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Biomedical subjects

H J Ward

Publications and source records attributed to H J Ward.

At least 19 recordsLinked to original sources
PubMed2001

Cocaine use, hypertension, and end-stage renal disease.

Cocaine use has been associated with both acute renal failure and hypertension (HTN), but only recently have data suggested it may lead to a chronic insidious form of renal failure. We designed a cross-sectional study to compare the association of cocaine use in hemodialysis patients with and without a diagnosis of HTN-related end-stage renal disease (HTN-ESRD). Two hundred one black patients from two outpatient hemodialysis units in an urban community were evaluated. There were 193 eligible patients, 106 men and 87 women, aged 49.28 +/- 14.4 years. A history of significant cocaine use before dialysis was reported by 55 of 193 subjects (28.5%). A diagnosis of HTN-ESRD was reported in 49 of 55 cocaine users (89.1%) compared with 64 of 138 nonusers (46.38%; odds ratio, 9.44; 95% confidence interval, 3.79 to 23.49; P < 0.0005). Of the 113 subjects with HTN-ESRD, 49 subjects (43.4%) had a history of cocaine abuse, either alone or in combination with other drugs. Subjects with HTN-ESRD with cocaine use were younger than those without cocaine use (40.7 +/- 9.0 versus 53.8 +/-15.3 years; P < 0.0005) and had a shorter reported duration of HTN (5.3 +/- 5.4 versus 12.7 +/- 9.8 years; P < 0.0005, adjusted for age and sex). In our urban dialysis population, a clinical diagnosis of HTN-ESRD was strongly associated with a history of cocaine use and earlier onset of ESRD. Cocaine should be considered as a cause of ESRD in patients without a clear cause of renal failure.

Adult↗
PubMed2000

A clinic and community-based approach to hypertension control for an underserved minority population: design and methods.

This paper describes the design and methodology of the Community Hypertension Intervention Project (CHIP). CHIP is investigating the environmental and psychosocial factors related to treatment adherence and examining the effects of combining usual hypertension care with the effects of three interventions designed to improve patient compliance with treatment for high blood pressure in a high-risk, underserved minority population. Thirteen hundred and sixty-seven inner-city hypertension patients (75% black and 25% Hispanic) have agreed to participate in the 4-year longitudinal study. These participants were randomized to usual care or one of three intervention groups: individualized counseling sessions; home visits/discussion groups; or computerized appointment-tracking system. Participants are representative of the surrounding, predominantly low-income minority community and are treated in a hospital-based clinic and in a private clinic in the community. About 65% have blood pressure levels considered to be out of control. It was concluded that structural changes at the clinic site, along with the targeted interventions, would improve patient satisfaction, increase treatment adherence, and improve blood pressure control.

Adolescent↗
PubMed1999

Technology evaluation: gene therapy (FGF-5), Vical.

Vical, in collaboration with Merck, is developing gene-based therapies, including its 'naked DNA', for the potential treatment of ischemic heart disease. Vical has obtained preclinical data in animal models showing that a gene for a potent growth factor, FGF-5, can be delivered and expressed in coronary arteries stimulating the formation of new blood vessels. This new blood vessel formation may provide supplemental blood flow and necessary cardiac tissue oxygenation in areas of the heart where atherosclerotic blockages are present. Vical anticipates that its FGF-5 gene-based product would be used in conjunction with balloon angioplasty to stimulate new blood vessel formation at the site of the blockage. A series of experiments have been conducted in rats, whereby genes encoding FGF-5 were injected directly into rat heart muscle. The DNA was absorbed and the FGF-5 protein was expressed by cardiac myocytes. Active FGF-5 was released into the extracellular spaces of the heart muscle cells and new blood vessels formed throughout the local area. Quantitative measurements of blood vessel formation indicated that capillary density increased significantly in the hearts of treated rats compared to untreated controls. Further studies are underway to evaluate the persistence of new blood vessels following FGF-5 gene injection, and measurements will be made to assess the extent of improved blood flow in the affected region [177118]. In December 1996, the US patent office issued patent number US-05580859, covering Vical's naked DNA technology [227199].

Animals↗
PubMed1998

Low density lipoprotein receptors mediate intracellular calcium signals in microalbuminuric hypertensives.

Hyperlipidemia is an established risk factor for progressive renal damage and proteinuria. Platelets and vascular smooth muscle cells (VSMC) are known to possess low density lipoprotein (LDL) cholesterol receptors. We used platelet LDL receptors to investigate the hypothesis that elevated lipids could activate intracellular calcium [Ca2+]i signals, leading to altered vascular tone and permeability. We divided essential hypertensives into microalbuminuric positive (MA+) and negative (MA-) groups and measured baseline and LDL stimulated levels of [Ca2+]i. The MA+ group demonstrated a significantly higher mean baseline [Ca2+]i level (119.0 +/-24.5 v 86.2 +/- 25.4 micromol/mL, P = .001). The MA+ group also displayed greater elevations in [Ca2+]i levels after stimulation with LDL in concentrations of 10 and 25 microg/mL (100.9 +/- 54.8 v 40.9 +/- 20.2, P = .04 and 111.6 +/- 51.0 v 52.9 +/- 39.9 micromol/mL, P = .03, respectively). Our data indicate that hypertensive patients with early glomerular capillary injury display exaggerated influx of [Ca2+]i after LDL receptor stimulation. Heightened LDL receptor sensitivity may facilitate LDL mediated [Ca2+]i signals, leading to increased VSMC tone and proliferation and progressive renal disease.

Adult↗
PubMed1998

Erythropoietin upregulates angiotensin receptors in cultured rat vascular smooth muscle cells.

OBJECTIVE: Plasma renin is not elevated in recombinant human erythropoietin (rhEPO)-induced hypertension but angiotensin converting enzyme inhibitors reduce blood pressure in both human and animal studies. Since rhEPO elevates renin and angiotensinogen messenger RNAs in angiotensin II target tissues such as the aorta, we explored the actions of rhEPO on renin-angiotensin system-related gene transcription of cultured rat vascular smooth muscle cells. DESIGN AND METHODS: To separate direct actions of rhEPO from those mediated secondarily by potential activation of the renin-angiotensin system, vascular smooth muscle cells were cultured with rhEPO and enalapril to inhibit the angiotensin converting enzyme and losartan to inhibit angiotensin II type 1 receptors. RESULTS: Vascular smooth muscle cells cultured with rhEPO (6-8 units/ml) demonstrated elevations (40-120%) in messenger RNAs of the renin-angiotensin system (renin, angiotensinogen, angiotensin receptor types 1 and 2) and increased levels of several messenger RNAs known to respond to angiotensin II (transforming growth factor-beta, insulin-like growth factor-II, epidermal growth factor, c-fos and platelet-derived growth factor). In contrast, cells cultured in the presence of rhEPO and enalapril or losartan showed elevations of messenger RNA for only the two types of angiotensin II receptor. This increase was higher than that obtained when cells were cultured with rhEPO or either antagonist alone. The increase in specific binding of angiotensin II to cells cultured in the presence of rhEPO and enalapril or rhEPO and losartan paralleled the changes in receptor messenger RNA. CONCLUSIONS: rhEPO exerts its primary action on vascular smooth muscle cells via an increase in angiotensin receptor messenger RNA, resulting in a parallel increase in angiotensin II receptor expression. We suggest that increased receptor expression secondarily mediates the expression of other renin-angiotensin system messenger RNAs, which leads to angiotensin II-responsive gene transcription. The elevation in angiotensin II receptors, as observed in response to rhEPO, may provide a mechanism by which other forms of renin-dependent hypertension are initiated.

Animals↗
PubMed1997

The efficacy of lovastatin in lowering cholesterol in African Americans with primary hypercholesterolemia.

PURPOSE: To evaluate the efficacy of lovastatin in African Americans (AA) diagnosed with primary hypercholesterolemia. PATIENTS AND METHODS: Forty-seven AA patients from the King/Drew Medical Center in Los Angeles were recruited from the Hypertension, Family Practice, and General Medicine Clinics for a double-blinded, placebo-controlled trial. Forty-one patients completed the 10 week study. Eligibility for entrance into the study was determined by patient lipid profiles meeting the criteria for pharmacological intervention outlined by the National Cholesterol Education Program II guidelines. Patients were randomized into 2 groups: lovastatin 20 mg per day, or placebo. A registered dietitian counseled both groups on two visits during the study to ensure compliance with a low fat, low cholesterol diet. Lipid levels were compared at the first and last visit of the study. RESULTS: The lovastatin-treated group demonstrated significant reductions in mean total cholesterol (TC) (14.7%, 95% confidence interval [CI]-6.6 to -22.8, P < 0.01) and low-density lipoprotein (LDL) cholesterol (20.0%, 95% CI-7.9 to -32.1, P < 0.01) from baseline. Plasma triglyceride (TG) levels decreased by 10.5% (95% CI-2.4 to -18.6) and total cholesterol/high density lipoprotein (HDL) ratio fell below five in the lovastatin group, but neither reduction reached statistical significance. Placebo administration was not associated with any significant changes in TC, LDL, or TG. There were no significant differences between baseline and post-treatment hepatic transaminase levels in either group. CONCLUSIONS: The HMG-CoA (3-hydroxyl-3 methylglutary coenzyme A) reductase inhibitor lovastatin in a dose of 20 mg per day was effective in decreasing TC, LDL, and TG levels in an AA population. Considering that the AA population is at substantially increased risk for hypertension and cardiovascular morbidity, more aggressive and wider use of HMG-CoA reductase inhibitors should be employed in reducing elevated plasma cholesterol levels.

Anticholesteremic Agents↗
PubMed1997

Paracellular phosphate absorption in rat colon: a mechanism for enema-induced hyperphosphatemia.

The mechanism of colonic phosphate absorption is not well defined. We measured unidirectional phosphate fluxes across rat distal colon epithelium in the absence of transepithelial electrochemical gradients. Steady-state mucosal-to-serosal flux (Jms) was not different from the serosal-to-mucosal flux (Jsm), generating no net flux (Jnet = Jms - Jsm, was not different from "0'). Simultaneous fluxes of mannitol, a paracellular probe, exhibited an identical flux pattern, suggesting that phosphate flux across the colonic epithelium may be mediated through the paracellular pathway. Tight junction permeability was increased with mucosal addition of taurodeoxycholate (TDC, 2 mM) which caused a prompt increase in transepithelial conductance from 7.03 +/- 0.35 to 13.88 +/- 0.35 mS/cm2 (p < 0.001). This was associated with an increase in Jsm, but no change in Jms, for mannitol, resulting in a net flux in the secretary direction. Identical TDC-induced changes were observed in phosphate fluxes, again suggesting phosphate permeation through the intercellular, mannitol pathway. A significant correlation was observed between the permeability of phosphate and the permeability of mannitol, measured both in the mucosal-to-serosal and the serosal-to-mucosal directions and under both control and experimental (mucosal TDC) conditions. Thus, colonic phosphate transport is mediated through the paracellular pathway and enema with high phosphate concentrations (1,760 times blood concentration), can trigger rapid and massive phosphate absorption through this diffusive pathway.

Animals↗
PubMed1992

Acquired cystic disease in chronically rejected renal transplants.

Acquired cystic disease has been documented to complicate most forms of chronic renal damage; it has only infrequently been described in transplanted kidneys. Five patients with noncystic ESRD and chronically rejected transplants in which acquired cystic disease arose are reported. The diagnosis of acquired cystic disease was established in examination of transplant nephrectomies from four patients and a core biopsy from the fifth. The allografts were in place from 44 to 80 months; three patients were treated with hemodialysis before the diagnosis of acquired cystic disease, whereas two received peritoneal dialysis. Three of the four patients evaluated had cysts in the native kidneys. Although papillary hyperplasia of lining epithelium was evident in four specimens, only one kidney was the site of neoplasms in the form of multiple small tubular adenomas. No malignant neoplasms were noted in this study or in the few similar previous ones; however, it is possible that chronically rejected transplanted kidneys may harbor neoplasms with the same malignant potential as those in acquired cystic disease in native kidneys.

Adult↗
PubMed1991

The beneficial effect of blood transfusion and the DR 1 gene dose on renal transplant outcome in blacks.

We performed a retrospective analysis of the factors determining renal allograft survival in 70 black recipients from a single center and 1212 black recipients from multicenter registry data. One and two-year graft survival in single-center blacks was comparable to the result achieved in the general population (81% and 77%, respectively). Two-year graft survival in multicenter blacks was significantly worse than nonblacks (73% versus 55%, respectively; P less than 0.01). Graft survival in untransfused blacks receiving cyclosporine was no better than the result achieved during the azathioprine era. A beneficial effect upon graft survival was seen in blacks transplanted at the centers that have consistently displayed the best overall allograft survival over the years. Matching for HLA antigens was consistently poorer in blacks compared with whites and did not confer additive benefit over cyclosporine and blood transfusion. Our data indicate that cyclosporine immunosuppression, blood transfusion, and individual center expertise contribute significantly toward optimal transplant outcome in the higher-risk black end-stage renal disease population.

Age Factors↗
PubMed1990

Quantitative studies of tubular immune complex formation and clearance in rats.

Tubular antibody deposition and clearance was quantitatively studied using affinity-purified rabbit antibodies to rat Tamm-Horsfall protein (TH), a surface membrane glycoprotein of the tubular cells of the thick ascending limb of the loop of Henle. Immune complexes are formed in situ at the base of these cells in rats injected with antisera to TH. The renal binding of I125-anti-TH was determined in pair label studies. Kidneys and other organs were removed from groups of rats for isotope counting at four hours to 14 days after an injection of I125-anti-TH and I131-normal rabbit IgG. The greatest total renal anti-TH binding after injection of 500 micrograms of anti-TH was observed at 24 hours in normal rats (18.55 +/- 1.6 micrograms). During the period of most rapid clearance (day 2 to day 7) the half life of renal anti-TH binding (84.2 hours) and the half life of anti-TH in the serum (68.5 hours) were shorter than that of IgG in the serum (117.8 hours). There was no substantial uptake of anti-TH by other organs. A close relationship between serum levels and renal uptake of anti-TH at 24 hours was also observed in rats given from 50 to 6000 micrograms of anti-TH; renal saturation was evident only at the highest dose. This close relationship was also present during the clearance phase in rats injected with 3700 micrograms of anti-TH; the half life of anti-TH was 96.2 hours in kidneys and 110 hours in serum while the half life of rabbit IgG in serum was 151.8 hours. Markedly increased renal uptake of anti-TH was observed in protein-uric rats with passive Heymann nephritis. In very proteinuric rats, 14.1% of the injected dose was bound to kidneys at 24 hours. In these rats, serum anti-TH levels decreased very rapidly to 4% of control serum levels by five days. Throughout the period of study, the serum levels of anti-TH determined by direct radiometric assay corresponded very closely to those obtained by enzyme-linked immunosorbent assay (ELISA). Urinary excretion was a major mechanism for the clearance of anti-TH in proteinuric rats; more than 10% of the injected I125-anti-TH was recovered intact (that is, protein bound) during the first day after injection. During the clearance phase for renal deposits, urinary clearance of anti-TH exceeded urinary clearance of IgG due to release of renal bound antibody into urine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Implications of recombinant erythropoietin therapy for renal transplantation.

We previously reported on the efficiency by which endogenous erythropoietin production corrects anemia after successful renal transplantation. Recent clinical experience with recombinant human erythropoietin in renal failure has demonstrated major benefit in correcting anemia with few adverse consequences. This article reviews our experience to date with recombinant human erythropoietin use in transplant recipients and explores the impact of therapy for the dialysis population awaiting transplantation. The issues of ongoing need for pretransplant blood transfusion, presensitization, organ transplant demand, therapeutic use of human recombinant erythropoietin for chronic rejection, and impact of an expanding, high-quality transplant recipient pool are discussed in the context of the recombinant erythropoietin era.

Anemia↗
PubMed1989

Serum erythropoietin levels after renal transplantation.

We measured serum erythropoietin levels serially in 31 renal-transplant recipients treated with cyclosporine, using the recently developed recombinant human erythropoietin-based radioimmunoassay. The mean (+/- SEM) serum erythropoietin concentration in these patients before transplantation (14 +/- 2 U per liter) was similar to that in normal subjects who did not have anemia. A transient postoperative 9-fold increase (range, 0- to 74-fold) in the serum erythropoietin levels was followed by a smaller (3-fold) and sustained (28 +/- 3 days) second elevation. The initial increase occurred in the absence of graft function and was not accompanied by an erythropoietic response, whereas the second increase was associated with graft recovery and the complete resolution of the anemia. Serum erythropoietin levels returned to normal as the hematocrit rose above 0.32. Thereafter, the hematocrit continued to rise toward normal, while the serum erythropoietin levels remained normal. The patients in whom erythrocytosis or iron-deficiency anemia developed had persistently elevated serum erythropoietin levels. We conclude that in patients who have undergone renal transplantation, slight increases in endogenous erythropoietin levels induce erythropoiesis to the same extent as do large doses of exogenous erythropoietin in patients with uremia. Moreover, once initiated, erythropoiesis in renal-transplant recipients may be sustained by normal serum erythropoietin levels. These results suggest that the restoration of renal function improves the erythropoietic response to erythropoietin.

Adult↗
PubMed1989

Erythropoietin in renal transplant recipients: studies based on recombinant human erythropoietin radioimmunoassay.

In posttransplant patients, modest increases in endogenous EPO induce erythropoiesis similar to that observed in uremic patients who are given large doses of exogenous rHuEPO that generate vastly higher circulating EPO levels. Moreover, once it is initiated, erythropoiesis may be sustained by normal levels of EPO. These observations raise the possibility that the restoration of renal function may alter the EPO-erythropoiesis response pattern. It is also possible that the resolution of uremic anemia is dependent on factors in addition to the level of circulating EPO.

Biomarkers↗