Biomedical subjects

J E Moulder

Publications and source records attributed to J E Moulder.

At least 55 records · Page 3Linked to original sources

PubMed1996

Angiotensin II receptor antagonists in the prevention of radiation nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors can be used to prevent the development of radiation nephropathy. Current studies were designed to determine whether blocking the angiotensin II (AII) receptor, rather than preventing the creation of AII, would be effective in the prophylaxis of radiation nephropathy. Rats received 17 Gy total-body irradiation (TBI) in six fractions followed by syngeneic bone marrow transplantation (BMT). Prior to TBI the rats were randomized to groups receiving an ACE inhibitor (captopril), an AII type 1 (AT1) receptor antagonist (L-158,809) or no treatment. Renal function was assessed over 40 weeks, and a subset of animals were sacrificed for histopathology at 33 weeks. Renal function deteriorated progressively in animals receiving TBI alone, leading to renal failure by 34 weeks. Renal function was significantly better in animals receiving either captopril or L-158,809, and none of these animals had progressed to renal failure by 43 weeks. Analysis of both renal function and histopathology shows that the AII receptor antagonist is more effective than the ACE inhibitor in the prophylaxis of BMT nephropathy. This indicates that a reduction of activation of the AT1 receptor by AII, by itself, is sufficient for the prophylaxis of radiation nephropathy.

Angiotensin Receptor Antagonists↗

PubMed1996

Captopril preserves function and ultrastructure in experimental radiation nephropathy.

Captopril protects rat lung from radiation-induced pneumonitis and fibrosis and preserves function and survival in experimental radiation nephropathy. This study determined the structural benefit of captopril used preventively in radiation nephropathy. Twenty-eight Wag/RijMCW rats, divided in six groups, received 0 to 17 Gray total body irradiation followed by syngeneic bone marrow transplant. Captopril 0, 62.5, 125, 250, or 500 mg/l was given in the drinking water from the time of irradiation, and the rats were killed at 20 weeks. Using light and electron microscopy, kidneys of irradiated no-drug rats showed glomerular tuft capsular adhesions and hyalinization, focal tubular necrosis, severe interstitial fibrosis, and marked thickening and hyaline degeneration of the wall of interlobular arteries and arterioles, with intimal proliferation and periadventitial edema and inflammation. Lumens of the smaller arteries were often occluded. Significant collagen deposition was present in glomeruli, interstitium, and adventitia of interlobular arteries. Marked reduction of glomerular, tubular, vascular, and interstitial damage was seen in irradiated, captopril-treated animals, with only mild focal tubular interstitial injury and fibrosis seen. alpha smooth muscle actin-positive cells, probably myofibroblasts, were enhanced in the irradiated kidneys, and this expression was reduced in a dose-related fashion by captopril. There was also reduction in the arteriolar wall thickening, luminal occlusion, and collagen deposition in captopril-treated animals. The presence of elastin was not affected by radiation or drug treatment. Blood pressure and azotemia were lower and survival was higher in irradiated drug-treated rats compared with irradiated no-drug rats. We conclude that captopril exerts significant functional and structural protection against renal radiation injury. There was notable reduction in radiation-induced fibrosis in captopril-treated animals in this model, as in experimental lung radiation injury.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Fractionated irradiation alters enteric neuroendocrine products.

Radiation profoundly alters the contractile activity of the small intestine and colon. We hypothesized that some motor changes of the gut might be secondary to impaired neural input to smooth muscle or abnormal release of gut endocrine peptides. The density of products within peptidergic and cholinergic nerves and gut endocrine cells was estimated in six normal controls and six dogs who had received 1500 cGy in six equal fractions of 250 cGy. Choline acetyltransferase, acetylcholinesterase, vasoactive intestinal peptide (VIP), substance P, peptide YY (PYY), and motilin were measured in tissue specimens divided into mucosal-submucosal (MS) and muscularis externa (ME) layers. Tissue samples were obtained from the duodenum, jejunum, ileum, and proximal and distal colon. In addition, serum levels of motilin and PYY were determined before and during the administration of 1500 cGy in four separate dogs instrumented to record upper gut contractile activity. Intrinsic cholinergic activity as estimated by choline acetyltransferase activity was unchanged, while acetylcholinesterase activity increased in the MS layers of distal small bowel and colon. VIP was increased in the MS layers of jejunum and proximal colon as well as in the ME layers the jejunum and ileum. By contrast, substance P increased in the jejunal and proximal colonic MS layers and in the ME layers of the jejunum and ileum. Duodenal and jejunal motilin levels markedly decreased after radiation exposure, while serum motilin levels continued to cycle at a decreased peak level with migrating motor complexes. Colonic PYY remained unchanged but serum PYY levels decreased after irradiation. Increased neuronal synthesis and inhibition of neurotransmitter release are potential explanations for elevated tissue concentrations of VIP, substance P, and acetylcholinesterase. There appeared to be differences in the sensitivity of gut endocrine cells to irradiation. Changes in gut regulatory peptides and cholinergic enzyme activity occur with fractionated doses of abdominal irradiation, while the same schedule of irradiation produces striking changes in the canine small intestinal and colonic motor activity. It is therefore likely that alterations of contractile events may be produced by changes in gut neuroendocrine products.

Acetylcholinesterase↗

PubMed1995

Bone marrow transplant nephropathy: radiation nephritis revisited.

Late-onset renal failure occurs in up to 20% of survivors of bone marrow transplantation. Total body irradiation is a major factor in this syndrome, so-called bone marrow transplant nephropathy (BMT NP), which is defined by disproportionate anemia, hypertension, and azotemia. Previous or concurrent chemotherapy may potentiate the effect of radiation on the kidney. Kidney function may decline acutely or more gradually, with eventual long-term stabilization. Patient survival is associated with control of the blood pressure. BMT NP is a recognized complication of bone marrow transplantation, which will require ongoing attention.

Adolescent↗

PubMed1995

Biological effects of power-frequency fields as they relate to carcinogenesis.

There is a widespread public perception that exposure to electricity is linked to cancer. The public concern stems largely from epidemiological studies which appear to show a relationship between cancer incidence and exposure to power-frequency electromagnetic fields. This review will discuss the biophysics of power-frequency electromagnetic fields as it relates to biological effects, summarize the current state of the cancer epidemiology, and then concentrate on the laboratory studies that are relevant to addressing the possibility that power-frequency fields are carcinogenic. Review of the epidemiological evidence shows that the association between exposure to power-frequency fields and cancer is weak and inconsistent, and generally fails to show a dose-response relationship. The laboratory studies of power-frequency fields show little evidence of the type of effects on cells or animals that point towards power-frequency fields causing or contributing to cancer. Finally, from what is known about the biophysics of power-frequency fields, there is no reason to even suspect that they would cause or contribute to cancer. Application of "Hill's criteria" to epidemiological and laboratory studies shows that the evidence for a causal association between exposure to power-frequency fields and the incidence of cancer is weak.

Animals↗

PubMed1995

Correlation of radiobiological assays of hypoxic fraction with phosphorus-31 magnetic resonance spectroscopy across multiple tumor lines.

Hypoxic fractions were measured in multiple tumor models and compared to 31P magnetic resonance spectroscopy (MRS) parameters. Hypoxic fractions were measured by excision assays in intramuscular and subcutaneous RIF-1 tumors, large and small SCCVII tumors, and KHT tumors. The hypoxic fractions ranged from 3% (small SCCVII) to 21% (KHT). Measurements of 31P MRS parameters (indices of tumor metabolism) were made under the same conditions used in the hypoxic fraction assays. The PCR/Pi ratios in the five tumor models were strongly correlated (r2 = 0.98, tau = 1.00, P < 0.02) with their hypoxic fractions, and the NTP/Pi ratio was weakly correlated (r2 = 0.67, tau = 0.60, P < 0.17) with hypoxic fraction. Smaller values of the PCr/Pi and NTP/Pi ratios were found in the tumors with larger hypoxic fractions. These experiments indicate that 31P MRS may provide a relative measurement of hypoxic fractions across different tumor lines that can be applied non-invasively to individual tumors.

Animals↗

PubMed1994

Effect of nephrotoxic drugs on the development of radiation nephropathy after bone marrow transplantation.

PURPOSE: Chronic renal failure is a significant cause of late morbidity in bone marrow transplant patients whose conditioning regimen includes total body irradiation (TBI). Radiation is a major cause of this syndrome (bone marrow transplant nephropathy), but it may not be the only cause. These studies use a rat syngeneic bone marrow transplant model to determine whether nephrotoxic agents used in conjunction with bone marrow transplantation (BMT) could be enhancing or accelerating the development of radiation nephropathy. METHODS AND MATERIALS: Rats received 11-17 Gy TBI in six fractions over 3 days followed by syngeneic bone marrow transplant. In conjunction with the bone marrow transplants, animals received either no drugs, cyclosporine, amphotericin, gentamicin, or busulfan. Drugs were given in schedules analogous to their use in clinical bone marrow transplantation. Drug doses were chosen so that the drug regimen alone caused detectable acute nephrotoxicity. Animals were followed for 6 months with periodic renal function tests. RESULTS: Gentamicin had no apparent interactions with TBI. Amphotericin increased the incidence of engraftment failure, but did not enhance radiation nephropathy. Cyclosporin with TBI caused late morbidity that appeared to be due to neurological problems, but did not enhance radiation nephropathy. Busulfan resulted in a significant enhancement of radiation nephropathy. CONCLUSION: Of the nephrotoxins used in conjunction with bone marrow transplantation only radiation and busulfan were found to be risk factors for bone marrow transplant nephropathy.

Amphotericin B↗

PubMed1994

Altered motility causes the early gastrointestinal toxicity of irradiation.

PURPOSE: Total abdominal radiation produces symptoms of nausea, vomiting abdominal cramping and diarrhea. Each of these symptoms is associated with disordered intestinal motility. This article reviews studies of large and small intestinal contractile activity following radiation exposure. METHODS AND MATERIALS: Studies of motility utilize strain gauge transducers surgically implanted on the seromuscular layer of the small intestine. All studies were performed in mixed breed dogs to record the occurrence of normal contractions, giant migrating contractions (GMCs) and retrograde giant contractions (RGCs) before, during and after irradiation (22.5 Gy in 9 fractions at 3 fractions/week). Giant migrating contractions and retrograde giant contractions are infrequent in the healthy state. However, in diseased states, GMCs are associated with abdominal cramps and diarrhea, and RGCs precede vomiting. RESULTS: In fasted animals, fractionated abdominal irradiation dramatically increased the frequency of GMCs, with the incidence peaking after the second dose. The increased frequency of GMCS occurred as early as a few hours after the first radiation fraction, and returned to normal within days of cessation of radiation. RGCs were also significantly increased after abdominal irradiation. The frequency of RGCs was greatest on the first and sixth dose of radiation. Clinically, the dogs developed nausea, vomiting and diarrhea as early as the first day of irradiation. In dogs studied in the fed state, decreased amplitude, duration, and frequency of postprandial contractions occurred. These changes may slow intestinal transit during irradiation. Radiation also produced a striking increase in the frequency of colonic GMCs; these changes in colonic motor activity were associated with diarrhea as early as the second irradiation. CONCLUSION: Changes in GI motility during fractionated irradiation precede the appearance of histopathological lesions in the GI tract. Thus, the symptoms of nausea, vomiting, and diarrhea experienced during radiotherapy (particularly those within the first week) are directly related to changes in bowel motility. It is hoped that further understanding of the etiology of these distressing symptoms will help to guide their treatment.

Animals↗

PubMed1994

Prophylaxis of experimental bone marrow transplant nephropathy.

Renal radiation injury is a known complication of both local kidney irradiation and total body irradiation (TBI). TBI is felt to play an important role in the late-onset chronic renal failure seen after bone marrow transplantation in human beings. Two-hundred and eleven WAG/Rij/MCW rats underwent 0 to 20 Gy TBI followed by syngeneic bone marrow transplant (BMT). Rats received either no drug or verapamil, enalapril, or captopril in the drinking water starting 9 days before TBI and continuing thereafter. Follow-up continued up to 55 weeks after TBI/BMT. No-drug irradiated animals developed significant proteinuria 6 weeks after TBI, were azotemic by 9 weeks after TBI, and were hypertensive by 13 weeks after TBI. Survival was inversely related to the dose of TBI. There was a dose-related reduction in proteinuria, blood pressure, and azotemia with increasing doses of captopril. At 500 mg/L, captopril was more effective than 50 mg/L enalapril in controlling proteinuria, blood pressure, and azotemia and in enhancing survival of irradiated animals. Verapamil, 700 mg/L, did not control proteinuria, blood pressure, or the development of renal failure and did not enhance survival when compared with no-drug irradiated animals. We conclude that angiotensin-converting enzyme inhibitors are beneficial in preventing radiation nephropathy and that control of proteinuria may be of particular importance in preventing progression of renal failure in this model.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1993

Treatment of radiation nephropathy with ACE inhibitors.

PURPOSE: A previous study showed that radiation nephritis could be treated with captopril, an angiotensin-converting-enzyme inhibitor. These studies were designed to determine whether other angiotensin-converting-enzyme inhibitors would be effective, whether captopril would inhibit the development of the histopathologic lesions typical of radiation nephritis, and whether captopril could be used to treat the nephropathy observed in bone marrow transplant recipients conditioned with total body irradiation. METHODS AND MATERIALS: In radiation nephritis studies, rats were given 17-27 Gy bilateral renal irradiation in 5 fractions. Six months after irradiation animals were stratified by blood urea nitrogen and assigned to no treatment, or treatment with captopril (500 mg/l) or enalapril (50 mg/l) in the drinking water. A subset of animals was sacrificed for histopathology after 3 months; the remaining animals continued on drugs for 7 months. In the bone marrow transplant nephropathy study, rats received 14-17 Gy total body irradiation in 6 fractions over 3 days followed by syngeneic bone marrow transplant. Six months after irradiation, animals were stratified by blood urea nitrogen and assigned to no treatment, or treatment with captopril (500 mg/l). Animals remained on drugs for 6 months. In all studies animals were followed with periodic renal function tests. RESULTS: In the radiation nephritis study, survival and renal function were significantly enhanced by both captopril and enalapril, but there were no significant differences between the drugs. The histopathologic severity of the lesions of radiation nephritis correlated with the degree of renal dysfunction; and in irradiated animals with equal initial azotemia, captopril-treated rats developed less severe renal lesions. Finally, captopril also prolonged survival and preserved renal function in this rat bone marrow transplant nephropathy model. CONCLUSION: Angiotensin-converting-enzyme inhibitors are an effective treatment for both radiation nephritis and bone marrow transplant nephropathy.

Animals↗

PubMed1993

Clinical course of late-onset bone marrow transplant nephropathy.

Late-onset renal insufficiency is an increasingly recognized complication of bone marrow transplantation (BMT) which occurs between 6 and 12 months after BMT. This syndrome, which has occurred in 25% of our 2-year survivors, is characterized by azotemia, hypertension, and disproportionate anemia. A minority of our subjects have had a presentation similar to hemolytic-uremic syndrome, with rapid decline in kidney function. The others have had slower declines in kidney function, without apparent ongoing hemolysis. Stabilization of function has occurred in about one third of cases. Light microscopy has shown mesangial and endothelial cell dropout with widening of glomerular capillary loops. Electron microscopy has shown a striking subendothelial expansion of the glomerular basement membrane. This syndrome is similar to acute radiation nephritis. Stabilization of kidney function has occurred in some cases, perhaps reflecting control of the blood pressure. Studies of the prevention of this condition are needed because of the frequency of its occurrence and the growing number of BMT worldwide.

Adolescent↗

PubMed1993

The role of photodynamic therapy in posterior fossa brain tumors. A preclinical study in a canine glioma model.

Photodynamic therapy was studied in dogs with and without posterior fossa glioblastomas. This mode of therapy consisted of intravenous administration of Photofrin-II at doses ranging from 0.75 to 4 mg/kg 24 hours prior to laser light irradiation in the posterior fossa. Tissue levels of Photofrin-II were four times greater in the tumor than in the surrounding normal brain. Irradiation was performed using 1 hour of 500 mW laser light at a wavelength of 630 nm delivered through a fiberoptic catheter directly into the tumor bed via a burr hole. All animals receiving a high dose (4 or 2 mg/kg) of Photofrin-II developed serious brain-stem neurotoxicity resulting in death or significant residual neurological deficits. A lower dose (0.75 mg/kg) of Photofrin-II produced tumor kill without significant permanent brain-stem toxicity in either the control animals or the animals with cerebellar brain tumors receiving photodynamic therapy.

Animals↗

PubMed1993

Prophylaxis of bone marrow transplant nephropathy with captopril, an inhibitor of angiotensin-converting enzyme.

Chronic renal failure occurs in about 20% of long-term survivors treated with bone marrow transplant (BMT) regimens that include total-body irradiation (TBI); this syndrome is called BMT nephropathy. In a previous study in a syngeneic rat BMT model it was shown that captopril (an inhibitor of angiotensin-converting enzyme) could be used to treat experimental BMT nephropathy. Current studies were designed to determine whether captopril could also be used to prevent BMT nephropathy. Rats received 14 to 18.5 Gy TBI in six fractions over 3 days followed by syngeneic BMT. Seven days before TBI half the rats were started on captopril (500 mg/liter in the drinking water). Blood urea nitrogen, ratios of urine protein to creatinine, serum creatinine, and blood pressure were used to assess renal function. In animals receiving TBI alone, BMT nephropathy developed 3 to 6 months after transplant. At 6 months after TBI, captopril-treated animals had lower systolic blood pressure and better-preserved renal function than animals receiving TBI alone, with dose-modifying factors of about 1.3. The captopril treatment had no effect on bone marrow ablation by TBI. Captopril appears to be safe and effective in the prophylaxis of BMT nephropathy.

Animals↗

PubMed1992

Effects of local irradiation on spin-lattice relaxation time of phosphate metabolites in mouse tumors monitored by 31P magnetic resonance spectroscopy.

An inversion-recovery pulse sequence and solenoidal surface coil were employed to determine the spin-lattice relaxation time (T1) in murine tumors (RIF-1 and SCCVII). Reduction in T1s of inorganic phosphate (Pi) and nucleotide triphosphates (NTP) has been observed in irradiated tumors compared with unirradiated tumors. The reduction is accompanied by tumor regression and improved tumor energetic status in both tumor lines. The results of the T1 measurement of phosphate metabolites in tumors suggest that partial saturation effects may exist in spectra and could effect quantitative analysis when short repetition time is used. The reduction in T1s of Pi and NTP may be attributed to the active biochemical exchange and better tumor oxygenation in irradiated tumors.

Animals↗

PubMed1992

Influence of renal shielding on the incidence of late renal dysfunction associated with T-lymphocyte deplete bone marrow transplantation in adult patients.

Late renal dysfunction following allogeneic bone marrow transplantation has been described by a number of centers including our own. Total body irradiation appears to play a major causative role in the development of this syndrome. In an effort to decrease the incidence of this renal toxicity we have added customized partial transmission renal blocking to our total body irradiation regimen. This partial renal shielding decreases the total dose to the kidneys from 14 Gy to 12 Gy. This report compares 71 adult patients who have received total body irradiation associated with bone marrow transplantation using renal shielding with 72 adult patients who were treated without the shielding; all of the patients have survived a minimum of 100 days post-BMT. Eighteen months following BMT, 26% of patients who did not have renal shielding have developed late renal dysfunction compared to only 6% of patients with renal shielding (p less than .05). Median follow-up in the nonblocked patients is 536 days post-transplant versus 341 days for the blocked patients. This added renal blocking has not adversely affected engraftment rates or relapse rates to date. Customized renal shielding as part of 14 gray total body irradiation in preparation for bone marrow transplantation appears to have decreased the incidence of late renal dysfunction in this group of adult patients and should be considered for all patients undergoing total body irradiation in conjunction with bone marrow transplantation.

Adolescent↗

PubMed1992

Effects of fractionated doses of ionizing radiation on colonic motor activity.

The colonic motor effects of fractionated irradiation were studied in five conscious dogs. Seven colonic and two ileal strain gauge transducers were implanted. After control recordings, an abdominal dose of 250 cGy was administered three times a week on alternate days for three successive weeks (total dose 2,250 cGy). Recordings were then continued for 3 wk after the completion of radiation. Colonic giant migrating contractions (GMCs) occurred at a frequency of 0.15 +/- 0.05 contractions/h in the control state. Only one of these contractions (8.3%) originated in the small bowel and propagated into the colon. Abdominal field irradiation significantly increased the incidence of colonic GMCs to 0.51 +/- 0.11 contractions/h (P < 0.05). Fifty-four percent of GMCs originated in the small intestine. GMCs during the radiation schedule were associated with explosive diarrhea on seven occasions. Irradiation did not alter the frequency of colonic migrating motor complexes, but the mean duration of contractile states decreased in the middle and distal colon. Diarrhea occurred as early as the second dose of radiation. Pathological changes in the colon were correlated with motor activity. Both small intestinal and colonic GMCs reverted to control frequencies after cessation of radiation exposure. Abdominal irradiation significantly altered the contractile activity of the colon. These changes are associated with abdominal cramping and diarrhea.

Animals↗

PubMed1992

Treatment of radiation nephropathy with captopril.

Both experimental and clinical radiation nephropathy are typically progressive, evolving to kidney failure over weeks to months. Other late radiation injuries (spinal cord, lung) are also progressive and have no known specific antidote. Recent reports of the efficacy of captopril in modifying radiation injury of the lung prompted this trial of captopril in treating established radiation nephropathy. Six months after 15-27 Gy in 12 fractions bilateral renal irradiation, 72 rats with blood urea nitrogen > 4.1 mmol/liter were started on captopril (500 mg/liter) or no drug in the drinking water. Subsequent survival was significantly enhanced in rats receiving captopril as opposed to no drug (P = 0.0013), and the rate of rise of blood urea nitrogen was significantly diminished (P < 0.0001) in the animals on captopril. Urine protein excretion was also reduced from initially elevated levels in the rats on captopril compared to levels in rats given no drug. We conclude that captopril therapy preserves kidney function, reduces proteinuria, and enhances survival in experimental radiation nephropathy.

Animals↗

PubMed1992

A decade of changes in radiation protection.

Although radiation protection standards have changed remarkably little over the past decade, there have been changes in our understanding of radiation hazards that may affect the practice of radiation medicine over the next decade. With recognition of indoor radon exposure has come a new focus for public health concerns, because it is now clear that radon rather than medical exposure is the largest controllable source of radiation exposure to the general public. Continued follow-up of irradiated populations has led to an increase in our estimate of the cancer risk for high-dose exposures; this increased risk estimate is, in turn, leading to decreases in radiation exposure limits. Although our concern about the carcinogenic risk for radiation exposure has increased, our concern about genetic consequences has decreased, because no genetic effects have yet been observed in the offspring of atomic bomb survivors. Studies of atomic bomb survivors have also led to a change in the focus of concern over prenatal radiation exposure; the principle risk now appears to be mental retardation rather than childhood cancer.

Accidents↗