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J Rozga

Publications and source records attributed to J Rozga.

At least 19 recordsLinked to original sources
PubMed2001

Bioartificial liver support.

Orthotopic liver transplantation is the only definitive therapy for patients with fulminant hepatic failure (FHF). However, due to shortage of organs, a large number of patients die before a liver can be procured for transplantation. In FHF the need for a liver is particularly urgent because of rapid deterioration in the patients' condition with the onset of cerebral edema and intracranial hypertension leading to irreversible brain damage. It is thus necessary to develop an extracorporeal liver support system to help maintain patients alive and neurologically intact until an organ becomes available for transplantation. Multiple attempts have been made, ranging from the use of plasma exchange to utilization of charcoal columns and extracorporeal devices loaded with liver tissue to develop liver support systems for treating patients with acute severe liver failure. None of these systems has achieved wide clinical use, and FHF due to multiple causes continues to be associated with significant morbidity and mortality. In this paper, the authors review the history of extracorporeal liver support for acute liver failure and discuss their experience with a hollow fiber bioartificial liver support system utilizing porcine hepatocytes in the treatment of patients with acute liver failure.

Acute Disease↗
PubMed2000

Inhibition of signal transducer and activator transcription factor 3 in rats with acute hepatic failure.

In fulminant hepatic failure, survival is not possible without recovery of sufficient hepatocyte mass. Remarkably, only a few studies exist that provide insight into the mechanisms that control proliferation of residual hepatocytes after extensive hepatocyte loss. In this regard, the role of growth-regulatory factors, including pro-inflammatory cytokines such as interleukin-6 (IL-6), is not well understood. In the present study we show that in rats with critically low (10%) hepatocyte mass, whether with or without ongoing liver cell necrosis, inhibition of liver regeneration is associated with early and sustained increase in blood IL-6 levels. Under these conditions, the signal transducer and activator of transcription (Stat3) DNA binding activity was lowered at the time of G1/S cell-cycle transition. We further demonstrate that the protein inhibitor of activated Stat3 (PIAS3) and the suppressor of cytokine signaling (SOCS-1) were up-regulated early after induction of liver failure (6-12 h). In vitro, IL-6 induced PIAS3 expression in HGF stimulated rat hepatocytes. These findings suggest that after massive hepatocyte loss, an early and rapid rise in blood IL-6 levels may weaken the hepatic regenerative response through up-regulation of Stat3 inhibitors PIAS3 and SOCS-1.

Animals↗
PubMed1999

Intracranial pressure during liver transplantation for fulminant hepatic failure.

During orthotopic liver transplantation (OLT) for fulminant hepatic failure (FHF), some patients develop cerebral injury secondary to intracranial hypertension. We monitored intracranial pressure (ICP) and cerebral perfusion pressure (CPP) before and during OLT in 12 FHF patients undergoing transplantation. All four patients who had normal ICP preoperatively maintained normal ICP/CPP throughout OLT. During OLT, four of the eight patients with pretransplant intracranial hypertension had six episodes of ICP increase. These episodes of intracranial hypertension occurred during failing liver dissection (n=3) and graft reperfusion (n=3). At the end of the anhepatic phase, the ICP was lower than the preoperative ICP in all patients, and was below 15 mmHg in all but one patient. These data suggest that in FHF patients who develop intracranial hypertension before OLT, dissection of the native liver and graft reperfusion are associated with a risk of brain injury resulting from intracranial hypertension and cerebral hypoperfusion.

Adult↗
PubMed1999

Bioartificial liver treatment in rats with fulminant hepatic failure: effect on DNA-binding activity of liver-enriched and growth-associated transcription factors.

BACKGROUND: We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobe necrosis. In FHF rats, lack of regeneration of the residual liver was associated with delayed expression of HGF and HGF receptor c-met and elevated blood HGF and TGF-beta1 levels. We then found that intrasplenic hepatocyte transplantation prolonged survival in FHF rats and triggered hepatocyte proliferation in the native liver. The latter effect was associated with accelerated expression of HGF and c-met mRNA in the liver and lowering of blood HGF and TGF-beta1 levels. In the present study we show that in FHF rats, treatment with a bioartificial liver (BAL) had similar effects. MATERIALS AND METHODS: FHF was induced in inbred Lewis rats and after 4 h, Group 1 rats were subjected to a 4-h whole blood perfusion through the BAL loaded with 3 x 10(8) microcarrier-attached syngeneic hepatocytes, whereas Group 2 control rats were treated with the BAL containing microcarriers only. RESULTS: Compared to sham-BAL-treated rats, the test rats lived longer (28 +/- 5 vs 17 +/- 2 h; P = 0.0005), had better coagulation parameters, maintained higher body core temperature, and showed decreased plasma TGF-beta1 levels. In addition, their liver remnants were HGF positive and showed increased DNA binding of transcription factors engaged in the modulation of hepatocyte proliferation (e.g., STAT3) and liver-specific gene expression (e.g., HNF1, HNF4, C/EBP). CONCLUSIONS: This study demonstrates that hepatocyte-based extracorporeal support not only can provide metabolic support by increasing the available functional liver mass but also is capable of modifying humoral and molecular mechanisms which are responsible for proliferation and organ-specific functions of residual hepatocytes.

Animals↗
PubMed1999

Transforming growth factor beta1 helps maintain differentiated functions in mitogen-treated primary rat hepatocyte cultures.

Mechanisms that control function and repair of the injured liver remain unclear. We hypothesized that after liver injury, elevated blood TGF-beta1 levels may reflect an adaptive response to help maintain differentiated functions in surviving hepatocytes affected by excessive amounts of HGF. We thus studied the effect of HGF, EGF, TGF-beta1, HGF + TGF-beta1, or EGF + TGF-beta1 on the expression of liver-enriched transcription factors and genes which remain under their regulatory activity. The peak [3H]thymidine uptake induced by 20 ng/ml of either HGF or EGF was seen after 72 h; however, DNA binding of C/EBP and HNF1 decreased already after 6 h (electrophoretic mobility shift assay). Addition of TGF-beta1 antagonized these effects. Also at the mRNA level, TGF-beta1 counteracted at one point or another the decrease in C/EBPalpha, C/EBPbeta, HNF1beta, and HNF4 expression; HNF1alpha and COUP-TF showed similar responses and, additionally, were downregulated by TGF-beta1 at 24 h (Northern blot). Albumin and apolipoprotein B mRNA levels were decreased after 24-h treatment with HGF, whereas addition of TGF-beta1 increased their levels. The same pattern was found with EGF, but not until 48 h. PEPCK mRNA was dramatically lowered with either EGF or HGF, and TGF-beta1 did not counteract these effects. Id-1 was expressed only in cultures treated for 24 and 48 h with both the mitogen (EGF, HGF) and TGF-beta1 and in those treated for 48 h with TGF-beta1 alone.

Animals↗
PubMed1999

Miniature laparoscopy: quo vadis? The basic parameters of image relay and display systems.

BACKGROUND: Endoscopy created a new epoch in gynecology and general surgery. After a decade of learning experiences and expansion of laparoscopic surgery in a variety of areas, the need to further miniaturize the endosurgical approach surfaced. This, however, requires a better knowledge about the tools that surgeons must or wish to employ in minimal access surgery. For miniaturization, the quality of the image on the TV monitor is critical. METHODS: We examined two miniature optical systems: the quartz-fiber (2.0-2.2 mm) and the rod-lens (3.3-mm) relay technologies. RESULTS: The smaller quartz telescope image was found to be brighter but lacking in other important features that are important in diagnosis and surgical manipulations. CONCLUSIONS: Because the detail, clarity, and the color display affect decision making and the course taken, the brand of telescope has to be selected according to the particular application. By following this guideline, a number of diagnostic and therapeutic procedures can be performed using smaller instruments with the patient under local anesthesia with sedation or under general anesthesia in an outpatient setting.

Endoscopes↗
PubMed1999

Clinical use of a bioartificial liver in the treatment of acetaminophen-induced fulminant hepatic failure.

Patients with acetaminophen-induced fulminant hepatic failure (FHF) who meet the King's College Hospital criteria have a high mortality risk (>90%) if they do not undergo liver transplantation. We have developed a treatment strategy for these patients based on the use of an extracorporeal bioartificial liver (BAL) support system. In this study, we report the results of the clinical application of BAL support in patients with acetaminophen-induced FHF. All patients were admitted to a dedicated surgical intensive care unit. They were evaluated for urgent liver transplantation and received the standard medical measures, including N-acetylcysteine administration and intracranial pressure monitoring. Moreover, they underwent daily 6-hour BAL treatments. Eight patients were treated. Three patients were bridged to liver transplantation, and five patients recovered without a transplant. All patients experienced neurological and metabolic improvement after treatments with the BAL support system. The BAL support system seems to improve the outcome of high-risk patients with acetaminophen-induced FHF, even in the absence of liver transplantation. Avoiding liver transplantation is particularly important in an era of organ shortage and high cost of transplants.

Acetaminophen↗
PubMed1998

Intrasplenic transplantation of allogeneic hepatocytes prolongs survival in anhepatic rats.

To examine whether hepatocytes transplanted in the spleen can function as an ectopic liver, we performed hepatocyte transplantation in rats that were rendered anhepatic. Total hepatectomy was performed by using a novel single-stage technique. Following hepatectomy, Group 1 rats (n = 16) were monitored until death to determine survival time without prior intervention. Group 2 anhepatic rats (n = 20) were sacrificed at various times to measure blood hepatocyte growth factor (HGF) and transforming growth factor beta1 (TGF-beta1) levels. Group 3 (n = 16) rats received intrasplenic injection of isolated hepatocytes (2.5 x 10(7) cells/rat) followed by total hepatectomy after 3 days. Group 4 (n = 12) sham-transplanted rats received intrasplenic saline infusion, and after 3 days they were rendered anhepatic. Group 2, 3, and 4 rats were maintained on daily Cyclosporine A (10 mg/kg; intramuscularly). Group 1 anhepatic rats survived for 22.4 +/- 5.2 hours (standard deviation). The anhepatic state was associated with a progressive and statistically significant rise in blood HGF and TGF-beta1 levels. Rats that received hepatocyte transplantation before total hepatectomy had a significantly longer survival time than sham-transplanted anhepatic controls (34.1 +/- 8.5 vs. 15.5 +/- 4.8 hrs, P < .01). Additionally, at 12 hours post-hepatectomy, transplanted rats had significantly lower blood ammonia, prothrombin time, international normalized ratio, and TGF-beta1 levels when compared with sham-transplanted controls. In conclusion, intrasplenic transplantation of allogeneic hepatocytes prolonged survival, improved blood chemistry, and lowered blood TGF-beta1 levels in rats rendered anhepatic.

Ammonia↗
PubMed1998

In vitro morphological and functional characterization of isolated porcine hepatocytes for extracorporeal liver support: bile acid uptake and conjugation.

Recently, researchers have focused on the use of bioartificial liver (BAL) to support patients with fulminant hepatic failure (FHF). We have developed a cell-based BAL, consisting of porcine hepatocytes in a hollow-fiber bioreactor. To better characterize BAL metabolic functions in vitro, bioreactors were inoculated with 48-h-cultured, microcarrier-attached hepatocytes and perifused with recirculating human plasma that contained either 1 microCi of [24-14C] plasma-enriched cholate or 1 microCi of [24-14C] plasma-enriched taurocholate. Bile acids were sampled hourly and separated into four fractions (unconjugated, glycoconjugated, tauroconjugated, and sulfated) for radioactivity determination. Following 3 h perifusion, the glycoconjugated and sulfated bile acid fractions in the bioreactor extrafiber space were significantly elevated when compared to the recirculating plasma. During perifusion with taurocholate-enriched plasma, a relative decrease in the tauroconjugated fraction and an increase in the glycoconjugated fraction were observed. Cholate was accumulated by hepatocytes to a level threefold lower than taurocholate; however, a significant proportion of radioactivity (<25%) was detected in the glycoconjugated fraction. Ultrastructural examination of microcarrier-attached hepatocytes illustrated that the features typical of metabolically active liver cells were maintained. Our data demonstrate the ability of BAL to clear bile acids from the circulation, to accumulate cholate and taurocholate, and to conjugate a substantial amount of cholic acid.

Animals↗
PubMed1998

Artificial liver: review and Cedars-Sinai experience.

During the past decade, whole organ transplantation has become the only clinically effective method of treating fulminant hepatic failure and chronic liver failure due to specific genetic, hepatocellular, and anatomic defects of liver function. However, wider application of liver transplantation is restricted by shortage of organ donors, high cost, relatively high morbidity, and need for life-long immunosuppression. As a result, investigators have attempted to develop alternative methods to treat liver insufficiency. These ranged from use of plasma exchange to utilization of detoxification columns and extracorporeal devices loaded with various liver tissue preparations. Recently, advances in hepatocyte isolation and culture techniques, improved understanding of hepatocyte-matrix interactions, availability of new biomaterials, improved hollow-fiber technology, and better understanding of flow and mass transport across semipermeable membranes have resulted in the development of a new generation of liver assist devices. Some of these devices, including the one developed by the authors, are currently being tested in the clinical setting. In this paper, the past experience with liver support systems is reviewed, the present status of the field is critically examined, and the results of a phase I clinical trial with the bioartificial liver, utilizing primary porcine hepatocytes, are summarized.

Adult↗
PubMed1998

Growth of intraportally transplanted islets under liver regeneration stimulus and restoration of normoglycemia in streptozocin-diabetic rats.

BACKGROUND: Limitation of beta-cell growth after intraportal islet transplantation plays an important role in graft failure. To induce transplanted beta-cell proliferation, we studied the effect of compensatory liver growth in diabetic rats that had a subtherapeutic islet mass previously injected into the liver. METHODS: Syngeneic rats were used as islet donors or recipients; diabetes was induced by streptozocin. Three groups of streptozocin-treated rats were studied. In group 1, 250 islets were selectively transplanted into the posterior liver lobes and 10 days later anterior portal branch ligation (PBL) was performed (n = 18); in group 2, 250 islets were transplanted into the posterior lobes and 10 days later sham PBL was performed (n = 13); in group 3, rats underwent a sham transplantation and PBL (n = 6). Nonfasting blood glucose levels and body weight were monitored. Six rats in groups 1 and 2 were killed 48 hours after PBL, liver sections were stained for proliferating cell nuclear antigen, and islet cell labeling index was calculated. The remaining rats were killed 30 days later. Liver compensatory growth or atrophy was calculated and morphometric determination of beta-cell area was assessed on insulin-immunostained sections of the liver. RESULTS: In group 1 rats killed 48 hours after PBL, islet cell labeling index was significantly higher than in group 2 (p < 0.0001). After PBL, we observed normalization of nonfasting blood glucose levels in 10 of 12 rats. At 30 days, posterior liver lobes showed compensatory growth (218.5% +/- 18.6%) accompanied by atrophy of the anterior lobes; morphometric study of liver-engrafted islets showed a significant increase of individual beta-cell area, compared with group 2 (p < 0.0001). In groups 2 and 3, normoglycemia was not achieved. CONCLUSIONS: In streptozocin-diabetic rats, normoglycemia was restored after transplantation of a sub-therapeutic islet mass, followed by PBL-induced liver regeneration. Histologic and morphometric results indicating islet cell proliferation suggest that compensatory liver growth might have induced a hypertrophic/hyperplastic response in the intraportally transplanted beta-cells.

Animals↗
PubMed1998

Liver assist systems: state of the art.

Attempts to develop liver support systems for the treatment of patients with liver failure have ranged from use of plasma exchange to utilization of charcoal columns and extracorporeal devices loaded with liver tissue. However, no system has achieved wide clinical use and - in the absence of liver transplantation - severe hepatic failure continues to be associated with significant morbidity and mortality. In this paper, the authors review the current status of liver assist systems and summarize their clinical experience with a xenogeneic cell based-bioartificial liver.

Animals↗
PubMed1997

Treatment of severe liver failure with a bioartificial liver.

Orthotopic liver transplantation (OLT) is the definitive therapy for severe liver failure. However, many patients die before an organ becomes available, mostly from cerebral edema. To provide temporary liver support, we developed a bioartificial liver (BAL) based on porcine hepatocytes and a charcoal column. Fifty-four consecutive BAL treatments were carried out in three groups of patients: Group I (n = 15) patients presented with FHF were listed for emergent OLT, Group II (n = 3) patients with primary non-function (PNF) of their liver grafts required urgent re-transplantation and Group III (n = 10) patients with acute exacerbation of chronic liver disease were not candidates for OLT. Patients were managed in a critical care unit receiving maximal standard support. Each BAL treatment was conducted for 6 hours. In Group I, all patients showed significant neurologic improvement, intracranial pressure (ICP) decreased and cerebral perfusion pressure (CPP) increased; other significant improvements, included lowered plasma ammonia and liver enzymes and increased glucose. One patient recovered spontaneously without OLT, all other patients were "bridged" to OLT, and recovered. Group II: PNF patients showed similar benefits. Group III: Chronic liver patients demonstrated transient beneficial effects after BAL treatment(s), however, most (n = 8) eventually succumbed to sepsis and multiple organ failure as they were not candidates for OLT; two patients, recovered, later were successfully transplanted and survived. Our clinical experience demonstrates that the BAL can serve as a bridge to OLT in patients with acute liver failure.

Adult↗
PubMed1997

Fetal rat hepatocytes: isolation, characterization, and transplantation in the Nagase analbuminemic rats.

BACKGROUND: In contrast to adult hepatocytes, fetal hepatocytes (FH) are thought to be highly proliferative, less immunogenic, and resistant to cryopreservation and ischemic injury. These qualities could enhance FH engraftment, proliferation, and gene transfer requiring active DNA synthesis. METHODS: Rat FH were obtained using the nonperfusion collagenase/DNase digestion method. Free and cultured cells were studied using electron microscopy, fluorescence-activated cell sorting, and Northern analysis using alpha-fetoprotein and albumin as markers of hepatocyte lineage. DNA synthetic activity was measured in quiescent and mitogen-stimulated fetal and adult hepatocytes by [3H]thymidine incorporation. Susceptibility of cultured FH to retrovirally mediated gene transfer was studied using an amphotropic retroviral vector carrying the Escherichia coli lac-Z gene. Nagase analbuminemic rats were used as recipients to study the effects of intraportal FH transplantation. Analysis of serum albumin was carried out by enzyme-linked immunosorbent assay. RESULTS: In fetal liver, 87+/-2% of the cells showed morphological and molecular features of hepatocytes. DNA synthetic activity in nonstimulated cultured FH was 10 times greater than the maximal hepatocyte growth factor-driven response in adult rat hepatocytes. A total of 5-15% FH stained positive for X-gal; results of transduction in adult hepatocyte cultures were negative. In Nagase analbuminemic rat recipients, FH produced significant amounts of albumin only when a hepatic regenerative stimulus was applied. Immunohistochemistry confirmed presence of albumin-positive hepatocytes. CONCLUSIONS: Fetal rat liver from the late gestation period is highly enriched with hepatocyte progenitors. They are highly proliferative and susceptible to retroviral transduction and can engraft and function in the adult rat liver if transplanted under a hepatic regenerative stimulus.

Acetylglucosaminidase↗
PubMed1997

Loss and recovery of liver regeneration in rats with fulminant hepatic failure.

We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobes necrosis. After this procedure, lack of regenerative response in the residual viable liver tissue (omental lobes) was associated with elevated plasma hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-beta1) levels and delayed expression of HGF and c-met mRNA in the remnant liver. Here, we investigated whether syngeneic isolated hepatocytes transplanted in the spleen will prolong survival and facilitate liver regeneration in FHF rats. Inbred male Lewis rats were used. Group I rats (n = 46) received intrasplenic injection of 2 x 10(7) hepatocytes and 2 days later FHF was induced. Group II FHF rats (n = 46) received intrasplenic injection of saline. Rats undergoing partial hepatectomy of 68% (PH; n = 30) and a sham operation (SO; n = 30) served as controls. In 20 FHF rats (10 rats/group), survival time was determined. The remaining 72 FHF rats (36 rats/group) were used for physiologic studies (liver function and regeneration and plasma growth factor levels). In Group I rats survival was longer than that of Group II controls (73 +/- 22 hr vs. 33 +/- 9 hr; P < 0. 01). During the first 36 hr, Group I rats had lower blood ammonia, lactate, total bilirubin, PT, and PTT values, lower activity of liver enzymes, and higher monoethylglycinexylidide (MEGX) production than Group II rats. In Group I rats, livers increased in weight at a rate similar to that seen in PH controls and showed distinct mitotic and DNA synthetic activity (incorporation of bromodeoxyuridine and proliferation cell nuclear antigen expression). Plasma HGF and TGF-beta1 levels in these rats decreased and followed the pattern seen in PH rats; additionally, c-met expression in the remnant liver was accelerated. Hepatocyte transplantation prolonged survival in FHF rats and facilitated liver regeneration. Even though the remnant liver increased in weight four times reaching 30% of the original liver mass, the transplant-bearing rats expired due to inability of the regenerating liver to support the rat.

Albumins↗
PubMed1997

Clinical experience with a bioartificial liver in the treatment of severe liver failure. A phase I clinical trial.

OBJECTIVE: The purpose of this study was to develop a bioartificial liver (BAL) to treat patients with severe liver failure until they can be either transplanted or recover spontaneously. SUMMARY BACKGROUND DATA: Severe acute liver failure is associated with high mortality. Liver transplantation has emerged as an effective therapy for patients who did not respond to standard management. However, because of the donor organ shortage and urgent need for transplantation, many patients die before they can be transplanted and others do not survive after transplantation, primarily because of intracranial hypertension. METHODS: Three groups of patients with severe acute liver failure were treated with the BAL. In group 1 (n = 18) were patients with fulminant hepatic failure (FHF), in group 2 (n = 3) were patients with primary nonfunction (PNF) of a transplanted liver, and in group 3 (n = 10) were patients with acute exacerbation of chronic liver disease. Patients in groups 1 and 2 were candidates for transplantation at the time they entered the study, whereas patients in group 3 were not. RESULTS: In group 1, 16 patients were "bridged" successfully to transplantation, 1 patient was bridged to recovery without a transplant, and 1 patient died because of concomitant severe pancreatitis. In group 2, all patients were bridged successfully to retransplantation. In group 3, two patients were supported to recovery and successful transplants at later dates; the other eight patients, although supported temporarily with the BAL, later died because they were not candidates for transplantation. CONCLUSIONS: The authors' clinical experience with the BAL has yielded encouraging results. A randomized, controlled, prospective trial (phase II-III) is being initiated to determine the efficacy of the system.

Adult↗