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Biomedical subjects

P J Conlon

Publications and source records attributed to P J Conlon.

At least 19 recordsLinked to original sources
PubMed2006

A population-based study of skin cancer incidence and prevalence in renal transplant recipients.

BACKGROUND: Cancers occurring following solid organ transplantation are a rapidly growing public health concern. Defining the extent of the problem has been limited by surveillance systems with incomplete registration of cases and the paucity of reliable national incidence data. OBJECTIVES: To determine the incidence of all cancers following renal transplantation and to make a detailed examination of trends and patterns associated with postrenal transplant skin cancers. METHODS: Integration of data from the national renal transplant database and the national cancer registry in Ireland enabled accurate determination of the number of renal transplant recipients (RTRs) with skin cancers and other malignancies in the time period 1 January 1994 to 31 December 2001. RESULTS: We demonstrated a biphasic increase in skin cancer incidence following renal transplantation, determined by the age at transplantation. There was a steady increase in risk for older RTRs (age 50+ years) from year 2 post-transplant, whereas the increased risk in younger RTRs (age < 50 years) occurred later but much more significantly, reaching 200 times the risk for an age-matched nontransplanted population by year 6 post-transplant. The number of nonmelanoma skin cancers (NMSCs) registered in RTRs accounted for 1% of all NMSCs registered nationally over the study period. The standardized incidence rates for invasive NMSC (33-fold increase) and in situ carcinoma of the skin (65-fold increase) were significantly increased (P < 0.05). The risk for invasive squamous cell carcinoma (SCC) was increased 82-fold compared with the nontransplanted population. Male RTRs were at particular risk of invasive SCC at sun-exposed sites such as the scalp and the external ear. Risk of malignant melanoma and Kaposi sarcoma were also increased relative to the nontransplanted population. CONCLUSIONS: This comprehensive national study illustrates how rates of skin cancer in Irish RTRs have influenced the national incidence of skin cancer. The high incidence of SCC, basal cell carcinoma and Bowen's disease in the early post-transplant period for older patients and the cumulative risk in younger patients with increased duration of transplantation highlight the importance of implementing early and continued cancer surveillance regimens post-transplant.

Adult↗
PubMed2006

Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope.

NBI-6024 is an altered peptide ligand (APL) corresponding to the 9-23 amino acid region of the insulin B chain (B(9-23)), an epitope recognized by inflammatory interferon-gamma-producing T helper (Th)1 lymphocytes in type 1 diabetic patients. Immunomodulatory effects of NBI-6024 administration in recent-onset diabetic patients in a phase I clinical trial (NBI-6024-0003) were measured in peripheral blood mononuclear cells using the enzyme-linked immunosorbent spot assay. Analysis of the mean magnitude of cytokine responses to B(9-23) and NBI-6024 for each cohort showed significant increases in interleukin-5 responses (a Th2 regulatory phenotype) in cohorts that received APL relative to those receiving placebo. A responder analysis showed that Th1 responses to B(9-23) and NBI-6024 were observed almost exclusively in the placebo-treated diabetic population but not in nondiabetic control subjects and that APL administration (five biweekly subcutaneous injections) significantly and dose-dependently reduced the percentage of patients with these Th1 responses. The results of this phase I clinical study strongly suggest that NBI-6024 treatment shifted the Th1 pathogenic responses in recent-onset type 1 diabetic patients to a protective Th2 regulatory phenotype. The significance of these findings on the clinical outcome of disease is currently under investigation in a phase II multidose study.

Adolescent↗
PubMed2006

Rabbit antithymocyte globulin related decrease in platelet count reduced risk of pediatric renal transplant graft thrombosis.

Graft thrombosis is a serious complication in pediatric renal transplantation. We assess a potential protective effect for the decrease in platelet count associated with RATG therapy against pediatric renal transplant graft vascular thrombosis. Between January 1986 and December 1998, 120 kidney transplants were performed in 95 pediatric recipients. Patients were divided into two groups. Group 1 (n = 61), non-RATG group received cyclosporine, azathioprine and steroids, while group 2 (n = 59), RATG group, received in addition, RATG at day 1 and continued for 4-10 days postoperatively. Platelet count prior to transplant, median change in absolute platelet count at 1 and 3 days post-transplant was recorded. Graft thrombosis incidence was examined. Six grafts (5%) developed thrombosis. All were in group 1 (p = 0.028). Median pretransplant platelet count (x10(9)/L) in group 1 was 283 vs. 280 in group 2 (p = 0.921). Median decrease in absolute platelet count (x10(9)/L) from pretransplant levels at one and three days post-transplant for group 1 and 2 was 18 vs. 83 (p </= 0.001) and 39 vs. 105 (p </= 0.001), respectively. Graft thrombosis risk factors were similar in both groups. RATG use was statistically significant (p = 0.044) for reduced risk of graft thrombosis in multivariate analysis. Patients receiving RATG showed significant decrease in both platelet count and graft thrombosis incidence. A role for RATG related effect on platelet count is assumed.

Adolescent↗
PubMed2005

The impact of skin disease following renal transplantation on quality of life.

BACKGROUND: The immunosuppressive therapy a patient requires to sustain a functioning renal allograft in the long term is associated with various skin complications. While quality of life (QoL) after renal transplantation has been studied, no publications document the effect of post-transplant dermatological complications on QoL. OBJECTIVES: The objective of the study was to document the prevalence of the skin diseases that commonly occur in association with post-transplant immunosuppression. A general dermatological quality of life questionnaire, the Dermatology Life Quality Index (DLQI), was used to assess the QoL effect of these cutaneous complications. The study was designed to examine further the impact of age, sex, duration since transplant and immunosuppressive regimen on the DLQI score of renal transplant recipients (RTR). METHODS: One hundred and seventy-three RTR completed the DLQI, were interviewed and examined for evidence of common post-transplant skin diseases. RESULTS: Sixteen per cent of RTR had DLQI scores >6, reflecting a significant impact on their QoL. Dry skin, itch, hypertrichosis, sebaceous gland hyperplasia, acne, genital warts and a history of >4 herpes simplex virus type 1 infections in the past year were all found to have a significant impact on the quality of life (P < 0.05). Multivariate analysis revealed that the greatest impact on QoL was in RTR who were younger, female and with multiple skin problems (P < 0.05). CONCLUSIONS: The dermatological complications of immunosuppressive therapy are common in RTR and can significantly impair QoL in certain individuals. Visible, infectious and cosmetic skin problems had most impact on QoL while a history of skin cancer had a lesser impact. Early dermatological referral and careful choice of immunosuppression may enhance the QoL, particularly in young and female RTR.

Adult↗
PubMed2005

Renal transplantation, immunosuppression and the skin: an update.

Transplant medicine has seen many innovations over past decades and continues to evolve into the 21st century. Newer immunosuppressive strategies in renal transplantation are associated with better patient and graft survival rates; however, the adverse toxicities and long-term side effects associated with these agents present a number of challenges. Certain immunosuppressants are commonly used in dermatologic disorders, however, dermatologists may be less familiar with the clinical efficacy, side-effect profile, and dosage of newer immunosuppressive agents. A knowledge of the molecular and cellular mechanisms of action of these agents gives us a better understanding of how these agents contribute to the cutaneous and mucosal complications frequently seen post-transplant. With the advent of new immunosuppressive therapies and different treatment regimens, there is an increasing need for a multidisciplinary approach to balancing the risks and benefits of these medications to the individual transplant recipient. This review will highlight the different immunosuppressive agents and their effect on the skin while focusing on the evidence base to support the commonly used immunosuppressive regimes, newer protocols aimed at achieving maximum graft survival with minimal side effects, and important drug interactions with which all dermatologists should be familiar.

Dermatologic Agents↗
PubMed2005

Multi organ transplantation: a review of the Irish experience.

As the criteria for organ transplantation have broadened, multi organ transplantation has become more common. Calcineurin inhibitor induced end stage renal failure is a common indication for kidney transplantation. We present our experience of 12 kidney transplants, in 11 patients, over a period of 9 years all in the setting of multi-organ transplantation. Kaplan-Meier survival estimates were applied. Estimated patient survival at 1, 3 and 5 years post transplant was 100%, 83% and 66% respectively. Estimated graft survival at 1, 3 and 5 years was 90%, 79% and 63% respectively. The estimated median renal graft survival was 6.2 years. Calcineurin inhibitor toxicity was the most common cause of end stage renal failure in this series of patients. There is a very fine balance between ideal immunosuppression for kidney and other organ transplants. Patients who avoid morbidity such as sepsis or graft rejection enjoy good graft function at 5 years post transplant.

Cyclosporine↗
PubMed2002

Persistence of immune responses to altered and native myelin antigens in patients with multiple sclerosis treated with altered peptide ligand.

Altered peptide ligands (APLs) can modulate responses of T cells to native peptide antigens implicated in the pathogenesis of autoimmune diseases. An APL of the putative target antigen myelin basic protein (MBP) peptide 83-99 has been used in abbreviated clinical trials in patients with multiple sclerosis (MS). Our objective was to assess the long-term persistence, and characteristics, of the APL-induced immune response in such patients. We measured the ex vivo proliferative frequency to the APL and native MBP, the cross-reactivity, and the cytokine production by these lines. We found that a 4- to 16-week course of APL therapy could induce a persistent (2-4.5 year) increase in the frequency of T cells responsive to both the APL and the native MBP in a select number of patients. These T cells produced high levels of IL-5, contrasting with the pretreatment observation that the responses to either antigen were IFNgamma (Th1) dominant. Our results indicate that APL therapy can induce persistent Th2-directed immune deviation. Understanding the impact of such APL-induced immune responses on MS disease activity will require additional clinical trials that incorporate careful monitoring of both clinical and immunological parameters.

Adult↗
PubMed2001

Effect of fluvastatin on acute renal allograft rejection: a randomized multicenter trial.

BACKGROUND: Statin therapy has been reported to reduce the acute rejection rate following renal transplantation in a pilot study. The present study is the first randomized, double-blind and adequately powered study to examine the effect of statins on acute rejection of renal allografts. METHODS: A total of 364 patients were randomly assigned to receive either fluvastatin 40 mg or placebo in combination with conventional cyclosporine-based immunosuppressive therapy. The primary end point was treated first acute rejection. Secondary end points included biopsy-proven rejection, histological severity of rejection, occurrence of steroid-resistant rejection, and serum creatinine at three months following transplantation. RESULTS: Fluvastatin was well tolerated; no patients developed myositis or rhabdomyolysis. There was no difference in the acute rejection rate [86 (47.3%) fluvastatin vs. 87 (47.8%) placebo] and no significant difference in the severity of rejection, steroid resistant rejection or mean serum creatinine at three months (160 micromol/L vs. 160 micromol/L). Total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglyceride levels increased following renal transplantation. With the exception of the increase in HDL-C, which was augmented, the increases in lipid parameters were significantly reduced by fluvastatin (total cholesterol +17.5% vs. 35.7%; LDL-C +6.3% vs. 46.7%; HDL-C +43.3% vs. 38.1%; triglyceride +52.2% vs 77.6%). CONCLUSIONS: Contrary to the reported effects of statins, fluvastatin had no effect on the incidence or severity of acute rejection following renal transplantation. There were no increases in adverse events. A significant and potentially beneficial alteration in the lipid profile was observed in the early post transplant period. We conclude that fluvastatin may be used safely to correct dyslipidemia in patients with end-stage renal failure through the peri-transplant period.

Acute Disease↗
PubMed2001

Severity of renal vascular disease predicts mortality in patients undergoing coronary angiography.

BACKGROUND: Renal artery stenosis (RAS) is a relatively uncommon but potentially reversible cause of renal failure. In a previous report, we demonstrated that the presence of RAS is independently associated with mortality in a group of patients undergoing coronary angiography. Our current study expands on this cohort, investigating the effect of the severity of RAS on all-cause mortality. METHODS: A total of 3987 patients underwent abdominal aortography immediately following coronary angiography. For the purpose of survival analysis, significant RAS was defined as > or =75% narrowing in the luminal diameter. RESULTS: Significant RAS was present in 4.8% of patients studied and was bilateral in 0.8%. Factors associated with the presence of RAS included female gender, older age, hypertension, congestive heart failure, elevated serum creatinine, and congestive heart failure. The four-year unadjusted survivals for patients with and without significant RAS were 57 and 89%, respectively (P < 0.001). Using the Cox proportional hazards model, the factors independently associated with decreased survival were the presence of RAS, increased age, the severity of coronary artery disease, the presence of comorbid disease, reduced ejection fraction, symptoms of congestive cardiac failure, and the mode of treatment of coronary artery disease. In the multivariate model, the presence of RAS conferred a hazard ratio of 2.01 (95% CI, 1.51 to 2.67, P < 0.001). We demonstrated an incremental effect on mortality according to the severity of RAS at baseline. Four-year adjusted survival for patients with 50%, 75%, and > or =95% stenosis was 70%, 68%, and 48%, respectively. In addition, bilateral disease was associated with four-year survival of 47% as compared with 59% for patients with unilateral disease (P < 0.001). The impact of RAS on survival remained robust regardless of the manner of treatment of coronary artery disease [that is, medical, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass graft (CABG)]. CONCLUSIONS: In this patient population, the presence of RAS is a strong independent predictor of mortality. Increasing severity of RAS has an incremental effect on survival probability.

Aged↗
PubMed2001

A prospective study of complications associated with cuffed, tunnelled haemodialysis catheters.

BACKGROUND: Despite the US Dialysis Outcome Quality Initiative )DOQI( guidelines, for various reasons, increasing numbers of end-stage renal disease patients are becoming dependent on cuffed haemodialysis catheters (HCs) for chronic haemodialysis access. Their use is complicated by frequent failure due to thrombosis and catheter-related sepsis. In our unit, all HCs are put in place by the radiology department. METHODS: In a prospective study we looked at the outcome of all HCs over a three-year period, during which time 573 consecutive HCs were placed in 336 patients. Each line was followed individually until it was removed or until the end of the study. RESULTS: In a survival analysis of those HCs removed following HC failure, HC half-life was 312 days and one-year HC survival was 47.5%. The most frequent indications for HC removal were non-function (36.6%), clinical suspicion of line sepsis (16.4%) and patient death (14.4%). Using a Cox proportional hazards model, catheter number in a given patient and the presence of diabetes mellitus were found to be independent predictors of HC failure. The total incidence of HC-related sepsis was 1.3 episodes/1000 catheter days. The probability of developing bacteraemic HC-related sepsis was 27.5% at one year. CONCLUSIONS: Less than half of the HCs were removed electively because of availability of a more permanent mode of renal replacement, thereby illustrating the level of dependence that has developed on them as permanent access. Consequently, their limitations (infection and malfunction) are placing an ever increasing burden on the healthcare services.

Catheters, Indwelling↗
PubMed2001

A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin.

The 9-23 amino acid region of the insulin B chain (B9-23) is a dominant epitope recognized by pathogenic T lymphocytes in nonobese diabetic mice, the animal model for type 1 diabetes. We describe herein similar (B9-23)-specific T-cell responses in peripheral lymphocytes obtained from patients with recent-onset type 1 diabetes and from prediabetic subjects at high risk for disease. Short-term T-cell lines generated from patient peripheral lymphocytes showed significant proliferative responses to (B9-23), whereas lymphocytes isolated from HLA and/or age-matched nondiabetic normal controls were unresponsive. Antibody-mediated blockade demonstrated that the response was HLA class II restricted. Use of the highly sensitive cytokine-detection ELISPOT assay revealed that these (B9-23)-specific cells were present in freshly isolated lymphocytes from only the type 1 diabetics and prediabetics and produced the proinflammatory cytokine IFN-gamma. This study is, to our knowledge, the first demonstration of a cellular response to the (B9-23) insulin epitope in human type 1 diabetes and suggests that the mouse and human diseases have strikingly similar autoantigenic targets, a feature that should facilitate development of antigen-based therapeutics.

Adolescent↗
PubMed2001

SJL and NOD macrophages are uniquely characterized by genetically programmed, elevated expression of the IL-12(p40) gene, suggesting a conserved pathway for the induction of organ-specific autoimmunity.

Genetic susceptibility of the SJL mouse to experimental autoimmune encephalomyelitis (EAE) appears, in part, to be a result of genes that promote abnormal development of the pathogenic Type 1 (Th1) phenotype of neuroantigen-specific T-cells. Because antigen-presenting/accessory cells (APCs) produce cytokines that can modulate the development of Th1 and Th2 phenotypes, we addressed whether APCs from SJL mice were genetically programmed for elevated expression of the Th1-promoting cytokine, IL-12. Activated peritoneal macrophages (Mphi; i.e., APC) from naïve SJL mice produced levels of TNF-alpha, IL-1, IL-6, IL-10, and TGF-beta within the range of six normal strains. In contrast, SJL IL-12p40 (in addition to IL-12p70) production was consistently five- to 20-fold greater than that of any normal strain tested, which arose from elevated expression of the IL-12p40 but not the IL-12p35 gene, because p40 mRNA levels were eight- to 15-fold greater than those of normal strains. This aberrancy in IL-12p40 expression appears identical to that observed in the NOD mouse, another strain prone to organ-specific autoimmunity. A genetically programmed bias toward elevated expression of IL-12 in Mphi from the SJL and NOD strains of autoimmunity provides a conserved mechanism for the dominant Th1 development of naive, autoantigen-specific T-cells in these strains. This study is the first demonstration of a genetically programmed aberrant phenotype that is intrinsically expressed within a cell type in the SJL mouse and provides insight into its predisposition for EAE.

Animals↗
PubMed2000

Characterization of gamma-aminobutyric acid receptor GABAB(1e), a GABAB(1) splice variant encoding a truncated receptor.

We have identified a splice variant encoding only the extracellular ligand-binding domain of the gamma-aminobutyric acid B (GABA(B)) receptor subunit GABA(B(1a)). This isoform, which we have named GABA(B(1e)), is detected in both rats and humans. While GABA(B(1e)) is a minor component of the total pool of GABA(B(1)) transcripts detected in the central nervous system, it is the primary isoform found in all peripheral tissues examined. When expressed in a heterologous system, the truncated receptor is both secreted and membrane associated. However, GABA(B(1e)) lacks the ability to bind the radiolabeled antagonist [(3)H]CGP 54626A, activate G-protein coupled inwardly rectifying potassium channels, or inhibit forskolin-induced cAMP production when it is expressed alone or together with GABA(B(2)). Interestingly, when co-expressed with GABA(B(2)), not only does the truncated receptor heterodimerize with GABA(B(2)), the association is of sufficient avidity to disrupt the normal GABA(B(1a))/GABA(B(2)) association. Despite this strong interaction, GABA(B(1e)) fails to disrupt G-protein coupled inwardly rectifying potassium activation by the full-length heterodimer pair of GABA(B(1a))/GABA(B(2)).

Alternative Splicing↗
PubMed2000

The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia.

Fractalkine is a CX3C-family chemokine, highly and constitutively expressed on the neuronal cell surface, for which a clear CNS physiological function has yet to be determined. Its cognate receptor, CX3CR-1, is constitutively expressed on microglia, the brain-resident macrophages; however, these cells do not express fractalkine. We now show that treatment of microglia with fractalkine maintains cell survival and inhibits Fas ligand-induced cell death in vitro. Biochemical characterization indicates that this occurs via mechanisms that may include 1) activation of the phosphatidylinositol-3 kinase/protein kinase B pathway, resulting in phosphorylation and blockade of the proapoptotic functions of BAD; 2) up-regulation of the antiapoptotic protein Bcl-xL; and 3) inhibition of the cleavage of BH3-interacting domain death agonist (BID). The observation that fractalkine serves as a survival factor for primary microglia in part by modulating the protein levels and the phosphorylation status of Bcl-2 family proteins reveals a novel physiological role for chemokines. These results, therefore, suggest that the interaction between fractalkine and CX3CR-1 may play an important role in promoting and preserving microglial cell survival in the CNS.

Animals↗
PubMed2000

New insights into the epidemiologic and clinical manifestations of atherosclerotic renovascular disease.

Atherosclerotic renovascular disease (ARVD) continues to challenge the clinician as we enter the third millenium. ARVD frequently complicates patients with other vascular pathological states, and it is an increasingly common cause of end-stage renal failure. Although renovascular interventional procedures are now widely available and are of benefit to some patients with ARVD, a large proportion still progress to dialysis. Recent epidemiological investigations have emphasized the relationship between ARVD and other vascular diseases, and these are notable in patients with coronary artery disease and/or cardiac failure. Increased awareness of the possible coexistence of ARVD in patients with these latter conditions may allow earlier diagnosis and a minimization of complications (eg, angiotensin-converting enzyme inhibitor-related uremia or flash pulmonary edema). Contemporary studies also highlight the importance of intrarenal vascular and parenchymal injury in the cause of chronic renal failure in many patients with ARVD. Severe renal structural damage often coexists with proximal renal arterial narrowing, and this can explain the variability of renal functional outcomes known to accompany revascularization procedures. More appropriate selection of those patients likely to benefit from renovascular revascularization is now required. Large-scale trials that will identify the optimal approach to improving renal functional and survival outcomes in this high-risk group of patients are now long overdue.

Arteriosclerosis↗