Biomedical subjects

Craig J Taylor

Publications and source records attributed to Craig J Taylor.

14 recordsLinked to original sources

PubMed2006

Micromechanical adhesion force measurements between tetrahydrofuran hydrate particles.

Adhesion forces between tetrahydrofuran (THF) hydrate particles in n-decane were measured using an improved micromechanical technique. The experiments were performed at atmospheric pressure over the temperature range 261-275 K. The observed forces and trends were explained by a capillary bridge between the particles. The adhesion force of hydrates was directly proportional to the contact force and contact time. A scoping study examined the effects of temperature, anti-agglomerants, and interfacial energy on the particle adhesion forces. The adhesion force of hydrates was found to be directly proportional to interfacial energy of the surrounding liquid, and to increase with temperature. Both sorbitan monolaurate (Span20) and poly-N-vinyl caprolactam (PVCap) decreased the adhesion force between the hydrate particles.

Journal Article↗

PubMed2006

Molecular hydrogen storage in binary THF-H2 clathrate hydrates.

The hydrogen storage capacity of binary THF-H(2) clathrate hydrate has been determined as a function of formation pressure, THF composition, and time. The amount of hydrogen stored in the stoichiometric hydrate increases with pressure and exhibits asymptotic (Langmuir) behavior to approximately 1.0 wt % H(2). This hydrogen concentration corresponds to one hydrogen molecule occupying each of the small 5(12) cavities and one THF molecule in each large 5(12)6(4) cavity in the hydrate framework. Contrary to previous reports, hydrogen storage was not increased upon decreasing the THF concentration below the stoichiometric 5.6 mol % solution to 0.5 mol %, at constant pressure, even after one week. This provides strong evidence that THF preferentially occupies the large 5(12)6(4) cavity over hydrogen, for the range of experimental conditions tested. The maximum amount of hydrogen stored in this binary hydrate was about 1.0 wt % at moderate pressure (<60 MPa) and is independent of the initial THF concentration over the range of conditions tested.

Journal Article↗

PubMed2006

Utility of HLAMatchmaker and single-antigen HLA-antibody detection beads for identification of acceptable mismatches in highly sensitized patients awaiting kidney transplantation.

BACKGROUND: In highly sensitized patients (HSP) awaiting renal transplantation, accurate delineation of acceptable human leukocyte antigen (HLA) mismatches (AMM) aids identification of suitable crossmatch negative donors. Comparison of differences in polymorphic triplet amino acid sequences in antibody accessible regions of HLA may predict immunogenicity. We have examined the ability of the HLAMatchmaker computer algorithm to predict AMM determined by antibody screening using the full repertoire of single-antigen HLA-A and -B specificities. METHODS: The HLA types of 24 HSP awaiting kidney transplantation were analyzed using HLAMatchmaker to determine the number of triplet amino acid (TAA) mismatches for each of 64 mismatched HLA-A and -B specificities. Patient sera with the highest immunoglobulin (Ig)G HLA-specific antibody reactivity were tested against the 64 individual HLA-A and -B specificities using single-antigen HLA antibody detection beads. Logistic regression analysis was performed to determine the association between AMM and the number of TAA mismatches. RESULTS: There was a strong positive association between the number of TAA mismatches and the presence of HLA-specific antibody. HLA specificities with zero TAA mismatches were antibody positive in only 4 of 47 (9%) cases. A single TAA mismatches was sufficient to invoke an antibody response in 40 (41%) of 98 cases, increasing to 97 (87%) of 112 cases with 9 or more TAA mismatches. However, there was considerable heterogeneity between individual patients, and only 16 (67%) of the 24 HSP studied fitted the logistic regression model for TAA mismatches and HLA-specific antibody. CONCLUSIONS: Identification of TAA mismatches using HLAMatchmaker is a helpful tool for predicting potential donors with an acceptable HLA mismatch in HSP.

Adult↗

PubMed2006

The cumulative effect of acute rejection on development of cardiac allograft vasculopathy.

BACKGROUND: Acute rejection increases the inflammatory burden of the transplanted organ and predisposes to cardiac allograft vasculopathy (CAV). In this study we aim to determine the magnitude of the association, and to differentiate between the effects of mild vs severe rejection episodes. METHODS: Between 1988 and 2003, 489 1-year survivors of heart transplantation underwent 1,435 angiograms. These patients were classified as having no CAV (0% stenosis), mild/moderate CAV (<70%) or severe CAV (>70%). Acute rejection was considered either mild (Grades 1A, 1B and 2 untreated) or moderate/severe (Grade 2 treated on a clinical basis and Grades 3A, 3B and 4). We used multi-state Markov models to examine risk factors for the onset of CAV. RESULTS: Expressed as relative risk, the onset of CAV was significantly increased by donor age (1.26 per 10 years, 95% confidence interval [CI] 1.12 to 1.42), male recipient (1.72, 95% CI 1.01 to 2.94), pre-transplant recipient ischemic disease (1.53, 95% CI 1.14 to 2.06) and cumulative number of moderate/severe rejections (1.10 per episode, 95% CI 1.03 to 1.18). Human leukocyte antigen (HLA) and cytomegalovirus (CMV) matching, donor gender, recipient age, smoking, cumulative CMV infections and mild rejections were not significant risk factors. Estimated annual onset rate of CAV was 11.3% for patients with no moderate/severe rejection, rising to 13.6% for those with two and 18.0% for those with five such rejections. CONCLUSIONS: Acute moderate/severe cellular rejection has a cumulative impact on CAV onset, whereas mild, untreated rejection is not associated with CAV.

Acute Disease↗

PubMed2006

Perforated diverticulitis managed by laparoscopic lavage.

BACKGROUND: Traditionally the management of acute diverticulitis complicated by perforation has been the Hartmann's procedure, which may be associated with significant morbidity and mortality and the unpleasantness of a colostomy. We present our early experience in managing perforated diverticulitis acutely by laparoscopic lavage and drainage. METHODS: A retrospective review was conducted of all patients with surgically confirmed perforated diverticulitis. Details concerning the nature of presentation, operative findings, postoperative course and medium-term progress were investigated. RESULTS: Fourteen patients with a mean age of 57.2 years were identified over a 3-year period. All patients presented with peritonitis and systemic sepsis. Ten patients had extraluminal gas on preoperative imaging. Laparoscopic lavage and drainage, without resection or stoma, was the initial management in all cases. Sigmoid diverticulitis was confirmed in all cases, complicated by Hinchey grade 3 purulent peritonitis in 10 patients, grade 2 contamination in 2 patients and grade 4 faeculent peritonitis in 2 patients. Eleven patients (79%) improved and were discharged following a median of 6.5 days (range, 5-32 days). Three patients did not improve and underwent acute resection. Eight patients have subsequently undergone elective resection without a stoma at a mean interval of 6 weeks, which was carried out laparoscopically in all but one case. CONCLUSION: Laparoscopic lavage and drainage in the acute management of perforated acute diverticulitis may be a promising alternative to more radical procedures, including the Hartmann's procedure. Acute resection should still be carried out in patients found to have faecal peritonitis or who fail to improve following lavage.

Adult↗

PubMed2005

Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching.

BACKGROUND: Human embryonic stem (hES) cells are a promising source for transplantation to replace diseased or damaged tissue, but their differentiated progeny express human leucocyte antigens (HLAs) that will probably cause graft rejection. The creation of a bank of HLA-typed hES cells, from which a best match could be selected, would help reduce the likelihood of graft rejection. We investigated how many hES cell lines would be needed to make matching possible in most cases. METHODS: The number of hES cell lines needed to achieve varying degrees of HLA match was estimated by use of, as a surrogate for hES-cell donor embryos, blood group and HLA types on a series of 10,000 consecutive UK cadaveric organ donors. The degree of blood group compatibility and HLA matching for a recipient population consisting of 6577 patients registered on the UK kidney transplant waiting list was determined, assuming all donor hES cell lines could provide a transplant for an unlimited number of recipients. FINDINGS: A bank of 150 consecutive donors provided a full match at HLA-A, HLA-B, and HLA-DR for a minority of recipients (<20%); a beneficial match (defined as one HLA-A or one HLA-B mismatch only) or better for 37.9% (range 27.9-47.5); and an HLA-DR match or better for 84.9% (77.5-90.0). Extending the number of donors beyond 150 conferred only a very gradual incremental benefit with respect to HLA matching. A panel of only ten donors homozygous for common HLA types selected from 10,000 donors provided a complete HLA-A, HLA-B and HLA-DR match for 37.7% of recipients, and a beneficial match for 67.4%. INTERPRETATION: Approximately 150 consecutive blood group compatible donors, 100 consecutive blood group O donors, or ten highly selected homozygous donors could provide the maximum practical benefit for HLA matching. The findings from these simulations have practical, political, and ethical implications for the establishment of hES-cell banks.

Biological Specimen Banks↗

PubMed2005

Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation--efficacy and safety at five years.

Alemtuzumab is a powerful lymphocyte depleting antibody currently being evaluated in solid organ transplantation. This paper describes 5-year results of a single center study of alemtuzumab as induction in renal transplantation. Thirty-three renal transplant recipients received 20 mg alemtuzumab on day 0 and 1, followed by half-dose cyclosporin monotherapy (trough concentration 75-125 ng/mL) from day 3. They were compared in a retrospective contemporaneous-controlled manner with 66 kidney transplant recipients transplanted in the same period and center who received conventional immunosuppression with cyclosporin, azathioprine and prednisolone. In the alemtuzumab group 12% of recipients died compared to 17% in the control group (p = 0.48); likewise graft loss was similar in both groups (21% vs. 26%, respectively, p = 0.58). Incidence of acute rejection was also comparable at 5 years (31.5% vs. 33.6%), although the pattern of rejection was different with 14% patients in the alemtuzumab group experiencing rejection over 1 year post-transplant compared to none in the control group. There was no significant difference between groups in terms of infection or serious adverse events. While acknowledging the limitations of a relatively small single-center study, results suggest that alemtuzumab induction allowed satisfactory long-term patient and graft survival equivalent to that seen with standard triple immunosuppression, while avoiding steroid therapy.

Adult↗

PubMed2004

Recipients who receive a human leukocyte antigen-B compatible cadaveric liver allograft are at high risk of developing acute graft-versus-host disease.

Acute graft-versus-host disease (GvHD) is an uncommon but often fatal complication after orthotopic liver transplantation (OLT). To determine whether there is an association between human leukocyte antigen (HLA) matching and the development of GvHD after cadaveric OLT, we undertook a retrospective, single-center analysis of 412 consecutive adult recipients where HLA typing data was available. Seven (1.7%) recipients developed acute GvHD, and six died from their disease. Donor compatibility at HLA-B but not at HLA-A or -DR was identified as a significant risk factor for the development of GvHD. Of 14 recipients with no HLA-B mismatches, 3 (21%) developed GvHD (odds ratio 27, P<0.001). Conversely, of 262 recipients mismatched at both HLA-B loci, only 1 (0.4%) developed GvHD (odds ratio 0.09, P<0.01). Our findings suggest that patients receiving a liver allograft with no HLA-B mismatched antigens are at increased risk of developing GvHD.

Acute Disease↗

PubMed2004

Monitoring systemic donor lymphocyte macrochimerism to aid the diagnosis of graft-versus-host disease after liver transplantation.

BACKGROUND: The diagnosis of graft-versus-host disease (GvHD) after liver transplantation can be difficult because early symptoms are often nonspecific. In this study, the presence of donor lymphocyte macrochimerism in recipient peripheral blood was examined as a diagnostic aid for GvHD after cadaveric donor liver transplantation. METHODS: Between 1996 and 2002, 33 liver transplant recipients with a clinical suspicion of GvHD (skin rash, diarrhea, pyrexia, pancytopenia, or anemia, without an obvious alternative cause) were investigated for peripheral blood donor lymphocyte macrochimerism. Donor macrochimerism was determined at the time of first clinical presentation by a low-sensitivity polymerase chain reaction (PCR) to detect donor human leukocyte antigen (HLA) alleles using genomic DNA extracted from recipient peripheral blood. Where donor HLA alleles were detected, the percentage of donor T cells was quantified by two-color flow cytometric analysis using antibodies specific for mismatched donor and recipient HLA alleles. The relationship between the presence or absence of donor lymphocyte macrochimerism and final diagnoses based on clinical and histological criteria was examined. RESULTS: Seven of the 33 patients were PCR positive for donor HLA alleles. All had macrochimerism, with donor T lymphocyte levels ranging from 4% to 50% of circulating lymphocytes. All seven patients had normal liver function tests, skin rash, and diagnosis of GvHD histologically confirmed by skin or gut biopsies. Twenty-six patients were PCR negative, and, in 23, an alternative diagnosis was eventually established. The remaining three patients made a rapid and spontaneous recovery with no further symptoms suggestive of GvHD. CONCLUSIONS: Donor lymphocyte macrochimerism was present in all patients in whom the diagnosis of GvHD was confirmed. In patients with symptoms consistent with GvHD and a negative PCR for donor HLA, an alternative diagnosis was eventually established or the patients recovered spontaneously. Detection of donor HLA alleles in recipient peripheral blood by PCR is a useful diagnostic tool for GvHD after liver transplantation.

Aged↗

PubMed2004

Does exposure to swine leukocyte antigens after pig-to-nonhuman primate xenotransplantation provoke antibodies that cross-react with human leukocyte antigens?

BACKGROUND: A potential concern of using pig kidney xenografts for human transplantation is that antibodies produced to swine leukocyte antigens (SLA) may cross-react with human leukocyte antigens (HLA) and thereby limit the scope for a subsequent human organ donor transplant. We therefore investigated whether exposure to SLA after pig-to-nonhuman primate kidney xenotransplantation gives rise to HLA cross-reactive antibodies. METHODS: Serum samples were obtained from 52 cynomolgus monkeys that received kidney transplants from human decay-accelerating factor (hDAF) transgenic pigs. Samples were collected pre-transplant and at time of autopsy (mean 20 days post-transplantation, range 1 to 53 days) and analyzed for IgG HLA class I and HLA class II specific antibodies by enzyme-linked immunosorbent assay (ELISA) against pooled purified HLA antigens. To ensure the ability of the HLA ELISA to detect cynomolgus monkey IgG binding, parallel experiments were performed to detect IgG Gal-alpha-1,3-Gal-specific antibodies known to be present in cynomolgus monkey serum. RESULTS: Analysis of both pre- and post-transplantation serum samples by ELISA demonstrated no detectable IgG antibody binding to HLA class I or class II antigens. Using the same ELISA antibody detection reagents, IgG Gal-alpha-1,3-Gal-specific antibodies were identified in 13 of 38 (34%) sera obtained before transplantation and 21 of 52 (40%) sera collected post-transplantation, confirming that the negativeHLA ELISA results were not due to a technical aspect of the assay. CONCLUSION: This study suggests that exposure to SLA following transplantation of porcine kidneys in nonhuman primates does not give rise to antibodies that cross-react with HLA.

Animals↗

PubMed2003

Comparison of allogeneic and xenogeneic in vitro T-cell proliferative responses in sensitized patients awaiting kidney transplantation.

Highly sensitized patients awaiting kidney transplantation may be potential candidates for future clinical trials using pig organ donors. Because of crossreactivity between human leucocyte antigens (HLA) and swine leucocyte antigens (SLA), such patients might have heightened T-cell responses to porcine xenoantigens. We determined whether lymphocytes from allo-sensitized patients displayed secondary (cyclosporine resistant) T-cell proliferative responses against porcine xenoantigens. Lymphocytes from six non-sensitized, seven sensitized [immunoglobulin G (IgG) panel reactive antibodies (PRA) 11 to 84%], 14 highly sensitized patients (IgG PRA > 84%) and 12 healthy individuals were tested [in the presence and absence of Cyclosporin A (CsA)] to determine their proliferative response to human (allogeneic) and to porcine (xenogeneic) stimulator cells. Lymphocytes from all study groups showed a strong proliferative response to allogeneic and xenogeneic stimulator cells with no significant difference between non-sensitized and sensitized individuals. Addition of CsA (100 and 500 ng/ml) inhibited (>90%) proliferation of lymphocytes from all non-sensitized patients to both allogeneic and xenogeneic stimulators. CsA was less effective at inhibiting proliferation of lymphocytes from sensitized patients and highly sensitized patients to allogeneic stimulators [29% (n=21) and 50% (n=42) respectively were resistant to CsA inhibition (100 ng/ml)]. In contrast, cyclosporine inhibited proliferation of lymphocytes from the majority of sensitized and highly sensitized patients to xenogeneic stimulator cells [14% (n=21) and 14% (n=42) respectively were resistant to CsA inhibition (100 ng/ml)]. HLA sensitized patients awaiting renal transplantation display cyclosporine resistant proliferative T-cell responses to allogeneic stimulators but proliferative responses to xenogeneic stimulators are more amenable to suppression by CsA. This finding suggests that humoral sensitisation to HLA antigens is not necessarily indicative of a heightened in vitro T-cell response to SLA antigens.

Animals↗

PubMed2003

Potential implications of ABO blood group for vascular rejection in pig to human kidney xenotransplantation.

BACKGROUND: A substantial hurdle for successful xenotransplantation is to negate the effect of xenoreactive natural antibodies [mainly Galalpha1-3Galbeta1-4GlcNAc (alpha-Gal) specific] that cause hyperacute xenograft rejection. Galalpha1-3Gal molecules (alpha-Gal) have close structural homology with human ABO blood groups and therefore an individual's blood group might influence the formation of alpha-Gal specific antibodies. Genetic heterogeneity controlling alpha-Gal specific antibody formation could have important implications for future pig to human xenotransplantation clinical trials. We have investigated the relationship between ABO blood group and immunoglobulin M (IgM) and immunoglobulin G (IgG) alpha-Gal specific antibody titres in sera obtained from renal dialysis patients and healthy blood donors. METHODS: Serially diluted sera (n = 166) obtained from renal dialysis patients awaiting kidney transplantation (n = 116) and healthy blood donors (n = 50) were tested for IgM and IgG alpha-Gal antibodies using an enzyme-linked immunosorbent assay (ELISA) specific for alpha-Gal. The study cohort comprised 62, 48, 36 and 20 sera obtained from blood group O, A, B and AB individuals, respectively. Reciprocal alpha-Gal specific antibody titres were calculated from ELISA titration curves and stratified by individual blood group. RESULTS: No significant heterogeneity was found in IgM alpha-Gal specific antibody titres across ABO blood groups. In contrast, marked heterogeneity was observed in IgG alpha-Gal specific antibody titres when stratified by blood group. IgG alpha-Gal specific antibody titres were higher in sera obtained from blood group O renal dialysis patients [median titre 40, interquartile range (IQR) 14 to 72], compared with blood group A (median titre 18, IQR 7 to 54, P = 0.05), blood group B (median titre 6, IQR 0 to 15, P < 0.001) and blood group AB patients (median titre 3.5, IQR 0 to 16, P = 0.002). A similar correlation was found for IgG alpha-Gal specific antibody titres in sera obtained from healthy blood donors with median titres of 20 (IQR 12 to 34), 37 (10 to 91), 9 (0 to 20), and 5.5 (0 to 12) in blood groups O, A, B and AB individuals, respectively. There was a strong interrelationship between alpha-Gal specific antibody class and blood group, with both IgM and IgG alpha-Gal specific antibodies found in 84% of the blood group O sera, 73% of blood group A sera, 50% of blood group B sera and 40% of blood group AB sera (P < 0.001). In a subgroup of 39 renal dialysis patients, IgM and IgG alpha-Gal specific antibody titres were measured in two serum samples obtained at different time-points (median time interval 581 days, range 42 to 4414), and showed a high degree of stability (correlation coefficient 0.88 and 0.90 for IgM and IgG, respectively). CONCLUSION: IgG alpha-Gal specific antibody titres are significantly higher in the sera of blood group O and A renal dialysis patients and healthy individuals compared with blood groups B and AB. These data indicate that future clinical trials of pig to human xenotransplantation may be more problematic for non-blood group B patients who are likely to have high levels of IgG alpha-Gal specific antibodies that are associated with acute vascular rejection.

ABO Blood-Group System↗

PubMed2002

Interleukin 1 and chronic rejection: possible genetic links in human heart allografts.

Chronic rejection is a leading cause of graft loss in thoracic transplant recipients. Studies on the pathogenesis of chronic rejection have suggested a contributory role for certain cytokines and growth factors. The activity of these mediators is subject to genetic variation if a polymorphism alters expression, or function, of the ligand or its receptor. Here we have asked if certain cytokine and growth factor gene polymorphisms correlate with chronic rejection in recipients of thoracic allografts. In a retrospective analysis of 179 recipients of thoracic organ transplants (128 heart; 36 heart-lung; and 15 lung), polymorphisms in 8 genes that influence the inflammatory process, namely IL1B, IL1R1, IL1RN, IL6, IL10, TNFA, TGFB1 and FCGRIIA, were examined. Genotypic data from recipients who had either died or been re-transplanted as a result of chronic rejection (n = 96) were then compared to those of recipients who had a functioning graft for more than 11 years (n=83). In the heart graft recipients, only those polymorphisms that influenced expression of the IL1 receptor antagonist gene had a significant correlation with graft survival, with homozygosity for the IL1RN*1 allele being associated with rejection. The alternative, less frequent IL1RN alleles emerged as genomic predictors of long-term allograft survival. This association was especially strong when IL1 region haplotypes were considered, particularly when analysis was confined to heart transplant recipients who had had multiple acute rejection episodes (OR>20). This case-control study indicates that gene polymorphisms which influence IL1 bioactivity also influence the progression of chronic rejection in heart grafts.

Adult↗

PubMed2002

Sensitisation to swine leukocyte antigens in patients with broadly reactive HLA specific antibodies.

We have previously shown that IgG HLA specific antibodies in the sera of highly sensitised patients awaiting renal transplantation can cross-react with swine leukocyte antigens (SLA). In this study we determined the frequency of patient serum IgG HLA specific antibody binding to a porcine lymphocyte panel and the likelihood of locating a cross-match negative pig donor for sensitised patients. Serum samples (n = 82) were obtained from 35 sensitised [current IgG panel reactive antibodies (PRA) > 10%] and seven nonsensitised patients awaiting renal transplantation at Addenbrooke's Hospital, Cambridge, UK. Fifty sera had IgG HLA specific PRA of 11-84%, 20 had IgG PRA of >84% and 12 had 0% PRA (negative controls). Sera were absorbed with porcine erythrocytes to remove xenoreactive natural antibodies and tested for cross-reactive IgG HLA specific antibody binding by flow cytometry against a panel of porcine lymphocytes obtained from 23 human decay accelerating factor (hDAF) transgenic pigs. A total of 1,884 cross-match combinations were tested and 369 (20%) gave a positive porcine lymphocyte cross-match. For sera from sensitised patients with IgG PRA (11-64%), only 6 of 805 (0.75%) cross-match tests were positive. In contrast, for sera from patients with high IgG PRA (>64%), 363 of 805 (45%) cross-match tests were positive (p < 0.0001). There was no difference in the frequency of positive cross-matches between patient sera with IgG PRA 65-84% and highly sensitised patient sera with IgG PRA 85-100% [156/345 (45%) vs. 207/460 (45%)]. This study demonstrates that only patient sera with broadly reactive IgG HLA specific PRA (>64%) cross-react with porcine lymphocytes. If future clinical trials of xenotransplantation are undertaken, it may be of value to select a cross-match-negative pig organ donor for such patients.

Animals↗