Cytokines and cytokine therapy.
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Journal Article↗
Biomedical subjects
P Foster
Publications and source records attributed to P Foster.
The portosystemic shunt protects liver against ischemic reperfusion injury.
BACKGROUND: The goal of this study was to characterize the importance of splanchnic viscera in liver ischemic reperfusion injury and to enhance the tolerance of liver to warm ischemia injury with portosystemic shunt. METHODS: The hepatic blood flow of male Sprague Dawley rats was subjected to 45, 60, 120, and 150 min liver warm ischemia with or without portosystemic shunt (splenic-caval shunt). The production of tumor necrosis factor a (TNFa), nuclear factor-kappaB activation, inducible NO synthase (iNOS) expression, and apoptosis were examined. RESULTS: A total of 67% of rats with 45 min liver warm ischemia (n=6) and 100% of rats with 60 min liver warm ischemia (n=6) died within 1 day. However, all rats with 120 min (n=8) liver warm ischemia in splenic-caval shunt group survived for over 1 day, 6/8 for over 3 days, and 5/8 for over 5 days without significant histological changes of the liver. Serum tumor necrosis factor levels in liver warm ischemic rats were increased, This increase was significantly reversed after portosystemic shunt. After challenge with lipopolysaccharide (1 mg/kg, p.v.), naive rats survived for over 5 days (n=4) with the peak value of rat tumor necrosis factor (240 pg/ml) at 90 min. In contrast, all rats died within one day (n=5) with the peak value of rat tumor necrosis factor a (465 pg/ml) at 45 min after administration of lipopolysaccharide in the rats with liver warm ischemia plus splenic-caval shunt. iNOS expression and nuclear factor-kappaB activation were very strongly increased in the hepatocytes after liver warm ischemia with portosystemic shunt, compared with liver ischemia without portosytemic shunt. CONCLUSIONS: We conclude that the splanchnic viscera can contribute to liver ischemic reperfusion injury. Portosystemic shunt enhances the tolerance of liver to warm ischemia through the protective role of iNOS and nuclear factor-kappaB (NF-kappaB).
Animals↗
In vivo activity of leflunomide: pharmacokinetic analyses and mechanism of immunosuppression.
BACKGROUND: Leflunomide is an experimental drug with demonstrated ability to prevent and reverse acute allograft and xenograft rejection. The two biochemical activities reported for the active metabolite of leflunomide, A77 1726, are inhibition of tyrosine phosphorylation and inhibition of dihydroorotate dehydrogenase, an enzyme necessary for de novo pyrimidine synthesis. These activities can be distinctly separated in vitro by the use of uridine, which reverses the anti-proliferative effects of A77 1726 caused by inhibition of de novo pyrimidine synthesis. We report the effect of uridine on the in vivo immunosuppressive activities of leflunomide. METHODS: We first quantified the serum levels of A77 1726, the active metabolite of leflunomide, after a single treatment of leflunomide (5, 15, and 35 mg/kg). Additionally, we quantified the levels of serum uridine and of nucleotide triphosphates in the liver, spleen, and lymph nodes of Lewis rats after the administration of a single dose of uridine (500 mg/kg; i.p.). Lewis rats heterotopically transplanted with brown Norway or Golden Syrian hamster hearts were treated for 50 or 75 days with leflunomide (5, 15, and 35 mg/kg/day; gavage) alone or in combination with uridine (500 mg/ kg/day; i.p.). Hematocrits were determined and the levels of alloreactive or xenoreactive immunoglobulin (Ig)M and IgG were determined by flow cytometric analysis. The allograft and xenografts, small bowel, liver, kidney, and spleen were subjected to pathological examination. RESULTS: A linear relationship was observed between the serum A77 1726 concentrations in Lewis rats and the dose of leflunomide administered. Peak A77 1726 concentrations were 20.9, 71.8 and 129.3 mg/l (77.5, 266.1 and 478.8 microM) for the 5, 15, and 35 mg/kg doses of leflunomide, respectively. The concentration of uridine in the serum of normal Lewis rats is 6.5 microM; after i.p. administration of 500 mg/kg uridine, the serum uridine concentrations peaked at 384.1 microM in 15-30 min. The rapid elimination of uridine was not reflected in the lymphoid compartments, and the pharmacokinetics of pyrimidine nucleotides in the spleen resembled that of A77 1726. This dose of uridine, when administered daily (500 mg/kg/day, i.p.), weakly antagonized the immunosuppressive activities of leflunomide (5, 15, and 35 mg/kg/day) in the allotransplantation model. In contrast, in the xenotransplantation model, the same concentration of uridine completely antagonized the immunosuppressive activities of low-dose leflunomide (15 mg/kg/day) and partially antagonized the immunosuppressive activities of high-dose leflunomide (35 mg/kg/day). Toxicities associated with high-dose leflunomide (35 mg/kg/day) were anemia, diarrhea, and pathological changes in the small bowel and liver. These toxicities were significantly reduced by uridine co-administration. CONCLUSION: These studies reveal that the blood levels of A77 1726 in Lewis rats satisfy in vitro requirements for both inhibition of de novo pyrimidine synthesis and protein tyrosine kinase activity. Our data also illustrate that the in vivo mechanism of immunosuppression by leflunomide is complex and is affected by at least the following four factors: type and vigor of the immune response, availability of uridine for salvage by proliferating lymphocytes, species being investigated, and concentration of serum A77 1726.
Aniline Compounds↗
Relationship between serum and urinary insulin-like growth factor-I through childhood and adolescence: their use in the assessment of disordered growth.
OBJECTIVE: Serum insulin-like growth factor-I (sIGF-I) measurement as an index of growth hormone status has become a common test in the investigation of disordered growth. IGF-I may also be measured in the urine. The aims of this study were to investigate the correlation between serum and urinary IGF-I in normal children and compare their use in the evaluation of growth disorders. DESIGN: Normal ranges for serum and urinary IGF-I were devised from a cross-sectional study of normal schoolchildren. These were then used to assess the sensitivity and specificity of serum and urinary IGF-I in the diagnosis of childhood GH deficiency. PATIENTS: A cohort of 333 (M = 156, F = 177) healthy schoolchildren aged 5-19 years were recruited and data previously collected from 22 growth hormone deficient (GHD) and 47 short normal (SN) children were compared with those of the normal children. MEASUREMENTS: Height, weight and pubertal status were assessed in all children. Serum IGF-I (sIGF-I) (n = 305) and total amount of urinary IGF-I excreted overnight (TuIGF-I) (n = 205) were measured by RIA using excess IGF-II to block the interference of IGFBPs. RESULTS: Serum IGF-I was loge transformed and overall levels (geometric mean +/- 1 tolerance factor) were higher in females than males (F: 569 (329, 985) micrograms/l; M: 398 (227, 696) micrograms/l). LogeIGF-I correlated with age (F: r = +0.76, P < 0.001, M: r = +0.71, P < 0.001) and was significantly affected by both sex and Tanner stage of puberty (TS) (both P < 0.001). The distribution of TuIGF-I was normalized by performing a square root transformation (square root of TuIGF-I). square root of TuIGF-I was correlated with age (F: r = +0.36, P < 0.001; M: r = +0.5, P < 0.001) and was significantly affected by TS (P < 0.001). In both sexes there was a highly significant correlation between logeIGF-I and square root of TuIGF-I (F: r = +0.39, P < 0.001; M: r = +0.41, P < 0.001). Using the third centile of our normal ranges as a cut off to identify GHD, sIGF-I had a sensitivity of 82% and specificity of 62%, whereas TuIGF-I had a sensitivity of 18% and specificity of 79%. CONCLUSIONS: This study demonstrates that although urinary IGF-I has no place in the diagnosis of growth disorders, in normal children there is a highly significant relationship between serum and urinary IGF-I with levels of each changing in a similar manner through childhood and adolescence. Thus, TuIGF-I could be used as a valid surrogate for sIGF-I in the physiological assessment of the relationship between IGF-I status and the normal growth process.
Adolescent↗
Factors determining end-expiratory alveolar pressure after cardiac surgery.
Intrinsic positive end-expiratory pressure can occur when the sternum is closed following cardiac surgery, causing anaesthetic and surgical problems. We measured intrinsic positive end-expiratory pressure after sternal closure in two studies of patients undergoing coronary artery bypass grafting with the same anaesthetic regime. In one, patients were ventilated at 10 breaths min-1, in the other they were randomized to be ventilated at 10 or 20 breaths min-1. After sternal closure, intrinsic positive end-expiratory pressure increased significantly, especially in patients in whom it had been present before sternotomy. Multiple linear regressions with the pooled data from the studies showed that intrinsic positive end-expiratory pressure was positively correlated with ventilatory rate (P < 0.005), age (P < 0.005) and Body Mass Index (P < 0.0005), and negatively with FEV1, as percentage of predicted (P < 0.01). There was no correlation between intrinsic positive end-expiratory pressure and a history of smoking. As there was no difference in expiratory resistance between patients ventilated at the two different rates, any effect on intrinsic positive end-expiratory pressure of the higher ventilatory rates could have been due only to the shorter expiratory time.
Age Factors↗
An approach to the development of quantitative models to assess the effects of exposure to environmentally relevant levels of endocrine disruptors on homeostasis in adults.
The workshop "Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels" was held to provide a forum for discussions and recommendations of methods and data needed to improve risk assessments of endocrine disruptors. This article was produced by a working group charged with determining the basic mechanistic information that should be considered when designing models to quantitatively assess potential risks of environmental endocrine disruptors in adults. To reach this goal, we initially identified a set of potential organ system toxicities in males and females on the basis of known and/or suspected effects of endocrine disruptors on estrogen, androgen, and thyroid hormone systems. We used this integrated, systems-level approach because endocrine disruptors have the potential to exert toxicities at many levels and by many molecular mechanisms. Because a detailed analysis of all these untoward effects was beyond the scope of this workshop, we selected the specific end point of testicular function for a more detailed analysis. The goal was to identify the information required to develop a quantitative model(s) of the effects of endocrine disruptors on this system while focusing on spermatogenesis, sperm characteristics, and testicular steroidogenesis as specific markers. Testicular function was selected because it is a prototypical integrated end point that can be affected adversely by individual endocrine disruptors or chemical mixtures acting at one specific site or at multiple sites. Our specific objective was to gather the information needed to develop models in the adult organism containing functional homeostatic mechanisms, and for this reason we did not consider possible developmental toxicities. Homeostatic mechanisms have the potential to ameliorate or lessen the effects of endocrine disruptors, but these pathways are also potential target sites for the actions of these chemicals.
Adult↗
Case conferencing. An effective means of managing ADHD.
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Attention Deficit Disorder with Hyperactivity↗
FK506 treatment in combination with leflunomide in hamster-to-rat heart and liver xenograft transplantation.
BACKGROUND: In the experiment described here, we investigated the effects of the immunosuppressants FK506 and leflunomide (Lef) on the survival of hamster hearts and liver xenografts in Lewis rats. METHODS: Lewis rats were used as recipients of hamster heart or liver grafts using different regimens of FK506 and Lef. Donor-matched heart grafts were transplanted into long-term surviving Lewis rat recipients of hamster xenografts to test donor-specific prolongation of xenograft survival. Hyperimmune, late xenograft rejection, and naive sera were transferred into long-term surviving Lewis rat recipients of hamster heart xenografts to determine whether these sera could inhibit the efficacy of donor-specific long-term survival. Anti-donor-specific antibodies were analyzed by flow cytometry. RESULTS: After a short induction with FK506 plus Lef, maintenance treatment with FK506 alone was sufficient to prolong survival of hamster xenografts. All hamster heart and four of six hamster liver xenografts survived for more than 3 months. Second hamster hearts were permanently accepted by Lewis rats bearing long-term surviving hamster heart xenografts when rats were treated with FK506 monotherapy (mean survival time >60 days, n=4). Long-term surviving hamster heart grafts were rejected after transfer of hyperimmune serum but not late xenograft rejection serum or naive serum. Lef and FK506 significantly reduced the production of anti-donor-specific antibodies in Lewis rats transplanted with hamster liver and heart xenografts. CONCLUSION: Long-term survival of hamster liver and heart xenografts in Lewis rats could be induced by a regimen of short-term FK506 in combination with Lef followed by FK506 monotherapy. The acquired sensitivity of late xenoreactivity to FK506 reflects primarily a modification in the host immune response to the hamster graft.
Animals↗
Histological characterization and pharmacological control of chronic rejection in xenogeneic and allogeneic heart transplantation.
BACKGROUND: Chronic allograft rejection remains a major barrier to successful long-term allograft transplantation in humans. Chronic allograft rejection is characterized by the appearance of arterial lesions with concentric intimal thickening. This study investigates the development and control of chronic rejection in hamster cardiac xenografts transplanted into Lewis rats. METHODS: Chronic rejection in the xenograft model involves transplantation of hamster hearts into Lewis rats treated with leflunomide (Lef) continuously at 15 mg/kg/day. The allograft model involves transplantation of Lewis hearts into Fisher-334 rats treated with cyclosporine (CsA) at 2.5 mg/kg for 5 days. RESULTS: The average scores of arterial intimal thickening on day 45 after transplantation were 1.89+/-0.43 in the xenograft and 2.50+/-0.72 in the allograft. The basic pathology of both xenografts and allografts undergoing chronic rejection was arterial intimal thickening comprising smooth muscle cell proliferation, mononuclear cell infiltration, and fibrosis. The majority of cells infiltrating the arterial intima and myocardium were T cells and macrophages. Compared with the allograft, intimal edema, matrix deposition and fibrinoid necrosis were specifically presented in the xenografts and generally involved the larger arteries. The predominant isotype of antibody deposited was IgM in xenografts and IgG in allografts. When combined Lef and CsA therapy was initiated on day 45 after transplantation, the changes of chronic rejection were reversed in both xenografts and allografts by day 90. The scores of intimal thickening were significantly reduced to 0.97+/-0.45 and 1.48+/-0.56, respectively. CONCLUSIONS: We conclude that chronic rejection can be induced in xenografts under conditions of inadequate immunosuppression. Chronic rejection in xenografts involves arterial lesions that bear some histological similarities to, as well as differences from, those observed in chronically rejected allografts. Finally, combination therapy with CsA and Lef reduced the incidence and severity of the intimal lesions in both chronically rejecting xenografts and allografts.
Animals↗
Protective effect of ischemic preconditioning on liver preservation-reperfusion injury in rats.
BACKGROUND: Ischemic-preconditioning is a process whereby a brief ischemic episode confers a state of protection against subsequent long-term ischemia-reperfusion injury. Ischemic preconditioning has been studied in heart and liver ischemia-reperfusion injury; however, few studies have been performed in the model of preservation-reperfusion injury in liver transplantation. The current study was designed to evaluate the ability of ischemic preconditioning to protect liver grafts from long-term preservation-reperfusion injury. METHODS: Male Sprague Dawley rats were used as donors and recipients of orthotopic liver transplantation. Ischemic preconditioning was done by interruption of the portal vein and hepatic artery for 5, 10, and 20 min (5-10, 10-10, and 20-10 groups). Reflow was initiated by removal of the clamp for another 10 min in all groups. The liver was removed and placed in a bath with Euro-Collins solution for different preservation times. Tolerance of the transplanted liver to cold ischemia was determined by survival time and liver function tests. Rat tumor necrosis factor was analyzed by a bioassay. Nomega-Nitro-L-arginine methyl ester, L-arginine, or adenosine was administered to block or stimulate the synthesis of nitric oxide (NO) in the rats that received long-term-preserved liver grafts. RESULTS: Twenty percent of syngeneic rats (n=10) that received a liver graft with a 16-hr cold ischemia time in Euro-Collins solution survived for more than 1 day and 10% survived for more than 5 days. In contrast, 87.5% of rats (n=8) that received a liver graft with ischemic preconditioning (10-10 group) and 16 hr of cold ischemia survived for more than 1 day and 75% for more than 5 days. Recipients of liver grafts with ischemic preconditioning had significantly reduced levels of serum aspartate transaminase and tumor necrosis factor-alpha, as well as increased bile flow, compared with recipients of liver grafts without ischemic preconditioning. Blockage of the NO pathway using Nomega-nitro-L-arginine methyl ester, a stereospecific competitive inhibitor of NO formation, attenuated the protective effect of ischemic preconditioning. Administration of one of two precursors of NO synthesis, L-arginine or adenosine, prolonged the survival of rats that received 16-hr-preserved liver grafts. In addition, L-arginine synergized with short-term ischemic pre conditioning (5-10 group) to increase the survival of rats that received a liver graft with a 16-hr cold ischemia time, and the survival rate was 83% after 5 days. Finally, prolonged ischemic preconditioning (> or = 20 min; 20-10 group) resulted in liver damage and loss of function. CONCLUSION: The current results show that ischemic preconditioning protects the liver graft from subsequent long-term cold preservation-reperfusion injury in a rat liver transplantation model. The protective role of ischemic preconditioning may be mediated by the endogenous production of NO.
Animals↗
Anti-CD4 therapy in combined heart-kidney, heart-liver, and heart-small bowel allotransplants in high-responder rats.
BACKGROUND: In these experiments, we studied the role of anti-CD4 (Ox38) monoclonal antibody in the induction of allograft unresponsiveness in high-responder Lewis rats in the single liver, kidney, small bowel, and heart versus the combined heart-kidney, heart-liver, and heart-small bowel transplantation models. METHODS: ACI heart, kidney, liver, and small bowel allografts were transplanted into untreated and anti-CD4 treated Lewis rats. In selected animals bearing long-surviving ACI liver or kidney allografts for over 3 months, donor-matched second heart or third-party (Brown Norway) heart allografts were transplanted. Simultaneously, heart-liver, heart-kidney, and heart-small bowel transplants were performed on the day of operation. Rejected allografts were verified by autopsy and pathology. RESULTS: ACI liver allografts were permanently accepted by Lewis recipients treated with either regular-dose (5 mg/kg for 4 days) or low-dose (5 mg/kg for 2 days) of anti-CD4 monoclonal antibody. Pretransplant anti-CD4 therapy (5 mg/kg for 4 days but not 5 mg/kg for 2 days) resulted in a long-term survival of kidney allografts (mean survival time [MST] > 100.0 days, n=5). Pretransplant anti-CD4 treatment (5 mg/kg for 4 days) could not induce tolerance when single ACI hearts were transplanted; however, long-term survival of ACI heart allografts could be induced when heart transplants were combined with liver (n=7) or kidney (n=8) transplants. The survival of both ACI heart allografts (MST=25.0 days, n=4) and small bowel allografts (MST=28.0 days, n=4) was also prolonged when simultaneous heart and small bowel transplantation was performed in anti-CD4-treated recipients. The second ACI heart allograft was permanently accepted by tolerant Lewis recipients of ACI liver or kidney allografts induced by anti-CD4 treatment, and third-party heart grafts were acutely rejected without affecting survival of the primary allografts. CONCLUSION: Our current results show that: (1) there is a vigorous rejection of heart > or = small bowel > kidney > liver in high-responder Lewis rats after pretransplant anti-CD4 therapy; and (2) simultaneous or metachronous combined liver-heart and kidney-heart transplants may protect heart allografts from rejection.
Animals↗
Immunosuppression preventing concordant xenogeneic islet graft rejection is not sufficient to prevent recurrence of autoimmune diabetes in nonobese diabetic mice.
BACKGROUND: We and others have reported previously that the immunosuppressant, leflunomide (Lef), can prevent allogeneic and xenogeneic islet graft rejection in streptozocin (STZ)-induced diabetic animals. However, whether Lef required to prevent islet graft rejection is sufficient to prevent the recurrence of autoimmune diabetes has not been addressed. METHODS: The effect of Lef on concordant xenogeneic islet graft in STZ-induced diabetic mice and autoimmune nonobese diabetic (NOD) mice were studied. Then, whether Lef prevents the onset of spontaneous diabetes in young NOD mice and the recurrence of diabetes after major histocompatibility complex (MHC)-matched islet transplantation in diabetic NOD mice were investigated. RESULTS: In STZ-induced diabetic BALB/c mice, Lef treatment significantly prolonged rat islet graft survival. However, Lef could not significantly prolong rat islet graft survival in autoimmune diabetic NOD mice. For prevention studies, treatment with Lef at 30 mg/ kg/day from 4 weeks to 20 weeks of age significantly reduced the incidence of spontaneous diabetes in NOD mice. However, when the NOD mice were treated from 8 to 24 weeks of age, the incidence of spontaneous diabetes was not significantly reduced as compared to the incidence of diabetes in the untreated female NOD mice at 28 weeks of age. Finally, in the MHC-matched islet transplant model, Lef could not significantly prolong MHC-matched nonobese diabetes-resistant mice islet graft survival in NOD mice. CONCLUSIONS: Lef preventing concordant xenogeneic islet graft rejection is not sufficient to prevent the recurrence of autoimmune diabetes in NOD mice. We believe that controlling autoimmunity after islet transplantation will lead the way to promote successful clinical islet transplantation in the future.
Animals↗
From compliance to concordance: a challenge for contraceptive prescribers.
In 1997 the Royal Pharmaceutical Society of Great Britain published a report entitled From Compliance to Concordance: Achieving Shared Goals in Medicine Taking. This article applies this new model--of doctors and patients working together towards a shared goal--to the prescribing of hormonal forms of contraception. It begins by critically evaluating the current dominant model of contraceptive prescribing. It claims that this model tends to stereotype all women, but particularly young, poor and black women, as unreliable and ill-informed contraceptors who need to be advised and even controlled by much more knowledgeable and socially responsible family planning experts. The article then suggests how a much more egalitarian model of contraceptive prescribing might be put into practice, whilst acknowledging the existence of many serious obstacles to such a radical shift within family planning services. In conclusion, the article suggests that until contraceptive prescribers begin to take women's experiences of, and concerns about, hormonal contraceptives seriously they will fail to develop a potentially much more effective and liberating model of family planning.
Adolescent↗
Differential effect of leflunomide on concordant xenogeneic islet graft rejection and recurrence of autoimmune diabetes.
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Animals↗
Leflunomide-based immunosuppression for porcine islet xenotransplantation.
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Animals↗
Effect of gene gun-mediated CTLA4IG and Fas ligand gene transfection on concordant xenogeneic islet graft rejection.
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Abatacept↗
Reaching targets in the national cervical screening programme: are current practices unethical?
The principle of informed consent is now well established within the National Health Service (NHS) in relation to any type of medical treatment. However, this ethical principle appears to be far less well established in relation to medical screening programmes such as Britain's national cervical screening programme. This article will critically examine the case for health care providers vigorously pursuing women to accept an invitation to be screened. It will discuss the type of information which women would need in order to make an informed decision about whether or not to be screened. The lack of such information in current patient leaflets on the "smear test" will then be documented. Finally, the article will explore possible ways of maximising women's autonomy in relation to the cervical screening programme without sacrificing any of its main benefits.
Adult↗
Neighbor to neighbor: working together for healthy families through an urban community partnership.
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Adult↗