ToxSci Advance Access originally published online on October 23, 2006
Toxicological Sciences 2007 95(1):289-296; doi:10.1093/toxsci/kfl138
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Pulmonary Biochemical and Histological Alterations after Repeated Low-Level Blast Overpressure Exposures
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* Department of Scientific Affairs, Hurley Consulting Associates, Chatham, New Jersey 07928
Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203
Division of Military Casualty Research, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910
1 To whom correspondence should be addressed at Celgene Corp. Summit, NJ 07901. Fax: (908) 673-2792. E-mail: nelsayed{at}celgene.com.
Received July 19, 2006; accepted October 14, 2006
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ABSTRACT |
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Blast overpressure (BOP), also known as high energy impulse noise, is a damaging outcome of explosive detonations and firing of weapons. Exposure to BOP shock waves alone results in injury predominantly to the hollow organ systems such as auditory, respiratory, and gastrointestinal systems. In recent years, the hazards of BOP that once were confined to military and professional settings have become a global societal problem as terrorist bombings and armed conflicts involving both military and civilian populations increased significantly. We have previously investigated the effects of single BOP exposures at different peak pressures. In this study, we examined the effects of repeated exposure to a low-level BOP and whether the number of exposures or time after exposure would alter the injury outcome. We exposed deeply anesthetized rats to simulated BOP at 62 ± 2 kPa peak pressure. The lungs were examined immediately after one exposure (1 + 0), or 1 h after one (1 + 1), two (2 + 1), or three (3 + 1) consecutive exposures at 3-min interval. In one group of animals, we examined the effects of repeated exposure on lung weight, methemoglobin, transferrin, antioxidants, and lipid peroxidation. In a second group, the lungs were fixed inflated at 25 cm water, sectioned, and examined histologically after one to three repeated exposures, or after one exposure at 1, 6, and 24 h. We found that single BOP exposure causes notable changes after 1 h, and that repeating BOP exposure did not add markedly to the effect of the first one. However, the effects increased significantly with time from 1 to 24 h. These observations have biological and occupational implications, and emphasize the need for protection from low-level BOP, and for prompt treatment within the first hour following BOP exposure.
Key Words: blast overpressure; explosive detonation; lung injury; repeated blast exposures; pulmonary biochemical and histological responses.
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INTRODUCTION |
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Blast overpressure (BOP) is a damaging outcome of explosive detonation and firing of weapons (Benzinger, 1950
; De Palma et al., 1991; Elsayed, 1997; Harrocks and Brett 2000; Phillips and Richmond). When an incident blast shock wave hits the body, it transmits its energy through the body wall (Benzinger, 1950) typically as two types of energy waves; shear waves and stress waves Cooper and Taylor, 1989). Shear waves are transverse waves of long duration and low velocity, capable of disrupting tissue structures when they generate local motions that overcome natural tissue elasticity (Cooper and Taylor, 1989). Stress waves are high frequency and low amplitude waves that travel in tissues faster than sound velocity where peak body wall velocity determines their amplitude. In a study using pigs, it was found that a frequency band between 0.5 and 1 kHz is generally associated with lung injury (Axelsson and Yelverton, 1996). The lungs are particularly susceptible to injury from stress waves due to "spalling" where the air/blood interfaces provide abrupt density changes from one medium to the other. Spalling is a term used by the mining industry to describe flaking or splintering of incident shock waves due to the difference between compressive and tensile strengths of the surfaces they hit. The kinetic energy of an air blast shock wave or the energy of motion of that wave can be described by the amplitude of the generated blast wave, i.e., the maximum change in pressure relative to ambient level (Elsayed, 1997; Gorbunov et al., 2004; Guy et al., 1998).
Observations in experimental animals and in humans suggest that the major primary manifestations of BOP-induced lung injury are pulmonary contusions and hemorrhagic lesions. In addition, the extravasated blood may be responsible for initiating a cascade of systemic reactions that involve expression and release of various vasoactive and proinflammatory humoral factors and vascular components (Elsayed et al., 1997b; Gorbunov et al., 2004). It has been shown previously that exposure to high-level BOP causes internal injuries with no observable external manifestations that can be lethal (Benzinger, 1950; Elsayed, 1997; Gorbunov et al., 1997; Phillips and Richmond, 1991). The most sensitive targets of BOP-induced injury are the hollow organs systems in the body such as auditory, respiratory, and gastrointestinal systems (Argyros, 1997; Benzinger, 1950; Elsayed, 1997; Gorbunov et al., 1997; Mayorga, 1997; Patterson and Hamernik, 1997; Phillips and Zajtchuck, 1991). Exposure to BOP can also affect cardiopulmonary functions (Dodd et al., 1997) and at sufficiently high amplitude can also damage solid organs such as the spleen, heart, liver, and brain (Brown et al., 1993; Clifford et al., 1984; Rössle, 1950; Sharpnack et al., 1991; Tsokos, 2003). Unprotected occupational exposures to low-level BOP primarily cause hearing loss. For example, soldiers repeatedly firing weapons or detonating high-energy munitions during operations or training, and workers in certain industries repeatedly exposed to low levels of BOP are at risk sustaining injury and hearing loss (Hamernik et al., 1987; Ylikoski and Ylikoski, 1994; Ylikoski et al., 1995). However, injuries to other organs are not well recognized. Moreover, in recent years the societal risk of exposure to BOP has increased significantly with increased frequency of terrorist bombings and military conflicts globally affecting both military and civilians alike (de Ceballos et al., 2005; Feeney et al., 2005; Hiss and Kahana, 1998; Lockey et al., 2005; Teague, 2004).
In general, BOP-induced injuries are classified as primary when caused by the sudden increase in ambient pressure, secondary when caused by objects (fragments, glass, projectiles) propelled by the blast shock waves, tertiary when caused by physical displacement of the body by the blast wind against a solid surface, and quaternary when the effects of BOP shock waves are combined with other factors such as fire, smoke, or released toxic gases causing burns and/or asphyxia (DePalma et al., 2005; Harrocks and Brett, 2000). The studies presented in this report examined only the effects of primary blast injury simulated in the laboratory at a constant amplitude and frequency.
Studies of the injury from repeated BOP exposure are scant, and are limited mostly either to explosive detonation in air simulating battlefield conditions (Vassout et al., 1978), or assessment of lethality and incapacitation in order to establish safety standards (Richmond et al., 1981). Almost none examined the biochemical mechanism of injury or the microscopic changes that may lead to structure-function alterations. Although such pioneering studies helped establish the thresholds of survivability and incapacitation in the battlefield, they did not investigate the mechanism of injury or take into consideration today's low-intensity terrorist bombings or the potential consequences of repeated occupational exposure to sublethal, low-level blasts. Other studies that examined the effects of repeated BOP exposure were limited to the auditory system and normal vital signs such as blood pressure (Hamernik et al., 1987; Ylikoski and Ylikoski, 1994; Ylikoski et al., 1995).
We have previously reported that BOP exposure results in increased lipid peroxidation and depletion of endogenous antioxidants in the blood and lung tissue of several animal species including rats, rabbits, and sheep (Elsayed et al., 1996, 1997a; Gorbunov et al., 1997). We have also observed that the lung response was peak overpressure dependent and that some biochemical perturbations continue to develop after cessation of exposure. Consequently, we proposed that free radical–mediated reactions occur after BOP exposure, and that oxidative stress may constitute an iron-dependent mechanism that could contribute to primary blast injury (Elsayed et al., 1997b; Gorbunov et al., 1997, 2003, 2004, 2005, 2006).
In the present study, we examined the effect of repeated low-level BOP exposure, similar to what may be encountered occupationally by military or civilian personnel such as demolition workers and miners on the lung response, and whether the damage from one low-level BOP exposure would accumulate if the exposure is repeated. Several military reports have indicated that the number of exposures reduces the peak pressure and duration of BOP required to induce injury. Such scenarios are often encountered in military and occupational environments; therefore, it has important implications for setting of safety standards that are mostly limited to hearing protection from high-level exposures. For example, the mortar crews are generally exposed to high peak pressure with short duration (low impulse). In contrast, large-caliber artillery crews experience low peak pressures with long durations (high impulse) suggesting that the occupational standards should represent a wide range of occupational overpressure conditions (Dodd et al., 1990).
The current criteria for nonauditory injury from blast (impulse noise) is based on the Bowen et al. (1968) curves, which form the basis for the Ammunition and Explosive Safety Standard developed by the Department of Defense accepted by the civilian occupational health community. It lists a single peak pressure of 15.8 kPa (2.3 psi) as the level over which no exposure should occur (DoD 6055.9-STD) (Department of defense, 1984). Military Standard 1474B(MI) (Department of Defense, 1979) lists a more comprehensive criteria based on peak pressure, duration number of exposures, and type of hearing protection (Dodd et al., 1990).
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METHODS |
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Animals and BOP Exposures
We purchased certified virus free, male Sprague-Dawley rats from Charles River Laboratories, Wilmington, MA. Upon arrival, the rats were housed two rats per cage on a bedding of shredded recycled paper products that was changed daily, and allowed food and water ad libitum.
Before use in the study, the animals were quarantined for 7 days according to established institutional standard operating procedures. Environmental room temperature was kept at 22 ± 2°C, and lighting was regulated to provide 12-h photoperiods. After the quarantine period, the rats were randomly divided into five groups, and anesthetized deeply before exposure using intraperitoneal injections of sodium pentobarbital, 50 mg/kg body weight (Abbott Laboratories, St Louis, MO) to avoid animal pain and discomfort.
Anesthetized rats were suspended in an orthopedic stockinet sling in front of a 30-cm (12 in.) diameter, 525-cm (17.5 in.)-long compressed air-driven shock tube as described in detail earlier (Elsayed, 1997). One group was similarly treated but not exposed to BOP and served as sham-exposed controls. The other groups were exposed to simulated BOP shock waves at a peak pressure of 62.0 ± 2 kPa (9.0 ± 0.3 psi). This peak pressure was selected based on open-field studies using charges that would result in trivial or no lung injury. One group was exposed once then euthanized immediately (group 0+0), and the remaining three groups were exposed to one, two, or three consecutive BOP exposures at 3-min intervals, then euthanized 1 h after exposure (groups 1 + 1, 2 + 1, and 3 + 1), respectively.
Biochemical Analysis
Electron Paramagnetic Resonance Spectroscopy of Intact Lung Tissue
An intact lung lobe selected for Electron Paramagnetic Resonance (EPR) spectroscopy was placed into an aluminum cylinder 60 mm long, and 4 mm inner diameter, then immersed immediately in liquid nitrogen at – 196°C. The resulting frozen tissue cast was kept at – 80°C until analyzed. Low-temperature EPR spectroscopy was conducted using a JOEL-RE1X (X-band) spectrometer (JOEL Instruments, Tokyo, Japan) fitted with a variable temperature controller (Research Specialists, Chicago, IL). The spectra were recorded at – 170°C, as described earlier (Gorbunov et al., 1997). The g-factor values were determined relative to external standards containing manganese oxide. Low-temperature EPR signals of methemoglobin (metHb) at g = 6.0 and transferrin (TR) at g = 4.3 were recorded in frozen lung tissue samples. Intensity of the signals was calculated using a program developed by David Duling at the National Institute of Environmental Health, Research Triangle Park, NC (Duling, 1994).
Preparation of Lung Tissue Homogenates
Six rats from each exposure group were used for biochemical analysis. The lungs were extracted free of major airways and connective tissues, rinsed in cold saline then blotted dry on gauze, and weighed. After recording whole lung weights, and removing one lung lobe for EPR spectroscopy as described above, the remaining lung lobes were weighed again then homogenized using a Polytron homogenizer (Kinematika GmbH, Luzern, Switzerland) in five volumes of an ice-cold medium containing 20% glycerol, 50mM KCl, 0.1mM ethylenediaminetetraacetic acid, 0.1mM phenylmethylsulphonylflouride, and 10mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, pH 7.2, and stored at – 80°C until analyzed.
Determination of endogenous antioxidants (vitamins C and E).
Vitamin C (ascorbic acid), a water-soluble vitamin, and vitamin E (
-tocopherol), a lipid-soluble vitamin, contents were determined in aliquots of lung tissue homogenate by the method of Lang et al. (1986) as described previously (Elsayed et al., 1996). Basically, protein was precipitated in an aliquot of lung tissue homogenate, using 10% acetic acid, centrifuged at 2000 x g for 10 min, and the supernatant used for high-performance liquid chromatography analysis. We used a Supelcosil LC-8 column (4.6 x 159 mm, 3 mm particle size, Supelco) and a mobile phase composed of 1:24 v/v methanol:water, pH 3.0, at a flow rate of 1.0 ml/min.
Estimation of lipid peroxidation.
Lipid peroxidation estimated as thiobarbituric acid reactive substances (TBARS) formation was determined by the method of Buege and Aust (1978), in which an aliquot of lung homogenate (0.5 ml, 1 mg protein/ml) was mixed 1:1 v/v with 30% trichloroacetic acid:0.72% thiobarbituric acid. The mixture was heated at 100°C for 20 min then centrifuged at 5000 x g for 15 min. The absorbance of the supernatant was determined at 535 nm using a Shimadzu UV 160U spectrophotometer. A molar extinction coefficient of 1.36 x 10–5M/cm was used for calculations.
Measurement of total protein content.
Total protein content was determined by the method of Lowry et al. (1951), and bovine serum albumin was used to establish the standard curve.
Histological Evaluation
Three rats from each exposure group were examined for histological alterations. In each rat, a thoracotomy was performed, and the lungs evaluated macroscopically for gross changes, then a cannula was inserted in the trachea, secured in place with silk sutures, and the lungs fixed inflated at 25 cm H2O pressure with 10% formalin-phosphate buffer. Fixed lungs were embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H&E) stain, and the sections examined under light microscopy.
Statistical Analysis
The biochemical data are presented as mean ± SD, n = 6, and the differences between the control and exposed groups were compared using one-way analysis of variance at the 95% significance level.
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RESULTS |
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All rats survived the three repeated low-level BOP exposures and body weight was not altered after exposure. Lung weights—both absolute and relative to body weight—tended to increase slightly with increasing number of exposures (3–9%) but these increases were not statistically significant.
Biochemical Changes
Examination of intact frozen lung tissue by low-temperature EPR (Fig. 1) revealed a significant increase in metHb relative to unexposed control immediately after exposure (59%, p < 0.05) that grew further by approximately four-fold after 1 h. However, the magnitude of change was not different among the three exposures. Unlike metHb, TR did not change markedly with time or with increasing number of exposures.
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The changes in lung antioxidants and lipid peroxidation as a function of the number of exposures are shown in Figure 2. While both vitamin C and E decreased following the initial blast exposure, the changes after subsequent exposures were not different from each other. Vitamin C decreased 20–60% (Fig. 2A), and vitamin E decreased 25–40% (Fig. 2B) following repeated BOP exposures. Concomitant with the decrease in endogenous antioxidants, lipid peroxidation as TBARS formation was significantly elevated (25–50%) after the three consecutive exposures (Fig. 2C). Total protein contents measured in lung tissue homogenate did not change significantly with the number of exposures or with time after exposure.
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Histological Evaluation
Gross necropsy (Fig. 3) revealed minimal visible lesions, and minimal areas of ecchymosis involving less than 10% of the lung surface (arrows).
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Microscopic evaluation of lung tissue as a function of number of exposures (Fig. 4A–4D) showed that the most common lesions observed in rat lungs after a single low-level BOP exposure were multifocal, minimal to mild alveolar hemorrhage that were scattered throughout all lung lobes. The severity of the injury did not differ markedly with increasing the number of low-level BOP exposures. However, examination of the time course of changes at 1, 6, and 24 h after exposure showed a progressive increase in the manifestations of injury including increased intraalveolar infiltration of red blood cells and ruptured alveolar walls (Fig. 5A–5E).
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DISCUSSION |
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This study attempted to answer three questions about the lung response to repeated low-level BOP exposures. First, can low-level BOP exposure cause a significant effect measurable in the lung? Second, if a significant effect occurs, does repeating the exposure have an additive effect on the injury caused by the first one? Third, does the time elapsed after a single low-level BOP exposure alter the lung response to blast exposure?
Effect of Single Exposure to Low-Level BOP
Following a single low-level BOP exposure simulated in the laboratory, we have observed that significant biochemical and histological changes occur in the lung. These changes included depletion of endogenous antioxidants coupled with increased lipid peroxidation that are typical manifestations of oxidative stress. Rupture of the alveolar walls and infiltration of red blood cells to the alveolar spaces further suggested that significant structural changes have occurred as a result of the a single sublethal low-level BOP exposure.
Along with circulatory suppression, these injuries could potentially decrease the blood oxygen carrying capacity and thus contribute to a hypoxic condition that can be either reversible or irreversible depending mostly but not solely on the amplitude of the BOP peak pressure, direction of incident shock wave when it hits the body, as well as the individual's own capacity to recover from injury (Elsayed, 1997; Guy et al., 1998). The histological alterations were coupled with the observation that metHb measured in lung tissue was significantly greater than unexposed control, consequently causing alterations in iron metabolism. This observation supports the conclusion that even low levels of BOP exposure could cause physiologically significant biochemical and histological changes potentially altering the lungs' structure and function with no apparent marked outward manifestations of injury. We have also noted that when the lungs were analyzed immediately after exposure, the biochemical and histological changes were markedly less than those seen after 1 h, suggesting that the injury continues to progress until it was measurable with the biochemical and histological markers used in this study. It is possible that by using more sensitive markers injury could be detected earlier.
The observed concomitant biochemical and histological changes further support our earlier hypothesis that oxidative stress is a major biochemical mechanism that may contribute to BOP-induced lung injury additively or synergistically (Elsayed, 1997; Elsayed and Gorbunov, 2003; Elsayed et al., 1996, 1997b; Gorbunov et al., 1997).
Effect of Number of Exposures
When we compared the biochemical and histological alterations produced by a single BOP exposure to those occurring after two or three consecutive BOP exposures, we found only slight additional increases that were not statistically significant from the effect of single exposure or from each other. Nevertheless, the response following each individual exposure was significantly different from unexposed controls. These observations suggest that lung injury occurs following the first low-level BOP exposure, and that the subsequent exposures add little to compound the initial damage already inflicted. The results also indicate that the lungs continue to display greater sensitivity to BOP damage compared to other organs including liver, kidneys, heart, and brain (unpublished observations). This may be due to the presence of the gas-tissue interface in a hollow organ (lung), which can produce changes in the character of the incident shock wave as it travels through different forms of matter (Guy et al., 1998). This response is unlike solid organs, where the presence of a liquid-tissue interface could allow for smaller variations in the shock wave or spalling as it travels through the tissue (Stuhmiller et al., 1991). These observations are particularly important occupationally in two environments. First, the military environment where soldiers during training and military operations are exposed directly or indirectly to BOP shock waves of different intensities produced by repeated firing of weapons and detonation of explosives. Second, in BOP-producing industrial environments, where workers almost exclusively use ear protection but not chest protection devices. Based on the observations of this study, those workers may be at greater risk of sustaining lung injury that may go undetected.
Effect of Time after BOP Exposure
Histological examination of serial lung tissue sections at different time points from 1- to 24-h post-BOP exposure indicated that the damage continues to increase with time. Thus, at 24 h greater infiltration of red blood cells to the damaged alveoli was observed compared to that at 1 h. Although the present study was not designed to address how the injury progresses, it is possible that it proceeds via both physical and biochemical mechanisms, whereby the effects of ruptured alveolar walls and microvessels combined with a free radical–mediated oxidative stress contribute to the observed progressive damage as proposed before (Elsayed et al., 1997a,b; Gorbunov et al., 1997). Such an effect was described by Guy et al. (1998) as a progressive pulmonary insufficiency, a condition similar to adult respiratory distress syndrome (ARDS). These authors suggested that blast-induced pulmonary insufficiency "blast lung" and delayed respiratory failure occurring 24–48 h after blast exposure represent more than simple physical disruption of the lung architecture and is unlikely to result only from primary blast exposure. Moreover, unlike ARDS, where capillary endothelium damage causes leakage of proteins and fluids to the interstitium-producing pulmonary edema, blast lungs are associated with damaged alveolar type-II cells, and loss of cellular surfactant lamellar bodies and surfactant clumping in the alveolar space (Brown et al., 1993). Dysfunctional type-II pneumocytes can have a profound effect on the lung ability for repair following injury as shown previously in inhaled oxidant-damaged lungs (Evans, 1984).
The recent observations by Gorbunov, et al. (2005, 2006) of BOP-induced inflammation and leukocyte migration following BOP exposure demonstrated that iron-catalyzed oxidative stress in the lung contributes to the induction of vasoactive nitric oxide and development of hypotension and inflammatory alterations in the lungs and peripheral blood. The redox cascades driven by these events caused remodeling of the network of the vascular endothelial adhesion molecules and promoted transendothelial migration of the inflammatory leukocytes. The indirect effects of oxidative stress included redox-dependent release of proinflammatory chemokines, cytokines, and histamine in the lungs which has been demonstrated in a variety of iron-associated lung inflammation models including blast (Gorbunov et al., 2005), ultrafine particulates (Dick et al., 2003), and endothelial cell dysfunction (Lum and Roebuck, 2001). Although those observations were concerned with inflammatory leukocyte migration, they point to the dynamic nature of the process associated with BOP-induced pulmonary injury.
In summary, exposure to low-level BOP shock waves results in oxidative stress characterized by antioxidant depletion and increased lipid peroxidation, pulmonary hemorrhage and congestion, as well as rupture and/or thickening of the alveolar walls. On the other hand, the effect of repeated low-level exposure was only slightly cumulative, i.e., it causes slightly more damage than that caused by a single exposure. These observations stress the need for effective protection from any exposure even at low-level BOP as the first line of defense, and for the need to conduct thorough examination of those exposed to blast for early identification of a possible injury. Finally, it stresses the importance of initiating prompt treatment within the first "golden" hour following BOP exposure even in the absence of external manifestations of injury.
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SUPPLEMENTARY DATA |
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Supplementary data are available online at http://toxsci.oxfordjournals.org/.
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NOTES |
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Disclaimer: The views expressed are those of the authors and do not reflect those of the Department of the Army or the Department of Defense.
The authors certify that all research involving human subjects was done under full compliance with all government policies and the Helsinki Declaration.
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ACKNOWLEDGMENTS |
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This study was conducted under a protocol approved by the Institute's Laboratory Animal Care and Use Committee in accordance with the Guide for the Care and Use of Laboratory Animals (NRC, 1996). We thank Dr Valerian Kagan at the University of Pittsburgh for the use of the Electron Spin Resonance Spectrometer, Ms. Jennifer Morris, M.A.J. Mary Cooper, and S.F.C. Myron Williams for their technical assistance, M.A.J. Fonzie Quance-Fitch for slide preparation and pathological evaluation, and Ms. Nicole Steach for editorial assistance.
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