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Biomedical subjects

John Cunningham

Publications and source records attributed to John Cunningham.

At least 19 recordsLinked to original sources
PubMed2006

Pathogenesis and prevention of bone loss in patients who have kidney disease and receive long-term immunosuppression.

The coexistence of kidney disease with a need for immunosuppressive therapy leads to the convergence of several threats to bone. These comprise general effects of the primary disease, e.g., inflammatory state, more specific effects of acute renal failure or chronic kidney disease, and effects of therapies. Multisystem inflammatory disease that requires immunosuppression is associated frequently with kidney damage, and any reduction of kidney function that takes the patient into or beyond chronic kidney disease stage 2 for more than a short time is likely to have a negative impact on bone health. Bone mineral density frequently is low and fracture rates are high, although correlations often are poor. Chronic inflammation leads to local and systemic imbalance between bone formation and resorption. Upregulation of NF-kappabeta ligand (RANKL) and variable downregulation of osteoprotegerin are implicated, and bone health may improve in response to treatment of the inflammatory state. Certain immunosuppressive agents, especially glucocorticoids and calcineurin inhibitors, contribute further to bone loss. Antiresorptive agents such as bisphosphonates are used widely and, although able to prevent loss of bone mineral density, have uncertain effects on fracture rates. Augmentation of anabolic activity is desirable but elusive. Synthetic parathyroid hormone is untested but has potential. Manipulation of the RANKL/osteoprotegerin system now is feasible using antibodies to RANKL or synthetic osteoprotegerin. In the future, manipulation of the calcium-sensing receptor using calcimimetic or calcilytic agents may allow the anabolic effects of parathyroid hormone to be harnessed to good effect. With all of these therapies, it will be important to assess response in relation to important clinical end points such as fracture.

Arthritis, Rheumatoid↗
PubMed2005

Benzene increases protein-bound 3-nitrotyrosine in bone marrow of B6C3F1 mice.

Benzene, an environmental pollutant, is myelotoxic and leukemogenic in humans. The molecular mechanisms that can account for its biological effects have not been fully elucidated. We hypothesize that one of the underlying mechanism involves nitration of proteins by peroxynitrite and/or by bone marrow myeloperoxidase-dependent pathways in nitric oxide (NO) metabolism. Using 3-nitrotyrosine [Tyr(NO(2))] as a biomarker for NO-induced damage to proteins, we examined the effects of benzene on the levels of Tyr(NO(2)) in bone marrow in vivo. Groups of 8 weeks old B6C3F(1) male mice were given a single i.p. injection of benzene (50, 100, 200 or 400mg/kg bodyweight) in corn oil. The mice in control groups received either no treatment or a single injection of the vehicle. The mice were killed 1h after treatment and proteins were isolated from bone marrow, lung, liver and plasma. The proteins were enzymatically hydrolyzed; amino acids were separated and purified by high pressure liquid chromatography, derivatized, and quantified by electron capture-negative chemical ionization-gas chromatography/mass spectrometry (EC-NCI-GC/MS). In the GC/MS assay, 3-nitro-l-[(13)C(9)]tyrosine was used as an internal standard and l-[(2)H(4)]tyrosine served to monitor artifactual formation of 3-nitrotyrosine during sample preparation and analysis. We found that treatment of mice with benzene elevates nitration of tyrosine residues in bone marrow proteins. There was a dose (50-200mg benzene/kg b.w.)-dependent increase in protein-bound Tyr(NO(2)) formation (1.5- to 4.5-fold); however, the levels of Tyr(NO(2)) at 400mg benzene/kg b.w. were significantly higher than control but lower than that formed at 200mg benzene/kg b.w. The results of this study, for the first time, indicate that benzene increases protein-bound 3-Tyr(NO(2)) in bone marrow in vivo, and support our previous finding that benzene is metabolized to nitrated products in bone marrow of mice; collectively, these results may in part account for benzene-induced myelotoxicity.

Animals↗
PubMed2005

Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.

BACKGROUND: Patients with secondary hyperparathyroidism often require therapy that provides long-term control of parathyroid hormone concentrations without increasing calcium and phosphorus concentrations. Cinacalcet modulates the calcium-sensing receptor on the parathyroid gland to reduce secretion of parathyroid hormone and lower serum calcium, phosphorus and calcium-phosphorus product in haemodialysis patients. METHODS: Dialysis patients with secondary hyperparathyroidism [parathyroid hormone (PTH) level > or =300 pg/ml] who were enrolled in one of four phase 2 placebo-controlled studies were eligible to enroll in an open-label extension study in which all patients received cinacalcet. For this extension study, cinacalcet was initiated at 30 mg in all patients and the dose was escalated to a maximum of 180 mg once daily if PTH concentrations were >250 pg/ml. Use of concomitant vitamin D sterols and phosphate binders was not restricted. RESULTS: The analysis of all patients (n = 59) completing 100 weeks of cinacalcet treatment showed long-term control of PTH and calcium-phosphorus product. Approximately 55% achieved a PTH concentration < or =300 pg/ml at the week-100 study visit, and approximately 60% had at least a 30% reduction in PTH from baseline. Serum calcium, phosphorus and the calcium-phosphorus product did not increase during the study. Concomitant vitamin D sterol and phosphate binder therapy remained stable. Cinacalcet was safe and generally well tolerated at doses up to 180 mg/day. CONCLUSIONS: In this long-term study, cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing concentrations of serum calcium, phosphorus or calcium-phosphorus product.

Adult↗
PubMed2005

Posttransplantation bone disease.

Transplanted patients experience rapid loss of bone, high fracture rates, and increases in morbidity and mortality as a consequence of a posttransplant scenario that is highly deleterious to the skeleton. Immune suppressive drugs, especially glucocorticoids, are toxic to bone, often acting on a background of preexisting osteodystrophy resulting from long-standing renal, hepatic, cardiac, or pulmonary disease. Cyclosporin and tacrolimus lead to a severe osteopenic state in rats, but the skeletal toxicity of the calcineurin inhibitors in the clinical environment is less clear. Nor is it clear whether cyclosporin and tacrolimus differ in their skeletal actions. Mycophenolate mofetil and sirolimus do not appear to have important skeletal toxicity. Preventative strategies include minimizing glucocorticoid exposure and implementing therapies to counter the increase in bone resorption and decrease in bone formation that follows transplantation. Antiresorptive agents, especially bisphosphonates, appear capable of retarding or halting the early bone loss and possibly reduce fracture rates also. Vitamin D and calcium are ineffective, but calcitriol has utility in some reports. Bone anabolic agents, such as synthetic parathyroid hormone and growth hormone, have potential, but data are lacking.

Animals↗
PubMed2005

Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (HPT) and abnormal mineral metabolism are thought to play an important role in bone and cardiovascular disease in patients with chronic kidney disease. Cinacalcet, a calcimimetic that modulates the calcium-sensing receptor, reduces parathyroid hormone (PTH) secretion and lowers serum calcium and phosphorus concentrations in patients with end-stage renal disease (ESRD) and secondary HPT. METHODS: We undertook a combined analysis of safety data (parathyroidectomy, fracture, hospitalizations, and mortality) from 4 similarly designed randomized, double-blind, placebo-controlled clinical trials enrolling 1184 subjects (697 cinacalcet, 487 control) with ESRD and uncontrolled secondary HPT (intact PTH > or =300 pg/mL). Cinacalcet or placebo was administered to subjects receiving standard care for hyperphosphatemia and secondary HPT (phosphate binders and vitamin D). Relative risks (RR) and 95% CI were calculated using proportional hazards regression with follow-up times from 6 to 12 months. Health-related quality-of-life (HRQOL) data were obtained from the Medical Outcomes Study Short Form-36 (SF-36), and the Cognitive Functioning scale from the Kidney Disease Quality of Life instrument (KDQOL-CF). RESULTS: Randomization to cinacalcet resulted in significant reductions in the risk of parathyroidectomy (RR 0.07, 95% CI 0.01-0.55), fracture (RR 0.46, 95% CI 0.22-0.95), and cardiovascular hospitalization (RR 0.61, 95% CI 0.43-0.86) compared with placebo. Changes in HRQOL favored cinacalcet, with significant changes observed for the SF-36 Physical Component Summary score and the specific domains of Bodily Pain and General Health Perception. CONCLUSION: Combining results from 4 clinical trials, randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization, along with improvements in self-reported physical function and diminished pain. These data suggest that, in addition to its effects on PTH and mineral metabolism, cinacalcet had favorable effects on important clinical outcomes.

Adult↗
PubMed2005

Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl.

BACKGROUND: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQItrade mark) has established guidelines for treatment of secondary hyperparathyroidism (HPT). The ability of cinacalcet HCl (Sensipartrade mark) treatment to improve achievement of target levels of parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca x P) was investigated in subjects on dialysis with secondary HPT. METHODS: Data were combined from three placebo-controlled, double-blind, 26-week studies with similar design that randomized 1136 subjects on dialysis to receive traditional therapy plus cinacalcet or placebo. Oral cinacalcet was titrated from 30 to 180 mg/day. Achievement of K/DOQI goals was determined for each treatment group overall and for subgroups defined by baseline intact PTH (iPTH) and Ca x P levels. RESULTS: Cinacalcet-treated subjects were more likely to achieve a mean iPTH </=300 pg/mL (31.8 pmol/L) than were control subjects on traditional therapy (56% vs. 10%, P < 0.001). Cinacalcet-treated subjects were more likely to achieve concentrations of serum calcium within 8.4 to 9.5 mg/dL (2.10-2.37 mmol/L) and serum phosphorus within 3.5 to 5.5 mg/dL (1.13-1.78 mmol/L) than were control subjects (49% vs. 24% and 46% vs. 33%, P < 0.001 for each). Cinacalcet also improved achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and concurrent achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and iPTH </=300 pg/mL (31.8 pmol/L) (65% vs. 36% and 41% vs. 6%, P < 0.001 for each). CONCLUSION: In subjects on dialysis with secondary HPT, cinacalcet facilitates achievement of the K/DOQI-recommended targets for PTH, calcium, phosphorus, and Ca x P.

Adult↗
PubMed2005

Management of secondary hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) remains an inevitable consequence of untreated chronic uremia. It is the result of a combination of phosphate (P) retention, failure of calcitriol synthesis, and hypocalcemia. Therapies used to correct these abnormalities, namely active vitamin D replacement, calcium (Ca) supplementation, and phosphate (P) restriction, have moderate efficacy but are prone to unacceptable side-effects. However, there have been new developments in the control of P, vitamin D replacement and modulation of the Ca sensing receptor (CaSR) using calcimimetics. Sevelamer, and in the near future lanthanum, are offering a reasonable level of P control without the toxicities inherent with either aluminum- or Ca-based phosphate binders, and other phosphate binders are in development. 'Non calcemic' vitamin D metabolites include 22-oxacalcitriol, paricalcitol, and doxercalciferol. In various experimental models 22-oxacalcitriol, in particular, exhibits impressive suppression of parathyroid hormone (PTH) with minimal calcemia, although it has been less impressive when compared with calcitriol in controlled studies in hemodialysis (HD) patients. The advantages of these agents over conventional treatment with calcitriol or alfacalcidol remain uncertain. Cinacalcet, a calcimimetic agent that up-regulates the sensitivity of the CaSR in parathyroid and other cells, is a new type of therapy for SHPT that simultaneously reduces the concentrations of PTH, Ca, and P in HD patients, enabling a significant number to achieve K/DOQI or other national guidelines. The extent to which this new therapy will improve clinical outcomes remains uncertain. In conclusion, with the advent of new therapies the emphasis in the management of SHPT has evolved to incorporate reduction of Ca loading, control of PTH within specific target ranges, and avoidance of hypercalcemia, hyperphosphatemia and elevation of the calcium phosphorus product.

Calcium↗
PubMed2005

New prospects for the management of renal bone disease.

The last decade has been a remarkably productive one in the field of bone biology. New insights into the maintenance of a normal bone microenvironment have led to significant advances in our understanding of many important skeletal disorders, including renal osteodystrophy. Novel targets for therapeutic manipulation have been exposed and encouraging progress made towards new treatments. In addition, just as clinical studies have alerted us to the potential hazards of vascular calcification, basic science has unearthed the intimate nature of the relationship between the previously separate disciplines of bone and vascular biology. The clinical nephrologist, however, may be forgiven a little cynicism at this point. If such progress has been made, why do the same proverbial difficulties confront us in day-to-day practice? Control of phosphate remains inadequate, despite a literature which constantly reaffirms its crucial importance, and parathyroid hyperplasia seems inevitable in many patients. Furthermore, even the satisfaction of successful control of serum parathyroid hormone concentration must now be tempered by disquiet regarding the skeletal and cardiovascular consequences of oversuppression. This review aims to provide an update of the latest developments in relevant skeletal research and to assess how recently acquired knowledge may improve clinical nephrological practice over the next five years.

Animals↗
PubMed2005

Cross-national study of fighting and weapon carrying as determinants of adolescent injury.

OBJECTIVES: We sought to (1) compare estimates of the prevalence of fighting and weapon carrying among adolescent boys and girls in North American and European countries and (2) assess in adolescents from a subgroup of these countries comparative rates of weapon carrying and characteristics of fighting and injury outcomes, with a determination of the association between these indicators of violence and the occurrence of medically treated injury. DESIGN AND SETTING: Cross-sectional self-report surveys using 120 questions were obtained from nationally representative samples of 161082 students in 35 countries. In addition, optional factors were assessed within individual countries: characteristics of fighting (9 countries); characteristics of weapon carrying (7 countries); and medically treated injury (8 countries). PARTICIPANTS: Participants included all consenting students in sampled classrooms (average age: 11-15 years). MEASURES: The primary measures assessed included involvement in physical fights and the types of people involved; frequency and types of weapon carrying; and frequency and types of medically treated injury. RESULTS: Involvement in fighting varied across countries, ranging from 37% to 69% of the boys and 13% to 32% of the girls. Adolescents most often reported fighting with friends or relatives. Among adolescents reporting fights, fighting with total strangers varied from 16% to 53% of the boys and 5% to 16% of the girls. Involvement in weapon carrying ranged from 10% to 21% of the boys and 2% to 5% of the girls. Among youth reporting weapon carrying, those carrying handguns or other firearms ranged from 7% to 22% of the boys and 3% to 11% of the girls. In nearly all reporting countries, both physical fighting and weapon carrying were significantly associated with elevated risks for medically treated, multiple, and hospitalized injury events. CONCLUSIONS: Fighting and weapon carrying are 2 common indicators of physical violence that are experienced by young people. Associations of fighting and weapon carrying with injury-related health outcomes are remarkably similar across countries. Violence is an important issue affecting the health of adolescents internationally.

Adolescent↗
PubMed2004

Impaired release of interleukin-6 from human osteoblastic cells in the uraemic milieu.

BACKGROUND: Osteoblast-derived interleukin-6 (IL-6) affects bone metabolism and is linked with a number of pathological states characterized by increased bone resorption, including osteoporosis and renal osteodystrophy. To examine the possibility that uraemia directly influences the release of this cytokine in bone, we have investigated the effect of human uraemic serum on the release of IL-6 from human osteoblast-like cells. METHODS: Individual serum samples collected from healthy male volunteers or male haemodialysis patients prior to and during a dialysis treatment were assayed for IL-6, interleukin-1beta (IL-1beta) and soluble IL-6 receptor (sIL-6R) using specific enzyme-linked immunosorbent assays. MG-63 and SaOS-2 cells were cultured in media containing pooled sera from both groups and alongside matching charcoal-stripped sera. IL-6 concentrations were determined in harvested cell supernatants after 24 h. In further experiments, media containing individual sera obtained from five patients at regular intervals during their haemodialysis treatment were incubated with MG-63 cells to determine the effects of the dialysis process on IL-6 secretion. RESULTS: Haemodialysis patients had significantly higher (n = 10, P < 0.001) circulating concentrations of IL-6 (7.0 +/- 1.6 pg/ml) than normal subjects (0.4 +/- 0.1 pg/ml), but there were no significant differences in the concentrations of either IL-1beta or sIL-6R. These serum concentrations did not change significantly during 80 min of dialysis. IL-6 release by MG-63 cells incubated with charcoal-stripped serum from normal or from uraemic subjects was similar. Incubation with untreated sera from normal subjects increased IL-6 release by approximately 6-fold above the charcoal-stripped control, whereas sera from uraemic subjects increased IL-6 release by only approximately 2- to 3-fold (normal vs uraemic of 6878 +/- 595 and 2579 +/- 169 pg/ml, respectively, P < 0.001). Similar results were seen with SaOS-2 cells. Haemodialysis did not restore the capacity of uraemic serum to augment IL-6 release to the same degree as normal serum. CONCLUSIONS: These data show that the augmentation of IL-6 release from human osteoblastic cells after incubation with normal serum is greater than after uraemic serum. This may indicate the presence of an inhibitor of IL-6 release in uraemic serum that is involved in the deranged bone turnover of uraemic patients.

Cells, Cultured↗
PubMed2004

New Vitamin D analogues for osteodystrophy in chronic kidney disease.

Vitamin D therapy for patients with chronic kidney disease has until recently comprised alfacalcidol or calcitriol, both of which effectively attenuate secondary hyperparathyroidism and the target organ consequences thereof. Unfortunately, both these agents also have significant calcaemic and phosphataemic actions leading to frequent episodes of hypercalcaemia, hyperphosphataemia and an increase in the CaxP product. It is likely that these in turn have adverse effects on cardiovascular and survival outcomes by promoting soft tissue and vascular calcification. These drawbacks have fuelled a search for vitamin D compounds with a wider therapeutic window. Experimentally, some of these have exhibited remarkable dissociation between their ability to suppress parathyroid hormone (PTH) and concomitant calcaemic actions. In the case of 22-oxacalcitriol, the calcaemic potency relative to parathyroid suppression is 100th of that of calcitriol. 22-oxacalcitriol, with paricalcitol and doxercalciferol, are now widely used. Clinical studies of these agents, while confirming efficacy that is at least as good as alfacalcidol/calcitriol, have not consistently shown benefit in head to head comparison. Experience with these agents in the paediatric arena is very limited. One placebo-controlled study has now been completed in children-paricalcitol appeared effective and well tolerated. Calcimimetics, which simultaneously lower PTH, calcium and the CaxP product are about to enter the clinical arena-early studies in adults look promising, although they will need careful evaluation in children. These two therapies are likely to be additive and will probably complement one another effectively.

Child↗
PubMed2004

Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

Calcium↗
PubMed2004

Coronary artery calcification measured with electron-beam computerized tomography correlates poorly with coronary artery angiography in dialysis patients.

BACKGROUND: Coronary artery calcification measured by electron-beam computerized tomography (EBCT) correlates with plaque burden and vessel stenosis and is predictive of future cardiac events in the general population. Uremic vascular calcification is common and widespread, tends to be medial as well as intimal, and may not relate solely to atherosclerotic lesions. Despite this difference and in the absence of any direct evidence in uremic patients, it is generally implied that coronary artery calcification equates to occlusive atherosclerosis. METHODS: We set out to compare the predictive value of coronary artery calcification assessed by EBCT with contemporaneous coronary angiography. We studied 18 patients with end-stage renal disease undergoing maintenance dialysis. Seventy-two coronary vessels were analyzed for angiographic evidence of stenotic disease and correlated with individual vessel calcification score. RESULTS: There was no significant correlation between degree of vessel stenosis and calcification score for individual vessels in patients with a positive calcium scan. Specificity was 48% and the positive predictive value was 53%. However, a calcification score <20 strongly correlated with the absence of significant luminal narrowing, and a 0 calcification score had a negative predictive value of 87.5%. CONCLUSION: Coronary artery calcification measured by EBCT is not an accurate marker of the degree of vessel stenosis in coronary artery disease in uremic patients and should not be used as a single screening test for atherosclerotic coronary disease.

Calcinosis↗