to 48 hours after D-galactosamine administration (t = 0 hour). A dose of D-galactosamine exceeding 1.5 g/kg resulted in fulminant hepatic failure. Brain lactate levels increased to > 10 mmol/L in the two dogs that developed severe intracranial hypertension of > 50 mm Hg and sustained cerebral perfusion pressures of < 40 mm Hg. Both dogs experienced brain death, 42 and 48 hours after the administration of D-galactosamine. Brain lactate concentrations determined by magnetic resonance spectroscopy were in agreement with brain tissue concentrations of lactate determined by high-performance liquid chromatography at necropsy. Plasma lactate concentrations were only mildly elevated (3.2 and 4.2 mmol/L) at the time of brain death. Elevated levels of brain lactate are associated with intracranial hypertension and poor neurological outcome during fulminant hepatic failure.

Animals↗
PubMed1998

Resolution improvements in in vivo 1H NMR spectra with increased magnetic field strength.

The measurement of cerebral metabolites using highly homologous localization techniques and similar shimming methods was performed in the human brain at 1.5 and 4 T as well as in the dog and rat brain at 9.4 T. In rat brain, improved resolution was achieved by shimming all first- and second-order shim coils using a fully adiabatic FASTMAP sequence. The spectra showed a clear improvement in spectral resolution for all metabolite resonances with increased field strength. Changes in cerebral glutamine content were clearly observed at 4 T compared to 1.5 T in patients with hepatic encephalopathy. At 9.4 T, glutamine H4 at 2.46 ppm was fully resolved from glutamate H4 at 2.37 ppm, as was the potential resonance from gamma-amino-butyric acid at 2.30 ppm and N-acetyl-aspartyl-glutamate at 2.05 ppm. Singlet linewidths were found to be as low as 6 Hz (0.015 ppm) at 9.4 T, indicating a substantial decrease in ppm linewidth with field strength. Furthermore, the methylene peak of creatine was partially resolved from phosphocreatine, indicating a close to 1:1 relationship in gray matter. We conclude that increasing the magnetic field strength increases spectral resolution also for 1H NMR, which can lead to more than linear sensitivity gains.

Adult↗
PubMed1998

Hepatocyte liver-assist systems--a clinical update.

Liver failure is a serious problem that affects thousands of people in the United States each year. Other than liver transplantation, a supportive therapy has been unavailable for patients with liver failure that is refractory to medical treatment. An apparent solution to this problem is a hepatocyte liver-assist system. Such a system is composed of mammalian hepatocytes loaded in a mechanical apparatus, such as a hollow fiber cartridge. During extracorporeal perfusion of the system, the hepatocytes provide metabolic function to the patient with liver failure. At least two extracorporeal hepatocyte systems have shown promise in human clinical trials of acute liver failure. In fact, one system has gained approval from the Food and Drug Administration for testing in a randomized multicenter clinical trial. In this article, key issues of clinical testing are reviewed, and major contributions and questions that remain unresolved are emphasized.

Clinical Trials as Topic↗