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Biomedical subjects

J W Marsh

Publications and source records attributed to J W Marsh.

At least 55 records · Page 3Linked to original sources
PubMed1997

Treatment of fibrolamellar hepatoma with subtotal hepatectomy or transplantation.

Fibrolamellar hepatoma (FL-HCC) is an uncommon variant of hepatocellular carcinoma (HCC), distinguished by histopathological features suggesting greater differentiation than conventional HCC. However, the optimal treatment and the prognosis of FL-HCC have been controversial. Follow-up studies are available from 1 year to 27 years, after 41 patients with FL-HCC were treated with partial hepatectomy (PHx) (28 patients) or liver transplantation (13 patients). In this retrospective study, the effect on outcome was determined for the pTNM stage and other prognostic factors routinely recorded at the time of surgery. Cumulative survival at 1, 3, 5, and 10 years was 97.6%, 72.3%, 66.2%, and 47.4%. Tumor-free survival at these times was 80.3%, 49.4%, 33%, and 29.3%. The TNM stage was significantly associated with tumor-free survival. Patients with positive nodes had a shorter tumor-free survival than those with negative nodes (P < .015). Patient survival was most adversely affected by the presence of vascular invasion (P < .05). FL-HCC is an indolently growing tumor of the liver, which usually was diagnosed in our patients at a stage too advanced for effective surgical treatment of most conventional HCC. Nevertheless, long-term survival frequently was achieved with aggressive surgical treatment. When a subtotal hepatectomy could not be performed, total hepatectomy (THx) with liver transplantation was a valuable option.

Adolescent↗
PubMed1997

Hepatic resection and transplantation for peripheral cholangiocarcinoma.

BACKGROUND: Recent publications have questioned the role of orthotopic liver transplantation (OLT) in treating advanced or unresectable peripheral cholangiocarcinoma (Ch-Ca). STUDY DESIGN: We reviewed our experience with Ch-Ca to determine survival rates, recurrence patterns, and risk factors in 54 patients who underwent either hepatic resection or OLT between 1981 and 1994. Liver transplantation was performed in patients with unresectable tumors (n = 12) and in those with advanced cirrhosis (n = 8). There were 33 women (61%) and 21 men (39%), with a mean age of 54.3 years. The median followup period was 6.8 years. Prognostic risk factors were analyzed by univariate and multivariate analyses. RESULTS: Mortality within 30 days was 7.4%. Overall patient and tumor-free survival rates were 64% and 57% at 1 year, 34% and 34% at 3 years, and 26% and 27% at 5 years after operation. Thirty-two patients (59.3%) experienced tumor recurrence. Univariate analysis revealed that multiple tumors, bilobar tumor distribution, regional lymph node involvement, presence of metastasis, positive surgical margins, and advanced pTNM stages were significant negative predictors of both tumor-free and patient survival. Multivariate analysis revealed that positive margins, multiple tumors, and lymph node involvement were independently associated with poor prognosis. When patients with these three negative predictors were excluded, the patient survivals at 1, 3, and 5 years were 74%, 64%, and 62%, respectively. CONCLUSIONS: Both hepatic resection and OLT are effective therapies for Ch-Ca when the tumor can be removed with adequate margins, the lesion is singular, and lymph nodes are not involved.

Adult↗
PubMed1996

Physical linkage of the Vibrio cholerae mannose-sensitive hemagglutinin secretory and structural subunit gene loci: identification of the mshG coding sequence.

Vibrio cholerae O1 expresses a variety of cell surface factors which mediate bacterial adherence and colonization at the intestinal epithelium. The mannose-sensitive hemagglutinin (MSHA), a type IV pilus, is a potential attachment factor of the V. cholerae El Tor biotype. We describe a TnphoA mutant that is defective in its ability to hemagglutinate mouse erythrocytes. The TnphoA insertion maps to a recently identified genetic locus that encodes products that are predicted to be essential for assembly and export of the MSHA pilus. Insertional disruption at this locus in a mshA-phoA reporter strain provides evidence for a role of this locus in the latter stages of pilus assembly and/or export. These constructs have provided physical markers by which we have established close physical linkage of this secretion locus to a set of genes that includes the mshA structural gene. Sequence analysis of the intervening region between these two loci has revealed the presence of an open reading frame with homology to pilus biogenesis genes of several gram-negative bacteria. This genetic organization suggests an entire operon encoding the MSHA pilus and the components necessary for its assembly and secretion to the bacterial cell surface. The nomenclature of the MSHA structural and secretory locus has been redefined accordingly.

Animals↗
PubMed1996

Human immunodeficiency virus type 1 Nef associates with a member of the p21-activated kinase family.

Although human immunodeficiency virus (HIV) Nef is essential for the induction of AIDS, its biochemical function has remained an enigma. In this study, HIV Nef protein is shown to associate with a serine-threonine kinase that recognizes histone H4 as a substrate, is serologically related to rat p21-activated kinase (PAK), and is specifically activated by Rac and Cdc42. These characteristics define the Nef-associated kinase as belonging to the PAK family. PAKs initiate kinase cascades in response to environmental stimuli, and their identification as a target of Nef implicates these signaling molecules in HIV pathogenesis and provides a novel target for clinical intervention.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Recurrent hepatocellular carcinoma after liver transplantation: spectrum of CT findings and recurrence patterns.

PURPOSE: To correlate computed tomographic (CT) and serum tumor marker (alpha-fetoprotein [AFP] and des-gamma-carboxy-prothrombin [DGCP]) findings in recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT). MATERIALS AND METHODS: At retrospective review of the cases in 124 patients, CT findings were recorded by consensus of at least two nonblinded observers and compared with levels of AFP and DGCP. RESULTS: In 35 patients (68 sites), CT depicted recurrent HCC (most frequently in lungs [n = 18] and liver allograft [n = 16]) in a single site in 19 patients (54%) and in more than one site in 16 patients (46%). No stage I or II HCC recurred after 18-78 months (mean recurrence, 39 months). Stage IVA HCC recurred four times as often as stage III HCC (P < .001). Abnormally high serum AFP and DGCP levels indicated 69% and 43%, respectively, in patients with recurrent disease. CONCLUSION: HCC recurrence after OLT correlates with initial stage, and CT is more sensitive than serum tumor markers in its detection.

Adult↗
PubMed1996

Systemic gadolinium toxicity in patients with renal insufficiency and renal failure: retrospective analysis of an initial experience.

OBJECTIVE: To study the possible deleterious systemic effects of gadolinium in patients with impaired renal function. DESIGN: We retrospectively analyzed the routine laboratory data and clinical course of patients who had undergone a gadolinium-enhanced magnetic resonance imaging (MRI) examination of the brain and spine and had evidence of impaired glomerular filtration. MATERIAL AND METHODS: Between October 1988 and October 1992, 15,830 patients underwent gadolinium-enhanced MRI at our institution, 151 of whom had a serum creatinine value of more than 2 mg/dL. The clinical records of these 151 patients were thoroughly examined for the period from 3 days before to 30 days after the gadolinium-enhanced MRI examination. All data were analyzed in an attempt to detect any adverse events that could be related to free gadolinium as a result of dissociation from the chelating agent due to prolonged elimination times (that is, increased serum creatinine concentrations). In addition, we calculated the 90-day mortality rate for both the study group and a matched control population of 80 patients who had undergone MRI of the brain and spine before gadolinium was available. RESULTS: The overall incidence of adverse events in the study group was 3.6%. No event was severe or life threatening--nausea and rash occurred in two patients each, and seizure and headache occurred in one patient each. These findings were not significantly different from those in previous studies performed in populations with normal elimination times. Moreover, no significant difference was noted in the 90-day mortality rate (14.6% of the study group) in comparison with that in the control group (13.8%). CONCLUSION: On the basis of this initial retrospective analysis, we were unable to detect any clinical deleterious effects of administration of gadolinium for MRI examination in patients with impaired renal function. Further investigation with prospective studies is needed to confirm these initial retrospective findings.

Adult↗
PubMed1995

FK506 (tacrolimus) compared with cyclosporine for primary immunosuppression after pediatric liver transplantation. Results from the U.S. Multicenter Trial.

We report on the efficacy and safety of FK506 (tacrolimus) compared with a cyclosporine (CsA)-based immunosuppressive regimen after 1 year of treatment in pediatric liver allograft recipients (< 12 years) participating in a multicenter U.S. randomized trial. Patients received either FK506 or CsA as primary immunosuppression following a first ABO-compatible liver transplant. Intravenous FK506 was initiated at 0.1 mg/kg per day, followed by oral FK506 beginning at 0.3 mg/kg per day. The dose was adjusted to maintain plasma trough levels of 0.5-2.0 ng/ml. The CsA group was treated according to each center's usual protocol. Both groups received the same initial doses of corticosteroids. All rejection episodes were biopsy-proven and a standardized algorithm was adopted for the treatment of rejection. Thirty patients were randomized to the FK506 group and 20 to the CsA group. After twelve months of follow-up 20 patients remained in the FK506 group and 13 in the CsA group. Patient survivals were 80% and graft survival 70% in the FK506 group compared with 81% and 71% respectively, in the CsA group. 48% of the FK506 group remained rejection-free compared with 21% of the CsA group, and 79% of FK506-treated patients did not require OKT3 compared with 68% of CsA treated patients. The cumulative corticosteroid dose was less at each time point throughout the first year in the FK506 group. The incidence of serious and minor infections was similar in both groups. Nephrotoxicity, neurotoxicity, and gastrointestinal disturbances were the major toxicities reported. Differences did not reach statistical significance between the two groups although major neurologic events, diarrhea and dyspepsia were more often reported in the FK506 group. There was no difference in mean serum creatinine at 12 months between the two groups. There was a tendency toward lower mean serum cholesterol in the FK506 group. There was no hirsuitism in the FK506 group compared with a 30% incidence in the CsA group. In conclusion, compared with CsA, there is a trend toward less rejection in FK506-treated pediatric allograft recipients, while both drugs have a similar spectrum of side effects.

Adrenal Cortex Hormones↗
PubMed1995

Cytokine expression in large cell lymphoma associated with acquired immunodeficiency syndrome.

Cytokine expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) in a retrospective sampling of 16 AIDS-associated large cell lymphomas (LCL). IL-6 receptor (IL-6R) and IL-10 expression was detected in a majority of the tumor specimens tested, IL-6 expression was detected in 5 of 16 lymphomas that also expressed IL-6R, suggestive of an autocrine mechanism of disease. A subset of tumor samples described as mixed immunophenotype contained large numbers of infiltrating T lymphocytes and macrophages. Immunoperoxidase staining of a representative tumor of mixed immunophenotype demonstrated the presence of HIV-infected macrophages that also stained with anti-IL-6. This finding suggests that IL-6 produced by nonlymphoid cells may act as a paracrine growth factor for tumor cells that express IL-6R. Although earlier studies of AIDs burkitt's lymphoma cell lines suggested that IL-10 expression required EBV infection, 7 of 12 AIDS LCLs that expressed IL-10 did so in the absence of EBV by EBER in situ hybridization. Because AIDS LCLs frequently express cell surface CD5, we speculate that IL-10 may act as an autocrine or paracrine growth factor for this class of lymphoma. These studies suggest that IL-6 and IL-10 are involved in the pathogenesis of AIDS-associated large cell and mixed immunophenotype lymphoma.

Base Sequence↗
PubMed1995

FK 506 rescue therapy for hepatic allograft rejection: experience with an aggressive approach.

Although initial experiences with FK 506 rescue therapy for acute hepatic allograft rejection have provided promising results, analysis of available data indicates that inferior results are obtained when FK 506 rescue therapy is initiated in the latter stages of rejection. Since its initial availability, we have applied an aggressive approach towards FK 506 rescue therapy based on early conversion and assiduous dosing. We have reviewed our experience with this approach in patients with refractory hepatic allograft rejection to provide an assessment of this approach. Sixteen patients were treated for corticosteroid and OKT3-resistant acute hepatic allograft rejection. Fourteen patients were treated for cellular rejection and 2 for humorally-mediated rejection. Median follow-up was 7.3 months posttransplant and 6.0 months post-initiation of FK 506 therapy. Median time to first rejection was 8 days and median time to FK 506 therapy was 29 days. Laboratory values at the time of initiation of FK 506 therapy included: mean serum bilirubin, 4.0 +/- 3.1 mg/dl and SGPT 136 +/- 105 U/l. Prior to FK 506 therapy, patients received an average of 35.5 +/- 19.1 mg/kg of bolus/taper corticosteroids (prednisone equivalent) and 11.25 +/- 4.8 days of OKT3 therapy. FK 506 therapy was successful in reversing all episodes of rejection. Median time to rejection reversal with FK 506 rescue therapy was 23 days (mean +/- SD, 27.6 +/- 16.7 days) in patients with cellular rejection. Time to rejection reversal was 26 and 28 days in the 2 patients with humoral rejection. Patient and graft survival at 6 months were 100%/100%, and 94%/94% at 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Presurgical evaluation of the liver transplant candidate.

Determination of liver transplant candidacy requires an integrated approach contingent upon clinical, surgical, and radiologic evaluation. Imaging patients with end-stage liver disease is a challenging yet fascinating task. Chest radiographs, ultrasound with Doppler, and unenhanced and biphasic contrast CT provide sufficient preoperative information about the majority of patients. Problematic cases, however, may require a multimodality approach, for which chest CT, invasive abdominal CT techniques, MR imaging, cholangiography, angiography, and biopsy have all been useful adjuncts. In addition to providing important information for surgical planning, the radiologist must carefully look for any evidence of malignancy or other conditions that jeopardize successful OLTX and threaten meaningful postoperative survival.

Humans↗
PubMed1995

Survival after liver transplantation in patients with hepatocellular carcinoma.

During a 12-year period (1981-1992), 3,029 patients, including 220 with hepatocellular carcinoma (HCC), received their first orthotopic liver transplantation (OLTX) for various liver diseases. One-, three- and five-year survivals of these 220 patients with HCC were 68%, 46%, and 37%, respectively, and those of the 2,809 patients without HCC were 78%, 71%, and 67.0%, respectively. Among the 220 patients with HCC, the following factors were associated with a poor prognosis: multiple tumors, HCC in two lobes of the liver ("bilobar tumors"), micro- and macroscopic vascular invasion, lymph node metastasis, tumor within the surgical margin, Stage IV HCC, and male gender. Cirrhosis and detection of hepatitis B surface antigen (HBsAg) or antibody to hepatitis C virus (anti-HCV) did not influence the survival rates after OLTX in the presence of HCC. By multivariate analysis, the negative prognostic value of only vascular invasion, bilobar distribution, and lymph node metastasis reached significance. As vascular invasion of HCC was the most significant prognostic factor after OLTX, its incidence was examined according to the following three radiologic measurements of the HCC before operation: (1) size, (2) lobar distribution, and (3) number of HCC nodules. Fifty percent of the HCCs of greater than 5 cm diameter had macroscopic vascular invasion, and 1-, 3- and 5-year survivals of the patients with these HCCs were 60%, 30%, and 18%, respectively, after OLTX. Nearly 50% of the bilobar HCCs also had macroscopic vascular invasion, and 1-, 3- and 5-year survivals were 56%, 29%, and 15%, respectively, after OLTX. One-third of multiple tumors had macroscopic vascular invasion, and 1-, 3- and 5-year survivals were 64%, 38%, and 27%, respectively. However, survival after OLTX in patients with bilobar HCCs of < or = 2 cm diameter (even when these were Stage IV) was as good as in patients without HCC who had OLTX. The 5-year survival rate of the patients with unilobar, multiple HCCs without macroscopic vascular invasion, lymph node invasion and distant metastasis was 60%. These data indicate that HCCs of up to 5 cm diameter without macroscopic vascular invasion and nodal or distant metastasis can be effectively treated by OLTX.

Carcinoma, Hepatocellular↗
PubMed1994

HIV-1 Nef activity in murine T cells. CD4 modulation and positive enhancement.

Immediately after infection of the targeted cell by HIV-1, proviral gene expression is limited to the three regulatory proteins, Tat, Rev, and Nef, with the nef transcript representing nearly 80% of total expression. Additionally, simian immunodeficiency virus Nef has been shown to be essential for high in vivo titer and the development of immunodeficiency. Recent findings demonstrate that the negative effects of Nef expression, as first defined in transformed T cell lines, are not present when Nef is expressed in primary human T cells or in T cells from transgenic mice, in which one sees moderate positive enhancements of HIV replication and the T cell activation process, respectively. We find that Nef expression in an Ag-specific murine T cell hybridoma results in both the down-modulation of CD4, as seen in primary cells and human T cell lines, and a positive enhancement of the TCR response to stimuli. Examination of a CD4- cell demonstrated that the positive enhancement is independent of CD4 expression or modulation. CD4 down-modulation is shown to be caused by a post-Golgi, acid-dependent process, which dramatically decreases the lifespan of the CD4 molecule. The TCR, Thy Ag, and CD45 remained unchanged in their surface expression. These findings suggest that Nef alters the normal routing and residencies of the CD4 molecule and that the positive effect of Nef on T cell activation is independent of this modulation.

Animals↗
PubMed1994

HIV-1 Nef inhibits a common activation pathway in NIH-3T3 cells.

The human immunodeficiency virus type 1 (HIV-1) Nef is a myristylated 27-kDa, cytoplasmic protein. It is attributed to have suppressive effects on LTR-based expression and T cell activation. Additionally, SIV nef has been shown to possess an essential in vivo function in the development of immunodeficiency. To define the biochemical activity of HIV-1 Nef in a signal transduction pathway, we have transduced murine NIH-3T3 cells with a retroviral nef expression system. In nef-expressing cells, but not in controls, the proliferative response to bombesin and platelet-derived growth factor (PDGF) was eliminated. Analysis of an early signal pathway metabolite, inositol 1,4,5-trisphosphate, following bombesin and PDGF treatment to quiscent cells, revealed that both control and nef-transformed cells displayed similar kinetics of signal formation. Normally, inositol 1,4,5-trisphosphate mediates increase in the cytosolic free Ca2+ ([Ca2+]i). Upon stimulation with bombesin or PDGF, control cells displayed a 2-4-fold increase of [Ca2+]i over the basal level, while the [Ca2+]i response in nef-expressing NIH-3T3 cells was lacking or highly diminished. However, the release of [Ca2+]i from the intracellular store of the nef-expressing cells by an endomembrane Ca2+ ATPase inhibitor, thapsigargin, revealed that these cells contained normal Ca2+ stores. These results suggest a specific, definable biochemical activity for the HIV-1 Nef protein in the context of a well characterized cellular activation pathway. Our results thus define, for the first time, a unique function of Nef that is not limited to an alteration of T cell function or of expression of a T cell surface antigen.

3T3 Cells↗
PubMed1994

Quantitative micro P30 and reverse transcriptase assays for Moloney murine leukemia virus.

An anti-P30 immunohistochemical and a reverse transcriptase assay for Moloney murine leukemia virus (MoMLV) are adapted to 96-well plates. The assay results are shown to be directly proportional to the number of infectious particles, and can therefore be used to estimate the infective titers of a virus preparation. The micro P30 assay yields a direct estimate of infectious centers, and the reverse transcriptase assay quantitates progeny from a single cycle of replication. The semi-automated nature of these assays is well suited to the analysis of a large number of samples and therefore permits the examination of the efficiency of the process of retroviral/MoMLV infection under varied times or conditions.

3T3 Cells↗
PubMed1994

Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4.

Human immunodeficiency virus type 1 (HIV-1) Nef is a myristylated protein with a relative molecular mass of 27 kDa, is localized to the cytoplasmic surfaces of cellular membranes, and has been reported to down-modulate CD4 in human T cells. To understand the mechanism of HIV-1 Nef-mediated down-modulation of cell surface CD4, we expressed Nef protein in human T-cell line VB. Expression of HIV-1 Nef protein down-modulated surface CD4 molecules. In pulse-chase experiments, CD4 molecules in Nef-expressing cells were synthesized at normal levels. However, the bulk of newly synthesized CD4 protein was degraded with a half-life of approximately 6 h, compared with the 24-h half-life in control cells. This Nef-induced acceleration of CD4 turnover was inhibited by lysosomotropic agents NH4Cl and chloroquine as well as by the protease inhibitor leupeptin. Surface CD4 biotinylation experiments demonstrated that CD4 molecules in Nef-expressing T cells are transported to the plasma membrane with normal kinetics but are then rapidly internalized. Therefore, HIV-1 Nef-induced down-modulation of CD4 is due to rapid internalization of surface CD4 and subsequent degradation by an acid-dependent process, potentially lysosomal. Additionally, in a Nef-expressing cell, we find accelerated dissociation of the T-cell tyrosine kinase p56lck and CD4 but only after the complex reaches the plasma membrane. This implies that HIV-1 Nef protein might play a role in triggering a series of T-cell activation-like events, which contribute to p56lck dissociation and internalization of surface CD4 molecules.

Biological Transport↗
PubMed1993

Characterization of antiidiotypic antibodies to donor HLA that develop after liver transplantation.

Several studies have reported the development of antiidiotypic antibodies to anti-HLA alloantibodies in renal allograft transplant recipients, postulating their potential beneficial role in allograft survival. In order to evaluate the role of anti-HLA antiidiotypic antibodies in human liver transplant recipients and to differentiate them from circulating soluble donor HLA antigens, sera obtained from liver recipients, both pre- and posttransplantation, were analyzed for cytotoxicity inhibitory activity against alloantisera to mismatched donor HLA antigens. Prior to cytotoxicity inhibition assays, sera were absorbed with W6/32 coupled sepharose in order to remove circulating HLA antigens. Antiidiotypic antibodies to anti-HLA class I antibodies were detected in the sera of 7 out of 9 recipients, and antibodies to anti-HLA class II were found in the sera of 4 out of 7 recipients. Antiidiotypic antibodies were detected only during the immediate posttransplantation period. The specific inhibitory activity noted against both HLA class I and II mismatches showed no detectable preference for either HLA class or locus. Furthermore, the antiidiotypic antibodies to HLA developed in liver recipients also inhibited alloantisera to HLA-specific public epitopes or crossreactive groups (CREGS). Cytotoxicity inhibition by posttransplant sera was not mediated by circulating HLA antigens since absorption of the sera with monoclonal anti-HLA framework reagents did not change the specific inhibition of the alloantisera. In addition, the immunoglobulin fraction of the posttransplant sera retained its ability to inhibit cytotoxicity by donor-specific alloantisera. Thus these studies indicate that the development of antiidiotypic antibodies to anti-HLA is common during the immediate period following liver transplantation, even though circulating donor HLA antigens are present. The presence of circulating donor HLA antigens and the development of antiidiotypic antibodies to donor-specific anti-HLA during this period may be important for the successful adaptation of mismatched liver allografts.

Antibodies, Anti-Idiotypic↗
PubMed1993

Analysis of T cell responses in liver allograft recipients. Evidence for deletion of donor-specific cytotoxic T cells in the peripheral circulation.

Analysis of cell-mediated lympholysis in long-term liver allograft recipients indicated that there was a donor-specific unresponsiveness that could not be reversed by the addition of rIL-2 and/or mixed lymphocyte culture supernatant or by nonspecific stimulation of the cultures with PHA. Stimulation of recipient cells with semisyngeneic cells having both donor and third-party HLA antigens failed to reveal the presence of cytotoxic T cells (CTL) specific to the donor, whereas the CTL response to third-party antigens remained normal. Removal of B lymphocytes from the responding cell population did not influence the responses. Furthermore, limiting dilution analysis showed that the liver transplant recipients did not have detectable levels of CTL precursors (CTLp) reactive to the donor antigens, whereas their CTLp to third-party antigens remained normal. Donor-specific CTLp were present before and during the early post-transplant period; these cells were eliminated from the peripheral circulation by 10 mo after transplantation. Taken together, these results indicate that there is a deletion of CTLp specific to donor MHC antigens in the peripheral circulation of long-term liver allograft recipients that may account in part for the success of liver transplantation across MHC barriers.

Adult↗