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Biomedical subjects

J A Roake

Publications and source records attributed to J A Roake.

At least 19 recordsLinked to original sources
PubMed2004

The effect of Helicobacter pylori infection and dietary iron deficiency on host iron homeostasis: a study in mice.

BACKGROUND: Helicobacter pylori, which requires iron to survive, may cause host iron deficiency by directly competing with the host for available iron or by impairing iron uptake as a consequence of atrophy-associated gastric hypochlorhydria. The aim of this study was to examine the effect of H. pylori infection and dietary iron deficiency on host iron homeostasis in a mouse model. MATERIALS AND METHODS: H. pylori SS1-infected and uninfected C57BL/6 mice, fed either a normal diet or an iron-deficient diet, were assessed for iron status and infection-associated gastritis over a 30-week period. RESULTS: After 10 weeks, serum ferritin values were higher in H. pylori-infected mice than in uninfected controls, irrespective of dietary iron intake (p = .04). The infection-related increase in body iron stores persisted in the iron-replete mice but diminished over time in mice with restricted dietary iron intake (p < .0001). At 30 weeks serum ferritin levels were lower in these animals (p = .063). No significant difference in bacterial numbers was detected at the 30-week time point (p > .05) and the histological changes observed were consistently associated with infection (p < .01) and not with the iron status of the mice (p = .771). CONCLUSIONS: Infection with H. pylori did not cause iron deficiency in iron-replete mice. However, diminished iron stores in mice as a result of limited dietary iron intake were further lowered by concurrent infection, thus indicating that H. pylori competes successfully with the host for available iron.

Animals↗
PubMed2002

Nutritional and immune status following spinal cord injury: a case controlled study.

STUDY DESIGN: Case controlled study. OBJECTIVE: To compare nutritional status and immune response in a group of spinal cord injured (SCI) patients with age and gender matched non SCI control subjects. METHOD: Thirty past patients of the Burwood Hospital Spinal Injuries Unit living locally were enrolled in the study. Age and gender matched non SCI control subjects were selected volunteers from hospital staff. Nutritional status was assessed by generating a Nutritional Risk Score (NRS, Appendix 1) and drawing blood for full blood count, iron studies, red blood cell folate, vitamin B12, ferritin, magnesium, and zinc. Immune status was assessed by vaccination response index (VRI) to Pneumovax 23 vaccine. RESULTS: Full blood count, iron studies, and testing for red blood cell folate, albumin, prealbumin, vitamin B12, ferritin, magnesium and zinc were normal range for both groups. The SCI group had significantly different median values than controls (P < 0.01) for haemoglobin concentration, white blood cell count, albumin, prealbumin, serum iron and % saturation. Body Mass Index (weight kg/(height cm(2)) was 22.2 (range 15-30) for the SCI group, significantly less than the paired control group index of 26 (range 20-32, P = 0.0004). Median NRS for SCI patients was 2 (range 0-6), compared to 0 (range 2-4) for paired controls (P < 0.0001). Scores ranged from 0 to 2 for each of the five NRS components for the SCI patients and 0 to 3 for the control group. There was no significant difference in the pre- and post-vaccination ratio for IgG, IgA, and IgM response to Pneumovax 23 vaccine. CONCLUSION: We have not identified any nutritional or immune status abnormality in SCI patients, however the SCI patients have a lower value for certain nutritional parameters and BMI. SCI patients however are at only slight risk of nutritional problems given their NRS and their lower normal values for certain nutritional factors.

Adult↗
PubMed2001

Does a colostomy alter quality of life in patients with spinal cord injury? A controlled study.

STUDY DESIGN: Prospective controlled comparative analysis. OBJECTIVE: To determine whether a colostomy changes quality of life in patients with a spinal cord injury. METHOD: A previously validated questionnaire designed to assess quality of life in spinal injured patients (Burwood Questionnaire) was sent to 26 spinal cord injured patients with colostomies and 26 spinal cord injured patients without colostomy. The two groups were matched for level of injury, completeness of injury, length of time since injury, age (+/- 5 years) and gender. RESULTS: There was 100% completion of the questionnaire. There was no significant difference (P > 0.05) in the two groups of patients in regard to their general well being, emotional, social, or work functioning. CONCLUSIONS: Patients with colostomy following spinal injury are no worse off in regard to quality of life, than those without. The inference is that perhaps a colostomy should be considered earlier in patients with major bowel dysfunction following spinal cord injury. SPONSORSHIP: Financial support for Dr AC Lynch was provided by Royal Australian College of Surgeons with a Foundation Scholarship and Grant in aid by the Burwood International Spinal Trust. Mr N Randell was supported by the Canterbury Medical Research Foundation with a summer studentship.

Adult↗
PubMed2001

Endothelial cell protection against ischemia/reperfusion injury by lecithinized superoxide dismutase.

BACKGROUND: Organs used for transplantation may experience long periods of cold ischemic preservation and consequently oxygen free radical-mediated damage following reperfusion. Lecithinized superoxide dismutase (lec-SOD) is a novel free radical scavenger that has been shown to bind with high affinity to cell membranes. The aim of this study was to determine whether lec-SOD bound to endothelial cells under organ preservation conditions to mediate direct antioxidant activity at the endothelial cell surface and thus offer protection against the harmful effects of ischemia/reperfusion injury. METHODS: An in vitro study was performed on large vessel endothelial cells (HUVEC) and a human microvascular endothelial cell line HMEC-1, to investigate the potential therapeutic benefits of incorporating lec-SOD into organ preservation solution. A cold hypoxia/reoxygenation system was developed to examine lec-SOD binding affinity to endothelial cells, protection against hypoxia/reoxygenation-induced cell death, and neutrophil adhesion. RESULTS: Lec-SOD bound to endothelial cells with higher affinity than unmodified recombinant human superoxide dismutase (rhSOD) and significantly protected both HUVEC and HMEC-1 from cell death following 27 hours of cold hypoxia (P < 0.01). Furthermore, neutrophil adhesion to the endothelium stimulated by hypoxia and reoxygenation was significantly inhibited by treatment with lec-SOD but not by lecithin or rhSOD (P < 0.01). Analysis by flow cytometry demonstrated that E-selectin and ICAM-1 were up-regulated by hypoxia/reoxygenation that was inhibited in part by lec-SOD. CONCLUSIONS: The results from this study suggest that incorporation of lec-SOD into organ preservation solutions provides effective protection to endothelial cells against cold ischemia and reperfusion injury following transplantation.

Antioxidants↗
PubMed1999

Cadaver versus living donor kidneys: impact of donor factors on antigen induction before transplantation.

BACKGROUND: It is widely recognized that living-related donor (LRD) renal allografts have a higher overall graft survival than cadaver donor transplants. We tested the hypothesis that part of this is attributable to LRD kidneys being obtained under optimal conditions from healthy donors, whereas cadaveric kidneys may have experienced injury as a result of inflammatory events around the time of brain death. METHODS: We have performed a comparative immunohistochemical analysis of pretransplant donor biopsies from cadaveric (N = 65) and LRD (N = 29) kidneys to determine any differences that may predispose them to subsequent damage. Cryostat sections were stained with antibodies to leukocytes, adhesion molecules, and human leukocyte antigen (HLA)-DR antigens, and the expression was assessed semiquantitatively. RESULTS: High levels of endothelial E-selectin and proximal tubular expression of HLA-DR antigens, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 were detected in biopsies from cadaveric kidneys, whereas expression of these markers was markedly reduced in LRD kidneys. High levels of tubular antigen expression were significantly associated with traumatic death, prolonged ventilation, and episodes of infection in cadaver donors. Furthermore, the expression of pretransplant tubular antigens in cadaver donor kidneys was significantly associated with early acute rejection following transplantation, suggesting that such kidneys are predisposed to subsequent immune-mediated attack following transplantation. CONCLUSIONS: These results may explain, in part, the superior outcome of LRD allografts compared with cadaver renal allografts.

Adult↗
PubMed1998

Dendritic cell chemotaxis and transendothelial migration are induced by distinct chemokines and are regulated on maturation.

The capacity of dendritic cells (DC) to initiate immune responses is dependent on their specialized migratory and tissue homing properties. Chemotaxis and transendothelial migration (TEM) of DC were studied in vitro. Immature DC were generated by culture of human monocytes in granulocyte-macrophage colony-stimulating factor and IL-4. These cells exhibited potent chemotaxis and TEM responses to the CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, and monocyte chemotactic protein-3, and weak responses to the CC chemokine MIP-3beta and the CXC chemokine stromal cell-derived factor (SDF)-1alpha. Maturation of DC induced by culture in lipopolysaccharide, TNF-alpha or IL-1beta reduced or abolished responses to the former CC chemokines but markedly enhanced responses to MIP-3beta and SDF-1alpha. This correlated with changes in chemokine receptor expression: CCR5 expression was reduced while CXCR4 expression was enhanced. These findings suggest two stages for regulation of DC migration in which one set of chemokines may regulate recruitment into or within tissues, and another egress from the tissues.

Cell Differentiation↗
PubMed1998

Ischemia/reperfusion injury in human kidney transplantation: an immunohistochemical analysis of changes after reperfusion.

Organs used for transplantation undergo varying degrees of cold ischemia and reperfusion injury after transplantation. In renal transplantation, prolonged cold ischemia is strongly associated with delayed graft function, an event that contributes to inferior graft survival. At present, the pathophysiological changes associated with ischemia/reperfusion injury in clinical renal transplantation are poorly understood. We have performed an immunohistochemical analysis of pre- and postreperfusion biopsies obtained from cadaver (n = 55) and living/related donor (LRD) (n = 11) renal allografts using antibodies to adhesion molecules and leukocyte markers to investigate the intragraft changes after cold preservation and reperfusion. Neutrophil infiltration and P-selectin expression were detected after reperfusion in 29 of 55 (53%) and 24 of 55 (44%) cadaver renal allografts, respectively. In marked contrast, neutrophil infiltration was not observed in LRD allografts, and only 1 of 11 (9%) had an increased level of P-selectin after reperfusion. Immunofluorescent double-staining demonstrated that P-selectin expression resulted from platelet deposition and not from endothelial activation. No statistically significant association was observed between neutrophil infiltration and P-selectin expression in the glomeruli or intertubular capillaries despite the large number of cadaver renal allografts with postreperfusion changes. Neutrophil infiltration into the glomeruli was significantly associated with long cold ischemia times and delayed graft function. Elevated serum creatinine levels at 3 and 6 months after transplantation were also associated with the presence of neutrophils and platelets after reperfusion. Our results suggest that graft function may be influenced by early inflammatory events after reperfusion, which can be targeted for future therapeutic intervention.

Adult↗
PubMed1997

Effect of one-HLA-haplotype-matched and HLA-mismatched blood transfusions on recipient T lymphocyte allorepertoires.

BACKGROUND: Pretransplant blood transfusion has a well-known beneficial effect on posttransplant graft survival. Recently, it has been proposed that the clinical benefit of transfusion is due to HLA-DR antigen sharing between the blood donor(s) and the recipient. Immunological studies have suggested that this might result from a functional deletion of donor-reactive cytotoxic T lymphocytes. METHODS: We investigated frequencies of alloreactive lymphocyte precursors with cytotoxic or interleukin-2-producing helper function by limiting dilution analysis in 10 renal dialysis patients before and after transfusion with fresh, allogeneic whole blood. Five patients received blood transfusions from donors matched for one HLA haplotype (or one HLA-B-DR antigen) and the other five patients received blood from fully HLA-mismatched donors. RESULTS: Contrary to some previous reports, frequency analysis of cytotoxic T lymphocyte precursors revealed no significant differences between the two treatment groups in terms of development of blood donor-specific hyporesponsiveness after transfusion. Split-well analysis of cytotoxic T lymphocyte precursors reactive with single-mismatched HLA antigens demonstrated that the effects of transfusion on alloreactive specificity are complex and may vary depending on the particular antigens mismatched between the recipient and blood donor. Analysis of donor-specific helper T lymphocyte precursor frequencies revealed a significant decrease of interleukin-2-producing cells 3 months after transfusion in the total patient population. This effect was most prominent in the recipients of HLA-mismatched blood, but it also exhibited some degree of nonspecificity, as frequencies of third-party reactive helper T lymphocyte precursors were also significantly reduced. CONCLUSIONS: Our overall results suggest that the degree of HLA matching between blood donor and recipient does not greatly influence the effect of blood transfusion on the T lymphocyte allorepertoire. The apparent induced down-regulation of helper T lymphocyte activity may play a role in the reported immunosuppressive effects of allogeneic blood transfusion.

Adult↗
PubMed1997

Management of severe pancreatitis in renal transplant recipients.

OBJECTIVE: The authors determine if any aspects of the treatment of renal transplant patients with pancreatitis were of particular benefit with regard to graft and patient survival. BACKGROUND: The incidence of pancreatitis in renal transplant patients is low (1%-2%), but the mortality of the disease approaches 100%. Although several descriptive reports have been published, there is no consensus-regarding management. METHODS: The authors conduct a retrospective chart review. RESULTS: Twenty-one patients were identified with posttransplant pancreatitis (1.3% incidence). The cause of pancreatitis was presumed to be maintenance immunosuppression in all cases. Patients were classified by dynamic computed tomography (CT) scans having 1) mild/edematous disease (4 patients), 2) localized abscess or pseudocyst (6 patients), or 3) severe disease (11 patients). Patients with mild/edematous pancreatitis did well with medical management. The six patients with localized abscess or pseudocyst were successfully treated with standard operative intervention. Of the 11 patients with severe disease, 6 had several days of intensive medical management before operation, and all died. The other five patients underwent early operative intervention based principally on CT scan findings, and all survived. The latter group had multiple operations and four of five had functioning renal allografts at discharge. CONCLUSION: The severity of pancreatitis in the posttranplant patients may be difficult to assess by clinical criteria. Dynamic CT scanning is, therefore, essential in defining the extent of disease. Early, and perhaps repeated, operations may be lifesaving in those patients having CT scan findings of severe pancreatitis.

Adult↗
PubMed1996

Preemptive cadaveric renal transplantation--clinical outcome.

Preemptive cadaveric renal transplantation (PCRT) maximizes the chance of maintaining high quality of life and may avoid the morbidity of dialysis and the associated financial costs. These benefits are offset by disadvantages, which include the possibility of transplantation many months before the need for dialysis, resulting in wasted organ function; an immediate risk of graft failure with conversion to a dialysis-dependent state; and uncertainty of the safety of PCRT. Patients who underwent PCRT between June 1976 and December 1994 at the Oxford Transplant Centre were compared with a matched cohort of first cadaveric transplant recipients who were dialysis-dependent when transplanted. The 116 patients in the PCRT cohort were well matched to the control group with respect to sex, age, blood group, HLA match, degree of sensitization, donor age, immunosuppression, and year of transplantation. Patient and graft survival were significantly better in the PCRT group. The difference in graft survival did not appear to be completely explained by better patient survival, as suggested by a trend toward better graft survival after excluding death with a functioning graft as a cause of failure. Among surviving grafts there were no significant differences in graft function as assessed by 1, 2, and 3 year plasma creatinine levels. In conclusion, PCRT appears to be safe and may even be associated with superior graft survival when compared with conventional transplantation. Early inclusion on a transplant waiting list with a view to PCRT can be justified with respect to the clinical outcome but the financial costs and implications for the utilization of cadaveric donor kidneys must also be considered.

Adolescent↗
PubMed1996

Late reflush in clinical renal transplantation. Protection against delayed graft function not observed.

Mechanical flushing of cadaveric kidneys with organ preservation fluid immediately before transplantation has been reported to be associated with improved early graft function. We report here the results of a prospective randomized controlled study of cadaveric renal transplantation after late reflush with organ preservation fluid in which no benefit with respect to delayed graft function was observed and, indeed, the protocol may have been harmful. The study was terminated after recruitment of only 18 patients (9 to each arm) because postreperfusion biopsies of reflushed kidneys contained unusual features, including abnormal cellular debris within the tubules or eosinophilic proteinaceous material within Bowman's capsule. These features were not present in the control kidneys. Acute tubular necrosis and biopsy-proven acute rejection episodes were more frequently seen in the reflushed kidneys, but at 1 year there was no significant difference in the function of the surviving grafts.

Adult↗
PubMed1996

Cytomegalovirus infection and colonic perforation in renal transplant patients.

Cytomegalovirus (CMV) infection in immunocompromised patients is a major cause of morbidity and mortality. A well-documented manifestation of gastrointestinal CMV infection is gastrointestinal haemorrhage. In contrast, CMV-associated intestinal perforation has rarely been reported after transplantation, although it is well documented in AIDS patients. Three patients are reported who received their first cadaveric renal transplant in 1994 and subsequently developed CMV disease. During the course of their CMV illness, which was treated with ganciclovir, each presented with clinical suspicion of peritonitis and proceeded to laparotomy. All three were found to have sigmoid colon perforations with histological evidence of CMV infection. Following bowel resection and defunctioning, two patients made an uneventful recovery and have had the continuity of their bowel restored, but one died of overwhelming sepsis within hours of surgery. The explanation for the apparent clustering of this rare condition in transplant patients is uncertain.

Aged↗
PubMed1995

Dendritic cell loss from nonlymphoid tissues after systemic administration of lipopolysaccharide, tumor necrosis factor, and interleukin 1.

Dendritic cells (DC) in nonlymphoid organs can internalize and process foreign antigens before migrating to secondary lymphoid tissues to initiate primary immune responses. However, there is little information on which stimuli promote migration of DC from the tissues. Systemic administration of lipopolysaccharide (LPS), which induces in vivo production of cytokines, led to a reduction in the numbers of major histocompatibility complex class II-positive (Ia+) leukocytes in mouse hearts and kidneys: > 95% of DC were depleted 1-3 d after injection of 50 micrograms LPS. Several lines of evidence indicated that this response was due to migration of DC rather than loss of Ia expression or cytotoxic effects. In skin of treated mice, the number of Ia+ epidermal Langerhans' cells (LC) was reduced, and "cords" of Ia+ leukocytes became evident in the dermis. The latter cells expressed little NLDC145 and may have originated from recruited or resident DC progenitors. Systemic administration of recombinant tumor necrosis factor (rhTNF)-alpha resulted in a decrease in numbers of Ia+ cells in heart and kidney and of epidermal LC, and it also induced dermal cords. Administration of a rh-interleukin (IL)-1 resulted in a decrease in Ia+ cells only in renal medulla, appeared to activate a subset of epidermal LC, and induced dermal cords. Similar microgram doses of rhIL-2 had no obvious effect. Treatment with a neutralizing anti-TNF antiserum before LPS administration inhibited the depletion of LC from skin but not from heart or kidney. Therefore, TNF-alpha and IL-1 alpha may promote DC migration from nonlymphoid tissues and may have differential effects on different DC populations, but it is unclear whether they act on DC directly or indirectly (e.g., via other cytokines).

Animals↗
PubMed1995

Systemic lipopolysaccharide recruits dendritic cell progenitors to nonlymphoid tissues.

Dendritic cells (DC) are thought to be the "passenger leukocytes" that sensitize the recipients of organ transplants against graft antigens and trigger allograft rejection. DC originate from MHC class II-negative (Ia-) progenitors in the bone marrow, which enter the tissues and develop into migratory cells with the specialized capacity to initiate primary immune responses. There is little information on which stimuli recruit DC progenitors to the tissues. Systemic administration of LPS to mice depletes Ia+ leukocytes from heart and kidney but recruits Ia- leukocytes (Roake JA, et al., see footnote 6). When these leukocytes were isolated and cultured overnight, Ia+ low density leukocytes developed that could stimulate primary T cell responses in vitro. Hearts from LPS-treated mice were transplanted to allogeneic recipients. One to 4 days after grafting, Ia+ donor cells were present in recipient spleens, localized to peripheral white pulp, and associated with CD4+, but not CD8+, T cells. Cells with the migratory characteristics of DC, therefore, originated from Ia- progenitors in the transplanted hearts. We conclude that LPS recruits Ia- DC precursors to the heart and kidneys. Hearts from LPS-treated donors were rejected by allogeneic recipients at the same tempo as normal hearts, implying that Ia- DC progenitors might ultimately contribute to heart graft rejection (direct sensitization). However, since hearts from cyclophosphamide-treated donors, which do not give rise to Ia+ cells in recipient spleens, were also rejected at a similar tempo, indirect sensitization could also play a role in heart graft rejection in this model.

Animals↗