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Biomedical subjects

L Makowka

Publications and source records attributed to L Makowka.

At least 55 records · Page 3Linked to original sources
PubMed1994

Hepatic regeneration: current concepts and clinical implications.

Liver regeneration occurs as a result of hepatic tissue loss or injury. The process of liver regeneration is carefully regulated in a controlled biologic scheme with closely interactive relationships between hormones, free neurotransmitters, and nutrients; protooncogenes; and polypeptide and glycolipid growth factors. These relationships are now being studied at the molecular and cellular levels and attempts are being made to reconstruct the complete intricate process. Although significant breakthroughs have occurred in understanding the effects and regulation of several subsystems (such as insulin and its receptors; TGF-alpha and TGF-beta; HGF and its receptors), the integral process remains a mystery. Improved comprehension of the regeneration process will lead to rational treatment algorithms for now dreaded hepatic diseases.

Growth Inhibitors↗
PubMed1994

The pathogenesis of xenograft rejection.

The transplantation of vascularized organs between species stimulates an intense rejection reaction by the recipient of the graft. The classification of the xenograft rejection reaction on the basis of the degree of genetic disparity between donor and recipient species and the presence or absence of preformed antibody to the donor tissue does not provide for a precise classification schema. We have proposed that xenograft reactions be classified on the basis of the immunological mechanisms responsible for the loss of the graft. The rejection of xenografts would then be divided into those that are antibody-dependent and mediated by antidonor antibody, either preformed (i.e. pig-to-human xenografts) and present at the time of transplantation or antibody produced in response to placement of the graft (hamster-to-rat). A second group of xenograft reactions would consist of those for which the direct activation of the alternative complement pathway results in loss of the graft in the absence of the binding of antidonor antibody from the recipient (guinea pig-to-rat). The focus on the pathogenesis of xenograft reactions for classification purposes is a more consistent method of description and is more clearly related to future attempts to prevent rejection with immunosuppressive therapy.

Animals↗
PubMed1994

Late surgical complications of choledochal cystoenterostomy.

Choledochal cyst is a rare congenital abnormality of the biliary tract characterized by dilatation and stasis. Cyst excision is now preferred to internal drainage because of the predilection for development of cancer in the unresected cyst wall. We report on four patients who required reoperations for complications of prior cystoenteric drainage from 14 to 21 years after the original operations. Gastrointestinal bleeding from cyst ulceration as occurred in one patient is heretofore unreported. This reoperative experience emphasizes the importance of cyst excision as primary therapy and underscores these principles: 1) The spectrum of complications, including infection, pancreatitis, cancer, and bleeding may occur with or without intracyst and ductal stones; 2) Radical operative procedures may be required for treatment of the complications; 3) Despite these, cholangiocarcinoma has a dismal prognosis; 4) Patients whose cysts remain unexcised require meticulous lifelong scrutiny and strong consideration for planned reoperation at the time of the first complication.

Adult↗
PubMed1994

Hepatocellular adenoma in glycogen storage disease type IV.

The development of hepatocellular adenoma has been recognized in association with glycogen storage disease type I and, less often, with glycogen storage disease type III, but, to our knowledge, it has not been reported in glycogen storage disease type IV. We had the opportunity to study an 11-month-old male infant who underwent orthotopic liver transplantation for cirrhosis that developed in the setting of glycogen storage disease type IV. A clinically unsuspected hepatocellular adenoma was present in the explanted liver. Glycogen storage disease type IV should be considered as a potential precursor to the development of hepatocellular adenoma. Recognition of this association is important, both in terms of the differential diagnosis of tumors that occur in this setting and also to anticipate potential complications of this benign neoplasm.

Adenoma, Liver Cell↗
PubMed1994

Protective effect of the lazaroid U74006F in cold ischemia-reperfusion injury of the liver.

Lipid peroxidation may play a major role in the loss of liver graft viability after prolonged cold ischemia and reperfusion injury. The lazaroid compound U74006F is a potent inhibitor of lipid peroxidation, and this study was designed to evaluate the efficacy of this compound in preventing cold ischemia-reperfusion damage in three different models: pig endothelial cells in culture, ex vivo isolated pig liver perfusion and orthotopic transplantation of syngeneic rat livers. The addition of U74006F to University of Wisconsin preservation solution significantly prolonged endothelial cell viability after 48 and 72 hr of cold ischemia and reoxygenation (p < 0.01). Donor pigs were injected with vehicle or U74006F (4.5 mg/kg) before liver harvest. After 24 hr of cold storage in University of Wisconsin solution, the livers were perfused with pig blood for 180 min in an isolation chamber. Measurements of liver function parameters, including AST, ALT, bile production, superoxide anion and phospholipase A2 release, were assessed every 60 min. Although bile production was similar in the U74006F-treated and control groups, significant decreases of AST and ALT levels (p < 0.01) in the perfusate of the livers from treated donors were observed. In addition, the U74006F group displayed significantly reduced release of superoxide anion and phospholipase A2 compared with these parameters in the untreated group (p < 0.05 and p < 0.01, respectively). In the last model, donor rats were treated with U74006F before harvest; the rat liver grafts were preserved in cold University of Wisconsin solution for 24 hr and then transplanted into recipient rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Lymphocytes infiltrating rat cardiac allografts express a limited repertoire of T cell receptor V beta genes.

The T cell response to many self-MHC-restricted nominal Ag involves limited use of the TCR repertoire. The status of the TCR repertoire in allogeneic responses remains unclear. In this report, we have studied the TCR V beta gene repertoire involved in the rejection of cardiac allografts disparate for major and minor histocompatibility Ag in rats. Graft-infiltrating lymphocytes (GIL) were isolated from rejecting heart allografts and analyzed for the expression of the V beta repertoire using a cDNA library and a semiquantitative polymerase chain reaction (PCR). We report here that GIL isolated at early stages of the rejection reaction preferentially use the V beta 4 gene. First, V beta 4 comprised 36.4% (8/22) of randomly sequenced cDNA clones isolated from a TCR-beta chain-specific cDNA library established from GIL harvested 3 days posttransplantation. The V beta 4 gene in these clones was found in conjunction with several different J beta and N regions, suggesting a dominant role for the V beta 4 encoded domains in the recognition of allograft Ag. Second, the V beta 4 message comprised 56.6 to 65.7% of the transcripts expressed by the 20 rat V beta genes in three T cell lines established from GIL isolated 2 days posttransplantation. Third, fresh, unmanipulated GIL harvested at days 2 and 3 posttransplantation predominantly expressed the V beta 4 gene. Fourth, the expression of V beta 4 in naive splenocytes constituted only 5.4% of the V beta detected, suggesting that the predominant use of the V beta 4 gene by GIL was not a consequence of its high level of expression in the periphery. The limited use of the TCR repertoire in allograft rejection may provide the opportunity to interrupt the rejection process and induce donor-specific tolerance by targeting a select population of T cells for inactivation or elimination.

Amino Acid Sequence↗
PubMed1993

Control of cerebral oedema by total hepatectomy and extracorporeal liver support in fulminant hepatic failure.

Keeping a patient with fulminant hepatic failure (FHF) alive until a donor liver is available for transplantation can be a problem. We describe an 18-year-old woman with paracetamol-induced FHF, who was treated by total hepatectomy, hypothermia, plasma exchange, and extracorporeal liver support. The patient was anhepatic for 14 h. The liver-support system consisted of plasma separation and perfusion through a charcoal filter and a hollow-fibre module seeded with matrix-attached porcine hepatocytes. With artificial liver treatment there was reversal of severe neurological dysfunction, normalisation of intracranial pressure, and decreased serum ammonia. The patient underwent emergency transplantation with an ABO-incompatible liver, followed by transplantation with a compatible organ eight days later. The patient has fully recovered and is neurologically intact.

Adolescent↗
PubMed1993

Response of normal and reperfused livers to glucagon stimulation: NMR detection of blood flow and high-energy phosphates.

The effects of glucagon on blood flow and high-energy phosphates in control and in rat livers damaged by ischemia were studied using in vivo nuclear magnetic resonance (NMR) spectroscopy. Normal livers and livers which had been made ischemic for 20, 40, and 60 min followed by 60 min of reperfusion were studied. Ischemia led to a loss in adenosine triphosphate (ATP) within 30 min. Reperfusion after 20 min of ischemia led to complete recovery of ATP. 60 min of reperfusion after 40 or 60 min of ischemia led to only a 76% and 48% recovery of ATP, respectively. Glucagon, at doses up to 2.5 mg/kg body weight, caused no changes in the inorganic phosphate (P(i)) to ATP ratio in normal livers as measured by 31P-NMR spectroscopy. In livers which had been made ischemic for 20, 40, or 60 min, glucagon caused an increase in the P(i)/ATP ratio of 18%, 40%, and 40%, respectively. 19F-NMR detection of the washout of trifluoromethane from liver was used to measure blood flow. Glucagon-stimulated flow in the normal liver in a dose-dependent manner, with 2.5 mg glucagon/kg body weight leading to a 95% increase in flow. Ischemia for 20, 40, and 60 min followed by 60 min of reperfusion led to hepatic blood flows which were 63%, 68%, and 58% lower than control liver. In reperfused livers, blood flow after glucagon-stimulation was reduced to 56%, 43%, and 48% of control glucagon-stimulated flow after 20, 40, and 60 min of ischemia. These results indicate that ischemia followed by reperfusion leads to decreases in hepatic blood flow prior to alterations in ATP and the response of the liver to glucagon is altered in the reperfused liver.

Adenosine Triphosphate↗
PubMed1993

Structure and diversity of rat T cell receptor alpha-chain genes.

We have sequenced 22 TCR-alpha clones isolated from two cDNA libraries derived from rat thymocytes and heart allograft-infiltrating lymphocytes. Sixteen different V alpha and 17 J alpha genes were characterized in these clones. The V alpha genes could be divided into nine subfamilies, each containing from one to three members. Nucleotide sequence comparisons to mouse alpha genes revealed the existence of mouse homologues for all the J alpha s and 8 of 9 V alpha subfamilies. One of the rat V alpha subfamilies appeared to have no known mouse counterpart. Southern blot analysis of germ-line DNA with cDNA probes specific for six different subfamilies demonstrated the existence of two to nine V alpha genes per subfamily. A minimum number of 35 V alpha genes was estimated for the nine rat subfamilies characterized. These analyses also detected two different RFLP patterns among five different inbred rat strains, including strain-specific loss of hybridization bands for some V alpha, indicating that deletion events may have occurred in the rat alpha gene locus. The characterization of rat TCR V alpha genes should facilitate a better understanding of T cell role in pathologic conditions such as autoimmune diseases and graft rejection.

Amino Acid Sequence↗
PubMed1993

Gender of donor influences outcome after orthotopic liver transplantation in adults.

Because male and female livers not only differ with respect to estrogen and androgen receptor content, but also demonstrate sexual dimorphism of certain functions, we examined the effect of donor gender on graft survival following liver transplantation (OLTx) in adults. Between February 1981 and February 1988, 982 OLTx procedures were performed in 789 adult patients at the University of Pittsburgh. In this study, OLTx was categorized as a failure if the patient died or required retransplantation within 60 days of the surgery. When the donor-recipient gender combinations were male-male, male-female, and female-female, the failure rates were 28%, 28%, and 36%, respectively. In contrast, 60% of female donor livers failed in male recipients. Compared to the pooled donor-recipient gender combinations, the odds of failure for female-male liver grafts were increased 3.7-fold (95% confidence interval: 6.5, 2.1; P < 0.001). These findings may result, at least in part, from alterations in the sex hormone milieu or changes in the graft estrogen or androgen receptor content.

Adult↗
PubMed1993

Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs.

Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival--far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients.

Animals↗
PubMed1993

Removal of natural human xenoantibodies to pig vascular endothelium by perfusion of blood through pig kidneys and livers.

We have examined the nature of the binding of human xenoantibodies to pig liver and kidney vascular endothelium. Our results demonstrate that human serum contains IgM and IgG xenoantibodies that bind to pig vascular endothelium, and that the pattern of antibody binding is similar for both livers and kidneys. Immunohistochemical analysis of pig kidneys after perfusion with human blood demonstrated the binding of both IgM and IgG xenoantibodies, complement (C3), and fibrinogen to the vascular and glomerular endothelium. An ELISA assay of the perfusate after perfusion of 500 ml of human blood through a single pig kidney for 60 min demonstrated a significant reduction in the amount of human IgM (67%) and IgG (55%) binding to pig aortic endothelium. Similar perfusion experiments conducted with pig livers were associated with minimal immunohistochemical evidence of the binding of human xenoantibodies to liver vascular endothelium. Immunofluorescence staining for IgM, IgA, C3, and C1q was negative or minimally positive in the liver vascular endothelium. Sinusoidal endothelium were weakly positive for IgG and fibrinogen. The perfusion of the pig liver with human blood was, however, associated with a significant reduction in the subsequent binding of IgM and IgG to pig kidney vascular endothelium. Pig liver perfusion was also responsible for the removal of both IgM and IgG xenoantibodies capable of reacting with pig aortic endothelium, as measured by an ELISA assay of the perfusate. These results suggest that both pig kidney and livers are capable of absorbing the xenoantibodies that may be responsible for mediating a hyperacute rejection of pig xenografts and that the distribution of the target antigens for these antibodies is similar in the two organs.

Animals↗