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Biomedical subjects

L C Paul

Publications and source records attributed to L C Paul.

At least 19 recordsLinked to original sources
PubMed2003

Renal disease in relatives of Indo-Asian Type 2 diabetic patients with end-stage diabetic nephropathy.

AIMS/HYPOTHESIS: Indo-Asian immigrants in The Hague, The Netherlands, have a nearly 40-fold higher risk of end-stage diabetic nephropathy compared to the Caucasian population. To detect a genetic susceptibility for nephropathy within the Indo-Asian population, we assessed whether familial clustering of nephropathy occurs in families of Indo-Asian Type 2 diabetic patients. METHODS: We compared nephropathy prevalence between two groups of first-degree relatives of Indo-Asian patients with Type 2 diabetes; the first group (case relatives) consisted of 169 relatives of patients with end-stage diabetic nephropathy; the second group (control relatives) consisted of 161 relatives of diabetic patients who had no nephropathy. The case and control relatives were examined for diabetes, blood pressure, renal function, microalbuminuria and urine dipstick measurements. RESULTS: The mean age was 41 years and similar in the case and control relatives. Diabetes was distributed equally in both family groups. We did not find more nephropathy in first-degree relatives of Indo-Asian Type 2 diabetic patients with end-stage diabetic nephropathy in comparison with the control-relatives. CONCLUSION/INTERPRETATION: We could not detect a genetic susceptibility for diabetic nephropathy within the Indo-Asian population. The lack of familial clustering of renal disease in Indo-Asian diabetic patients points to a general genetic or environmental susceptibility for diabetic nephropathy in this population.

Adult↗
PubMed2003

Dietary intake, eating behavior, and physical activity-related determinants of high body mass index in rural communities in Wyoming, Montana, and Idaho.

OBJECTIVE: To assess the relation between body mass index (BMI) levels and various lifestyle variables related to physical activity and specific characteristics of a healthy eating pattern, using baseline cross-sectional data from the Wellness IN the Rockies project. SUBJECTS: A total of 928 males and 889 females, aged 18-99 y, recruited from six rural communities in Wyoming, Montana, and Idaho. MEASUREMENTS: Using BMI as the criterion, overweight was defined as a BMI >or=25 kg/m(2) and obesity was defined as a BMI >or=30 kg/m(2). All participants in this study completed a questionnaire that elicited sociodemographic information, self-reported height and weight, and data related to specific dietary intakes, eating-related behaviors, and physical activity behaviors and perceptions. RESULTS: Prevalence of overweight was 70% in men and 59% in women. Increased likelihood of overweight or obesity was associated with greater frequency of the following: drinking sweetened beverages such as soft drinks/soda pop, ordering supersized portions, eating while doing other activities, and watching television. Other predictors were lower frequency of participation in physical activity and the perception of not getting as much exercise as needed. CONCLUSIONS: The increased probability of having a high BMI in individuals who more often eat while doing another activity appears to be a novel finding that will need to be substantiated by additional research. The finding that the vast majority of overweight and obese respondents believed that they do not get as much exercise as needed strengthens the assertion that finding ways to increase participation in physical activity should remain a high priority in obesity prevention and intervention efforts at the community and individual levels.

Adolescent↗
PubMed2002

Pharmacotherapeutic approach to prevent or treat chronic allograft nephropathy.

In the current paper we will review the evidence that drug therapy may be of value to prevent or treat chronic allograft nephropathy. We will review the immunosuppressive therapy and non-immune therapies in use to treat risk factors associated with chronic allograft nephropathy and evaluate their efficacy with respect to long term outcome as well as their effect on markers of long-term survival. In the last part of this review, we will indicate possible benefits of new approaches being explored but most of these data are obtained in in vitro test systems and rodent models.

Animals↗
PubMed2001

Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages.

Rapamycin (Rapa), a recently introduced immunosuppressive drug, seems to be effective in preventing acute allograft rejection. Although its antiproliferative effect on T lymphocytes has been investigated extensively, its effect on the initiators of the immune response, the dendritic cells (DCs), is not known. Therefore, the effect of Rapa on monocyte- (mo-DCs) and CD34(+)-derived DCs in vitro but also on other myeloid cell types, including monocytes and macrophages, was examined. The present study shows that Rapa does not affect phenotypic differentiation and CD40L-induced maturation of mo-DCs. However, Rapa dramatically reduced cell recovery (40%-50%). Relatively low concentrations of Rapa (10(-9) M) induced apoptosis in both mo-DCs and CD34(+)-derived DCs, as visualized by phosphatidylserine exposure, nuclear condensation and fragmentation, and DNA degradation. In contrast, Rapa did not affect freshly isolated monocytes, macrophages, or myeloid cell lines. The sensitivity to Rapa-induced apoptosis was acquired from day 2 onward of mo-DC differentiation. Rapa exerts its apoptotic effect via a reversible binding to the cytosolic receptor protein FKBP-12, as demonstrated in competition experiments with FK506, which is structurally related to Rapa. Partial inhibition of Rapa-induced apoptosis was obtained by addition of ZVAD-fmk, which implies caspase-dependent and caspase-independent processes. The fact that Rapa exerts a specific effect on DCs but not on monocytes and macrophages might contribute to the unique actions of Rapa in the prevention of allograft rejection and other immune responses.

Antigen-Presenting Cells↗
PubMed2001

Immunologic risk factors for chronic renal allograft dysfunction.

Tissue injury is probably the central feature leading to CRAD, whether that injury is produced by immunological or nonimmunological factors. Tissue injury may expose cryptic antigens that, in an allogeneic situation, stimulate immune responses that further increase tissue damage. With acute rejection the immunological factor most strongly predictive of CRAD, HLA mismatches may facilitate rejection or otherwise lead to CRAD. However, clinical studies have not always demonstrated an increasing risk of CRAD with increased numbers of HLA mismatches. Antibodies produced against HLA or other donor-specific antigens may play a role in initiating the CRAD process or may occur secondary to tissue damage. Several human transplant studies have demonstrated an association between anti-HLA or anti-B cell antibodies and CRAD. In animal models of CRAD, antibodies are produced against antigens associated with glomerular and tubular basement membranes and mesangial cells, as well as antigens associated with vascular endothelial cells. The pathogenetic significance of these antibody responses is unclear at this time, but these responses may interfere with repair processes that follow tissue injury or otherwise facilitate mechanisms leading to CRAD. Whether similar antibody responses against components of basement membrane and mesangial cells occur in human renal transplant patients with CRAD is not yet known. The most effective way to prevent CRAD is to prevent tissue damage, especially immunity-related injury that involves maintaining appropriate immunosuppression. When using calcineurin inhibitors for immunosuppression, there is a risk of chronic calcineurin inhibitor-associated nephrotoxicity. Nonnephrotoxic immunosuppressive agents, such as sirolimus and mycophenolate mofetil, may be considered in therapeutic strategies designed to prevent acute rejection and to minimize renal tissue damage due to nephrotoxic drugs.

Animals↗
PubMed2001

[From gene to disease; from polycystines to polycystic kidney disease].

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that results in multiple cysts in the kidneys and other organs and leads to endstage renal failure relatively late in life. The disease results from mutations in one of two independently segregating genes that under normal conditions produce polycystines. Polycystines are membrane proteins that form a complex involved in signal transduction in epithelial cells. Genetic heterogeneity explains in part the various ADPKD phenotypes.

Calcium-Binding Proteins↗
PubMed2001

Risk factors of cyclosporine nephrotoxicity after conversion from Sandimmune to Neoral.

BACKGROUND: In 1995 - 1996, we switched from a once-daily Sandimmune dose to a twice-daily dose regimen of Neoral. Concurrent with the switch we changed our target trough level from 100 microg/l at 24 hours to the generally accepted 12-hour level of 150 microg/l. We performed a retrospective cohort study to assess cyclosporine toxicity following this switch and to identify risk factors for nephrotoxicity. PATIENTS AND METHODS: Of 212 patients with a stable graft function pre-conversion clinical parameters at 1 and 12 months post-conversion were compared with those at time of conversion. Cyclosporine nephrotoxicity was defined as a significant decline of the reciprocal of the serum creatinine concentration over time post-conversion in the absence of other obvious causes for declining graft function. Risk factors of cyclosporine nephrotoxicity were assessed using logistic regression analysis. RESULTS: The mean cyclosporine trough level rose from 87 microg/l at the time of conversion to 139 microg/l at 12 months post-conversion whereas the daily drug dose increased over the same period from 233 mg to 252 mg. Mean serum creatinine increased by 10% from 135 to 148 micromol/l (p < 0.001). Cyclosporine nephrotoxicity was present in 42 patients (20%). Cyclosporine dose and trough level did not predict nephrotoxicity but beta-blockers (OR 0.35, 95% CI 0.17-0.72) and calcium channel blockers (OR 0.35, 95% CI 0.19-0.82) reduced the risk of nephrotoxicity, independent from an effect on blood pressure. CONCLUSION: 20% of stable renal transplant patients experienced chronic cyclosporine nephrotoxicity after conversion from a once-daily Sandimmune regimen to a twice-daily Neoral regimen with dose adjustments to a trough level of 150 microg/l. beta-blockers and calcium channel blockers reduced the risk of nephrotoxicity.

Adrenergic beta-Antagonists↗
PubMed2000

Donor treatment with mycophenolate mofetil: protection against ischemia-reperfusion injury in the rat.

BACKGROUND: Mycophenolic acid, the active metabolite of mycophenolate mofetil, inhibits the glycosylation of cell membrane glycoproteins. We hypothesized that impaired glycosylation of cell adhesion molecules on endothelial cells in vivo results in decreased susceptibility to inflammation or immunogenicity after allogeneic transplantation. METHODS: The expression of mannose residues on cultured rat endothelial cells was examined after stimulation with interleukin 1 in the presence or absence of mycophenolic acid using labeled Galanthus nivalis agglutinin. The in vitro adhesion of blood leukocytes to heart tissue was examined using peripheral blood leukocytes of recipient origin and sections of donor heart tissue exposed to ischemia-reperfusion injury after pretreatment with vehicle or mycophenolic mofetil. (LEWxBN)F1 donor rats were treated with 20 or 60 mg/kg/day of mycophenolate mofetil for 1 or 2 weeks followed by transplantation of the heart into Lewis recipients after storage in heparin-containing normal saline for either 10 min at 4 degrees C or 120 min at room temperature. RESULTS: Endothelial cells stimulated in vitro with interleukin 1 showed an increase in a population of strongly mannose-positive cells, which was prevented by the addition of mycophenolic acid during the culture. The in vitro adhesion of peripheral blood leukocytes to cardiac tissue sections exposed to prolonged storage and reperfusion was significantly less if the donor had been treated with mycophenolate mofetil. Treatment of cardiac graft donors with mycophenolate mofetil protected the graft against early graft failure after prolonged storage at room temperature, because the mean graft survival was 9.4+/-0.6 days for grafts that came from donors treated with mycophenolate mofetil versus 1.2+/-0.9 days (P<0.05) for grafts that came from vehicle-treated donors. Donor pretreatment with mycophenolate mofetil did not affect the survival time of heart grafts transplanted after 15 min of standard cold storage or the survival of grafts transplanted into presensitized recipients. CONCLUSION: Donor treatment with mycophenolate mofetil protects cardiac grafts against primary nonfunction after prolonged tepid storage, which may be related to the inhibition of glycosylation of cell adhesion molecules involved in ischemia-reperfusion injury.

Animals↗
PubMed2000

The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells.

Corticosteroids and the calcineurin inhibitors cyclosporin A (CsA) and FK506 have been studied extensively regarding their effects on T lymphocytes, but their effects on dendritic cells (DC) are relatively unknown. Monocytes are one of the precursors of DC that differentiate into CD14-CD1a+ immature DC upon culture with IL-4 and GM-CSF. The presence of CsA or FK506 during differentiation did not affect DC development. In contrast, the presence of corticosteroids, either dexamethasone (Dex) or prednisolone (Pred), for as little as the first 48 h of culture blocked the generation of immature DC. Dex-DC were unresponsive to signals inducing maturation (CD40 ligand, lipopolysaccharide), as demonstrated by the absence of CD83, CD80/CD86 and HLA-DR up-regulation and their strongly reduced T cell stimulatory capacity. Furthermore, Dex-DC showed a decreased CD40 ligand-induced IL-6 and TNF-alpha production, a complete block in IL-12p40 production, while IL-10 production was unaffected. CsA-DC and FK506-DC showed a partial reduction in the production of TNF-alpha, whereas all other functional activities appeared to be similar to control DC. These data show that, when compared to calcineurin inhibitors, corticosteroids have a unique and profound inhibitory effect on the generation and function of DC.

Antigens, CD↗
PubMed2000

Delayed graft function influences renal function, but not survival.

BACKGROUND: In renal transplantation, the impact of delayed graft function (DGF) on prognosis is controversial. We analyzed the risk factors of DGF and its impact on graft function and prognosis. METHODS: Seven hundred thirty-four cadaveric renal transplants performed between 1983 and 1997 were analyzed. DGF was diagnosed when serum creatinine levels increased, remained unchanged, or decreased less than 10% per day in three consecutive days in the first week after transplantation. Creatinine clearances of more or less than 50 or 30 mL/min at one year were used as cut-off points for optimal and suboptimal graft function, respectively. The logistic regression model was used to identify independent risk factor related to DGF and renal function one year after transplantation. The Cox regression model was used to examine the influence of DGF on long-term graft survival. RESULTS: Multivariate analysis revealed the following risk factors for DGF: recipient pretransplantation mean arterial blood pressure of less than 100 mm Hg (OR = 2.08, 95% CI, 1.43 to 3.03), female donor to male recipient combination (OR = 1.55, 95% CI, 1.02 to 2.35), donor age of more than 50 years (OR = 2.21, 95% CI, 1.49 to 3.26), cold ischemia time of more than 28 hours (OR = 1.78, 95% CI, 1.19 to 2.63), and peak panel reactive antibodies of more than 50% (OR = 1.7, 95% CI, 1.15 to 2.55). The incidence of DGF was one of the independent risk factors for suboptimal graft function at one year (OR = 1.68, 95% CI, 1.14 to 2.48), together with donor age of more than 50 years (OR = 2.39, 95% CI, 1.61 to 3.57), female donor gender (OR = 1.99, 95% CI, 1.42 to 2.78), the occurrence of acute rejection episodes (OR = 2.66, 95% CI, 1.87 to 3.78), peak panel-reactive antibodies of more than 50% (OR = 1.67, 95% CI, 1.15 to 2.47), and sharing of 1 to 3 versus 4 to 8 cross-reactive antigens groups (OR = 1.65, 95% CI, 1.09 to 2. 49). Moreover, DGF was one of the two independent risk factors for acute rejection episodes, but it had no independent effect on graft survival. CONCLUSION: Several risk factors for DGF were identified, of which a low recipient pretransplant mean arterial blood pressure, the transplantation of kidneys from female donors to male recipients, and a prolonged cold ischemia time are potentially avoidable. Although DGF is one of the several risk factors of acute rejection and suboptimal function at one year, it is not independently associated with an increased rate of graft loss.

Acute Disease↗