PubMed Health⌕ Search

Biomedical subjects

J E Moulder

Publications and source records attributed to J E Moulder.

At least 37 records · Page 2Linked to original sources
PubMed1998

Radiation nephropathy is treatable with an angiotensin converting enzyme inhibitor or an angiotensin II type-1 (AT1) receptor antagonist.

BACKGROUND AND PURPOSE: Previous studies showed that progression of established radiation nephropathy could be delayed by continuous treatment with high doses of captopril, an angiotensin-converting-enzyme (ACE) inhibitor. The current studies were designed to determine whether a lower dose or a shorter treatment with captopril would be effective and whether an angiotensin II type-1 (AT1) receptor antagonist (AII blocker) would be effective. MATERIALS AND METHODS: In the captopril studies, rats were given renal irradiation at doses sufficient to produce radiation nephropathy. Six months after irradiation, animals were stratified by azotemia and assigned to no treatment, continuous high- or low-dose captopril, or 6 weeks of high-dose captopril. Captopril was given in drinking water at 62.5 mg/l (low dose) or 500 mg/l (high dose). The AII blocker study had a similar design, except that the nephropathy was the result of total body irradiation and bone marrow transplantation and the treatments were no treatment or continuous treatment with an AII blocker, L-158,809 (20 mg/l in drinking water). Animals were followed for 1 year with periodic studies of renal function. RESULTS: Survival and renal function were significantly enhanced by all treatments. Continuous captopril treatment was more effective than the 6-week course of treatment, but there was no difference in effectiveness between the high and low doses of captopril. In continuous therapy, captopril and the AII blocker had roughly equivalent efficacy. CONCLUSIONS: Both the ACE inhibitor and the AII blocker were effective treatments for established radiation nephropathy. The best results with the ACE inhibitor required continuous therapy, but could be achieved with a low dose of the drug.

Angiotensin Receptor Antagonists↗
PubMed1998

Angiotensin II receptor antagonists in the treatment and prevention of radiation nephropathy.

PURPOSE: Angiotensin-converting enzyme (ACE) inhibitors are effective in the prophylaxis of radiation-induced renal and lung injury. Studies were designed to determine whether blocking the angiotensin II (AII) receptor, rather than blocking AII synthesis with ACE inhibitors, would also be effective. MATERIALS AND METHODS: Rats received total body irradiation (TBI) followed by bone marrow transplantation (BMT), and were randomized to: an ACE inhibitor (captopril); an AII type 1 (AT1) receptor antagonist (L-158,809); or no treatment. Drug therapy began 9 days prior to BMT and continued for the duration of the study. RESULTS: Analysis of renal function, histopathology and animal survival showed that the AII blocker was more effective than the ACE inhibitor in the prophylaxis of BMT nephropathy. Further studies have shown that the AII blocker is as effective as captopril in the treatment of established radiation nephropathy, and that the AII blocker is at least as effective as captopril in the prophylaxis of lung injury induced by chemo-radiation therapy. CONCLUSIONS: These studies indicate that blockage of the AT1 receptor by itself is sufficient for the treatment of radiation-induced renal and lung injury, hence the renin-angiotensin system is fundamentally involved in the pathogenesis of these injuries. These studies provide further evidence that there is more to late radiation injuries than delayed mitotic cell death.

Angiotensin Receptor Antagonists↗
PubMed1998

End-stage renal disease (ESRD)after bone marrow transplantation: poor survival compar ed to other causes of ESRD.

Chronic renal failure after successful bone marrow transplantation (BMT) may diminish the quality of life and may also evolve to end-stage renal disease (ESRD) requiring chronic dialysis. Individual reports suggest poor survival of such patients. We evaluated the survival with ESRD after BMT by the case-control method. We found that patients who develop ESRD after BMT have a significantly decreased survival as compared with non-BMT patients. This was true for both diabetic and nondiabetic ESRD (both p < 0.03). These data demonstrate the poor outcome of ESRD after BMT which emphasizes the need for a better understanding of chronic renal failure after BMT.

Adolescent↗
PubMed1998

Power-frequency fields and cancer.

There is a widespread public perception that exposure to "EMF" is linked to cancer. This concern stems largely from a few epidemiological studies that appear to show an association between cancer and residence near power lines. However, the epidemiological evidence for such a link falls far short of that needed to conclude that a causal relationship exists, and examination of the biophysics leads to the conclusion that biological effects are implausible at the field strengths encountered in environmental settings. In a case such as this, where the epidemiological evidence for a link between an agent and a disease is weak to nonexistent and the effect is biophysically and/or biochemically implausible, laboratory evidence becomes critical for risk evaluation. The mechanisms of carcinogenesis are sufficiently well established that laboratory studies can be used to assess whether an agent has carcinogenic potential. There are approximately 100 published reports that have looked for evidence that power-frequency fields have genotoxic or epigenetic activity. These studies have found no replicated evidence that power-frequency fields have the potential to either cause or contribute to cancer. Of the few studies that have shown some evidence for carcinogenic activity, most have used exposure conditions with little relevance to real world exposure, none have been replicated, and many have failed direct attempts at replication. In conjunction with the epidemiology and biophysics, this leads to the conclusion that a causal association between power-frequency fields and cancer is not only unproven, but rather unlikely.

Animals↗
PubMed1998

Brief pharmacological intervention in experimental radiation nephropathy.

Brief postirradiation treatment with an angiotensin-converting enzyme (ACE) inhibitor has been shown to be effective in reducing the severity of radiation nephropathy in rats. The efficacy of brief treatment with an ACE inhibitor was shown to be greatest when the animals were young when irradiated and when the treatment was given 4 to 10 weeks after bone marrow transplantation (BMT). In further studies with a BMT nephropathy model, we have shown that brief treatment with an angiotensin II type I receptor antagonist (AII blocker) is even more effective than brief treatment with an ACE inhibitor. We have also shown that an NO synthase inhibitor, which exacerbated radiation nephropathy when given continuously, has no effect when given during the postirradiation interval when ACE inhibitors and AII blockers were most effective. Studies also showed that the loss of efficacy of brief treatment with increased age at irradiation parallels the decrease in radiosensitivity that occurs with increasing age at irradiation, but that this decrease in radiosensitivity is not sufficient to explain the loss of efficacy of brief treatment. These data indicate that the renin-angiotensin system is important in the expression of renal radiation injury, particularly between 4 and 10 weeks after irradiation.

Angiotensin II↗
PubMed1997

Angiotensin converting enzyme inhibitor captopril does not prevent acute gastrointestinal radiation damage in the rat.

Retrospective examination of acute gastrointestinal (GI) lethality in our rat bone marrow transplantation studies showed indication of a protective effect, with a dose modifying factor (DMF) of 1.06 (95% confidence interval: 0.99-1.12). A randomized study, using the same experimental design, was conducted specifically to look for GI protection. Animals were randomized into captopril or non-drug arms and irradiated in a 6-fraction total body irradiation regimen, followed by bone marrow transplantation. Rats received captopril in the drinking water at 500 mg/l (70 mg/kg/day), starting 9 days prior to irradiation and continuing throughout the experiment. The 50% lethal dose at 6 days was 20.8 (20.4-21.7) Gy in the non-drug arm and 20.6 (20.3-20.9) Gy in the captopril arm, for a DMF of 0.99 (0.94-1.04). If the randomized and historical studies are combined the DMF is 1.00 (0.93-1.05). We are unable to find any evidence that the angiotensin converting enzyme (ACE) inhibitor captopril provides protection from acute GI injury in this model. Clearly, it should not be assumed that captopril will modulate radiation reactions in all tissues.

Acute Disease↗
PubMed1997

Successful brief captopril treatment in experimental radiation nephropathy.

Experimental renal irradiation is followed by a well-defined sequence of events leading to kidney failure. Inhibitors of angiotensin-converting enzyme can prevent the structural and functional changes that occur after renal irradiation, which suggests that the renin-angiotensin system plays a key role in their evolution. We therefore evaluated captopril, used for short intervals, in a total body irradiation model of radiation nephropathy. Irradiated 7- to 8-week-old rats that were treated with captopril from 3.5 to 9.5 weeks after irradiation had better kidney function and survival than irradiated animals treated at earlier or later intervals. At 26 weeks after irradiation, kidney function of these animals was similar to that of irradiated animals treated continuously with captopril, but their subsequent survival was less. Animals irradiated at 7 to 8 weeks of age and treated with captopril from 6 to 9 weeks after irradiation had better function and survival than animals treated at earlier or later intervals. Irradiated 15-week-old animals had significant functional and survival benefit from continuous captopril treatment but no protection from a 6-week interval of therapy. We conclude that radiation nephropathy may be significantly attenuated by the use of captopril from 3.5 to 9.5 weeks after irradiation in young animals. Although older animals did not appear to benefit from a short course of captopril, these data suggest that the renin-angiotensin system is important in the sequential expression of renal radiation injury, particularly between 3.5 and 9.5 weeks after irradiation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Noncontinuous use of angiotensin converting enzyme inhibitors in the treatment of experimental bone marrow transplant nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors can be used to prevent the development of radiation nephropathy after BMT. In previous BMT nephropathy studies, ACE inhibitor therapy was started pre-BMT and continued indefinitely. In preparation for clinical trials, studies were designed to determine whether effective prophylaxis could be achieved if ACE inhibitor therapy was started after engraftment, and to determine whether ACE inhibitors needed to be given indefinitely. The present studies in our rat syngeneic BMT model showed that captopril therapy started 25 days post-BMT was as effective as therapy started prior to BMT. When ACE inhibitor therapy was discontinued 28 weeks after BMT, the protective effect was not lost if adequate control of azotemia had been maintained for 26 weeks. If adequate control of azotemia was not maintained for 26 weeks, BMT nephropathy progressed rapidly when ACE inhibitor therapy ended, and slowly when it was continued. Failure to control azotemia was a better predictor of renal failure than failure to control hypertension or proteinuria. Based on these preclinical studies, it would appear that ACE inhibitor therapy will be effective in the prophylaxis of BMT nephropathy even if begun after engraftment, and that ACE inhibitors may not need to be given indefinitely.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation.

The purpose of this study was to evaluate the effect of partial renal shielding used in conjunction with total body irradiation (TBI) on the incidence of bone marrow transplantation nephropathy (BMT Np) seen as a late sequelae after transplantation. Of 402 patients who have undergone bone marrow transplantation (BMT) at the Medical College of Wisconsin (MCW) 157 were greater than 18 years of age, received 14 Gy TBI and survived at least 100 days post-transplant. The incidence of BMT nephropathy was evaluated in these patients by dose to the kidneys. In the 72 patients who received 14 Gy TBI with no renal shielding, the actuarial risk of developing BMT Np at 2 1/2 years (30 months) post-BMT was 29 +/- 7%. Sixty-eight patients received 14 Gy TBI with partial renal shielding of 15% (renal dose = 11.9 Gy), the actuarial risk of developing BMT Np was 14 +/- 5% at 2 1/2 years. Seventeen patients received 14 Gy TBI with renal shielding of 30% (renal dose = 9.8 Gy); none of this group have developed BMT Np despite a median follow-up of over 2 1/2 years (985 days). The trend of decreasing BMT Np with increasing shielding is statistically significant (P = 0.012). Prognostic factors such as age, type of transplant and good-risk vs poor-risk disease status were evaluated and were similar in each cohort of patients described above. We conclude that given the statistically significant benefit seen here in the reduced incidence of BMT Np by the use of selective renal shielding, this should be seriously considered for all patients who receive TBI, but especially for patients whose renal doses exceed 10 Gy.

Actuarial Analysis↗
PubMed1997

Changes in rat corneal matrix metalloproteinases and serine proteinases under vitamin A deficiency.

PURPOSE: Vitamin A deficiency alters the transparency of the cornea due to epithelial cell keratinization and increases the susceptibility of the cornea to ulceration. The purpose of this study was to determine the effect of vitamin A deficiency on rat corneal matrix metalloproteinases and serine proteinases. METHODS: Four dietary groups of male WAG/RijMCW rats were prepared: (1) Vitamin A deficient rats were raised on a casein-based retinoid deficient diet; (2) Retinol repleted rats were raised on the retinoid deficient diet. On the eighty-sixth day on this diet, the rats were fed retinyl palmitate and then given free access to the retinyl palmitate-supplemented control diet; (3) The weight-matched, pair-fed rats were restricted in their intake of the retinyl palmitate-supplemented diet so that their weight gain matched that of the A-rats; (4) The non-restricted rats were given free access to the retinyl palmitate-supplemented diet. The animals were killed at the late plateau stage for weight of the deficiency (102-106 days). Zymography was used to study proteinases in the corneal extracts. RESULTS: Vitamin A deficient and control rat corneas contain multiple matrix metalloproteinases and serine proteinases. The matrix metalloproteinases at 90/92 kDa (gelatinase B) and 66/63/57 kDa (gelatinase A) were significantly decreased in the corneas of the vitamin A deficient rats relative to the control corneas. Corneas from the four groups of rats contained 76, 45, 38, 28 and 22 kDa proteinases that cleaved casein. Only the vitamin A deficient corneas contained a 50 kDa casein cleaving enzyme. The 76, 45, 38 and 28 kDa serine proteinases were significantly lower in the vitamin A deficient corneas. The major 22 kDa enzyme was not altered by the deficiency. All casein cleaving proteinases were inhibited by phenylmethylsulfonyl fluoride and chymostatin except for a minor 76 kDa band. The activity of this band was not altered by inhibitors for the other classes of proteinases, ethylenediaminetetraacetic acid, E-64 or pepstatin. The concentrations of the 61, 52 and 40 kDa plasminogen activators were not altered by the deficiency. CONCLUSIONS: Alterations in corneal proteinases under vitamin A deficiency conditions may be involved in the characteristic changes observed in the cornea under vitamin A deficiency conditions: decreased exfoliation of epithelial cells, increased levels of keratofibrils in the corneal keratocytes, increased stromal keratocyte degradation and increased susceptibility towards ulceration.

Animals↗
PubMed1997

Vitamin A deficiency alters rat neutrophil function.

Previous studies showed a higher percentage of neutrophils from vitamin A deficient rats are hypersegmented and contain lower levels of cathepsin G than the neutrophils from control rats. In this study chemotaxis, phagocytosis and oxidant generation were studied using either isolated neutrophils or neutrophils in whole blood from four dietary groups of rats: 1) vitamin A deficient rats; 2) vitamin A deficient rats that received vitamin A for 16, 8, 4 or 2 d prior to killing; 3) weight-matched rats pair-fed a vitamin A-complete diet; and 4) rats fed nonrestricted, vitamin A complete diet. Chemotaxis towards P. aeruginosa conditioned medium and formylated methinyl leucinyl phenylalanine was significantly lower for neutrophils from vitamin A-deficient rats than for neutrophils from weight-matched pair-fed rats, nonrestricted vitamin A sufficient rats and vitamin A deficient rats that received vitamin A for 16 d prior to killing. No differences in chemotaxis towards activated rat serum were noted among the neutrophils from the four groups of rats. Adhesion of P. aeruginosa organisms, phagocytosis of these organisms and generation of active oxidative molecules were significantly lower in the neutrophils from the vitamin A-deficient rats relative to these functions in the neutrophils from the vitamin A deficient rats that received vitamin A for 16 d, weight-matched rats pair-fed a vitamin A complete diet; and rats fed nonrestricted, vitamin A-complete diet. Eight days after vitamin A administration to vitamin A deficient rats, the ability of the neutrophils to phagocytose P. aeruginosa organisms and to generate active oxidant molecules was restored to the levels observed for weight-matched, pair-fed rats and rats fed nonrestricted, vitamin A complete diet. The elucidated alterations in neutrophil function in vitamin A deficient rats probably contribute to the altered ability of vitamin A deficient rats to fight infections.

Animals↗
PubMed1997

Age dependence of radiation nephropathy in the rat.

A higher incidence of radiation nephropathy is reported in pediatric than in adult patients. Preliminary experiments showed that juvenile rats had lower renal tolerance than adult rats. The experiments reported here were designed to determine the age at which tolerance changes and the magnitude of the change. Five- to 25-week-old rats were given bilateral kidney irradiation with 15-29 Gy X rays given in five fractions. Renal function was assessed 4 and 6 months after irradiation. Isoeffect doses for renal dysfunction were 15.5-17.5 Gy for rats irradiated at 5-8 weeks of age and 20.2-25.2 Gy for rats irradiated at 12+ weeks of age. At 23 Gy, rats irradiated at 5.5 weeks of age developed renal failure after 16 weeks; this increased to 21 weeks for irradiation at 7.5 weeks of age and to 27+ weeks for irradiation at 12-27 weeks of age. Renal tolerance increased steadily for irradiation at ages between 5-10 weeks, and maximum tolerance was reached by 12-15 weeks of age; a similar dependence on age at irradiation was found for bone marrow transplant nephropathy. The decrease in renal radiosensitivity with age may partially explain the increased incidence of radiation nephropathy in pediatric populations.

Age Factors↗
PubMed1996

Neutrophil cathepsin G is specifically decreased under vitamin A deficiency.

Vitamin A deficiency leads to an increased susceptibility to infections, increased severity of infections and increased mortality. Because the neutrophil is the first cell to respond to infection, this study explores the effect of vitamin A deficiency on neutrophil proteinases. We found that neutrophils from vitamin A-deficient rats had lower levels of two cathepsin G-like enzymes (28 and 24 kDa) when compared to neutrophils from weight-matched pair-fed rats, vitamin A-deficient rats which were repleted with retinyl palmitate and nonrestricted vitamin A complete diet rats. The 28 kDa cathepsin G-like enzyme, which migrated with the same mobility as elastase on SDS-polyacrylamide gels, was quantified using Western blots. The 24 kDa cathepsin G-like enzyme was quantified using zymogram gels. This activity was inhibited by chymostatin. Other neutrophil proteinases, elastase, plasminogen activators and gelatinase, were not altered significantly by vitamin A deficiency. The low levels of cathepsin G may contribute to differences in the inflammatory process observed under vitamin A deficiency.

Animals↗
PubMed1996

The role of nitric oxide in radiation nephropathy.

Sufficient radiation will cause kidney injury with hypertension, azotemia, and death from renal failure. There is early endothelial injury after radiation, which could lead to a deficit of constitutive nitric oxide (NO) synthesis, with capillary thrombosis and hypertension, both of which are seen in radiation nephropathy. In a rat radiation nephropathy model, the serial evolution of urinary cyclic guanosine monophosphate (cGMP), a marker of kidney NO, was studied and a deficit in urinary cGMP was found. This radiation-induced cGMP deficit was prevented by high-dose Captopril treatment. Low-dose Captopril treatment protected against radiation nephropathy without preventing the decrease in urinary cGMP. An inhibitor of NO synthesis, L-N-arginine-methylester, did not blunt the beneficial effect of Captopril treatment. We conclude that there is a deficit in urinary cGMP in radiation nephropathy, but that prevention of this deficit is not essential in the prevention of radiation nephropathy by Captopril.

Animals↗
PubMed1996

Retinol is sequestered in the bone marrow of vitamin A-deficient rats.

Retinoic acid bound to the nuclear retinoic acid receptor-alpha is required for the differentiation of promyelocytes to mature neutrophils. However, severely vitamin A-deficient rats have normal numbers of neutrophils in the blood and inflamed tissues. This paradox was explored using four dietary groups of rats: 1) vitamin A-deficient rats; 2) vitamin A-deficient rats subsequently receiving vitamin A; 3) weight-matched pair-fed rats; and 4) nonrestricted, vitamin A-complete diet-fed rats. Plasma and liver retinol concentrations of the vitamin A-deficient rats were < 1 % of those of the other three groups. In contrast, the bone marrow retinol concentrations of the vitamin A-deficient rats were fourfold higher than those in the other three groups. The distribution of myeloid-derived cells in the bone marrow was similar in all four groups of rats with the exception of a significantly greater (P < 0.05) occurrence of hypersegmented neutrophils (six or more lobes) in the vitamin A-deficient rats (2. 1 %) relative to the control groups (0-0.1%). The blood of the vitamin A-deficient rats also contained significantly higher numbers (P < 0.01) of hypersegmented neutrophils (67%) relative to those in the control groups (2-7%). The hypersegmentation of the neutrophils in this group of rats was not due to a concurrent deficiency of vitamin B-12 or folate. The importance of bone marrow-derived cells to the survival of the animal is suggested by retinol sequestration in the bone marrow of vitamin A-deficient rats, allowing the differentiation of myeloid cells to neutrophils.

Animals↗