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Biomedical subjects

A S MacDonald

Publications and source records attributed to A S MacDonald.

At least 37 records · Page 2Linked to original sources
PubMed2000

Calcified subcutaneous arterioles with infarcts of the subcutis and skin ("calciphylaxis") in chronic renal failure.

Patients with chronic renal failure (CRF) are at increased risk for pathological calcifications because of increased serum calcium-phosphorus products. A minority, including those undergoing dialysis, develop a syndrome of deep skin ulcerations in association with calcification of subcutaneous arterioles. The body distribution of the skin lesions may be proximal (central), distal (peripheral), or both. Since 1968, this syndrome has been called "calciphylaxis" in the belief that it is the human analogue of Selye's experimental models of tissue calcification. Our review emphasizes that this syndrome comprises two separate processes not found in calciphylaxis: calcification of subcutaneous arterioles and infarctions of subcutaneous adipose tissue (panniculus adiposus) and skin. The infarctions are acute and clinically dramatic, whereas the calcific arteriolopathy is preexistent, having developed slowly, sometimes over years, and silently. Separating these two processes facilitates analyses of pathogenetic factors, such as those that target subcutaneous arterioles for calcification and those that interfere with blood flow through the calcified arterioles, sufficient in some patients to cause the infarctions, and of why obesity in CRF is a syndrome risk factor. This approach further helps to provide a much needed standardized definition of the syndrome, thereby facilitating comparisons of the results of such treatments as parathyroidectomy, anticoagulants, and phosphate binders. Finally, the separation shows why the application of such terms as calciphylaxis and calcifying panniculitis to this syndrome is inappropriate.

Animals↗
PubMed2000

Effect of recipient sensitization (peak PRA) on graft outcome in haploidentical living related kidney transplants.

OBJECTIVE: To evaluate the influence of pre-transplant recipient sensitization on the outcome of 1-haploidentical live related donor (LRD) kidney transplants. METHOD: We reviewed 141 consecutive cyclosporine-treated adult haploidentical first transplants for which panel reactive antibody (PRA) levels were available. Patients were divided into three groups according to their peak PRA levels: group I, PRA = 0 (n = 97); group II, PRA = 1-50% (n = 24); and group III, PRA = 51-100% (n = 20). RESULTS: Differences in PRA were associated with significant differences in short- and longer-term graft survival, unrelated to patient survival. Graft survival at 1, 3, and 5 yr was only 74, 40, and 27% in group III, compared to 92, 87, and 52% in group II, and 96, 91, and 85% in group I (p < 0.001). Increasing PRA was associated with shorter time-to-graft failure. In group III, 20% lost their transplant from acute rejection in the first 6 months, versus 4% in group II and 3% in group I (p < 0.01). Graft survival in group II diverged from that of group I only after 3 yr, due to an increase in loss from chronic rejection. Hospitalization was longer in group III, in association with a significantly higher incidence of acute rejection during the first 3 months after transplantation (p < 0.02). Serum creatinine was higher in sensitized than nonsensitized patients at all time points. CONCLUSIONS: Sensitization has a significant negative impact on the outcome of haploidentical LRD kidney transplants. Sensitized potential recipients and their potential donors should be aware of this in arriving at informed decision-making for transplantation. These patients may benefit from more sensitive cross-match testing, more intense or more novel immunosuppression, or immunomodulation to modify their immune responsiveness.

Adult↗
PubMed1999

The Obesity Adjustment Survey: development of a scale to assess psychological adjustment to morbid obesity.

OBJECTIVE: To develop a reliable and valid measure of distress, related to extreme obesity. DESIGN: Items related to distress over obesity were selected from the literature, clinical experience and from input provided by a gastroplasty patient support group. The items were assessed in a longitudinal study, with the body mass index (BMI) and psychological assessment occurring 2-6 months prior to, and 12 months following, gastroplasty surgery. SUBJECTS: 81 females and eight males (mean age 35.9 y) who had been accepted for gastroplasty surgery. All but two of the patients had BMIs > 40 (Mean = 48.11, s.d. = 6.84). MEASUREMENTS: BMIs were calculated using weight and height. Psychological characteristics were assessed using the Mental Health Inventory (MHI), the Sickness Impact Profile (SIP), and the Eating Inventory (EI). Demographic information was collected with a questionnaire. RESULTS: Attempts to factor analyse the 95 item questionnaire were unsuccessful. Alternatively, a shorter, 20 item questionnaire was developed. The questionnaire shows good test-retest reliability (r = 0.867), good internal consistency (coefficient alpha = 0.719), good face and construct validity, and is sensitive to pre-post surgical change. CONCLUSIONS: The Obesity Adjustment Survey (OAS) may be useful as a brief measure of distress in obese individuals. This measure can be used to index the psychological impact of gastroplasty surgery on psychological functioning, and can be used in future research as a disease-specific measure to predict success of surgery.

Adaptation, Psychological↗
PubMed1999

Suppressive antigen-presenting cells in Helminth infection.

Infection with filarial nematodes is commonly associated with a failure of T cells to proliferate in response to parasite antigen. We have investigated the possibility that antigen-presenting cells recruited during filarial infection are responsible for impairment of T cell function. We have found that the human filarial parasite Brugia malayi, when implanted into the peritoneal cavity of mice, recruits a population of adherent cells that actively block the proliferation of T cells. Phenotypic analysis of the recruited cells reveals large numbers of both macrophages and eosinophils and cell sorting experiments demonstrate that these antiproliferative cells are Mac-1-positive. Studies in gene-deficient mice have demonstrated that proliferative suppression is dependent on the in vivo production of IL-4 but not IL-5 or IL-10, while suppression in vitro is not mediated by any known antiproliferative factor. Our results suggest that helminth infection can lead to the development and/or recruitment of an IL-4-dependent macrophage population that mediates suppression via a novel mechanism.

Animals↗
PubMed1999

The morbidity of prolonged wound drainage after kidney transplantation.

PURPOSE: The consequences of prolonged wound drainage, defined as extravasation of more than 50 ml. fluid daily for more than 1 week through a drain or wound after renal transplantation, have not been well described in the literature. We examine the association of prolonged wound drainage with other clinical events, and its impact on hospitalization, and patient and graft survival. MATERIALS AND METHODS: We prospectively documented prolonged wound drainage in 392 recipients of cadaver and live renal transplants from July 1993 to December 1997. Potential risk factors, associated outcomes within the first 6 months and effect on length of hospital stay due to prolonged wound drainage were determined. RESULTS: Prolonged wound drainage was significantly associated with pre-transplantation weight, weight gain by post-transplantation day 3, delayed graft function and continuous ambulatory peritoneal dialysis on univariate analysis but only with delayed graft function (odds ratio 2.8, 95% confidence intervals 1.4 to 5.6) on multivariate analysis. Post-transplantation lymphoceles (5.2, 9 to 14), wound infection (27, 5.7 to 130) and wound dehiscence (5.8, 1.7 to 20) were associated with prolonged wound drainage. Patients with prolonged wound drainage stayed 8.7 additional days during the first hospitalization and overall 11.3 additional days during the first 6 months after transplantation independent of other co-morbid events, such as delayed graft function, rejection or cytomegalovirus disease. CONCLUSIONS: Prolonged wound drainage is an important post-renal transplantation event that impacts patient outcomes and hospital resource use. Efforts to prevent this complication should be considered.

Adult↗
PubMed1998

Requirement for in vivo production of IL-4, but not IL-10, in the induction of proliferative suppression by filarial parasites.

Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-gamma production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.

Animals↗
PubMed1998

Requirement for in vivo production of IL-4, but not IL-10, in the induction of proliferative suppression by filarial parasites.

Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-gamma production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.

Animals↗
PubMed1998

Profound suppression of cellular proliferation mediated by the secretions of nematodes.

Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filarial infection. Down-regulation and modulation of host T cell responses during lymphatic filariasis has been investigated by implantation of parasite stages into inbred mice. Adherent peritoneal exudate cells (PEC) from mice transplanted with adult or larval Brugia malayi parasites are profoundly anti-proliferative but do not prevent antigen-specific cytokine production by T cells. We demonstrate here that the excretory/secretory (E/S) products of the adult parasite are sufficient to induce PEC that block proliferation if injected daily into mice. We have previously shown that in vivo production of host IL-4 is required for the generation of suppressive cells. Because the induction of host IL-4 is characteristic of infection with nematodes, we asked whether E/S from two other nematode parasites, Nippostrongylus braziliensis and Toxocara canis were also capable of generating a suppressor cell population. Injection of E/S from these two parasites also led to a reduction in T cell proliferation suggesting that this mechanism of down-regulating host responses is a feature common to nematode parasites.

Animals↗
PubMed1997

Focal segmental glomerulosclerosis in one of two "en bloc" pediatric transplanted kidneys.

Focal segmental glomerulosclerosis (FSGS) is thought to have several causes, including hypertension, reduction of nephron mass, or immunologic processes. Experimental studies have underlined the role of glomerular adaptation to capillary pressure in the growing kidney after partial nephrectomy. We report here the occurrence of FSGS in one of two "en bloc" pediatric kidneys transplanted in an adult recipient. One of the kidneys sustained early ureteral obstruction requiring reoperation and subsequently developed pathological changes on biopsy consistent with FSGS, whereas the mate kidney did not, although both kidneys grew at equal rates and to equivalent sizes.

Adult↗
PubMed1996

Importance of minor histocompatibility antigens in the development of allograft arteriosclerosis.

Although acute rejection has been mostly ameliorated with the use of powerful immunosuppressive drugs, kidney and heart transplants continue to succumb to a more chronic response characterized by intimal lesions in the graft vasculature. This late-stage response is referred to as allograft arteriosclerosis. Allorecognition is clearly involved in the initiation of this response but the relative importance of major histocompatibility (MHC) and minor histocompatibility (mH) antigens remains unclear. By taking advantage of the B10 congenic set of mice and our newly described mouse aortic interposition graft model we have been able to assess the contribution of these antigens to the development of the concentric intimal lesions characteristic of allograft arteriosclerosis. We performed transplants between syngeneic animals, animals which were disparate at both MHC and multiple mH, animals which were disparate at MHC only, and animals which were disparate at multiple mH antigens only. H-Y antigen variation was controlled for by performing all transplants between female mice. In all cases the recipients were C57BL/10 (H-2b) mice. Both cellular infiltration into the intima and resulting intimal thickness were measured at 2, 4, 8, and 13 weeks posttransplant. At all time points, the grafts from MHC disparate only donors showed less severe intimal lesions than the grafts from fully disparate or mH disparate donors. This difference reached statistical significance at 4 and 13 weeks. This suggests that mH antigens are as immunogenic as MHC antigens with respect to the generation of allograft arteriosclerosis. These findings are not unique to vascular grafts and may relate to the importance of indirect antigen presentation in the development of chronic rejection.

Animals↗
PubMed1996

Kidney transplantation, the Halifax experience.

In the absence of a national kidney sharing system in Canada, virtually all the cadaver kidneys we transplant come from donors within the 4 provinces we serve. Currently the only criteria we use for recipient selection of cadaver kidneys, apart from ABO blood group matching and a negative anti-T-cell crossmatch, are good HLA match and transplant wait-list seniority. All transplant recipients receive CsA-based immunosuppression. Antibody induction is used only for repeat transplants and pediatric transplants. Recipients of first cadaver kidney transplants with zero HLA-DR mismatches have significantly better graft survival than those with mismatches. Graft and patient survival rates for first cadaver transplants continue to improve within the CsA era, and are comparable to those seen in centers routinely using antibody induction and routine sequential quadruple immunosuppression. Chronic graft nephropathy continues to be the most important cause of graft loss after the first year, unchanged over the past 2 decades, followed closely by death with a functioning kidney. The latter is a more important cause of loss in recipients older than age 60, and in recipients of HLA-identical live donor transplants. Repeat cadaver transplant recipients have a 5-year graft survival rate today equivalent to that seen with first cadaver transplants. Graft loss from acute rejection is modest, but kidneys requiring rescue therapy for steroid-resistant rejection have significantly poorer one- and 5-year graft survival and ultimately are lost from rejection. Patients with HLA-identical live-related donor transplants have better long-term survival with CsA than with azathioprine due to a decrease in graft loss from chronic rejection. Pre-transplant sensitization has an adverse effect on graft survival for haploidentical but not HLA identical live-related transplants. Patients over age 60 have equivalent graft survival to younger recipients for at least 7 years, and should not be precluded from receiving transplants by age alone. Prolonged CIT > 24 hours is associated with a significantly increased incidence and duration of ATN and need for dialysis, significantly increased early and late graft loss from acute and chronic rejection respectively, significantly reduced QALY's, and significantly higher early and late costs of transplantation.

Adult↗
PubMed1995

Development of a mouse aortic transplant model of chronic rejection.

Chronic rejection is the most common cause of late graft failure after solid organ transplantation. A model of chronic rejection, the rat aortic allograft, has histologic features that parallel those in the vessels of human transplanted organs. However, the molecular tools required to dissect the immunology of chronic rejection are unavailable in the rat. We developed aortic transplantation in the mouse as a new model of chronic rejection. This will allow the use of the diversity of recombinant cytokines and monoclonal antibodies available for the mouse and its well-defined genetics to investigate chronic rejection in greater detail. We describe the perioperative care and surgical technique for the model in which a 1 cm segment of donor thoracic aorta was used to replace a section of recipient abdominal aorta below the renal arteries and above the aortic bifurcation. Mortality rates were initially high (70%) due to thrombosis and shock. Changes in technique and operator facility resulted in a high rate of success (75%). After 192 operations, the current success rate is > 80%. Mice free from complications at 12 hrs postop had indefinite survival, and after 2 months the typical vascular lesion of chronic rejection was present. This new model of chronic rejection will be a valuable tool to study the molecular immunology and genetics of chronic rejection.

Anastomosis, Surgical↗
PubMed1994

Integrating management of physician groups and hospitals.

This chapter discusses the management challenges facing hospitals as they enter into formal organizational and economic linkages with physician organizations. Managing physician organizations does not simply mean controlling physicians through employment arrangements, but rather providing an organizational structure through which physicians can work together and with the hospital toward a common goal of creating a high-quality, cost-effective system of patient care. Integration of the management approaches required to run hospitals and physician groups successfully represents a significant challenge. Meeting this challenge is key to creating an organization that will be able to truly manage care.

Group Practice↗