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Biomedical subjects

D Grant

Publications and source records attributed to D Grant.

At least 19 recordsLinked to original sources
PubMed2006

CSF neurofilament levels: a potential prognostic marker in Guillain-Barré syndrome.

Long-term morbidity from Guillain-Barré syndrome (GBS) is caused by axonal damage. This prospective study demonstrated that neurofilaments (NfHs), a biomarker for axonal damage, were of prognostic value in GBS. CSF NfH levels correlated with the F score and Medical Research Council summed score and were higher in patients with neurophysiologic evidence of axonal degeneration compared to those without. Pathologically high CSF NfH levels (>0.73 ng/mL) predicted worse motor and functional outcome.

Enzyme-Linked Immunosorbent Assay↗
PubMed2006

Properties of porcine and recombinant human collagen matrices for optically clear tissue engineering applications.

Porcine and recombinant human atelocollagen I solutions were cross-linked with a water soluble carbodiimide at various stoichiometries and collagen concentrations (5-20 w/w %). The resulting hydrogels were clear and, when used as cell growth matrices, allowed cell and nerve visualization in vitro and in vivo. We have previously reported that, after six months of implantation in pigs' and rabbits' corneas, these robust hydrogels allowed regeneration of host cells and nerves to give optically clear corneas with no detected loss in thickness, indicating stable engraftment. Here, the biocompatible hydrogel formulations leading to this novel in vivo performance were characterized for amine consumption, gel hydration, thermal properties, optical clarity, refractive index, nutrient diffusion, biodegradation, tensile measurements, and average pore diameters. Gels with excellent in vitro (epithelial overgrowth, neurite penetration) and in vivo performance (clarity, touch sensitivity regeneration) had 4-11 nm pores, yet had glucose and albumin diffusive coefficients similar to mammalian corneas and allowed neurite extension through the gels.

Amines↗
PubMed2006

Anastomotic ulceration following small bowel transplantation.

We describe, for the first time, anastomotic ulcers (AU) following bowel transplantation at the Hospital for Sick Children. Two children presented with rectal bleeding, 6 and 9 months, following the transplantation. Isolated ulcers were identified at the ileo-colonic and the colo-colonic anastomosis site. The ulcers resolved, but recurred 6 and 7 months after the initial presentation. Both patients were positive for adenovirus in the stool and were treated with rapamycin. The histology revealed granulation tissue formation with mild inflammation in the adjacent mucosa, without evidence of rejection or infection. A literature search revealed 10 studies reporting 29 patients who developed AU following various surgical etiologies, none of which was bowel transplant. Numerous factors that are unique to the post-transplant period may predispose to such ulcer and are discussed in detail. Physicians and surgeons should be aware of this multifactorial complication, among other etiologies, as a cause of anemia or rectal bleeding following intestinal transplantation.

Anastomosis, Surgical↗
PubMed2006

Gene expression profiling of acute liver stress during living donor liver transplantation.

During liver transplantation, the donor graft is subjected to a number of acute stresses whose molecular basis is not well-understood. The effects of surgical stress, preservation and reperfusion injury were studied in 24 consecutive living donor liver transplant (LDLT) operations. Liver biopsies were taken early in the donor operation (OPENING), after transection of the donor liver (PRECLAMP) and following implantation of the graft (post hepatic artery, [PHA]); these were evaluated for histology, tissue glutathione content and gene expression using a 19K-human cDNA microarray. LDLT was associated with an ischemia/reperfusion injury, with accumulation of small numbers of neutrophils and decreased glutathione in the PHA biopsies. Following reperfusion, the expression of 129 genes increased and 106 genes decreased when compared to OPENING levels (> or <2-fold, p < 0.01). By real-time PCR a subset of 25 genes was verified (15 increased, 10 decreased). These genes were similarly altered in another condition of acute liver stress (the response to brain-death), but not in three chronic liver disease states (HCV, HBV and PBC). This study has identified a set of genes whose expression is altered in acute, but not chronic, liver stress, likely to play a central role in the pathogenesis of acute liver injury of liver transplantation.

Adult↗
PubMed2005

Further monitoring for Salmonella species and Escherichia coli O86 at a bird table in south-west Scotland.

Pooled faeces collected from a garden bird table were screened for Salmonella species and Escherichia coli O86, two recognised causes of garden bird mortality. Dead birds found at the site were also screened for these organisms, and bird numbers and meteorological data were recorded. In the first year of the study, 48.5 per cent of the samples were positive for Salmonella Typhimurium DT56 (variant), decreasing to 38.9 per cent in the second year and 12.8 per cent in the third year. E. coli O86 was not recovered from any of the 288 samples of pooled faeces tested. S. Typhimurium DT56 (variant) was recovered from the carcases of eight birds found dead at the site, and E. coli O86 was isolated from three carcases. The degree of contamination of the bird table with S. Typhimurium DT56 (variant) was positively correlated with the number of house sparrows observed in the garden, but not with the number of blackbirds, chaffinches or greenfinches.

Animals↗
PubMed2005

Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study.

BACKGROUND: Neurofilament phosphoforms (Nf) are principal components of the axoskeleton released during axonal injury. Cerebrospinal fluid (CSF) levels of Nf phosphoforms might be useful surrogate markers for disability in multiple sclerosis (MS), aid in distinguishing clinical subtypes, and provide valuable prognostic information. METHOD: Thirty four patients with MS were included in a three year follow up study along with 318 controls with other non-inflammatory neurological diseases. CSF levels of two Nf heavy chain (NfH) phosphoforms (NfH(SMI35), NfH(SMI34)) were quantified at baseline and three year follow up using new ELISA techniques. Levels of NfH phosphoforms, the degree of phosphorylation (NfH(SMI34):NfH(SMI35) ratio), and changes in NfH levels between baseline and follow up (Delta NfH) were related to the clinical phenotype (RR or SP/PP), to three clinical scales (Kurtzke's EDSS, ambulation index (AI), and nine hole peg test (9HPT)), and to progression of disability. RESULTS: A significantly higher proportion (59%) of patients with SP/PPMS experienced an increase in NfH(SMI35) levels between baseline and follow up compared with those with RRMS (14%, p<0.05). CSF NfH(SMI34) levels at baseline were higher in patients with SP/PP (11 pg/ml) compared with RR (7 pg/ml, p<0.05) and NfH(SMI35) levels were higher at follow up in SP/PP (129 pg/ml) compared with levels below assay sensitivity in RR (p<0.05). NfH(SMI35) correlated with the EDSS (r(s) = 0.54, p<0.01), the AI (r(s) = 0.42, p<0.05), and the 9HPT (r(s) = 0.59, p<0.01) at follow up. CONCLUSION: The increase in NfH during the progressive phase of the disease together with the correlation of NfH(SMI35) with all clinical scales at follow up suggests that cumulative axonal loss is responsible for sustained disability and that high NfH(SMI35) levels are a poor prognostic sign.

Adolescent↗
PubMed2005

Acute axonal damage predicts clinical outcome in patients with multiple sclerosis.

The objectives of this study were (1) to determine how cerebrospinal fluid (CSF) neurofilament heavy chain (NfH(SM134) and NfH(SM135)) levels relate to clinical outcome in optic neuritis (ON) and multiple sclerosis (MS) relapse patients treated with high dose oral methylprednisolone; and (2) to correlate neurofilament and myelin basic protein (MBP) concentrations, particularly as the latter was previously associated with clinical disability. Fifty subjects participated in two double-blind, randomized, placebo-controlled clinical trials. Eight/18 patients in the ON trial and 15/32 subjects in the MS attack trial were treated with oral methylprednisolone. In the MS attack trial group, CSF NfH(SM134) and NfH(SM135) measured at week 3 and deltaCSF NfH(SMI34) levels from baseline to week 3 were predictive of clinical outcome at week 8 and 52. In the ON group, no such association was seen. When both groups were combined, baseline CSF NfH(SHM134) and NfH(SM135) correlated positively with baseline enhancing lesion volume (ELV) (r(s) =0.50, P <0.01 and rS =0.53, P <0.01, respectively). Levels of NfH(SM135) at baseline and week 3 also strongly correlated with the MBP concentration. This study supports the view that acute inflammation in ON and MS results in axonal pathology and that the latter has a role in determining functional impairment.

Acute Disease↗
PubMed2004

Optimization of cyclosporine for liver transplantation.

Our understanding of cyclosporine (CsA) administration for liver transplantation has significantly improved over the past decade. Cyclosporine is a highly lipophilic molecule, and the original galenic formulation, Sandimmune, was highly dependent on bile flow and gut motility for its absorption. Sandimmune's poor absorption profile produced erratic CsA levels after liver transplantation. A new microemulsification formulation of CsA, Neoral (CsA-ME), was developed to overcome these limitations. The NOF-1 study confirmed the superiority of CsA-ME's absorption compared with Sandimmune; CsA-ME had a more consistent and reliable absorption, with lower intrapatient variability and improved dose linearity with drug exposure as measured by area under the concentration-time curve (AUC). These advantages translated into more reliable CsA predose concentrations and less toxicity. An analysis of the pharmacokinetic data showed that 2-hour postdose CsA levels (C2) provided a better measure of immune suppression than did trough levels (C0). The LIS2T study recently confirmed and extended these data by showing equivalent efficacy between CsA-ME using C2 monitoring or tacrolimus in liver transplant patients, with a similar incidence of adverse events except for a higher rate of diabetes mellitus and diarrhea with tacrolimus. These data confirmed that the improved CsA-ME formulation, when used in conjunction with optimized drug-monitoring protocols, is well tolerated after transplantation and provides low rates of graft rejection.

Administration, Oral↗
PubMed2004

Cerebrospinal fluid levels of brain specific proteins in optic neuritis.

This study evaluates levels of cerebrospinal fluid (CSF) brain-specific proteins (BSP) in subjects with optic neuritis (ON) who are at high risk of progression to multiple sclerosis (MS). Forty-one subjects had acute ON and 17 subjects with other neurological diseases (OND) served as controls. Twenty-one subjects with ON had white matter lesions on magnetic resonance imaging (MRI) and intrathecal synthesis of oligoclonal IgG bands (OB) consistent with being at high risk of progression to MS; eight of whom later were diagnosed with clinically definite MS (CDMS). Levels of S100B, ferritin and two neurofilament heavy chain phosphoforms (NfH(SM134) and NfH(SM135)) were analysed using ELISA technique. A putative index of 'axonal health' was expressed as a ratio of NfH(SM134) to NfH(S135). NfH(SM134) and the NfH(SM134:SM135) were significantly elevated in subjects with ON compared to controls. No significant differences in levels of CSF BSP were seen between ON subjects with CDMS plus those at high risk of progression to MS and ON subjects with normal MRI and negative CSF analysis. In conclusion, there is evidence of axonal damage in subjects who present with ON, which is independent of the diagnosis of CDMS.

Adult↗
PubMed2003

Intestinal and hepatic lesions in mice, rats, and other laboratory animals after intravenous administration of gas-carrier contrast agents used in ultrasound imaging.

Single intravenous administration of three different gas-carrier contrast agents used in ultrasound imaging to mice caused inflammation, necrosis, and ulceration of cecum and proximal colon (cecocolonic area) and focal necrosis in the liver. Similar intestinal lesions were also found in rats after treatment with a single iv administration of a gas-carrier contrast agent. Strain differences in the incidences of these lesions were found in both rats and mice. HsdHan:NMRI mice were among the most sensitive of the strains of mice studied. Even at the lowest dose of Sonazoid technically possible to inject in HsdHan:NMRI mice, lesions were found and a no-effect dose could not be determined. In a time-course experiment in HsdHan:NMRI mice, it was found that the lesions began to develop in the cecum and colon within 15 to 30 min after dosing. Lesions in the liver were first observed 120-240 min after dosing. Diet played a role in the etiology of the lesions, as HsdHan:NMRI mice given a diet with reduced amounts of cellulose and starch had reduced incidences of lesions, and when glucose was the only carbohydrate source, no lesions were observed. No intestinal or hepatic lesions were found in guinea pigs or rabbits after repeated intravenous administrations of Sonazoid. In dogs, minimal to mild granulocytic inflammation of the cecum and/or colon was found after daily repeated intravenous injections for 28 days, but not after daily repeated administration for 14 days nor after a single administration. It is proposed that the intestinal and hepatic lesions in rats and mice after a single intravenous injection of gas-carrier contrast agents are caused by a common mechanism: intravascular growth of gas-carrier agents in tissues with gas supersaturation, as occurs in the cecal wall of rats and mice. In this particular environment the growing gas bubbles cause ischemia and necrosis in the cecal and colonic wall and liver. This proposed mechanism of action is consistent with the absence of clinical reports indicative of intestinal and/or hepatic lesions in humans after administration of gas-carrier contrast agents.

Administration, Oral↗
PubMed2003

Etiology of cecal and hepatic lesions in mice after administration of gas-carrier contrast agents used in ultrasound imaging.

The aim of the study was to investigate the etiology of cecal and hepatic lesions in mice and rats after intravenous administration of gas-carrier contrast agents (GCAs). A modified fluorescein flowmetry technique and 24 h necropsy were used in mice (conventional and germ free), rats, and guinea pigs after GCA administration. Different diets and oral nonabsorbable antibiotics were used. Nonfluorescence, edema, congestion, hemorrhage, and mucosal erosion in cecum and colon and nonfluorescent areas in the liver were observed from 16 min after GCA administration in conventional mice on standard diet. Numerous gas bubbles (>50 microm) were observed in the vasculature around the nonfluorescent areas of cecum and colon and in mesenteric vessels draining to the portal vein. Acute inflammation, edema, hemorrhage, and ulceration of the cecum and colon and liver necrosis were seen 24 h after GCA administration in conventional mice on standard diet. When mice were maintained on either a diet with glucose as the only carbohydrate source or on a standard diet supplemented with antibiotics, uniform fluorescence and no organ lesions were observed after GCA administration. Uniform fluorescence and no organ lesions were observed in germ-free mice, rats, and guinea pigs dosed with GCAs and in control animals (mice, rats, and guinea pigs) dosed with sucrose. The results indicate that intravascular growth of GCA microbubbles occurs in the cecal and colonic wall of mice, leading to occlusive ischemia and necrosis in these intestinal segments and secondary gas embolisation in the liver. Transmural gas supersaturation in the cecal wall may explain the intravascular bubble growth in mice.

Albumins↗
PubMed2001

Reconstruction of middle hepatic vein of a living-donor right lobe liver graft with recipient left portal vein.

Venous outflow problems in right lobe, living-donor liver transplantation are uncommon, but devastating when they occur. We describe the successful use of the recipient's left portal vein as an interposition graft to drain a dominant middle hepatic vein in a right lobe liver transplant. Two weeks after transplantation, the vein graft accounted for 56% of the total venous outflow of the liver.

Adult↗
PubMed2001

Pharmacokinetics and tolerability of 40-0-[2-hydroxyethyl]rapamycin in de novo liver transplant recipients.

BACKGROUND: 40-0-[2-Hydroxyethyl]rapamycin (RAD), a novel macrolide with potent immunosuppressive and antiproliferative activities, prevents rejection in animal allotransplantation models. This phase I trial assessed the effects of bile diversion, administration route, and time after transplant on RAD pharmacokinetics after single-dose administration in de novo liver allograft recipients. The influence of RAD on cyclosporine (CsA) pharmacokinetics and the safety of RAD were also evaluated. METHODS: Twenty-six de novo liver allograft recipients were assigned to one of four treatment groups based on the presence or absence of a T tube, administration route (nasogastric or nasoduodenal), and timing of RAD administration. Patients received a single 7.5-mg RAD dose on one to three occasions in addition to CsA (Neoral) and corticosteroids. Steady-state cyclosporine profiles with and without RAD coadministration were evaluated. Results. Recipients with bile diversion demonstrated lower peak concentration (Cmax) than those without, but overall drug exposure (AUC) was not altered. Cmax and AUC were not influenced by administration route. A trend towards higher Cmax on postoperative day 3 than on postoperative day 1 was noted, although AUC was not altered. Single-dose RAD coadministration did not affect steady-state CsA pharmacokinetics. RAD was well tolerated and caused few drug-related adverse effects. RAD administration did not increase infection rates or produce clinically significant changes in laboratory parameters. Conclusions. In de novo liver transplant recipients, the overall extent of RAD absorption was not influenced by bile diversion, administration route, or time of administration. CsA pharmacokinetics were not affected by single-dose RAD coadministration. RAD capsules administered in single doses of 7.5 mg were well tolerated and safe.

Administration, Oral↗
PubMed2001

IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis.

The International Programme on Chemical Safety (IPCS) is leading an activity to harmonize approaches to cancer risk assessment as a part of its larger project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. Through a series of workshops and the evaluation of case studies, a number of key components of risk assessments relating to harmonization were identified: transparency, terminology, weight of evidence, flexibility, and accessibility/communication. A major impediment to harmonization identified in the consideration of weight of evidence was the evaluation of mode of action. To address this need, a conceptual framework was developed, based on the general principles involved in considering the chemical induction of a specific tumor in animals. This is based partly on the Bradford Hill criteria for causality as modified by Faustman et al. (1997) for developmental toxicity. The framework is described in this paper followed by a worked example. It is recognized that the framework addresses only one stage in the overall characterization of hazard to humans of chemical carcinogens. Another important but separate step is the assessment of relevance to humans. This is a priority area for future work in this project.

Animals↗
PubMed2001

Expression and characterization of soluble human parainfluenza virus type 1 hemagglutinin-neuraminidase glycoprotein.

Human parainfluenza virus types 1 (hPIV-1), 2, and 3 represent significant respiratory pathogens for which no antiviral treatment is currently available. To characterize the biochemical functions of the hPIV-1 hemagglutinin-neuraminidase (HN) glycoprotein, a potential target for antiviral therapy, we cloned and expressed a soluble portion of hPIV-1 HN (amino acid residues 137-575), lacking the N-terminal hydrophobic membrane anchorage region, in insect cells using the baculovirus secretion expression system. The expressed HN protein was purified through cation-exchange chromatography followed by metal affinity chromatography, using the 6xHis epitope introduced at the carboxyl terminus of the recombinant protein. N-terminal amino acid sequence analysis of purified HN indicated that the honeybee melittin secretion signal peptide was correctly removed during post-translational processing. Further characterization revealed that the purified HN protein was N-glycosylated and exhibited neuraminidase activity whose characteristics resembled those of the native HN protein of hPIV-1 virions. The establishment of this expression and purification system has allowed us to further explore the biochemical characteristics of paramyxovirus HN and to obtain material that could be suitable for X-ray crystallography studies.

Amino Acid Sequence↗
PubMed2001

Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation.

Parenteral nutrition represents standard therapy for children with short bowel syndrome and other causes of intestinal failure. Most infants with short bowel syndrome eventually wean from parenteral nutrition, and most of those who do not wean tolerate parenteral nutrition for protracted periods. However, a subset of children with intestinal failure remaining dependent on parenteral nutrition will develop life-threatening complications arising from therapy. Intestinal transplantation (Tx) can now be recommended for this select group. Life-threatening complications warranting consideration of intestinal Tx include parenteral nutrition-associated liver disease, recurrent sepsis, and threatened loss of central venous access. Because a critical shortage of donor organs exists, waiting times for intestinal Tx are prolonged. Therefore, it is essential that children with life-threatening complications of intestinal failure and parenteral nutrition therapy be identified comparatively early, i.e. in time to receive suitable donor organs before they become critically ill. Children with liver dysfunction should be considered for isolated intestinal Tx before irreversible, advanced bridging fibrosis or cirrhosis supervenes, for which a combined liver and intestinal transplant is necessary. Irreversible liver disease is suggested by hyperbilirubinemia persisting beyond 3-4 months of age combined with features of portal hypertension such as splenomegaly, thrombocytopenia, or prominent superficial abdominal veins; esophageal varices, ascites, and impaired synthetic function are not always present. Death resulting from complications of liver failure is especially common during the wait for a combined liver and intestinal transplant, and survival following combined liver and intestinal Tx is probably lower than following an isolated intestinal transplant. The incidence of morbidity and mortality following intestinal Tx is greater than that following liver or kidney Tx, but long-term survival following intestinal Tx is now at least 50-60%. It is probable that outcomes shall improve in the future with continued refinements in operative technique and post-operative management, including immunosuppression.

Child↗
PubMed2001

Early referral is essential for successful pediatric small bowel transplantation: The Canadian experience.

PURPOSE: The mortality rate for pediatric patients on the waiting list for transplantation has a major impact on the overall effectiveness of pediatric small bowel transplantation. This review was undertaken to determine the fate of Canadian children assessed for small bowel transplant and the outcome of those who undergo transplant in the tacrolimus era. METHODS: The authors reviewed retrospectively all of the pediatric small bowel patients listed since 1988 through the Canadian Organ Replacement Register and all the children referred to our program in its first year. All children who received a small bowel transplant between January 1993 and December 1999 also were reviewed. RESULTS: The mortality rate for pediatric patients on the small bowel transplant list was 53% after an average of 105 days on the list compared with 212 days for those who underwent transplant. Patients who died while on the list were younger and had signs of advanced liver disease at the time of listing. Thirteen Canadian children have received a small bowel transplant with an overall 1-year patient and graft survival rate of 61% and 53%, respectively. Survivors are all independent from total parenteral nutrition. CONCLUSION: Many Canadian children miss their opportunity for a successful small bowel transplant because of late referrals and a shortage of donor organs.

Child↗