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Biomedical subjects

J E Moulder

Publications and source records attributed to J E Moulder.

At least 19 recordsLinked to original sources
PubMed2005

Mobile phones, mobile phone base stations and cancer: a review.

There have been reports in the media and claims in the courts that radiofrequency (RF) emissions from mobile phones are a cause of cancer, and there have been numerous public objections to the siting of mobile phone base antennas because of a fear of cancer. This review summarizes the current state of evidence concerning whether the RF energy used for wireless communication might be carcinogenic. Relevant studies were identified by searching MedLine with a combination of exposure and endpoint terms. This was supplemented by a review of the over 1700 citations assembled by the Institute of Electrical and Electronics Engineers (IEEE) International Committee on Electromagnetic Safety as part of their updating of the IEEE C95.1 RF energy safety guidelines. Where there were multiple studies, preference was given to recent reports, to positive reports of effects and to attempts to confirm such positive reports. Biophysical considerations indicate that there is little theoretical basis for anticipating that RF energy would have significant biological effects at the power levels used by modern mobile phones and their base station antennas. The epidemiological evidence for a causal association between cancer and RF energy is weak and limited. Animal studies have provided no consistent evidence that exposure to RF energy at non-thermal intensities causes or promotes cancer. Extensive in vitro studies have found no consistent evidence of genotoxic potential, but in vitro studies assessing the epigenetic potential of RF energy are limited. Overall, a weight-of-evidence evaluation shows that the current evidence for a causal association between cancer and exposure to RF energy is weak and unconvincing. However, the existing epidemiology is limited and the possibility of epigenetic effects has not been thoroughly evaluated, so that additional research in those areas will be required for a more thorough assessment of the possibility of a causal connection between cancer and the RF energy from mobile telecommunications.

Animals↗
PubMed2004

Post-irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review.

PURPOSE: Events of the recent past have focused attention on the possibility of radiological (nuclear) terrorism and on the implications of such terrorist threats for radiation accident preparedness. This review discusses recent advances in the knowledge about how radiation injuries from such events might be treated pharmacologically, and the practical barriers to clinical utilization of these approaches. CONCLUSIONS: A wide range of pharmacological approaches are being developed in the laboratory that could greatly expand the ability to treat acute and chronic radiation injuries. However, there are currently a variety of practical and legal barriers that would prevent the actual clinical use of most of the approaches. There are also the potential weaknesses in most of the current programmes for dealing with the consequences of radiation accidents or nuclear terrorism, including the absence of widespread radiation biodosimetry capabilities and the resulting inability to triage. If a major radiation accident or terrorist event occurs, the lack of biodosimetry and treatment capabilities will be compounded by widespread public fear of 'radiation'.

Abnormalities, Radiation-Induced↗
PubMed2003

ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Angiotensin Receptor Antagonists↗
PubMed2002

Dietary sodium modification and experimental radiation nephropathy.

PURPOSE: To determine whether suppression of the renin-angiotensin system (RAS) with high dietary sodium (salt) has the same beneficial effect on radiation nephropathy as suppression of the RAS with angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II (AII) receptor antagonists. MATERIALS AND METHODS: Normal and irradiated rats were placed on high- or low-salt diets and assessed for effects on blood pressure, on AII levels and on the development of radiation nephropathy. RESULTS: In unirradiated animals, a high-salt diet suppressed AII and caused hypertension, while a low-salt diet produced no detectable effects. Use of a high-salt diet 3-9 weeks after irradiation exacerbated radiation-induced hypertension but attenuated the development of radiation nephropathy. Continuous use of a high-salt diet slowed the progression of radiation nephropathy, but eventually exacerbated radiation-induced hypertension and accelerated renal failure. Use of a high-salt diet in animals with established radiation nephropathy was deleterious. A low-salt diet had no effect on the development of radiation nephropathy. CONCLUSIONS: These studies provide further support for the hypothesis that the beneficial effect of AII receptor antagonists, ACE inhibitors and high dietary sodium in the prophylaxis of radiation nephropathy is due to their suppression of the RAS, not to their anti-hypertensive effects.

Angiotensin Receptor Antagonists↗
PubMed2001

Loss of renal function following bone marrow transplantation: an analysis of angiotensin converting enzyme D/I polymorphism and other clinical risk factors.

Chronic renal failure is an acknowledged late complication of BMT. It is related to the intensive chemotherapy, radiation and supporting medications. Polymorphism in the angiotensin converting enzyme (ACE) gene is associated with progression of nephropathy caused by diabetes and IgA nephropathy. We sought to determine whether ACE genotype and other clinical factors were associated with loss of renal function after BMT. We determined the genotype of 106 adult allogeneic BMT recipients, who received a similar preparative regimen, survived 1 year, and had assessment of renal function up to 3 years after BMT. We found that the distribution of genotypes was similar to the general population; 29%, 51%, and 20% for the DD, DI, and II genotypes, respectively. There was no statistical difference in patient survival between the three groups. Among all patients, the average creatinine clearance declined from 124 (95% CI 117, 131) to 89 (95% CI 78, 100) ml/min over the 36 months after BMT. Decline in renal function over time was less for patients with the DD compared to the II genotype (P = 0.040). Renal function in patients with the DD genotype was also better than those with the DI genotype, but this was of borderline statistical significance (P = 0.055). Renal shielding reduced decline in renal function compared to no shielding (P = 0.026). We conclude that the ACE genotype does not seem to influence survival, but the DD genotype may be protective against renal injury after BMT. Furthermore, we confirm that renal shielding during TBI reduces the renal injury after BMT.

Adolescent↗
PubMed2001

Parathyroidectomy in chronic renal failure: has medical care reduced the need for surgery?

Subtotal or total parathyroidectomy is sometimes required for the management of severe secondary or tertiary hyperparathyroidism. Advances in medical and dialysis care may have a beneficial effect on hyperphosphatemia and vitamin D status, which could, in turn, reduce the need for parathyroidectomy. We used the United States Renal Data System to test this hypothesis. We found that the percentage of prevalent end-stage renal disease patients undergoing subtotal or total parathyroidectomy has declined significantly from 1988 to 1998. It is likely that improved medical and dialysis care has enabled this result.

Databases as Topic↗
PubMed2001

Prevention of radiation-induced nephropathy and fibrosis in a model of bone marrow transplant by an angiotensin II receptor blocker.

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.

Aldosterone↗
PubMed2001

Early detection of radiation-induced glomerular injury by albumin permeability assay.

Renal irradiation leads predictably to glomerular vascular injury, cell lysis, matrix accumulation, sclerosis and loss of renal function. The immediate effects of renal irradiation that may be associated with glomerular pathology and proteinuria are not clear in the human disease or its rat model. We hypothesized that radiation-induced injury causes immediate and subtle alterations in glomerular physiology independent of the neurohumoral and hemodynamic regulatory mechanisms. We employed a sensitive in vitro functional assay of glomerular albumin permeability (P(alb)) to demonstrate radiation-induced damage to the glomerular filtration barrier immediately after total-body irradiation of rats. In blinded experiments, control rats were sham-treated, and experimental rats received 9.5 Gy X rays. Rats were killed humanely at 1 h to 9 weeks after irradiation and glomeruli were isolated. In parallel experiments, glomeruli were isolated from normal rats and irradiated in vitro. The change in glomerular capillary permeability due to an experimental oncotic gradient was determined using videomicroscopy and P(alb) was calculated. Results show that in vivo or in vitro irradiation of glomeruli caused an increased P(alb) at 1 h. Increased P(alb) was observed up to 3 weeks after irradiation. Glomeruli from mice irradiated with 9.5 or 19.0 Gy X rays did not show increased P(alb) at 1 h postirradiation. We conclude that glomerular protein permeability of irradiated rats increases in a dose-dependent manner immediately after irradiation and that it appears to be independent of hemodynamic or systemic influences.

Albumins↗
PubMed2001

Induction of heme oxygenase 1 in radiation nephropathy: role of angiotensin II.

Datta, P. K., Moulder, J. E., Fish, B. L., Cohen, E. P. and Lianos, E. A. Induction of Heme Oxygenase 1 in Radiation Nephropathy: Role of Angiotensin II. Radiat. Res. 155, 734-739 (2001). In a rat model of radiation-induced nephropathy, we investigated changes in expression of heme oxygenase 1 (Hmox1, also known as HO-1), an enzyme that catalyzes conversion of heme into biliverdin, carbon monoxide and iron. The study explored whether radiation induces Hmox1 expression in the irradiated kidney and whether angiotensin II (AII) mediates Hmox1 expression in glomeruli isolated from irradiated kidneys. To assess the effects of radiation on Hmox1 expression, rats received 20 Gy bilateral renal irradiation and were randomized to groups receiving an AII type 1 (AT(1)) receptor antagonist (L-158,809) or no treatment. Drug treatment began 9 days prior to bilateral renal irradiation and continued for the duration of the study. Estimation of Hmox1 levels in glomerular protein lysates assessed by Western blot analysis revealed a significant increase in Hmox1 protein at 50 and 65 days postirradiation. In animals treated with the AT(1) receptor antagonist, there was no induction of Hmox1, suggesting that AII may be a mediator of Hmox1 induction. To confirm that AII stimulates Hmox1 expression, animals were infused with 200, 400 or 800 ng/kg min(-1) of AII for 18-19 days, and Hmox1 protein levels in glomeruli were assessed. There was a significant induction of Hmox1 in glomeruli of animals infused with 800 ng/kg min(-1) of AII. These studies demonstrate that glomerular Hmox1 expression is elevated in the middle phase of radiation nephropathy and that AII can increase glomerular Hmox1 levels.

Angiotensin II↗
PubMed2000

MRI measurements correctly predict the relative effects of tumor oxygenating agents on hypoxic fraction in rodent BA1112 tumors.

PURPOSE: We evaluate whether magnetic resonance imaging (MRI) with blood oxygenation level-dependent (BOLD) contrast correctly predicts the relative effects of tumor-oxygenating agents on hypoxic fraction in BA1112 rhabdomyosarcomas in WAG/Rij rats. METHODS AND MATERIALS: The response of ten tumors to carbogen (95% O(2)/5% CO(2)), a perfluorocarbon emulsion (PFC), and the combination of PFC + carbogen was studied with high spectral and spatial resolution MR imaging of the water resonance at 4.7 Tesla. Decreases in MR signal linewidth indicate increases in tumor blood oxygen levels. RESULTS: Average MR signal linewidth was decreased 2.0% by carbogen, 2.5% by PFC + air, and 4.9% by PFC + carbogen. PFC + carbogen caused a larger linewidth decrease than either treatment alone (p < 0.04 by ANOVA). Maps of pixels responding to treatment indicate that combining PFC with carbogen significantly enlarges the area of the tumor in which oxygen levels are increased (p < 0.01 by ANOVA). CONCLUSION: MRI predicts that PFC + carbogen will increase radiosensitivity more than either treatment alone; this agrees with the known effects of these treatments on hypoxic fraction. Utilizing MRI to choose the treatment that maximizes the size and extent of increases in tumor oxygenation could reduce hypoxic fraction.

Animals↗
PubMed2000

Stenotic glomerulotubular necks in radiation nephropathy.

Fibrosis of the renal interstitium is well correlated with kidney function and a greater extent of fibrosis predicts renal failure. Recent work has shown striking fibrotic constrictions at the glomerulotubular neck in porcine radiation nephropathy and in Wegener's granulomatosis in man. The present studies were designed to identify stenotic necks in a third species and to evaluate the effect of captopril treatment. Experimental radiation nephropathy was established with 17 Gy total body irradiation of barrier-maintained rats. Kidneys were obtained at 99 and 203 days for histology, using perfusion fixation. There was renal injury, with a rise in BUN, as expected, which was attenuated by captopril treatment. There was stenotic neck formation at 99 and 203 days. Captopril did not influence the absolute fraction of necks that were stenotic but it did prevent the evolution of glomeruli with necks to atubular glomeruli. It is concluded that stenosis of the glomerulotubular neck is a general phenomenon of any scarring kidney disease; that stenotic necks are probably an intermediate step in the evolution towards atubular glomeruli; and that timely use of captopril may prevent the progression of a stenotic neck towards an atubular glomerulus.

Animals↗
PubMed2000

Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker.

PURPOSE: This report summarizes our experiences on the protective effect of angiotensin-converting enzyme (ACE) inhibitors, especially captopril and an angiotensin II type 1 receptor blocker on radiation-induced pulmonary injury. METHOD: In the first series of experiments, adult male Sprague Dawley rats were given a single dose of either 20 or 30 Gy of gamma rays to a 35 cm2 right hemithorax port, whilst shielding the left, contralateral, lung. Perfusion scans and autopsies were performed at intervals up to 12 months post-radiation. Three different ACE inhibitors, penicillamine and pentoxifylline were given as radiation protectors and their activity compared. A model of irradiation for total bone marrow transplant (BMT) was used for the second group of experiments. Male WAC/Rij/MCW rats received total-body irradiation and a regimen of cyclophosphamide (CTX) in preparation for bone marrow transplant. The modifiers were two ACE inhibitors, captopril and enalapril, and L-158,809, an angiotensin II (A II) type 1 receptor blocker. All drugs were administered in the rats' drinking water and all were well-tolerated. RESULTS: In the irradiated rats, pulmonary damage progressed from the presence of blebs and detachment from basement membranes of endothelial cells a few days after injury, to severe arteritis and interstitial collagen deposition at 3 months, and then on to severe pneumonitis and extensive pulmonary fibrosis at 6 months. Marked increase of hydroxyproline was also found in the lungs at 6 months. These morphological changes were associated with significant decrease of ACE and plasminogen activator activity (PLA) and a marked increase of prostaglandins (PG12) and thromboxane (Txa2), substances considered as indicators of endothelial pulmonary damage. ACE inhibitors captopril, CL 24817, enalapril and CGS 13945 prevented the markers of endothelial dysfunction. Captopril and CL 24817, which contain a sulphydryl (-SH) radical in their moiety and the AII type 1 receptor blocker, L-158,809, were the most efficient in protecting the lung parenchyma from the inflammatory response and subsequent fibrosis. Penicillamine, an SH-containing compound with weak ACE inhibitory activity was also a strong antifibrotic agent but showed only modest anti-inflammatory properties. Additionally, in the irradiated rats, captopril also reduced the incidence of squamous cell skin carcinomas and subcutaneous sarcomas consequent to the highest doses of radiation. CONCLUSION: ACE inhibitors and one AII type 1 receptor blocker were effective in protecting lungs from radiation-induced pneumonitis and the development of lung fibrosis in two models of rat radiation injury. In the first series of experiments (unilateral irradiation), those ACE inhibitors containing a sulphydryl radical were more effective than those without it. This observation led to the question of whether this protective effect is related to inhibition of AII synthesis or rather to some of the collateral pharmacologic properties of these drugs, such as anti-oxidation or protease inhibition. The AII receptor blocker, however, was shown to be equally effective, if not better, in its antifibrotic capacity than any ACE inhibitor with or without an SH radical, reaffirming the role of AII in modulation of collagen synthesis.

Angiotensin Receptor Antagonists↗
PubMed2000

The electric and magnetic fields research and public information dissemination (EMF-RAPID) program.

In the United States, public concern that exposure to power-line fields was linked to cancer led to the establishment of a Congressionally mandated program, the Electric and Magnetic Fields Research and Public Information Dissemination (EMF-RAPID) Program. A major goal of the program was to "determine whether or not exposures to electric and magnetic fields produced by the generation, transmission, and use of electrical energy affect human health". Between 1994 and 1998, the EMF-RAPID program spent approximately $41 million on biological research. Much of the work funded by the EMF-RAPID program has not yet been published in the peer-reviewed literature. The U.S. National Institute of Environmental Health Sciences (NIEHS) asked that Radiation Research publish this special issue in an attempt to remedy this publication gap. The issue includes reviews of studies that were done to assess the biological plausibility of claims that power-frequency fields caused leukemia and breast cancer. The issue continues with two teratology studies and one immunology study. The section of the issue covering in vitro studies begins with an overview of the efforts NIEHS made to replicate a wide range of reported effects of power-frequency fields and continues with four papers reporting the absence of effects of power-frequency fields on the expression of stress-response genes and oncogenes. Other reports of in vitro studies and studies of mechanisms cover cytotoxicity, gap junction intracellular communication, calcium ion transport across the plasma membrane, and intracellular electric fields.

Animals↗
PubMed1999

Angiotensin II infusion exacerbates radiation nephropathy.

We hypothesized that angiotensin II will exacerbate radiation nephropathy in a time-specific manner. Experimental radiation nephropathy is treatable with angiotensin-converting enzyme inhibition or angiotensin II (AII) receptor blockers. These interventions are particularly important between 3 and 10 weeks after irradiation. We therefore undertook studies in which AII infusions were given at particular intervals after irradiation. Rats received total body irradiation (TBI) plus syngeneic bone marrow transplantation followed (or not) by AII infusion at 200 or 400 ng/kg/min. Infusions were given from 0 to 4 or 4 to 8 weeks after irradiation. An additional group was unirradiated but infused at 800 ng/kg/min for 8 weeks. Kidney function was assessed over 26 weeks, and histology was evaluated after the animals were killed. AII infusion alone did not cause azotemia. There was transient hypertension during AII infusion at 800 ng/kg/min but only minor histologic injury. Irradiation caused azotemia and hypertension, which were not exacerbated by AII infusion at 200 ng/kg/min. Irradiation plus AII infusion at 400 ng/kg/min from 4 to 8 weeks after TBI caused significantly greater azotemia than irradiation alone or irradiation with AII infusion from 0 to 4 weeks. The blood pressure was higher in irradiated rats infused with AII from 4 to 8 weeks. Arteriolar fibrinoid necrosis was a prominent feature in kidneys of rats infused with AII from 4 to 8 weeks after TBI. The worsening of radiation nephropathy by AII infusion from 4 to 8 weeks after irradiation strongly supports the idea of specific and sequential events in the pathogenesis of kidney failure in this model. Hypertension may play a role in these events in addition to the effect of AII alone. The occurrence of arteriolar fibrinoid necrosis in the irradiated, 4-to-8-week-infused animals suggests that vascular injury during that interval determines later outcome.

Angiotensin II↗
PubMed1999

TGF-beta 1 production in radiation nephropathy: role of angiotensin II.

PURPOSE: Angiotensin II receptor antagonists are effective in the prophylaxis of radiation nephropathy. Studies were designed to determine whether TGF-beta 1, a fibrogenic cytokine, plays a role in mediating the protective effect of AII antagonism. These studies explored the time-course of glomerular TGF-beta 1 production in the irradiated kidney, and whether AII mediates TGF-beta 1 production in glomeruli isolated from irradiated rats. MATERIALS AND METHODS: Rats received 20 Gy of bilateral renal irradiation in five fractions and were randomized to receive an AII type 1 receptor antagonist (L-158,809) at 20mg/l in their drinking water, or no treatment. Drug therapy began 9 days prior to irradiation and continued for the duration of the study. RESULTS: Analysis of renal function showed a significant increase in urinary proteinuria and blood urea nitrogen by 37 days and 63 days after irradiation, respectively. Estimation of glomerular TGF-beta1 levels by quantitative sandwich enzyme immunoassay technique revealed a significant increase in latent but not active TGF-beta 1 levels at 50 days and 63 days after irradiation. In animals treated with the AT1 receptor antagonist, there was a complete elimination in the rise of TGF-beta 1. CONCLUSIONS: These studies demonstrate that glomerular TGF-beta 1 production is elevated in the course of radiation nephropathy, and that AII mediates this induction of TGF-beta 1.

Angiotensin II↗
PubMed1999

Cell phones and cancer: what is the evidence for a connection?

There have been allegations in the media and in the courts that cell phones and other types of hand-held transceivers are a cause of cancer. There have also been numerous public objections to the siting of TV, radio and cell phone transmission facilities because of a fear of cancer induction. A recent publication in Radiation Research by Repacholi et al. (147, 631-640, 1997) which suggests that exposure to radiofrequency (RF) radiation may increase lymphoma incidence in mice has contributed to this controversy. The goal of this review is to provide biomedical researchers a brief overview of the existing RF radiation-cancer studies. This article begins with a brief review of the physics and technology of cell phones. It then reviews the existing epidemiological studies of RF radiation, identifying gaps in our knowledge. Finally, the review discusses the cytogenetics literature on RF radiation and the whole-animal RF-radiation carcinogenesis studies. The epidemiological evidence for an association between RF radiation and cancer is found to be weak and inconsistent, the laboratory studies generally do not suggest that cell phone RF radiation has genotoxic or epigenetic activity, and a cell phone RF radiation-cancer connection is found to be physically implausible. Overall, the existing evidence for a causal relationship between RF radiation from cell phones and cancer is found to be weak to nonexistent.

Animals↗