Biomedical subjects

David Grant

Publications and source records attributed to David Grant.

31 records · Page 2Linked to original sources

PubMed2004

Control of microbial contamination during surgical harvest of pig renal xenografts.

The pig has been identified as the most likely source of xenograft material for clinical use and studies are ongoing to overcome the immunological hurdles of pig-to-human transplantation. Attention is now being focussed on identifying and reducing the potential microbiological hazards associated with this technique. Studies have primarily addressed issues surrounding the production and health monitoring of xenograft source pigs and none have so far specifically evaluated the possible risks of microbial contamination during xenograft harvest. In this report, we evaluate the possible routes for contamination of a pig kidney xenograft during organ harvest and describe approaches to the control of these hazards, including the novel use of a custom designed airtight surgical canopy. A standard procedure for microbiological monitoring during xenograft harvest was devised and evaluated. This allowed the rapid identification and anti-microbial sensitivity testing of any isolated organisms. This would enable an early and appropriate pre-emptive treatment of infection because of transmission of pig micro-organisms.

Animals↗

PubMed2004

Mining EST databases to resolve evolutionary events in major crop species.

Using plant EST collections, we obtained 1392 potential gene duplicates across 8 plant species: Zea mays, Oryza sativa, Sorghum bicolor, Hordeum vulgare, Solanum tuberosum, Lycopersicon esculentum, Medicago truncatula, and Glycine max. We estimated the synonymous and nonsynonymous distances between each gene pair and identified two to three mixtures of normal distributions corresponding to one to three rounds of genome duplication in each species. Within the Poaceae, we found a conserved duplication event among all four species that occurred approximately 50-60 million years ago (Mya); an event that probably occurred before the major radiation of the grasses. In the Solanaceae, we found evidence for a conserved duplication event approximately 50-52 Mya. A duplication in soybean occurred approximately 44 Mya and a duplication in Medicago about 58 Mya. Comparing synonymous and nonsynonymous distances allowed us to determine that most duplicate gene pairs are under purifying, negative selection. We calculated Pearson's correlation coefficients to provide us with a measure of how gene expression patterns have changed between duplicate pairs, and compared this across evolutionary distances. This analysis showed that some duplicates seemed to retain expression patterns between pairs, whereas others showed uncorrelated expression.

Computational Biology↗

PubMed2004

Interactions between emergency medicine programs and the pharmaceutical industry.

OBJECTIVES: To examine the beliefs and practices of emergency medicine program directors regarding interactions with the pharmaceutical industry. The authors also sought to study the prevalence of program policies and the desire for organizational policies. METHODS: The Board of the Council of Emergency Medicine Residency Directors (CORD) requested and approved a member survey. An institutional review board-approved, Web-based, 30-item survey was sent to all CORD members subscribed to the organization's listserv in May 2002 and was completed by June 2002. Program director respondents were surveyed as to their beliefs and practices regarding industry sponsorship of speakers, social events, drug samples, travel to conferences, and the educational value of marketing representatives. Subjects were queried about their awareness of existing guidelines and whether they desired policy development by CORD. RESULTS: Surveys were returned from 106 programs (85%). The majority of program directors (72%) "never" or "very rarely" allowed unrestricted interactions between pharmaceutical representatives and residents at work. However, only 52% of program directors said they "never" or "very rarely" allowed pharmaceutical representatives to give residents free drug samples at work. Only 46% said they "never" or "very rarely" allowed pharmaceutical representatives to teach residents. Two thirds of program directors desired CORD guidelines regarding interactions with the pharmaceutical industry. Program directors seeking guidelines were less likely to allow pharmaceutical representatives to teach residents (p = 0.001). They were also less likely to allow pharmaceutical representatives unrestricted interactions with residents (p = 0.05). CONCLUSIONS: A wide range of practices exist among emergency medicine residency program directors, and most desire organizational guidelines regarding interactions with the pharmaceutical industry.

Attitude of Health Personnel↗

PubMed2004

Ethical guidelines for the evaluation of living organ donors.

Transplantation is an effective, life-prolonging treatment for organ failure. Demand has steadily increased over the past decade, creating a shortage in the supply of organs. In addition, the number of deceased organ donors has reached a plateau. Living-donor transplantation is increasingly an option, influenced by favourable clinical outcomes and increased waiting times at most transplant centres across North America. Living-donor kidney transplants have exceeded deceased-donor transplant rates at some centres. Organ donations from living donors have challenged transplant programs to develop a framework for determining donor acceptability. After a multidisciplinary consensus-building process of discussion and debate, the Multi-Organ Transplant Program of the University Health Network in Toronto has developed ethical guidelines for these procedures. These proposed guidelines address ethical concerns related to selection criteria and procedures, voluntariness, informed consent and disclosure of risks and benefits to both donor and recipient.

Ethics, Clinical↗

PubMed2003

Gallstone ileus.

Explore the source record for details and available documents.

Aged↗

PubMed2003

Efficacy and safety of itraconazole prophylaxis for fungal infections after orthotopic liver transplantation: a prospective, randomized, double-blind study.

BACKGROUND: There is significant morbidity and mortality related to fungal infections in the solid-organ transplant population. METHODS: A prospective, randomized, double-blind, placebo-controlled, restricted sequential design trial was performed in 71 adults undergoing orthotopic liver transplantation. Patients were randomly assigned to receive either itraconazole (5.0 mg/kg orally, preoperatively, 2.5 mg/kg orally, two times a day, postoperatively) or placebo. Therapy continued for a maximum of 56 days or until patient was discharged from hospital or met a predefined endpoint. Measurements included incidence of fungal colonization, superficial or systemic fungal infections requiring systemic therapy, adverse events, and mortality rate. RESULTS: This trial design supported the superiority of itraconazole in preventing fungal infections; nine patients in the placebo group (24%; 95% confidence interval, 0.118-0.412) and one patient in the itraconazole group (4%; 95% confidence interval, 0.001-0.204) developed fungal endpoints requiring therapy with amphotericin B (P=0.04, Fisher's exact test). At the time of enrollment, fungal colonization occurred in 40% and 37% of itraconazole and placebo patients (P=0.43), respectively. Adverse events were reported by 97% and 100% of the intraconazole and placebo groups, respectively, and one itraconazole and six placebo-group patients died within the study period. There was no relation to trial medication for serious adverse events. CONCLUSION: Prophylaxis with itraconazole reduces fungal infections in patients undergoing orthotopic liver transplantation and is well tolerated.

Administration, Oral↗

PubMed2003

Ex vivo and extracorporeal perfusion with hDAF pig kidneys.

The present study was undertaken to determine whether human decay accelerating factor (hDAF) transgene would prevent hyperacute rejection (HAR) while perfused with human blood or extracorporeally in baboons. Four hDAF pig kidneys and three non-hDAF pig kidneys were perfused ex vivo with fresh human blood for 6 h. Additionally four hDAF pig kidneys and four non-hDAF pig kidneys were extracorporeally perfused in baboons and pigs, respectively, for 3 h. In ex vivo perfusion, the color of hDAF pig kidneys remained pink at the end of 6-h perfusion and they had normal histology, while non-hDAF kidneys developed HAR. HDAF pig kidneys had superior function over non-transgenic pig kidneys. Urine output was 17.31 +/- 3.70 ml/h for hDAF pig kidneys, and only 5.81 +/- 0.26 ml/h for non-hDAF kidneys (P < 0.05). Creatinine clearance was 1.16 +/- 1.24 ml/min for hDAF kidneys and 0.22 +/- 0.15 ml/min for non-hDAF kidneys (P < 0.05). Other functional data including potassium, urine specific density, and osmolality were normal in the hDAF kidneys, while in non-hDAF kidneys, serum potassium was elevated to over 9 mmol/l by the end of perfusion (P < 0.01). Non-hDAF kidneys also lost more sodium through urine than hDAF kidneys (173.67 +/- 14.05 mmol/l vs. 109 +/- 31 mmol/l, P < 0.05). In the extracorporeal perfusion, all the baboons tolerated the procedure well with normal hemodynamic and hemotologic profiles. These baboons were well until killed 42 to 56 days after perfusion, although their antiporcine antibodies were greatly elevated. We conclude that hDAF transgene protects against HAR, allowing the pig kidney to function normally while perfused with human blood, and that extracorporeal perfusion using hDAF pig kidneys is a safe procedure in baboons.

Animals↗

PubMed2003

The long-term survival of baboon-to-monkey kidney and liver xenografts.

The present study was undertaken to develop an optimum immunosuppressive regimen in baboon-to-monkey life-supporting kidney xenografts. Baseline therapy for all groups include cyclosporine (CsA) and steroids. We compared adding (1) cyclophosphamide (CyP) at dose of 20 mg/kg/day given on post-operative day (POD) 0, 2, 5 and 7; (2) mycophenolic mofetil (MMF) at a dose of 40 mg/kg/day by daily gavage; or (3) CyP + rapamycin (Rap). The latter group was divided into high and low dose subgroups. Untreated xenografts were rejected on POD 6, CsA alone treated xenografts survived for 35 days and CsA + CyP treated xenografts survived for 45 days. Adding MMF significantly prolonged mean survival to 111 +/- 53 days, but the xenografts eventually developed rejection. Combination therapy including CsA, CyP and Rap reliably prevented xenogenic rejection and achieved a mean survival of 290 +/- 30 days. However, high dose CyP + Rap led to high incidence of post-transplant lymphoproliferation disorders (PTLD), while the incidence of PTLD was significantly less in the low dose subgroup (P < 0.01). Four animals in this subgroup survived for more than 300 days with normal renal function and histology. In addition, two liver recipients treated with CsA + CyP survived for 91 and 1,076 days. We conclude that long-term survival of kidney or liver xenografts can be achieved in a non-human concordant xenograft model using currently available immunosuppressive agents.

Animals↗

PubMed2003

Early steroid withdrawal after liver transplantation: the Canadian tacrolimus versus microemulsion cyclosporin A trial: 1-year follow-up.

Corticosteroid therapy contributes significant toxicity to liver transplantation. The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A (micro-CsA). The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation. From the seven Canadian adult liver transplant centers, 143 patients were randomly allocated oral treatment with either tacrolimus (n = 71) or micro-CsA (n = 72), together with corticosteroids and azathioprine. Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months, and prednisone </=0.15 mg/kg/d. In eligible patients, the daily steroid dose was reduced by 2.5 mg each month until complete discontinuation was achieved. At 1 year after transplantation, 75% of the tacrolimus patients and 63% of the micro-CsA patients were steroid-free (P =.20). Of all of the patients who became eligible for steroid withdrawal, steroid discontinuation was achieved in over 80%. One-year patient survival was 97% with tacrolimus and 89% with micro-CsA (P =.052). Graft survival was 97% and 86%, respectively (P =.017). The overall incidence of acute rejection during the first year was 35% with tacrolimus and 43% with micro-CsA (P =.26). There was no difference in survival, acute rejection, or rate of steroid withdrawal when adjusting for hepatitis C. All acute rejection episodes experienced during steroid withdrawal were steroid-responsive. Steroid-resistant rejection occurred in 5.6% of the tacrolimus and 9.7% of the micro-CsA patients. One patient, in the micro-CsA group, experienced refractory rejection. Chronic rejection was not observed in either group. The toxicity profiles were similar. Postoperative serum creatinine levels were similar, and dialysis was required in less than 10% of patients in each group. Infectious complications were similar in both groups. Neurotoxicity was a serious adverse event in 13% and 10% of patients receiving tacrolimus and micro-CsA, respectively. Early steroid withdrawal is safe and effective after liver transplantation using either tacrolimus plus azathioprine or micro-CsA plus azathioprine immunoprophylaxis.

Acute Disease↗

PubMed2002

Monoclonal antibody against beta7 integrins, but not beta7 deficiency, attenuates intestinal allograft rejection in mice.

BACKGROUND: beta7 integrins mediate homing and retention of lymphocytes to the normal and inflamed small bowel in a tissue-selective fashion. In the present study, we investigated the expression of beta7 integrins after small bowel transplantation (SBT) and tested the effects of blocking beta7-mediated pathways by using monoclonal antibody (mAb) or knockout mice. METHODS: Heterotopic SBT from BALB/c to C57BL/6 (B6) was used as a surgical model. Expression of beta7 integrins was measured on recipient lymphocytes (CD4 and CD8 ) in spleen, blood, and mesenteric lymph nodes (MLN) using flow cytometry. To analyze the effects of blocking beta7 integrins on graft survival, either beta7-deficient B6 or wild-type B6 mice that were treated with mAb against beta7 were studied. RESULTS: After allogeneic SBT, there were markedly increased levels of alpha4beta7 recipient CD8 lymphocytes in MLN, blood, and spleen as early as 3 days postoperatively. In contrast, alpha4beta7 integrin levels in isograft recipients were similar to those of normal mice. Mean survival time of intestinal allografts was not affected by beta7 deficiency (7.3+/-1 days) compared with wild-type mice (7.5+/-0.8 days). However, mAb against beta7 integrins significantly prolonged graft survival (12.8+/-1 days) compared with treatment with control mAb (7.3+/-1 days, <0.001). Histologic changes of SBT rejection were significantly attenuated when mice were given mAb against beta7. CONCLUSION: As indicated by the increased levels of alpha4beta7 CD8 lymphocytes, activation of this integrin contributes to the immune response in SBT rejection. Furthermore, blocking beta7 integrins with mAb provides a suitable target for immunosuppressive therapy. The discrepancy in survival data obtained by mAb and beta7 deficiency may be a result of the more rapid activation of compensatory mechanisms in the knockout mice.

Animals↗

PubMed2002

HDAF transgenic pig livers are protected from hyperacute rejection during ex vivo perfusion with human blood.

The aim of this study was to determine if human decay-accelerating factor (hDAF) protects against hyperacute rejection in an ex vivo liver perfusion system using human blood. Pig livers were perfused ex vivo via the portal vein for an average of 5-6 h using a membrane oxygenator. Three groups were studied. Group I: Wild-type pig livers were alloperfused with fresh pig blood (n = 5). Group II: Wild-type pig livers were xenoperfused with fresh human blood (n = 5). Group III: hDAF transgenic pig livers were xenoperfused with fresh human blood (n = 5). The graft ischemic time, ratio of perfusate volume to liver weight, flow rate, and perfusate hematocrit were similar in each group. The hDAF livers perfused with human blood (Group III) had a lower ALT level, less protein and albumin losses, lower bilirubin levels in the perfusate, less weight gain, and greater bile production than the wild-type livers perfused with human blood. Histology showed classic features of hyperacute rejection in Group II, including massive hemorrhage, severe vasculitits, fibrin and C5b-9 deposition, and endothelial damage within 1 h of perfusion, whereas liver histology studies in Groups I and III were near normal. IgG and IgM deposits were seen in the xenoperfused livers. Electron microscopy (EM) and immuno-EM showed loss of endothelial cells, trapping of white blood cells and platelets, and diffuse fibrin deposits in Group II only. hDAF pig livers perfused with human blood showed superior function and histology when compared with wild-type pig livers. These data suggest that (1) hyperacute rejection may contribute to the inconsistent results using wild-type pig livers for extracorporeal liver support and (2) genetically modified pigs that express hDAF may provide a better donor source than wild-type pigs for extracorporeal liver support.

Animals↗

PubMedDate not supplied

Clinical brain proton magnetic resonance spectroscopy for management of Alzheimer's and sub-cortical ischemic vascular dementia in older people.

This study examined the clinical usefulness of magnetic resonance spectroscopy (MRS) performed using an automated single voxel technique at 1.0 T field strength in a district general hospital magnetic resonance (MR) scanner in the assessment of older people referred to a memory clinic with suspected dementia. Of 50 elderly subjects (M:F 20:30) examined and followed-up clinically over more than 2 years, 20 had clinical Alzheimer's disease (AD), 18 had clinical vascular dementia, six had mixed features and three were normal. Three normal volunteers were also studied. MRS was performed at the same time as structural magnetic resonance imaging (MRI), added <15 min to the examination and was well-tolerated in all patients studied. Patients with AD had significantly higher myoinositol/creatine (MI/Cr) ratios (mean +/- S.D.: 0.82 +/- 0.04) compared to those with vascular dementia (mean +/-S. D.: 0.71 +/- 0.07, P<0.00001) and normal subjects (mean +/- S.D.: 0.72 +/- 0.036, P<0.0002); there was little overlap between the AD and vascular groups. The mixed dementia group also had significantly higher MI/Cr ratios (mean +/- S.D.: 0.80 +/- 0.05) than vascular dementia (P<0.01) and normal (P<0.03) groups, but with considerable overlap. No significant differences were shown for N-acetyl aspartate or choline/creatine ratios between the different clinical groups. These data suggest that MI/Cr ratios can distinguish patients with AD from normal subjects and those with sub-cortical ischemic vascular dementia and that MRS will be useful to clinicians managing persons with AD in a district general hospital setting.

Journal Article↗

PubMedDate not supplied

Expanding the genetic map of maize with the intermated B73 x Mo17 (IBM) population.

The effects of intermating on recombination and the development of linkage maps were assessed in maize. Progeny derived from a common population (B73 x Mo17) before and after five generations of intermating were genotyped at the same set of 190 RFLP loci. Intermating resulted in nearly a four-fold increase in the genetic map distance and increased the potential for improved genetic resolution in 91% of the intervals evaluated. This mapping population and related information should connect research involving dense genetic maps, physical mapping, gene isolation, comparative genomics, analysis of quantitative trait loci and investigations of heterosis.

Chromosome Mapping↗