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Biomedical subjects

G W McCaughan

Publications and source records attributed to G W McCaughan.

At least 55 records · Page 3Linked to original sources
PubMed2000

Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8.

Dipeptidyl peptidase (DPP) IV has roles in T-cell costimulation, chemokine biology, type-II diabetes and tumor biology. Fibroblast activation protein (FAP) has been implicated in tumor growth and cirrhosis. Here we describe DPP8, a novel human postproline dipeptidyl aminopeptidase that is homologous to DPPIV and FAP. Northern-blot hybridization showed that the tissue expression of DPP8 mRNA is ubiquitous, similar to that of DPPIV. The DPP8 gene was localized to chromosome 15q22, distinct from a closely related gene at 19p13.3 which we named DPP9. The full-length DPP8 cDNA codes for an 882-amino-acid protein that has about 27% identity and 51% similarity to DPPIV and FAP, but no transmembrane domain and no N-linked or O-linked glycosylation. Western blots and confocal microscopy of transfected COS-7 cells showed DPP8 to be a 100-kDa monomeric protein expressed in the cytoplasm. Purified recombinant DPP8 hydrolyzed the DPPIV substrates Ala-Pro, Arg-Pro and Gly-Pro. Thus recombinant DPP8 shares a postproline dipeptidyl aminopeptidase activity with DPPIV and FAP. DPP8 enzyme activity had a neutral pH optimum consistent with it being nonlysosomal. The similarities between DPP8 and DPPIV in tissue expression pattern and substrates suggests a potential role for DPP8 in T-cell activation and immune function.

Amino Acid Sequence↗
PubMed2000

Liver transplantation in patients with transjugular intrahepatic portosystemic shunts.

BACKGROUND: In patients with intractable oesophageal variceal bleeding, transjugular intrahepatic portosystemic shunts (TIPSS) are being used increasingly as a bridge to orthotopic liver transplantation (OLTx). There is little information in the literature concerning variations in the operative techniques of OLTx required because of the presence of TIPSS. METHODS: A retrospective review of patients treated by TIPSS prior to OLTx was undertaken. The aims were to assess the effectiveness of TIPSS in bridging patients to OLTx and to examine whether TIPSS influence the operative management of OLTx. RESULTS: Over a 4-year period eight adult patients underwent TIPSS insertion prior to OLTx in the Australian National Liver Transplant Unit (ANLTU). Transplantation was performed at a mean of 14.6 (0.3-53.8) months after TIPSS insertion. Prevention of major recurrent variceal haemorrhage prior to transplantation was achieved in six cases. In two patients the stents were predominantly intrahepatic and they did not interfere with OLTx. In five patients the stents extended into the portal vein, requiring removal during OLTx either by division of the stent with the recipient portal vein, followed by removal of the fractured stent wires from the portal veins (n = 3), or by 'endarterectomy' of the recipient portal vein, allowing removal of the intact stent (n = 2). In one case where the stent extended into the suprahepatic inferior vena cava, removal was achieved by traction without difficulty. All patients are alive at a mean of 24 (7-53) months post-transplant and none has portal vein abnormalities. When compared to 178 adult patients who had no TIPSS and underwent primary OLTx during the same study period, there was no difference in the length of operating time or the usage of blood products during OLTx. CONCLUSION: Transjugular intrahepatic portosystemic shunts offer a bridge to OLTx by providing effective control of variceal haemorrhage. In the present series TIPSS did not increase surgical morbidity or mortality, but emphasis is placed upon the need for optimal TIPSS placement within the liver to facilitate subsequent OLTx.

Adult↗
PubMed2000

Hepatitis C in injecting drug-using women during and after pregnancy.

BACKGROUND: A high proportion of female injecting drug users (IDU) have evidence of hepatitis C virus (HCV) infection. We undertook a prospective study of patients attending a clinic for pregnant IDU to determine the impact of pregnancy on the course of HCV infection and whether pregnancy is affected by HCV infection. METHODS: One hundred and thirty-one IDU were recruited and followed up with liver function tests, HCV serology and HCV-RNA tests. RESULTS: Of 131 patients, 125 had HCV antibodies (anti-HCV positive) at delivery, and of these 62% were HCV-RNA positive. The anti-HCV-negative women were younger and had a shorter duration of drug use than the anti-HCV-positive women. There were no differences between viraemic and non-viraemic women with respect to age, ethnicity, duration of injecting drug use, methadone maintenance dose, hepatitis B exposure or reported high-risk behaviour. Alanine aminotransferase (ALT) levels were higher and the proportion with ALT > 55 IU/L higher in viraemic women. Viraemia persisted in all 55 women who were viraemic at term. Eleven had an ALT flare post-partum that was unrelated to viral load and was clinically unsuspected. Four had concurrent elevated gamma-glutamyltranspeptidase and were considered to be drinking alcohol at hazardous levels. Four of 23 women who were HCV-RNA negative at term became positive during follow up. CONCLUSIONS: Pregnancy does not adversely affect the course of hepatitis C. A modest rebound in ALT levels, but not HCV-RNA, occurs after delivery in some viraemic women. This supports the theory that immune mechanisms rather than direct viral cytopathology are involved in hepatocyte injury during HCV infection. Hepatitis C infection did not influence pregnancy complications and outcomes.

Adult↗
PubMed2000

Asian perspectives on viral hepatitis: hepatitis C virus infection.

Hepatitis C virus (HCV) infection is widespread throughout Asia. Unusual features of HCV in Asia include a novel genotype distribution with a significant representation of 3a. This is particularly important as genotype 3 is very sensitive to interferon-based therapies. A major concern in the Asian region is the high prevalence of hepatocellular cancer complicating HCV-associated cirrhosis, particularly in Japan. Finally, liver transplantation for advanced HCV infection with cirrhosis is an option via cadaveric and living donor programmes.

Antiviral Agents↗
PubMed2000

Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B.

Although antiviral prophylaxis with lamivudine monotherapy appears to reduce post-liver transplantation recurrence of hepatitis B virus (HBV) infection, breakthrough infections occur in at least 20% of the patients because of the development of drug resistance. Combined lamivudine and intravenous hepatitis B immune globulin (HBIG) therapy (10,000-IU doses) may reduce this risk, but its use is limited by cost ( approximately US $45,000/yr) and availability. We report the experience at liver transplant centers in Australia and New Zealand in which lamivudine has been used in combination with much lower doses of HBIG than used in conventional HBIG prophylaxis. Lamivudine, 100 mg/d, was administered to hepatitis B surface antigen (HBsAg)-positive candidates on listing for transplantation and was continued posttransplantation. HBIG, 400 or 800 IU, was administered intramuscularly (IM) daily for 1 week from transplantation and monthly thereafter. Thirty-seven HBsAg-positive patients underwent transplantation using this protocol. Thirty-six of these patients were HBV DNA positive by polymerase chain reaction (PCR) or hybridization assay. Thirty-four patients had chronic HBV, 2 patients had hepatitis B and C, and 1 patient had hepatitis B, C, and D. Five patients died within 1 month of transplantation and are not included in the analysis. Mean follow-up in the remaining 32 patients was 18.4 months (range, 5 to 45 months). Treatment was well tolerated, with no significant adverse events. Thirty-one of 32 patients were HBsAg negative, and all 32 patients were HBV DNA negative by PCR at latest follow-up. The cost of treatment was US $967 for lamivudine and between $2,290 and $4,480/yr for IM HBIG. Lamivudine and low-dose HBIG treatment prevents posttransplantation recurrence of hepatitis B and is likely to be more cost-effective than high-dose HBIG regimens.

Adult↗
PubMed2000

Spontaneous clearance of hepatitis C virus infection post-liver transplantation is associated with rapidly changing quasispecies: a single case report.

Hepatitis C virus (HCV) clearance post-liver transplantation is uncommon. This is a case report of a patient who, after liver transplantation, developed cholestatic hepatitis characterized by severe graft dysfunction, in conjunction with high viral load. This was, however, followed by viral clearance and normalization of allograft function. The clinical features of this case and the quasispecies patterns during the illness and the clearance periods are described. In addition, management implications in terms of immunosuppressive therapy are discussed.

Amino Acid Sequence↗
PubMed2000

Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronic hepatitis C infection.

BACKGROUND: Upregulation of Th1 associated intrahepatic cytokines in chronic hepatitis C virus (HCV) infection should lead to a significant non-specific cellular immune response, a prerequisite for viral clearance. However, to date, the role of this non-specific response in HCV has been understudied. AIMS: To analyse the intrahepatic macrophage activity in chronic HCV infection by immunostaining and by quantitation of cytokine mRNA. METHODS: HCV positive liver tissues (chronic hepatitis, n=10; cirrhosis, n=5) were immunostained for CD68, MAC387, and semiquantitated by polymerase chain reaction for intrahepatic cytokine mRNAs (interferon gamma (IFNgamma), interleukin 1beta (IL-1beta), IL-6, IL-18, tumour necrosis factor alpha (TNFalpha), and macrophage inflammatory protein 1beta (MIP1beta)). HCV negative normal liver tissues (for cytokines, n=6; for immunostaining, n=5) were included as controls. RESULTS: MAC387(+) cells were focally increased in areas of erosion at the limiting plate while lobular staining was minimal. CD68(+) staining was diffuse in both portal (increased in HCV) and lobular areas. The portal tract (mean) density of CD68(+) and MAC387(+) cells was significantly increased in patients with HCV compared with normal tissue. IFNgamma and IL-18 mRNA levels were highly correlated and significantly upregulated in chronic hepatitis and cirrhotic tissue versus controls. TNFalpha mRNA was upregulated in chronic hepatitis without cirrhosis, while IL-6 mRNA was significantly downregulated. IL-1beta, IL-6, and MIP1beta mRNA levels were significantly correlated with portal tract MAC387(+) cell density. CONCLUSIONS: The significant upregulation of IFNgamma and IL-18 mRNA and significant correlations between IFNgamma and other proinflammatory cytokines, suggest a Th1/cell mediated intrahepatic immune response in chronic HCV infection. However, further clarification of the cellular sources of these cytokines is required.

Adult↗
PubMed2000

Polycystic disease: a rare indication for combined liver and kidney transplantation.

We report on a 52-year-old woman who presented with polycystic disease. Both of her kidneys had been removed and she had undergone one failed kidney transplantation. She had severe symptoms from the polycystic liver. The diseased liver and kidney were both treated successfully by performing a combined liver and kidney transplantation.

Female↗
PubMed2000

Liver transplantation in chronic hepatitis B and C.

The general indications for liver transplantation in hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and the issues surrounding treatment for HBV infection in the pre- and post-transplant periods, are discussed. In general, transplantation is reserved for patients with end-stage liver failure secondary to cirrhosis and a small population with acute liver failure. It is proposed that certain guidelines can be developed and that these should include any one of the following: a Child-Pugh score > or = 9, diuretic resistant ascites, recurrent portal hypertensive bleeding, recurrent encephalopathy, spontaneous bacterial peritonitis and the development of a small hepatocellular cancer (< or = 5 cm in diameter). Treatment for HBV infection now includes lamivudine therapy pre and post transplantation together with hepatitis B immunoglobulin. Such an approach has virtually abolished recurrence of HBV infection following liver transplantation.

Antiviral Agents↗
PubMed1999

Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance.

BACKGROUND: Fully allogeneic liver grafts from piebald virol glaxo to dark agouti rats are spontaneously tolerated, whereas kidney transplants between these strains are rejected. Liver tolerance is broken by donor irradiation or peritransplant corticosteroid treatment of recipient rats, both of which interfere with the activation of recipient cells. METHODS: In this study we used a combination of immunohistochemical staining, reverse transcription-polymerase chain reaction, and terminal deoxynucleotide transferase-mediated dUTP nick end labeling and Annexin-V apoptosis assays to compare donor cell migration, cytokine profiles, and leukocyte apoptosis in grafts and lymphoid organs from tolerant liver and rejecting kidney recipients. We then examined the effect on apoptosis of treatments which abrogate liver tolerance. RESULTS: Liver transplantation in this tolerant strain combination is accompanied by rapid migration of many passenger leukocytes to the recipient spleen and lymph node, concurrent with a marked but transient increase in the amount of mRNA for the cytokines interleukin-2 and interferon-gamma. Apoptotic cells appear promptly in the spleen, their numbers reaching a peak 2 days earlier than has been previously shown for the graft infiltrate. Both CD4+ and CD8+ T cells undergo apoptosis and apoptotic cells are most concentrated among CD25+ T cells. In contrast, renal transplant rejection is associated with limited donor cell migration to lymphoid tissues and significantly less up-regulation of interleukin-2 and interferon-gamma in the spleen. Few apoptotic cells are detected in spleen or graft infiltrate during rejection, whereas apoptotic renal tubular and glomerular cells are found from day 5. Either recipient steroid treatment or donor irradiation significantly reduced the number of apoptotic cells in liver graft infiltrates and recipient spleen. CONCLUSIONS: Taken together, these findings suggest that a mechanism akin to activation-induced cell death, with apoptosis of alloreactive recipient cells may be responsible for the induction of spontaneous liver transplant tolerance.

Animals↗
PubMed1999

Two highly conserved glutamic acid residues in the predicted beta propeller domain of dipeptidyl peptidase IV are required for its enzyme activity.

Dipeptidyl peptidase IV (DPP IV) is a member of the prolyl oligopeptidase family and modifies the biological activities of certain chemokines and neuropeptides by cleaving their N-terminal dipeptides. This paper reports the identification and possible significance of a novel conserved sequence motif Asp-Trp-(Val/Ile/Leu)-Tyr-Glu-Glu-Glu (DW(V/I/L)YEEE) in the predicted beta propeller domain of the DPP IV-like gene family. Single amino acid point mutations in this motif identified two glutamates, at positions 205 and 206, as essential for the enzyme activity of human DPP IV. This observation suggests a novel role in proteolysis for residues of DPP IV distant from the Ser-Asp-His catalytic triad.

Amino Acid Sequence↗
PubMed1999

Poisoning by Amanita phalloides ("deathcap") mushrooms in the Australian Capital Territory.

Amanita phalloides ("deathcap") mushrooms are widespread in south-eastern Australia. Seven patients presented to hospital in the Australian Capital Territory with poisoning by this mushroom between 1988 and 1998. Three developed hepatoxicity and one died. Because A. phalloides is becoming more widespread, increased community and medical awareness is needed to reduce the frequency and morbidity of poisoning.

Adult↗
PubMed1999

Vascular endothelial growth factor expression in human chronic renal allograft rejection.

BACKGROUND: Chronic renal allograft rejection is characterized by interstitial fibrosis and vasculopathy. Vascular endothelial growth factor (VEGF) is an endothelial mitogen with increased expression in inflammation and vasculopathy. METHODS: Renal tissue from 17 patients with chronic rejection was examined for VEGF protein and the presence of CD 68-positive macrophages, and compared to biopsies from patients with temporary allograft dysfunction, acute rejection, and native kidneys with thin membrane disease. RESULTS: In the chronic rejection group, there was markedly increased expression of VEGF protein in the interstitium (P<0.0001). In serial sections, VEGF colocalized with the expression of CD 68-positive macrophages. Significantly more macrophages were in the tubulointerstitium in tissue with chronic rejection than in those with temporary allograft dysfunction (P<0.005). Additionally, VEGF protein expression in the glomeruli and the vascular compartment of patients with chronic rejection was increased. CONCLUSION: The up-regulation of VEGF in chronic renal allograft rejection may be important in inflammation and development of fibrosis.

Antigens, CD↗