J Andrew Bradley

University of Cambridge, Cambridge, England, United Kingdom

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Publications (121)781.52 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The use of kidneys from controlled donation after circulatory death (DCD) donors has the potential to markedly increase kidney transplants performed. However, this potential is not being realized because of concerns that DCD kidneys are inferior to those from donation after brain-death (DBD) donors. The United Kingdom has developed a large and successful controlled DCD kidney transplant program that has allowed for a substantial increase in kidney transplant numbers. Here we describe recent trends in DCD kidney donor activity in the United Kingdom, outline aspects of the donation process, and describe donor selection and allocation of DCD kidneys. Previous UK Transplant Registry analyses have shown that while DCD kidneys are more susceptible to cold ischemic injury and have a higher incidence of delayed graft function, short- and medium-term transplant outcomes are similar in recipients of kidneys from DCD and DBD donors. We present an updated, extended UK registry analysis showing that longer-term transplant outcomes in DCD donor kidneys are also similar to those for DBD donor kidneys, and that transplant outcomes for kidneys from expanded-criteria DCD donors are no less favorable than for expanded-criteria DBD donors. Accordingly, the selection criteria for use of kidneys from DCD donors should be the same as those used for DBD donors. The UK experience suggests that wider international development of DCD kidney transplantation programs will help address the global shortage of deceased donor kidneys for transplantation.Kidney International advance online publication, 18 March 2015; doi:10.1038/ki.2015.88.
    Kidney International 03/2015; DOI:10.1038/ki.2015.88 · 8.52 Impact Factor
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    ABSTRACT: Acute umbilical hernia rupture in patients with hepatic cirrhosis and ascites is an unusual, but potentially life-threatening complication, with postoperative morbidity about 70% and mortality between 60%-80% after supportive care and 6%-20% after urgent surgical repair. Management options include primary surgical repair with or without concomitant portal venous system decompression for the control of the ascites. We present a retrospective analysis of our centre's experience over the last 6 years. Our cohort consisted of 11 consecutive patients (median age: 53 years, range: 36-63 years) with advanced hepatic cirrhosis and refractory ascites. Appropriate patient resuscitation and optimisation with intravenous fluids, prophylactic antibiotics and local measures was instituted. One failed attempt for conservative management was followed by a successful primary repair. In all cases, with one exception, a primary repair with non-absorbable Nylon, interrupted sutures, without mesh, was performed. The perioperative complication rate was 25% and the recurrence rate 8.3%. No mortality was recorded. Median length of hospital stay was 14 d (range: 4-31 d). Based on our experience, the management of ruptured umbilical hernias in patients with advanced hepatic cirrhosis and refractory ascites is feasible without the use of transjugular intrahepatic portosystemic shunt routinely in the preoperative period, provided that meticulous patient optimisation is performed.
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    ABSTRACT: Uniquely, alloantigen is recognised by two pathways: as intact antigen on the surface of donor antigen-presenting cells (direct) and as self-restricted processed allopeptide (indirect). The indirect pathway is believed to be longlasting, and is generally considered to be a single entity. Here we address how indirect responses against different alloantigens differ in their strength and longevity, and how this knowledge could be used to direct immunoregulatory therapy with antigen-specific regulatory T cells (Tregs).
    The Lancet 02/2015; 385. DOI:10.1016/S0140-6736(15)60332-4 · 39.21 Impact Factor
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    ABSTRACT: Memory T cells are known to reside in peripheral non-lymphoid tissue, but how their presence within solid organ allografts affects transplant outcomes is not known. We have previously described how graft-versus-host (GVH) allorecognition by passenger CD4 T cells within MHC class II-mismatched bm12 heart grafts provokes antinuclear humoral autoimmunity in C57BL/6 recipient mice. Here we aimed to examine how such GVH recognition affects the alloresponse to allografts with greater mismatching.
    The Lancet 02/2015; 385. DOI:10.1016/S0140-6736(15)60333-6 · 39.21 Impact Factor
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    ABSTRACT: Background: We have previously shown that qualitative assessment of surface electrostatic potential of HLA class I molecules helps explain serological patterns of alloantibody binding. We have now used a novel computational approach to quantitate differences in surface electrostatic potential of HLA B-cell epitopes and applied this to explain HLA Bw4 and Bw6 antigenicity.
    Transplantation 02/2015; Online First. DOI:10.1097/TP.0000000000000546 · 3.78 Impact Factor
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    ABSTRACT: The monoclonal anti-CD20 antibody rituximab depletes B cells in the treatment of lymphoma and autoimmune disease, and contributes to alloantibody reduction in transplantation across immunological barriers. The effects of rituximab on T cells are less well described. T follicular helper cells (Tfh) provide growth and differentiation signals to germinal center (GC) B cells to support antibody production, and suppressive T follicular regulatory cells (Tfr) regulate this response. In mice, both Tfh and Tfr are absolutely dependent on B cells for their formation and on the GC for their maintenance. Here, we demonstrate that rituximab treatment results in a lack of GC B cells in human lymph nodes without affecting the Tfh or Tfr cell populations. These data demonstrate that human Tfh and Tfr do not require an on-going GC response for their maintenance. The persistence of Tfh and Tfr following rituximab treatment may permit rapid reconstitution of the pathological GC response once the B cell pool begins to recover. Strategies for maintaining remission after rituximab therapy will need to take this persistence of Tfh into account.
    Blood 09/2014; 124(17). DOI:10.1182/blood-2014-07-585976 · 9.78 Impact Factor
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    ABSTRACT: Advances in developmental biology have shown that monozygous twins may not be as phenotypically identical as once believed, and the mechanisms responsible for such differences are now becoming clearer. Whether such phenotypic differences are capable of triggering graft rejection of an organ transplanted between identical twins remains unknown but the risks seem low, and long-term transplant outcome is excellent. Available evidence to guide immunosuppressive therapy in this setting is limited but a prudent approach would include the use of steroids together with a calcineurin inhibitor after transplantation. However, once the inevitable inflammatory response associated with transplant surgery has resolved, cautious reduction and eventually withdrawal of immunosuppression should be possible.
    Transplantation 08/2014; 98(5). DOI:10.1097/TP.0000000000000274 · 3.78 Impact Factor
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    ABSTRACT: Background: There is variation in time to listing and rates of listing for transplantation between renal units in the UK. While research has mainly focused on healthcare organization, little is known about patient perspectives of entry onto the transplant waiting list. This qualitative study aimed to explore patients' views and experiences of kidney transplant listing. Methods: Semi-structured interviews were conducted with patients aged under 75, who were on dialysis and on the transplant waiting list, not on the waiting list, undergoing assessment for listing or who had received a transplant. Patients were recruited from a purposive sample of nine UK renal units, which included transplanting and non-transplanting units and units with high and low wait-listing patterns. Interviews were transcribed verbatim and analysed using thematic analysis. Results: Fifty-three patients (5–7 per renal unit) were interviewed. Patients reported that they had received little information about the listing process. Some patients did not know if they were listed or had found they were not listed when they had thought they were on the list. Others expressed distress when they felt they had been excluded from potential listing based on age and/or comorbidity and felt the process was unfair. Many patients were not aware of pre-emptive transplantation and believed they had to be on dialysis before being able to be listed. There was some indication that pre-emptive transplantation was discussed more often in transplant than non-transplant units. Lastly, some patients were reluctant to consider family members as potential donors as they reported they would feel ‘guilty’ if the donor suffered subsequent negative effects. Conclusions: Findings suggest a need to review current practice to further understand individual and organizational reasons for the renal unit variation identified in patient understanding of transplant listing. The communication of information warrants attention to ensure patients are fully informed about the listing process and opportunity for pre-emptive transplantation in a way that is meaningful and understandable to them.
    Nephrology Dialysis Transplantation 07/2014; DOI:10.1093/ndt/gfu188 · 3.49 Impact Factor
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    ABSTRACT: : Renal transplantation is a successful treatment for patients with renal failure but its long-term efficacy is limited by untreatable transplant vasculopathy (TA). Endothelial damage contributes to TA and is potentially repairable by circulating endothelial progenitor cells (EPC). The frequency and function of EPC is variably influenced by end-stage renal failure (ESRF). This study aimed to characterise the late-outgrowth EPC (LO-EPC) from ESRF patients with a view to utilising autologous LO-EPC for endothelial repair following renal transplantation. LO-EPC isolated from ESRF patients and healthy volunteers were characterised phenotypically and functionally and their integrin expression profile was determined.ESRF patients generated more LO-EPC colonies than healthy controls, had higher plasma levels of IL-1rα, IL-16, IL-6, MIF, VEGF, Prolactin and PLGF. Patients' LO-EPC displayed normal endothelial cell morphology, increased secretion of PLGF, MCP-1 and IL-1β, decreased senescence and normal network formation in vitro and in vivo , but demonstrated decreased adhesion to extracellular matrix. Integrin gene profiles and protein expression were comparable in patients and healthy volunteers. In some patients, mesenchymal stem cells were co-isolated from peripheral blood and these could be differentiated into adipocytes and osteocytes in vitro . This is the first study to characterise LO-EPC from ESRF patients. Their behaviour in vitro reflects the presence of elevated trophic factors; their ability to proliferate in vitro and angiogenic function makes them candidates for prevention of transplant vasculopathy. Their impaired adhesion and the presence of MSC are areas for potential therapeutic intervention.
    Heart (British Cardiac Society) 06/2014; 100 Suppl 3:A113. DOI:10.1136/heartjnl-2014-306118.206 · 6.02 Impact Factor
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    ABSTRACT: We have analyzed the relationship between donor mismatches at each HLA locus and development of HLA locus-specific antibodies in patients listed for repeat transplantation. HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The number of HLA mismatches and the calculated reaction frequency of antibody reactivity against 10,000 consecutive deceased organ donors were determined for each HLA locus. Two-thirds of patients awaiting repeat transplantation were sensitized (calculated reaction frequency over 15%) and half were highly sensitized (calculated reaction frequency of 85% and greater). Antibody levels peaked after re-listing for repeat transplantation, were independent of graft nephrectomy and were associated with length of time on the waiting list (odds ratio 8.4) and with maintenance on dual immunosuppression (odds ratio 0.2). Sensitization was independently associated with increasing number of donor HLA mismatches (odds ratio 1.4). All mismatched HLA loci contributed to the development of HLA locus-specific antibodies (HLA-A: odds ratio 3.2, HLA-B: odds ratio 3.4, HLA-C: odds ratio 2.5, HLA-DRB1: odds ratio 3.5, HLA-DRB3/4/5: odds ratio 3.9, and HLA-DQ: odds ratio 3.0 (all significant)). Thus, the risk of allosensitization following failure of a first renal transplant increases incrementally with the number of mismatches at all HLA loci assessed. Maintenance of re-listed patients on dual immunosuppression was associated with a reduced risk of sensitization.Kidney International advance online publication, 9 April 2014; doi:10.1038/ki.2014.106.
    Kidney International 04/2014; 86(5). DOI:10.1038/ki.2014.106 · 8.52 Impact Factor
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    ABSTRACT: It is essential to minimize the unnecessary discard of procured deceased donor kidneys, but information on discard rates and the extent to which discard can be avoided are limited. Analysis of the UK Transplant Registry revealed that the discard rate of procured deceased donor kidneys has increased from 5% in 2002-3 to 12% in 2011-12. A national offering system for hard-to-place kidneys was introduced in the UK in 2006 (the Declined Kidney Scheme), but just 13% of kidneys that were subsequently discarded until 2012 were offered through the scheme. In order to examine the appropriateness of discard, 20 consecutive discarded kidneys from 13 deceased donors were assessed to determine if surgeons agreed with the decision that they were not implantable. Donors had a median (range) age of 67 (31-80) yr. Kidneys had been offered to a median of 3 (1-12) centers before discard. Four (20%) of the discarded kidneys were thought to be usable, and nine (45%) were possibly usable. As a result of these findings, major changes to the UK deceased donor kidney offering system have been implemented, including simultaneous offering and broader entry criteria for hard-to-place kidneys. Organizational changes are necessary to improve utilization of deceased donor kidneys.
    Clinical Transplantation 02/2014; 28(3). DOI:10.1111/ctr.12319 · 1.49 Impact Factor
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    ABSTRACT: Delayed graft function (DGF) after renal transplantation can be diagnosed according to several different definitions, complicating comparison between studies that use DGF as an endpoint. This is a particular problem after transplantation with kidneys from donation after circulatory death (DCD) kidneys, because DGF is common, and its relationship to early graft failure may differ depending on the definition of DGF. The presence of DGF in 213 donation after brain death (DBD) and 312 DCD kidney transplants from October 2005 to August 2011 was determined according to 10 different, but widely used, definitions (based on dialysis requirements, creatinine changes, or both). The relationship of DGF to graft function and graft survival was determined. The incidence of DGF varied widely depending on the definition used (DBD; 24%-70%: DCD; 41%-91%). For kidneys from DCD donors, development of DGF was only associated with poorer 1-year estimated glomerular filtration rate for 1 of 10 definitions of DGF, and no definition of DGF was associated with impaired graft survival. Conversely, for DBD kidneys, DGF, as defined in 9 of 10 different ways, was associated with poorer 1-year estimated glomerular filtration rate and inferior graft survival. Importantly, the predictive power for poorer transplant outcome was comparable for all definitions of DGF. No definition of DGF is superior. We suggest that the most widely used and most easily calculated definition-the use of dialysis in the first postoperative week-should be universally adopted as the definition of DGF clinically and as a study endpoint.
    Transplantation 09/2013; DOI:10.1097/TP.0b013e3182a19348 · 3.78 Impact Factor
  • 09/2013; 33(5):479-81. DOI:10.3747/pdi.2013.00141
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    ABSTRACT: B cells play an important role in renal allograft pathology, particularly in acute and chronic antibody-mediated rejection (AMR). B-cell activating factor belonging to the tumor necrosis factor family (BAFF; also known as BLyS) is a cytokine that enhances B-cell survival and proliferation. We analyzed serum BAFF levels in 32 patients undergoing antibody-incompatible (Ai) renal transplantation and 319 antibody-compatible transplant recipients and sought to determine whether there was a correlation with acute rejection and with transplant function and survival. We demonstrate that, in patients undergoing Ai transplantation, elevated serum BAFF levels at baseline (before both antibody removal/desensitization and transplantation) are associated with an increased risk of subsequent AMR. In antibody-compatible transplant recipients at lower risk of AMR, no statistically significant association was observed between pretransplantation serum BAFF and AMR. These data raise the possibility that, in high immunologic risk patients undergoing Ai transplantation, the presence of elevated pretransplantation serum BAFF might identify those at increased risk of AMR. BAFF neutralization may be an interesting therapeutic strategy to explore in these patients, particularly because such agents are available and have already been used in the treatment of autoimmunity.
    Transplantation 07/2013; DOI:10.1097/TP.0b013e318298dd65 · 3.78 Impact Factor
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    ABSTRACT: With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.
    Transplantation 05/2013; DOI:10.1097/TP.0b013e31829853ce · 3.78 Impact Factor
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    ABSTRACT: In transplantation, direct-pathway CD8 T cells that recognize alloantigen on donor cells require CD4 help for activation and cytolytic function. The ability of indirect-pathway CD4 T cells to provide this help remains unexplained, because a fundamental requirement for epitope linkage is seemingly broken. The simultaneous presentation, by host dendritic cells (DCs), of both intact MHC class I alloantigen and processed alloantigen would deliver linked help, but has not been demonstrated definitively. In this study, we report that following in vitro coculture with BALB/c DCs, small numbers (∼1.5%) of C57BL/6 (B6) DCs presented acquired H-2(d) alloantigen both as processed allopeptide and as unprocessed Ag. This represented class I alloantigen provides a conformational epitope for direct-pathway allorecognition, because B6 DCs isolated from cocultures and transferred to naive B6 mice provoked cytotoxic CD8 T cell alloimmunity. Crucially, this response was dependent upon simultaneous presentation of class II-restricted allopeptide, because despite acquiring similar amounts of H-2(d) alloantigen upon coculture, MHC class II-deficient B6 DCs failed to elicit cytotoxic alloimmunity. The relevance of this pathway to solid-organ transplantation was then confirmed by the demonstration that CD8 T cell cytotoxicity was provoked in secondary recipients by transfer of DCs purified from wild-type, but not from MHC class II-deficient, C57BL/6 recipients of BALB/c heart transplants. These experiments demonstrate that representation of conformationally intact MHC alloantigen by recipient APC can induce cytotoxic alloimmunity, but simultaneous copresentation of processed allopeptide is essential, presumably because this facilitates linked recognition by indirect-pathway CD4 Th cells.
    The Journal of Immunology 04/2013; 190(11). DOI:10.4049/jimmunol.1300458 · 5.36 Impact Factor
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    ABSTRACT: BACKGROUND: Use of kidneys donated after controlled circulatory death has increased the number of transplants undertaken in the UK but there remains reluctance to use kidneys from older circulatory-death donors and concern that kidneys from circulatory-death donors are particularly susceptible to cold ischaemic injury. We aimed to compare the effect of donor age and cold ischaemic time on transplant outcome in kidneys donated after circulatory death versus brain death. METHODS: We used the UK transplant registry to select a cohort of first-time recipients (aged ≥18 years) of deceased-donor kidneys for transplantations done between Jan 1, 2005, and Nov 1, 2010. We did univariate comparisons of transplants from brain-death donors versus circulatory-death donors with χ(2) tests for categorical data and Wilcoxon tests for non-parametric continuous data. We used Kaplan-Meier curves to show graft survival. We used Cox proportional hazards regression to adjust for donor and recipient factors associated with graft-survival with tests for interaction effects to establish the relative effect of donor age and cold ischaemia on kidneys from circulatory-death and brain-death donors. FINDINGS: 6490 deceased-donor kidney transplants were done at 23 centres. 3 year graft survival showed no difference between circulatory-death (n=1768) and brain-death (n=4127) groups (HR 1·14, 95% CI 0·95-1·36, p=0·16). Donor age older than 60 years (compared with <40 years) was associated with an increased risk of graft loss for all deceased-donor kidneys (2·35, 1·85-3·00, p<0·0001) but there was no increased risk of graft loss for circulatory-death donors older than 60 years compared with brain-death donors in the same age group (p=0·30). Prolonged cold ischaemic time (>24 h vs <12 h) was not associated with decreased graft survival for all deceased-donor kidneys but was associated with poorer graft survival for kidneys from circulatory-death donors than for those from brain-death donors (2·36, 1·39-4·02, p for interaction=0·004). INTERPRETATION: Kidneys from older circulatory-death donors have equivalent graft survival to kidneys from brain-death donors in the same age group, and are acceptable for transplantation. However, circulatory-death donor kidneys tolerate cold storage less well than do brain-death donor kidneys and this finding should be considered when developing organ allocation policy. FUNDING: UK National Health Service Blood and Transplant; Cambridge National Institute for Health Research Biomedical Research Centre.
    The Lancet 12/2012; DOI:10.1016/S0140-6736(12)61685-7 · 39.21 Impact Factor
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    ABSTRACT: Essential help for long-lived alloantibody responses is theoretically provided only by CD4 T cells that recognize target alloantigen, processed and presented by the allospecific B cell. We demonstrate that in an alloresponse to multiple MHC disparities, cognate help for class-switched alloantibody may also be provided by CD4 T cells specific for a second "helper" alloantigen. This response was much shorter-lived than when help was provided conventionally, by Th cell recognition of target alloantigen. Nevertheless, long-lasting humoral alloimmunity developed when T cell memory against the helper alloantigen was first generated. Costimulatory blockade abrogated alloantibody produced through naive Th cell recognition of target alloantigen but, crucially, blockade was ineffective when help was provided by memory responses to the accessory helper alloantigen. These results suggest that memory Th cell responses against previously encountered graft alloantigen may be the dominant mechanism for providing help to generate new specificities of alloantibody in transplant patients receiving immunosuppression.
    The Journal of Immunology 11/2012; 189(12). DOI:10.4049/jimmunol.1202257 · 5.36 Impact Factor
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    ABSTRACT: Fcγ receptors (FcγR) provide important immunoregulation. Targeting inhibitory FcγRIIb may therefore prolong allograft survival, but its role in transplantation has not been addressed. FcγRIIb signaling was examined in murine models of acute or chronic cardiac allograft rejection by transplanting recipients that either lacked FcγRIIb expression (FcγRIIb(-/-)) or overexpressed FcγRIIb on B cells (B cell transgenic [BTG]). Acute heart allograft rejection occurred at the same tempo in FcγRIIb(-/-) C57BL/6 (B6) recipients as wild type recipients, with similar IgG alloantibody responses. In contrast, chronic rejection of MHC class II-mismatched bm12 cardiac allografts was accelerated in FcγRIIb(-/-) mice, with development of more severe transplant arteriopathy and markedly augmented effector autoantibody production. Autoantibody production was inhibited and rejection was delayed in BTG recipients. Similarly, whereas MHC class I-mismatched B6.K(d) hearts survived indefinitely and remained disease free in B6 mice, much stronger alloantibody responses and progressive graft arteriopathy developed in FcγRIIb(-/-) recipients. Notably, FcγRIIb-mediated inhibition of B6.K(d) heart graft rejection was abrogated by increasing T cell help through transfer of additional H2.K(d)-specific CD4 T cells. Thus, inhibitory FcγRIIb signaling regulates chronic but not acute rejection, most likely because the supra-optimal helper CD4 T cell response in acute rejection overcomes FcγRIIb-mediated inhibition of the effector B cell population. Immunomodulation of FcγRIIb in clinical transplantation may hold potential for inhibiting progression of transplant arteriopathy and prolonging transplant survival.
    The Journal of Immunology 11/2012; 189(12). DOI:10.4049/jimmunol.1202084 · 5.36 Impact Factor
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    ABSTRACT: The likelihood for immunological rejection of Human Leukocyte Antigens (HLA)-mismatched induced pluripotent stem cells (iPSCs) limits their therapeutic potential. Here we show how a tissue bank from 150 selected homozygous HLA-typed volunteers could match 93% of the UK population with a minimal requirement for immunosuppression. Our model provides a practical approach for using existing HLA-typed samples to generate an iPSC stem cell bank that circumvents prospective typing of a large number of individuals.
    Cell stem cell 08/2012; 11(2):147-52. DOI:10.1016/j.stem.2012.07.014 · 22.15 Impact Factor

Publication Stats

3k Citations
781.52 Total Impact Points

Institutions

  • 1999–2015
    • University of Cambridge
      • Department of Surgery
      Cambridge, England, United Kingdom
  • 2011
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
  • 2008–2010
    • Cambridge University Hospitals NHS Foundation Trust
      Cambridge, England, United Kingdom
  • 2005
    • University of Leicester
      Leiscester, England, United Kingdom
  • 1992–2003
    • University of Glasgow
      • Division of Immunology
      Glasgow, Scotland, United Kingdom