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Biomedical subjects

J Fung

Publications and source records attributed to J Fung.

At least 109 records · Page 6Linked to original sources
PubMed1997

Brain abscess in solid organ transplant recipients receiving cyclosporine-based immunosuppression.

OBJECTIVE: To determine the incidence, clinical presentation, and outcome and confounding factors associated with the development of a brain abscess in solid organ transplant recipients. DESIGN: A 14-year retrospective survey. SETTING: A single, multiorgan, academic transplantation center. PATIENTS: A total of 2380 liver transplant recipients, 1650 kidney transplant recipients, and 598 heart, heart-lung, or lung transplant recipients of all ages (pediatric and adult) were included. All patients were given cyclosporine-based immunosuppression during this period. MAIN OUTCOME MEASURE: A brain abscess was determined to be present it there was histological and/or microbiological confirmation of a brain lesion seen by a computed tomographic scan. A brain abscess was considered suspicious if radiographic findings were seen in the clinical setting of neurologic symptoms and fever without histological or microbiological confirmation. RESULTS: A brain abscess developed in a total of 28 patients (0.61%) of the total study population. The frequency of brain abscess according to organ type was as follows: 0.63%, liver; 0.36%, kidney; and 1.17%, heart and heart-lung. The overall mortality was 86%. Complicating factors associated with fungal (Candida and Aspergillus sp) abscess formation included major subsequent operations, retransplantations, antirejection therapy, associated bacteremia or viremia, and multiorgan failure. The lung was the primary site of dissemination in 18 patients. Low-dose prophylactic amphotericin was ineffective in preventing a fungal brain abscess in 10 high-risk patients. Because of the ineffective therapy and the deadly nature of established fungal abscesses, full-dose antifungal therapy and reduced immunosuppression were warranted on identification of a high-risk clinical setting. Nonfungal abscesses (Nocardia and Toxoplasma sp) occurred in healthy graft recipients long after transplantation. The existing medical therapy is usually effective in these patients, provided that rapid tissue diagnosis is established. CONCLUSIONS: The epidemiological features of brain abscess formation after solid organ transplantation suggest 2 populations of patients exist that differ in timing, clinical setting, and response to therapy. For the chronically immunosuppressed outpatient, an established abscess should be empirically treated with sulfonamides until tissue diagnosis is confirmed. On the other hand, the acutely immunosuppressed posttransplant recipient, with defined risk factors, should receive full-dose therapy with amphotericin B and concomitantly lowered immunosuppression.

Adolescent↗
PubMed1997

Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome.

Using Down syndrome as a model for complex trait analysis, we sought to identify loci from chromosome 21q22.2 which, when present in an extra dose, contribute to learning abnormalities. We generated low-copy-number transgenic mice, containing four different yeast artificial chromosomes (YACs) that together cover approximately 2 megabases (Mb) of contiguous DNA from 21q22.2. We subjected independent lines derived from each of these YAC transgenes to a series of behavioural and learning assays. Two of the four YACs caused defects in learning and memory in the transgenic animals, while the other two YACs had no effect. The most severe defects were caused by a 570-kb YAC; the interval responsible for these defects was narrowed to a 180-kb critical region as a consequence of YAC fragmentation. This region contains the human homologue of a Drosophila gene, minibrain, and strongly implicates it in learning defects associated with Down syndrome.

Animals↗
PubMed1997

Hepatitis G virus infection in American patients with cryptogenic cirrhosis: no evidence for liver replication.

It is unclear whether hepatitis G virus (HGV) can lead to chronic liver disease and cirrhosis. Eighty-nine patients with end-stage liver disease undergoing liver transplantation were studied: 50 were diagnosed as having cryptogenic cirrhosis while 39 had nonviral chronic liver disease. Five (10%) in the former and 1 (2.6%) in the latter group (not significantly different) were positive for HGV RNA in serum. All 6 HGV-infected patients were negative for the presence of the HGV RNA minus strand in the liver when tested with a strand-specific Tth-based reverse transcription-polymerase chain reaction, and 5 were positive for the presence of the plus strand, albeit at low levels. This implies that the liver is not the primary replication site for HGV, at least in a significant proportion of patients. Absence of liver replication explains the reported lack of association between HGV infection and liver pathology encountered in many clinical settings.

Flaviviridae↗
PubMed1997

Carrier-specific breakpoint-spanning DNA probes: an approach to preimplantation genetic diagnosis in interphase cells.

Carriers of chromosomal inversions or other balanced rearrangements represent a significant fraction of patients in in-vitro fertilization (IVF) programmes due to recurrent reproductive problems. In most cases, chromosomal imbalance in fertilized oocytes is incompatible with embryo survival leading to increased rates of spontaneous abortions. Assuming that a fraction of the germ cells is karyotypically normal, these patients would greatly benefit from efficient procedures for generation and use of breakpoint-specific DNA hybridization probes in preconception and preimplantation genetic diagnosis (PGD). We describe the generation of such patient-specific probes to discriminate between normal and aberrant chromosomes in interphase cells. First, a large insert DNA library was screened for probes that bind adjacent to the chromosomal breakpoints or span them. Then, probe and hybridization parameters were optimized using white blood cells from the carrier to increase in hybridization signal intensity and contrast. Finally, the probes were tested on target cells (typically polar bodies or blastomeres) and a decision about the colour labelling scheme was made, before the probes can be used for preconception or preimplantation genetic analysis. Thus, it was demonstrated that cells with known structural abnormalities could be detected, based on hybridization of breakpoint spanning yeast artificial chromosome (YAC) DNA probes in interphase cells.

Blastomeres↗
PubMed1997

Distribution of infecting hepatitis C virus genotypes in end-stage liver disease patients at a large American transplantation center.

The distribution of hepatitis C virus (HCV) genotypes was studied in 202 anti-HCV-positive liver transplant candidates with end-stage liver disease. HCV sequences were successfully amplified from 185 patients: In the first 100, the genotype was determined by direct sequencing in the NS5 region, and in the remaining 85, type-specific primers were used for genotyping. Eighty-five patients (46.0%) were infected with type 1a HCV strains, 52 (28.1%) with type 1b, 14 (7.6%) with type 2b, 13 (7.0%) with type 4, 5 (2.7%) with type 3a, 2 (1.1%) with type 2a, and 1 (0.5%) with type 2c. Thirteen HCV-positive patients (7.0%) could not be genotyped. The relatively low prevalence of genotype 1b in this population of end-stage liver disease patients speaks against postulated higher pathogenicity of this genotype.

Adult↗
PubMed1997

Postural orientation, equilibrium, and the spinal cord.

In summary, adequate control of postural orientation and equilibrium is a prerequisite for virtually all skilled motor acts, even those apparently simple tasks of standing and walking. In the cat, certain aspects of postural orientation appear to be organized at the spinal level. In contrast, postural equilibrium is not achieved by spinal circuits in isolation, but seems to require input from higher centers. The challenge is to identify those higher centers and the means by which they produce appropriate postural reactions for maintaining balance. If, indeed, postural equilibrium is a function of descending systems, then in the future, the amount of recovery of postural equilibrium after injury and/or treatment could provide a quantitative measure of the degree of sparing and/or re-establishment of functional connections between higher centers and the spinal cord.

Animals↗
PubMed1997

Leuconostoc bacteremia after liver transplantation: another cause of vancomycin resistant gram-positive infection.

Leuconostoc sp. are gram-positive bacteria intrinsically resistant to vancomycin, which can be confused with streptococci based on routine microbiological-characteristics. Infections secondary to Leuconostoc are uncommon, and usually affect patients with underlying diseases, prior use of vancomycin and those with central lines. The most common clinical presentation is fever secondary to a central line infection. We report the first case of Leuconostoc infection in a solid organ transplant recipient. The patient developed Leuconostoc bacteremia secondary to peritonitis, 60 d after undergoing liver transplantation. He was treated with clindamycin, gentamicin and underwent surgical debridement, but succumbed to other complications.

Adult↗
PubMed1996

Dynamic behavior of hepatitis C virus in chronically infected patients receiving liver graft from infected donors.

We studied the outcome of hepatitis C virus (HCV) infection in 14 patients with end-stage HCV-related liver disease who received HCV-positive liver allografts. Viral sequences specific for donor and recipient were established by direct sequencing of PCR products from the NS5 region and by single-strand conformation polymorphism. Within a few months after transplantation the donor strain took over the recipient strain in 8 patients while in 6 patients it was the recipient strain which ultimately prevailed. Donor and recipient were infected by identical genotypes in 6 donor/recipient pairs and by different genotypes in the remaining 8 pairs. Subtype 1b and type 1 (1a + 1b) became the predominant strains in all recipient/donor pairs in which they were present. Patients retaining their own strain were found to have significantly more active liver disease than those infected by the donor strain. We show that HCV superinfection and overtake phenomena occur in humans and suggest that genotypes 1b and 1 (1a + 1b) may possess replicative advantages over other genotypes. Furthermore, we provide evidence of the existence of interference preventing simultaneous continuous infection even by the same genotype strains. The development of active liver disease associated with recipient strain infection and mild or no disease associated with infection from the donor suggests various pathogenic abilities of different HCV strains.

Adult↗
PubMed1996

Lack of susceptibility of baboons to infection with hepatitis B virus.

Historically, hepatitis B virus (HBV) has been considered species specific and unable to infect baboons. Based on this premise, two patients with HBV endstage liver disease underwent baboon liver xenotransplantation. To study whether baboons are susceptible to HBV infection, four baboons (two receiving immunosuppressive therapy) were inoculated with HBV. Animals were followed for 6 months: clinical examinations and biochemical studies were normal, hepatitis B surface antigen and hepatitis B core antigen staining of biopsies was negative, and HBV serology remained negative. HBV polymerase chain reaction was transiently positive in one animal, which most likely reflects the initial inoculation. This pilot study corroborates historical evidence and beliefs that baboons are resistant to HBV.

Animals↗
PubMed1996

Cryptococcal meningitis after liver transplantation.

We present our experience with 10 liver transplant recipients in whom cryptococcal meningitis developed after liver transplantation. Disease developed a median period of 3.5 months (range, 2-36 months) after transplantation and patients were diagnosed a median period of 9 days (range, 2-90 days) after initial symptoms. Headache, fever, and mental status changes were the most frequent clinical presentations, while meningismus was found in only 30% of patients. Cerebrospinal fluid analysis was diagnostic in all cases. All patients were treated with amphotericin B and flucytosine. Immunosuppression was either decreased or discontinued during therapy. Five patients died, four as a direct result of cryptococcal infection and one as a result of chronic rejection. Three patients had long-term survival without any sequelae. One long-term survivor suffered blindness consequent to the disease. We conclude that cryptococcal meningitis is a rare complication in liver transplant recipients (0.25%), and has a high mortality rate (50%). Early recognition, combination antifungal therapy, and decrease or discontinuation of immunosuppression are important for cure. No relapse has been seen in surviving patients.

Adult↗
PubMed1996

In vitro characterization of rat bone marrow-derived dendritic cells and their precursors.

Although the rat is commonly used for basic immunology and transplantation research, phenotypic and functional characterization of rat dendritic cells (DCs) lags behind similar studies in the human and mouse. Therefore, these features were examined using DCs propagated from cultures of rat bone marrow maintained in a medium supplemented with granulocyte-monocyte colony-stimulating factor. Analysis of cytospin preparations of cultured cells showd that DCs arise from OX7+ myelomonocytic precursors. Typical mature rat DCs were morphologically similar to their mouse and human counterparts and expressed major histocompatibility complex (MHC) class II (common part determinant of Ia), OX62 (integrin molecule), OX7 (CD90), ICAM-1 (CD54), and CTLA4 counterreceptor, but were negative for OX8 (CD8), OX19 (CD5), W3/25 (CD4), and ED2, a rat macrophage marker. Functional analysis of OX62+ sorted DCs showed that they could effectively present the soluble antigen ovalbumin to naive T cells in vitro. A combination of anti-MHC class II monoclonal antibody and CTLA4-immunoglobulin inhibited allostimulatory ability more effectively than either reagent alone. Implications for studying the role of DCs in immune responses in the rat are discussed.

Abatacept↗
PubMed1996

Altered endothelin homeostasis in patients undergoing liver transplantation.

The liver is a major site of synthesis, clearance, and actions of the powerful vasoactive peptide endothelin-1 (ET-1). We investigated the role of the liver in ET-1 homeostasis by comparing circulating and hepatic ET-1 levels and hepatic ET receptors in patients undergoing orthotopic liver transplantation (OLTx) for end-stage liver disease (ESLD) with those in patients undergoing liver resection for focal lesions with otherwise normal hepatic synthetic function. Central venous and radial arterial blood was drawn immediately after induction of anesthesia (point I), 10 minutes before beginning of resection or the anhepatic stage (point II), and 30 minutes after completion of resection or reperfusion of the grafted liver (point III). Portal and hepatic venous blood was drawn at points II and III. Plasma ET-1 levels were higher in ESLD patients than in resection patients. Plasma ET-1 levels rose both during resection and transplantation; the increase in ET-1 was more pronounced during transplantation. In ESLD patients, hepatic venous ET-1 was higher than portal venous ET-1, suggesting reduced clearance and/or enhanced synthesis of the peptide in the cirrhotic liver. Conversely, hepatic venous ET-1 was lower than portal venous ET-1 in resection patients at all time points and at point III in the ESLD patients. Hepatic concentration of ET-1 was greater and the capacity of the liver to catabolize ET-1 was reduced in ESLD patients as compared to the resection patients. Further, hepatic ET receptor density was higher in ESLD than in resection patients. These results suggest that the cirrhotic liver may contribute to elevated plasma ET-1 in ESLD. Considering its potent hemodynamic and metabolic effects in the liver, increased hepatic ET-1 and ET receptors and plasma ET-1 could play a role in the pathophysiology of liver disease and perioperative complications of OLTx.

Adult↗
PubMed1995

A new concept for successful long-term pulmonary preservation in a dog model.

We developed a dextran-glucose-based extracellular perfusion solution (DGX) that supports limited aerobic metabolism to maintain cellular integrity of an inflated donor lung during long-term ischemia and a storage temperature of 10 degrees C. In a dog model, we compared respiratory and hemodynamic function of orthotopically transplanted left lungs preserved using this method (DGX, group I, n = 6) with function of those preserved with EuroCollins solution (EC) stored at a temperature of 4 degrees C (group II, n = 6). All lungs were inflated with room air and stored for 12 hr. Pulmonary function was monitored for 5 hr of reperfusion. Values expressed below are group means with standard deviation. Statistical significance was calculated using a two-tailed t test. For PO2 (mmHg) (FiO2 = 0.4), group I (EC): control = 193 +/- 8, 30 min p.o. = 87 +/- 20*, 300 min p.o. = 174 +/- 13*; and group II (DGX): control = 217 +/- 28, 30 min p.o. = 184 +/- 46*, 300 min p.o. = 248 +/- 5*. For pulmonary vascular resistance (dynes), group I: control = 389 +/- 22, 30 min p.o. = 1209 +/- 301, 300 min p.o. = 1025 +/- 204*; and group II: control = 401 +/- 31, 30 min p.o. = 522 +/- 129, 300 min p.o. = 458 +/- 137* (*P < 0.05 DGX vs. EC). Gas analysis performed on air samples taken from the ischemic donor lung immediately after harvest and after 12-hr storage showed (calculated as group means) a significant decrease of PO2 and a significant increase of PCO2, respectively. Histology of the lungs after 5 hr of reperfusion showed essentially normal-appearing lungs in the DGX group, whereas lungs in the EC group showed thickening of the intra-alveolar septi, marked cellular infiltration, and accumulation of protein-like material in the alveoli. In this study, preservation with DGX resulted in satisfactory respiratory and hemodynamic function of the transplanted lung even after 12 hr of ischemia. It does not cause an increase of pulmonary vascular resistance as seen after preservation with EC. Data from the intrabronchial air analysis of the donor lung suggest that aerobic metabolism continues even under preservation conditions.

Animals↗
PubMed1995

A new protocol for the propagation of dendritic cells from rat bone marrow using recombinant GM-CSF, and their quantification using the mAb OX-62.

Bone marrow (BM)-derived dendritic cells (DC) are the most potent known antigen (Ag) presenting cell in vivo and in vitro. Detailed analysis of their properties and mechanisms of action requires an ability to produce large numbers of DC. Although DC have been isolated from several rat tissues, including BM, the yield is uniformly low. We describe a simple method for the propagation of large numbers of DC from rat BM and document cell yield with the rat DC marker, OX-62. After depletion of plastic-adherent and Fc+ cells by panning on dishes coated with normal serum, residual BM cells were cultured in gelatin coated flasks using murine rGM-CSF supplemented medium. Prior to analysis, non-adherent cells were re-depleted of contaminating Fc+ cells. Propagation of DC was monitored by double staining for FACS analysis (major histocompatibility complex (MHC) class II+/OX-62+, OX-19-). Functional assay, morphological analysis and evaluation of homing patterns of cultured cells revealed typical DC characteristics. MHC class II and OX-62 antigen expression increased with time in culture and correlated with allostimulatory ability. DC yield increased until day 7, when 3.3 x 10(6) DC were obtained from an initial 3 x 10(8) unfractionated BM cells. Significant numbers of DC can be generated from rat BM using these simple methods. This should permit analysis and manipulation of rat DC functions in vivo and in vitro.

Animals↗