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D R Grant

Publications and source records attributed to D R Grant.

At least 37 records · Page 2Linked to original sources
PubMed1997

Expression of functional ICAM-1 and VCAM-1 adhesion molecules by an immortalized epithelial cell clone derived from the small intestine.

The role of small bowel-derived epithelial cells in regulating the accumulation of inflammatory cells within the inflamed gut epithelium is poorly understood because of the difficulties in culturing the epithelial cells in vitro. We have recently developed a cloned epithelial cell line (IEC-4.1) derived from the small intestine of BALB/c mice. In the present study, we examined whether IEC-4.1 cells could express adhesion molecules ICAM-1 and VCAM-1 and the molecular basis of macrophage adhesion to the epithelial cells. Northern blot analysis demonstrated that IEC-4.1 cells constitutively expressed ICAM-1 and VCAM-1 mRNA at low levels. Stimulation with LPS (12 microg/ml) or TNF-alpha (2.5 ng/ml) markedly upregulated ICAM-1 and VCAM-1 gene expression in IEC-4.1 cells. ICAM-1 mRNA started to increase 2 hr after LPS stimulation, peaked at 4 hr, and then decreased rapidly to the basal level at 8 hr. VCAM-1 mRNA had the similar pattern of upregulation but the increased VCAM-1 mRNA sustained over a longer period of time and did not return to the basal level until 24 hr after the stimulation. IEC-4.1 cells expressed very low basal levels of ICAM-1 and VCAM-1 on the cell surface as demonstrated by immunofluorescence staining and FACS analysis. Stimulation of IEC-4.1 cells with LPS or TNF-alpha markedly increased the surface expression of both ICAM-1 and VCAM-1, which correlated with the increased binding of macrophages to the stimulated IEC-4.1 cells. Adherence of macrophages to the IEC-4.1 cells was mediated by both LFA-1/ICAM-1 and VLA-4/VCAM-1 since blocking both adhesion pathways inhibited macrophage adhesion by about 90%. These findings suggest that small bowel-derived epithelial cells may be capable of expressing a defined set of functional adhesion molecules during mucosal inflammation.

Animals↗
PubMed1997

Biliary reconstruction without T tubes or stents in liver transplantation: report of 502 consecutive cases.

Although T tubes and stents are widely used as part of the routine biliary reconstruction in liver transplantation, they have inherent complications and there is no proof that they are beneficial to healing. We do not use T tubes or anastomotic stents, and we reviewed our experience with 502 consecutive, whole-size liver grafts to determine the incidence and nature of biliary complications. Duct-to-duct (D-D) and Roux-en-Y loop-to-duct (RY-D) anastomoses were performed in 321 and 176 cases, respectively. In 62% of cases, the donor gallbladder was transplanted and an external catheter cholecystostomy was fashioned to provide for postoperative cholangiography. In the remaining cases the gallbladder was removed. Biliary complications of all types occurred after 13.5% of the transplants. Anastomotic complications (stricture, obstruction, or leak) occurred in 8.2% of the cases, and they were least frequent (4.0%) with RY-D reconstructions. Gallbladder-related complications accounted for one quarter of all biliary complications, and they outweighed the advantage of convenient access to the biliary tree for cholangiography. Four patients (0.9%) died of biliary complications. We conclude that routine reconstruction of the biliary tract without T tubes or stents is a safe technique in liver transplantation. Retaining the donor gallbladder as a method of providing cholanglography is not necessary.

Adolescent↗
PubMed1997

Key features distinguishing post-transplantation lymphoproliferative disorders and acute liver rejection.

Post-transplantation lymphoproliferative disorder (PTLD) and acute rejection are two serious complications of orthotopic liver transplantation that can have a similar histologic appearance. We undertook the present study to assess the best way to distinguish these two entities. We studied histologic features, immunophenotyping, and Epstein-Barr virus (EBV) status, as assessed by immunohistochemical stain and in situ hybridization (ISH), in three groups: Group I, 8 cases of PTLD post-orthotopic liver transplantation with liver involvement; Group II, 15 cases diagnosed with acute liver rejection (control group); and Group III, a subset of 6 biopsy specimens from 4 patients of Group I whose graft rejection was diagnosed within the 2 months preceding the diagnosis of PTLD. The mean proportion of plasma to plasmacytoid cells in most cases from Group I was more than 40%, whereas from Group II it was less than 25% (P = .0001). There was a higher number of B lymphocytes than T lymphocytes in Group I. The numbers of mitotic figures and immunoblasts were significantly different in the two groups (P < .0001 and P = .0005, respectively), being higher in the patients with PTLD. EBV immunostain was most specific for the diagnosis of PTLD (75% positive in Group I, negative in Group II). ISH for EBV-encoded RNA was positive in 87% of cases in Group I and only 6.6% of cases in Group II (P = .0005). In Group III, four of the six liver biopsy specimens had a low plasma cell count and were negative for EBV studies. The other two biopsy specimens in this group had 70 to 80% plasma cell infiltrate, in addition to positive EBV immunostain and ISH in one, for which tissue was available for study. We conclude that viral studies and assessment of the number of plasma cells and B lymphocytes can help to distinguish between acute rejection and early PTLD.

Adult↗
PubMed1996

Central pontine myelinolysis and cyclosporine neurotoxicity following liver transplantation.

In a recent series of 44 liver transplants we identified both extrapontine myelinolysis (EPM) - characteristic of cyclosporine neurotoxicity - and central pontine myelinolysis (CPM) in 5 recipients posttransplant. An additional 2 recipients had EPM only posttransplant. MRIs performed in 4 asymptomatic recipients were normal. Large perioperative shifts in serum sodium, hypomagnesemia, and high cyclosporine levels may play a role in the development of these lesions, although the evidence from this study is inconclusive. In addition to supportive care, dilantin was started in patients who had seizures; aggressive magnesium replacement was initiated for hypomagnesemia, and cyclosporine levels were reduced in all patients. All patients demonstrated a slow steady recovery and all but 2 are at home at the time of writing. CPM may be more prevalent than previously appreciated following liver transplantation, although its prognosis may not be as dismal.

Adult↗
PubMed1996

Rats with portal-caval vein transposition show hyperinsulinemia and insulin resistance.

To compare the metabolic effects of portal and systemic delivery of insulin, we used portal-caval transposition (PCT) in rats to provide total systemic diversion of splanchnic venous blood. PCT rats exhibited normal weight gain, liver histology, liver-function tests, glycosylated hemoglobin, arterial blood pressure, and hepatic blood flow. Mean liver weight relative to body weight was 12% lower in PCT rats than in sham-operated control (CTR) rats 30 days following transposition. Indwelling venous catheters were established to facilitate metabolic studies in conscious, minimally restrained animals. Postabsorptive plasma glucose and C-peptide (CPEP) levels were similar in PCT and CTR rats; however, postabsorptive immunoreactive insulin (IRI) levels were elevated in PCT rats (67 +/- 3.1 v 49 +/- 3.5 pmol.L-1, P < .002, n = 11 v 11), as were postabsorptive plasma glucagon levels (570 +/- 67 v 240 +/- 11 ng.L-1, P < .001, n = 11 v 16) at similar body weights. The postabsorptive CPEP/IRI concentration ratio was lower in PCT than in CTR rats (4.0 +/- 0.3 v 6.0 +/- 0.6, P < .02), suggesting reduced hepatic extraction of insulin. Insulin sensitivity (IS), determined by minimal model analysis of frequently sampled intravenous glucose tolerance tests yielding the sensitivity index (SI), was reduced in PCT compared with CTR (61 +/- 5.6 v 86 +/- 9.0 (mumol.L-1)-1.min-1, P < .04, n = 9 v 10). During euglycemic-hyperinsulinemic clamps, glucose infusion rates (GIRs) from 60 to 120 minutes were lower in PCT than in CTR rats (6.0 +/- 0.3 v 8.0 +/- 0.4 g.kg-1.min-1, P < .002, n = 9 v 7) with matching plasma IRI levels, confirming the reduced IS in PCT rats. Areas under the concentration curves ([AUCs] 0 to 150 minutes) for glucose tolerance tests (gavage) indicated that plasma glucose excursion was similar in PCT and CTR rats whereas AUC IRI was significantly higher in PCT than in CTR rats (23 +/- 1.3 v 18 +/- 0.6 nmol.L-1.min, P < .009, n = 11 v 11). However, AUC CPEP for oral glucose tolerance tests was lower in PCT than in CTR rats (55 +/- 3.4 v 68 +/- 4.8 nmol.L-1.min, P < .05), indicating decreased insulin secretion. Thus, the mean ratio AUC CPEP/AUC IRI was significantly lower in PCT rats (2.5 +/- 0.2 v 3.8 +/- 0.3, P < .002), again suggesting reduced hepatic extraction of insulin. Thus, euglycemia after PCT was accompanied by elevated postabsorptive and glucose-stimulated levels of IRI in systemic blood, postabsorptive hyperglucagonemia, and decreased insulin secretion in response to glucose challenge (gavage), with diminished hepatic extraction of insulin and decreased IS. The PCT model illustrates the insulin-resistant adaptive state that results from systemic delivery of insulin, and indicates the importance of hepatic portal delivery of insulin and possibly of other gastroenteropancreatic hormones in the maintenance of IS and physiological metabolic control.

Animals↗
PubMed1995

Employment after liver transplantation.

The objective of this study was to study the factors affecting employment after liver transplantation. The employment status and health status of 203 adult liver transplant recipients was assessed retrospectively in a survey comprising an employment questionnaire, the Sickness Impact Profile (SID), and the Medical Outcomes Survey (MOS). The patient population consisted of all surviving adult patients who had undergone liver transplantation between 1982 and 1992 at our institution and who had survived a minimum of 9 months. Fifty-seven percent of the recipients were employed and 43% of the recipients were unemployed. Eighteen percent of the recipients considered themselves not well enough to work. Other reasons cited for not working in the unemployed patients were early retirement (8%), return to school (3%), family reasons (3%), no work available (3%), and chose not to work (3%). Patient age, duration of disability before transplantation, and type of job before transplantation significantly affected posttransplantation employment status. Health status measurements predicting employment were ambulation, home management, physical functioning, and pain. Older recipients and those who were continuously out of the workforce for several years before transplantation were the least likely to return to gainful employment after liver transplantation. These findings have implications for assessing the success of liver transplantation and the implementation of strategies to fully rehabilitate patients after liver grafting.

Adolescent↗
PubMed1995

Use of OKT3 monoclonal antibody as induction therapy for control of rejection in liver transplantation.

This report details a single center's experience with OKT3 induction immunosuppression for liver transplantation. One hundred ninety-nine consecutive, unselected adult liver recipients received OKT3 therapy for 9-10 days combined with low-dose steroids and azathioprine. Cyclosporine was begun to overlap with the last few days of OKT3 therapy. The average dose of OKT3 was 45 mg. Fifty-two patients (26.1%) experienced 57 episodes of acute rejection. The median time of onset of rejection was 18 days after grafting. Seventy-eight percent of the rejection episodes were steroid-sensitive. Recurrent rejection was uncommon and the need for OKT3 retreatment was infrequent. One year actuarial graft and patient survival was 79.7% and 82.3% respectively. Based on this evidence, it appears that OKT3 prophylaxis provides good control of acute rejection with a very low incidence of recurrent rejection.

Acute Disease↗
PubMed1994

Altered gene expression of cytokine, ICAM-1, and class II molecules precedes mouse intestinal allograft rejection.

Rapid and severe rejection remains a major obstacle to successful clinical intestinal transplantation (IT). The aggressive nature of rejection in IT has been attributed to the increased massive immune stimulus provided by large numbers of resident lymphocytes, antigen presentation capacity of enterocytes, and graft damage mediated by luminal microflora. Early small bowel expression of proinflammatory cytokines, MHC class II, and adhesion molecules may also promote IT rejection, but the lack of a mouse model has hampered extensive studies of gene expression in IT. Using a recently developed surgical model, we examined the temporal pattern of gene expression in CB6F1 (H-2b/d) vascularized, heterotopic intestinal allografts transplanted into BALB/c (H-2d) mice. Although histological evidence of rejection was not present until day 7 in allografts, Northern blot analysis demonstrated increases in TNF alpha gene transcripts as early as day 3, followed by the expression of IL-1 beta, intercellular adhesion molecule-1, and MHC class II by day 5. Using reverse-transcriptase polymerase chain reaction, IFN-gamma was detected in allografts by day 3 and persisted to day 10. In contrast, IL-2, IL-4, IL-5, and IL-6 mRNA transcripts peaked by day 5 and then decreased, suggesting that both Th1 and Th2 subsets are involved in the rejection of unmodified small bowel allografts. The early and progressive expression of TNF alpha and IL-1 beta as well as IFN-gamma, intercellular adhesion molecule-1, and MHC class II in IT rejection may contribute to the difficulty in controlling IT rejection with present immunosuppression.

Animals↗
PubMed1994

Treatment with FK506 prevents rejection of rat colon allografts.

Colon transplantation has been proposed as a method to improve the function of an intestinal allograft. The present study examined the risk of colon rejection and the effect of FK506 on colon rejection in BN-->LEW rats with orthotopic bowel transplants. The first 4 groups included rats with untreated allografts (group 1), rats with isografts treated with 0.6 mg/kg FK506 (group 2), rats with allografts treated with 0.6 mg/kg FK506 (group 3), and rats with allografts treated with 0.4 mg/kg FK506 (group 4). In each of these groups (10-12 rats), half of the animals received a small bowel graft only (SB), while the other half received a small bowel, ascending colon, and cecum graft (SBC). The animals were followed daily until they died or were killed at 4 weeks. In group 5, an additional 18 untreated rats with SBC allografts were randomly killed on the third, fifth, seventh, and tenth postoperative days to study the sequential histopathologic and immunopathologic changes of colon rejection. There was no difference in survival, body weight, nutritional parameters, or bacterial contamination after SB and SBC transplantation. Intestinal transit was slower after SBC than SB transplantation (P < 0.05). Sequential histopathologic studies revealed that (1) the severity and time course of colon rejection was similar to small intestine rejection, and (2) the features of colon rejection were similar to ulcerative colitis. There was no evidence of graft-versus-host disease after SBC transplantation. In summary, adding a segment of large bowel to a small bowel allograft does not increase the risk of rejection or surgical complications. The transplanted colon slows intestinal transit. Treatment with FK506 effectively prevents colon rejection. These data suggest that adding a colon graft may improve the outcome of clinical small bowel transplantation.

Animals↗
PubMed1994

Transplantation of segmental rat intestinal grafts including the ileocecal value and the ascending colon.

Extrinsic denervation and lymphatic disruption impair nutrient absorption after small bowel transplantation. The present study was undertaken to determine whether adding the ileocecal valve with or without the ascending colon would improve the function of a segmental intestinal graft. Five groups of Lewis rats (n = 10/group) were studied. Group I had a sham laparotomy. Groups II, III, IV, and V had the native jejunum, ileum, and cecum replaced with a graft. Inbred Lewis rats were used as isogeneic donors for the transplants to avoid the confounding effect of graft rejection. Group II had the entire jejunum and ileum transplanted. Group III had 20 cm of terminal ileum transplanted. Group IV had 20 cm of the terminal ileum including the ileocecal valve transplanted. Group V had 20 cm of the terminal ileum, the ileocecal valve, and the ascending colon transplanted. The terminal ileum-transplanted and terminal ileum/ileocecal valve-transplanted groups lost more than 25% of their preoperative weight by the end of the second postoperative week; most of these animals were killed because of inanition. In contrast, the sham laparotomy, jejunum/ileum-transplanted, and ascending colon-transplanted groups remained healthy until completion of the study on the 28th postoperative day. The ascending colon-transplanted group had slower intestinal transit and less bacterial contamination of the terminal ileum compared with the terminal ileum-transplanted and terminal ileum/ileocecal valve-transplanted groups (P < 0.05). Transplantation of the ascending colon and the ileocecal valve significantly improves the function of segmental small bowel isografts in rats. These data suggest that adding a colonic segment may be a simple method to improve the function of short-segment cadaveric and living-related intestinal grafts in humans.

Animal Nutritional Physiological Phenomena↗
PubMed1994

Normal fasting volume and postprandial emptying of the denervated donor gallbladder in liver transplant recipients.

BACKGROUND/AIMS: Truncal vagotomy causes gallbladder dilatation and possibly cholelithiasis. During liver transplantation, when the gallbladder is transplanted with the donor liver, the gallbladder and liver are extrinsically denervated. The aim of this study was to determine whether extrinsic denervation affects gallbladder volume and postprandial emptying. METHODS: To evaluate fasting gallbladder volume, 26 transplant recipients underwent ultrasonography. Twenty-eight normal volunteers were controls. To evaluate postprandial contractility, seven transplant recipients underwent radionuclide gallbladder-emptying studies. Gastric emptying and cholecystokinin release were simultaneously determined after a fatty meal to exclude a difference in gallbladder stimulus. Sixteen normal volunteers were controls. RESULTS: There were no differences in fasting gallbladder volume or postprandial contractility, gastric emptying, and cholecystokinin release between transplant patients and controls. Median fasting and postprandial gallbladder volumes for the transplant recipients (95% confidence) were 16 mL (12-34 mL) and 3 mL (0-8 mL), respectively, and for controls were 18 mL (13-21 mL; P = 0.73) and 3 mL (1-6 mL; P = 0.97), respectively. CONCLUSIONS: These data do not show gallbladder dilatation or impaired postprandial gallbladder contraction in the extrinsically denervated gallbladder. This finding suggests that gallbladder dilatation may be caused by the unopposed activity of the sympathetic system after truncal vagotomy.

Adult↗
PubMed1994

Anti-B cell antibodies for the treatment of monoclonal Epstein-Barr virus-induced lymphoproliferative syndrome after multivisceral transplantation.

Epstein-Barr virus-induced lymphoproliferative syndrome (EBV-LPS) is associated with OKT3 therapy in transplant patients. Response to chemotherapy or radiation is generally poor, while polyclonal EBV-LPS has had favorable responses to therapy with CD21 and CD24 monoclonal antibodies. Oligoclonal disease has not been previously reported to respond to therapy with CD21 and CD24. We report a 27-y old woman who developed a monoclonal EBV-LPS (confirmed by southern analysis of tumour for EBV DNA) after 180 mg of OKT3 for a multivisceral transplant. The patient achieved clinical remission for more than 2 months, but later died from cytomegalovirus pneumonia. Levels of CD21 and CD24 were > 2000 ng/ml during therapy and no human anti-mouse antibodies were formed. Peripheral blood B cells were cleared during therapy. We conclude that CD21 and CD24 monoclonal antibodies may be of value in the therapy of oigoclonal EBV-LPS, and merit further study.

Adult↗
PubMed1993

Right phrenic nerve injury in orthotopic liver transplantation.

Right hemidiaphragm paralysis has been previously documented in patients after orthotopic liver transplantation (OLT) and it may contribute to the development of postoperative pulmonary problems. It has been postulated that a crush injury to the right phrenic nerve during OLT is the cause of dysfunction of the right hemidiaphragm. To assess the incidence and effect of right phrenic nerve injury after OLT, we prospectively studied 48 adult liver recipients. Twelve patients who underwent liver resection (LR), in whom the suprahepatic vena cava was not clamped, were used as a comparison group. Diaphragm excursion by ultrasound and pulmonary function were performed preoperatively and postoperatively; transcutaneous phrenic nerve conduction studies were performed postoperatively. Right phrenic nerve injury and hemidiaphragm paralysis occurred in 79% and 38% of the liver recipients but not after LR. Conduction along the right phrenic nerve was absent in 53% and reduced in another 26%. Left phrenic nerve conduction and left hemidiaphragm excursion were normal in both liver recipients and the patients who had LR. Liver recipients with no conduction in the right phrenic nerve had a significantly greater decrease in vital capacity in the supine position (29 +/- 9.8%) compared with those with some conduction (14 +/- 6.9%, P < 0.001). However, neither the time on the ventilator nor the hospital stay was significantly different in the latter two groups. Complete recovery of phrenic nerve conduction and diaphragm function took until nine months in some patients. Right phrenic nerve injury is common after OLT and it is the cause of right hemidiaphragm dysfunction.

Adolescent↗
PubMed1993

[Right diaphragmatic paralysis after liver transplantation].

Right hemidiaphragm paralysis has been previously documented in patients after orthotopic liver transplantation (OLT) and it may contribute to the development of postoperative pulmonary problems. It has been postulated that a crush injury to the right phrenic nerve during OLT is the cause of dysfunction of the right hemidiaphragm. To assess the incidence and effect of right phrenic nerve injury after OLT, we prospectively studied 51 adult liver recipients that we compared with twelve patients who underwent liver resection (LR) without suprahepatic vena cava clamping. We studied the diaphragm excursion by ultrasound, the pulmonary function tests and the transcutaneous phrenic nerve conduction. Righ phrenic nerve injury and hemidiaphragm paralysis occurred respectively in 79% and 38% of the liver recipients but not after LR. Conduction along the right phrenic nerve was absent in 53% of the patients and reduced in another 26%. Left phrenic nerve conduction and left hemidiaphragm excursion were normal in both groups. Liver recipients with no conduction in the right phrenic nerve had a significantly greater decrease in vital capacity in the supine position compared to those with some conduction (29% vs 14%; P < 0.001). However, neither the time on the ventilator or the hospital stay were significantly different between the two groups. Complete recovery of phrenic nerve conduction and diaphragm function may take up to nine months. Right phrenic nerve injury is common after OLT and causes right hemidiaphragm dysfunction.

Adolescent↗