Rapid in vitro activity of telavancin against Bacillus anthracis and in vivo protection against inhalation anthrax infection in the rabbit model.

Inhalation anthrax is the most severe form of Bacillus anthracis infection, often progressing to fatal conditions if left untreated. While recommended antibiotics can effectively treat anthrax when promptly administered, strains engineered for antibiotic resistance could render these drugs ineffective. Telavancin, a semisynthetic lipoglycopeptide antibiotic, was evaluated in this study as a novel therapeutic against anthrax disease. Specifically, the aims were to (i) assess in vitro potency of telavancin against 17 B. anthracis isolates by minimum inhibitory concentration (MIC) testing and (ii) evaluate protective efficacy in rabbits infected with a lethal dose of aerosolized anthrax spores and treated with human-equivalent intravenous telavancin doses (30 mg/kg every 12 hours) for 5 days post-antigen detection versus a humanized dose of levofloxacin and vehicle control. Blood samples were collected at various times post-infection to assess the level of bacteremia and antibody production, and tissues were collected to determine bacterial load. The animals' body temperatures were also recorded. Telavancin demonstrated potent bactericidal activity against all strains tested (MICs 0.06-0.125 µg/mL). Further, telavancin conveyed 100% survival in this model and cleared B. anthracis from the bloodstream and organ tissues more effectively than a humanized dose of levofloxacin. Collectively, the low MICs against all strains tested and rapid bactericidal in vivo activity demonstrate that telavancin has the potential to be an effective alternative for the treatment or prophylaxis of anthrax infection.

Effects of 100MeV protons delivered at 0.5 or 1cGy/min on the in vivo induction of early and delayed chromosomal damage.

Little is known about in vivo cytogenetic effects of protons delivered at the dose and dose rates encountered in space. We determined the effects of 100MeV protons, one of the most abundant type of protons produced during solar particle events (SPE), on the induction of chromosome aberrations (CAs) in bone marrow (BM) cells collected at early (3 and 24h) and late (6 months) time-points from groups of BALB/cJ mice (a known radiosensitive strain) exposed whole-body to 0 (sham-controls), 0.5, or 1.0Gy of 100MeV protons, delivered at 0.5 or 1.0cGy/min. These doses and dose-rates are comparable to those produced during SPE events. Additionally, groups of mice were exposed to 0 or 1Gy of (137)Cs γ rays (delivered at 1cGy/min) as a reference radiation. The kinetics of formation/reduction of gamma-histone 2-AX (γH2AX) were determined in BM cells collected at 1.5, 3, and 24h post-irradiation to assess the early-response. There were five mice per treatment-group per harvest-time. Our data indicated that the kinetics of γH2AX formation/reduction differed, depending on the dose and dose rate of protons. Highly significant numbers of abnormal cells and chromatid breaks (p<0.01), related to those in sham-control groups, were detected in BM cells collected at each time-point, regardless of dose or dose-rate. The finding of significant increases in the frequencies of delayed non-clonal and clonal CAs in BM cells collected at a late time-point from exposed mice suggested that 0.5 or 1Gy of 100MeV protons is capable of inducing genomic instability in BM cells. However, the extent of effects induced by these two low dose rates was comparable. Further, the results showed that the in vivo cytogenetic effects induced by 1Gy of 100MeV protons or (137)Cs γ rays (delivered at 1cGy/min) were similar.

Persistence of apoptosis and inflammatory responses in the heart and bone marrow of mice following whole-body exposure to ²8Silicon (²8Si) ions.

It has been well established that the bone marrow (BM) is a radiosensitive tissue, but the radiosensitivity of the heart is poorly understood. In this study, we investigated the comparative effects of ²8Silicon (²8Si) ions (one type of heavy ion found in space) on tissue from the heart and the BM of exposed mice. We gave adult male CBA/CaJ mice a whole-body exposure to a total dose of 0, 0.1, 0.25, or 0.5 Gy of 300 MeV/nucleon (n) ²8Si ions, using a fractionated schedule (two exposures, 15 days apart that totaled each selected dose). The heart and BM were collected from 5 mice per treatment group at various times up to 6 months post-irradiation. In each mouse, we obtained tissue lysates from the heart and from the total population of BM cells for measuring the levels of cleaved poly (ADP-ribose) polymerase (cleaved PARP, a marker of apoptotic cell death) and the levels of activated nuclear factor-kappa B (NF-κB) and selected NF-κB-regulated cytokines known to be involved in inflammatory responses. Our data showed that, up to 6 months post-irradiation, the levels of apoptotic cell death and inflammatory responses in tissues from the heart and BM collected from exposed mice were statistically higher than those in sham controls. Hence, these findings are suggestive of chronic apoptotic cell death and inflammation in both tissues after exposure to ²8Si ions. In summary, our data are indicative of a possible association between exposure to ²8Si ions during space flight and long-term health risk.

Sensorimotor adaptation training's effect on head stabilization in response to a lateral perturbation in older adults.

The goal of this study was to determine if exposure to sensorimotor adaptation training improved head stabilization in older adults. Sixteen participants, age 66-81 yr, were assigned at random to the control group (n = 8) or the experimental group (n = 8). Both groups first completed 6 trials of walking a foam pathway consisting of a moveable platform that induced a lateral perturbation during walking. Head-in-space and trunk-in-space angular velocities were collected. Participants from both groups then trained twice per week for 4 wk. Both groups walked on a treadmill for 20 min. The control group viewed a static scene. The experimental group viewed a rotating visual scene that provided a perceptual-motor mismatch. After training, both groups were retested on the perturbation pathway test. The experimental group used a movement strategy that preserved head stabilization compared with the controls (p < .05). This training effect was not retained after 4 wk.

Predictive role of arterial carboxyhemoglobin concentrations in ovine burn and smoke inhalation-induced lung injury.

Inhalation injury frequently occurs in burn patients and contributes to the morbidity and mortality of these injuries. Arterial carboxyhemoglobin has been proposed as an indicator of the severity of inhalation injury; however, the interrelation between arterial carboxyhemoglobin and histological alterations has not yet been investigated. Chronically instrumented sheep were subjected to a third degree burn of 40% of the total body surface area and inhalation of 48 breaths of cotton smoke. Carboxyhemoglobin was measured immediately after injury and correlated to clinical parameters of pulmonary function as well as histopathology scores from lung tissue harvested 24 hours after the injury. The injury was associated with a significant decline in pulmonary oxygenation and increases in pulmonary shunting, lung lymph flow, wet/dry weight ratio, congestion score, edema score, inflammation score, and airway obstruction scores. Carboxyhemoglobin was negatively correlated to pulmonary oxygenation and positively correlated to pulmonary shunting, lung lymph flow, and lung wet/dry weight ratio. No significant correlations could be detected between carboxyhemoglobin and histopathology scores and airway obstruction scores. Arterial carboxyhemoglobin in sheep with combined burn and inhalation injury are correlated with the degree of pulmonary failure and edema formation, but not with certain histological alterations including airway obstruction scores.

Effects of early neuronal and delayed inducible nitric oxide synthase blockade on cardiovascular, renal, and hepatic function in ovine sepsis.

BACKGROUND: Recent evidence suggests that nitric oxide produced via the neuronal nitric oxide synthase is involved mainly in the early response to sepsis, whereas nitric oxide derived from the inducible nitric oxide synthase is responsible during the later phase. We hypothesized that early neuronal and delayed inducible nitric oxide synthase blockade attenuates multiple organ dysfunctions during sepsis. METHODS: Sheep were randomly allocated to sham-injured, nontreated animals (n = 6); injured (48 breaths of cotton smoke and instillation of Pseudomonas aeruginosa into the lungs), nontreated animals (n = 7); and injured animals treated with a neuronal nitric oxide synthase inhibitor from 1 to 12 h and an inducible nitric oxide synthase inhibitor from 12 to 24 h postinjury (n = 6). RESULTS: The injury induced arterial hypotension, vascular leakage, myocardial depression, and signs of renal and hepatic dysfunctions. The treatment significantly attenuated, but did not fully prevent, the decreases in mean arterial pressure and left ventricular stroke work index. Although the elevation of creatinine levels was partially prevented, the decreases in urine output and creatinine clearance were not affected. The injury-related increases in bilirubin levels, international normalized ratio, and lipid peroxidation in liver tissue were significantly attenuated. Although plasma nitrite/nitrate levels were significantly increased versus baseline from 12-24 h in controls, plasma nitrite/nitrate levels were not increased in treated animals. CONCLUSIONS: The combination treatment shows potential benefit on sepsis-related arterial hypotension and surrogate parameters of organ dysfunctions in sheep. It may be crucial to identify the time course of expression and activation of different nitric oxide synthase isoforms in future investigations.

Teixobactin Provides Protection against Inhalation Anthrax in the Rabbit Model.

The use of antibiotics is a vital means of treating infections caused by the bacteria Bacillus (B.) anthracis. Importantly, with the potential future use of multidrug-resistant strains of B. anthracis as bioweapons, new antibiotics are needed as alternative therapeutics. In this blinded study, we assessed the protective efficacy of teixobactin, a recently discovered antibiotic, against inhalation anthrax infection in the adult rabbit model. New Zealand White rabbits were infected with a lethal dose of B. anthracis Ames spores via the inhalation route, and blood samples were collected at various times to assess antigenemia, bacteremia, tissue bacterial load, and antibody production. Treatments were administered upon detection of B. anthracis protective antigen in the animals' sera. For comparison, a fully protective dose of levofloxacin was used as a positive control. Rabbits treated with teixobactin showed 100% survival following infection, and the bacteremia was completely resolved by 24-48 h post-treatment. In addition, the bacterial/spore loads in tissues of the animals treated with teixobactin were either zero or dramatically less relative to that of the negative control animals. Moreover, microscopic evaluation of the tissues revealed decreased pathology following treatment with teixobactin. Overall, these results show that teixobactin was protective against inhalation anthrax infection in the rabbit model, and they indicate the potential of teixobactin as a therapeutic for the disease.

The physiologic responses of Dutch belted rabbits infected with inhalational anthrax.

Bacillus anthracis, the causative agent of anthrax, is a category A priority pathogen that causes extensive damage in humans. For this reason, B. anthracis has been the focus of numerous studies using various animal models. In this study, we explored physiologic parameters in Dutch belted rabbits with inhalation anthrax to characterize the disease progression in this model. To this end, we infected Dutch belted rabbits with 100 LD(50) B. anthracis Ames spores by nasal instillation and continuously recorded various physiologic parameters by using telemetry. In addition, samples were collected at selected times for serum chemistry, hematology, and blood gas analysis. The animals exhibited hemodynamic and respiratory changes that coincided with those reported in human cases of inhalational anthrax infection, including hypotension, altered heart rate, and respiratory distress. Likewise, hematology, serum chemistry, and blood gas analysis revealed trends comparable to human anthrax-related pathophysiology. The Dutch belted rabbit model of inhalational anthrax exhibited most of the physiologic, hematologic, and biochemical sequelae noted in human cases. Therefore, this rabbit model fulfills several of the criteria of a useful animal model for studying disease pathogenesis and evaluating therapeutics during inhalational anthrax.

gamma-Tocopherol nebulization by a lipid aerosolization device improves pulmonary function in sheep with burn and smoke inhalation injury.

Fire accident victims who sustain both thermal injury to skin and smoke inhalation have gross evidence of systemic and pulmonary oxidant damage and acute lung injury. We hypothesized that gamma-tocopherol (gT), a reactive O(2) and N(2) scavenger, when delivered into the airway, would attenuate lung injury induced by burn and smoke inhalation. Acute lung injury was induced in chronically prepared, anesthetized sheep by 40% total burn surface area, third-degree skin burn and smoke insufflation (48 breaths of cotton smoke, <40 degrees C). The study groups were: (1) Sham (not injured, flaxseed oil (FO)-nebulized, n=6); (2) SA-neb (injured, saline-nebulized, n=6); (3) FO-neb (injured, FO-nebulized, n=6); and (4) gT+FO-neb (injured, gT and FO-nebulized, n=6). Nebulization was started 1 h postinjury, and 24 ml of FO with or without gT (51 mg/ml) was delivered into airways over 47 h using our newly developed lipid aerosolization device (droplet size: 2.5-5 microm). The burn- and smoke inhalation-induced pathological changes seen in the saline group were attenuated by FO nebulization; gT addition further improved pulmonary function. Pulmonary gT delivery along with a FO source may be a novel effective treatment strategy in management of patients with acute lung injury.

Tissue-specific oxidative imbalance and mitochondrial dysfunction during Trypanosoma cruzi infection in mice.

In this study, we examined the tissue specificity of inflammatory and oxidative responses and mitochondrial dysfunction in mice infected by Trypanosoma cruzi. In acute mice, parasite burden and associated inflammatory infiltrate was detected in all tissues (skeletal muscle>heart>stomach>colon). The extent of oxidative damage and mitochondrial decay was in the order of heart>stomach>skeletal muscle>colon. In chronic mice, a low level of parasite burden and inflammation continued in all tissues; however, oxidant overload and mitochondrial inefficiency mainly persisted in the heart tissue (also detectable in stomach). Further, we noted an unvaryingly high degree of oxidative stress, compromised antioxidant status, and decreased mitochondrial respiratory complex activities in peripheral blood of infected mice. A pair-wise log analysis showed a strong positive correlation in the heart-versus-blood (but not other tissues) levels of oxidative stress markers (malonyldialdehyde, glutathione disulfide), antioxidants (superoxide dismutase, MnSOD, catalase), and mitochondrial inhibition of respiratory complexes (CI/CIII) in infected mice. T. cruzi-induced acute inflammatory and oxidative responses are widespread in different muscle tissues. Antioxidant/oxidant status and mitochondrial function are consistently attenuated in the heart, and reflected in the peripheral-blood of T. cruzi-infected mice. Our results provide an impetus to investigate the peripheral-blood oxidative responses in relation to clinical severity of heart disease in chagasic human patients.

Effects of sensorimotor adaptation training on functional mobility in older adults.

The goal of this study was to determine if prolonged exposure to perceptual-motor mismatch increased adaptability and retention of balance in older adults. Sixteen adults, aged 66 to 81 years, were randomized to one of two groups: either the control group (n=8) or the experimental group (n=8). Both groups first completed six trials of walking an obstacle course. Participants then trained twice a week for 4 weeks. In the training, the control group walked on a treadmill for 20 minutes while viewing a static visual scene and the experimental group walked on a treadmill for 20 minutes while viewing a rotating visual scene that provided a perceptual-motor mismatch. Following training, both groups were post-tested on the obstacle course. The experimental group moved faster through the obstacle course with fewer penalties. This training effect was retained for 4 weeks. Exposure to perceptual-motor mismatch induced an adaptive training effect that improved balance and locomotor control in older adults.

Persistent depletion of plasma gelsolin (pGSN) after exposure of mice to heavy silicon ions.

Little is known about plasma proteins that can be used as biomarkers for early and late responses to radiation. The purpose of this study was to determine a link between depletion of plasma gelsolin (pGSN) and cell-death as well as inflammatory responses in the lung (one of the tissues known to be radiosensitive) of the same exposed CBA/CaJ mice after exposure to heavy silicon (28Si) ions. To prevent the development of multiple organ dysfunctions, pGSN (an important component of the extracellular actin-scavenging system) is responsible for the removal of actin that is released into the circulation during inflammation and from dying cells. We evaluated the levels of pGSN in plasma collected from groups of mice (5 mice in each) at 1 week (wk) and 1 month (1 mo) after exposure whole body to different doses of 28Si ions, i.e. 0, 0.1, 0.25, or 0.5 Gy (2 fractionated exposures, 15 days apart that totaled each selected dose). In the same mouse, the measurements of pGSN levels were coupled with the quantitation of injuries in the lung, determined by (a) the levels of cleaved poly (ADP-ribose) polymerase (cleaved-PARP), a marker of apoptotic cell-death, (b) the levels of activated nuclear factor-kappa B (NF-κB) and selected cytokines, i.e. tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and IL-6, from tissue-lysates of the lung. Further, the ratio of neutrophils and lymphocytes (N/L) was determined in the same mouse. Our data indicated: (i) the magnitude of pGSN depletion was dependent to radiation dose at both harvest times, (ii) a persistent depletion of pGSN up to 1 mo post-exposure to 0.25 or 0.5 Gy of 28Si ions, (iii) an inverse-correlation between pGSN depletion and increased levels of cleaved-PARP, including activated NF-κB/pro-inflammatory cytokines in the lung, and (iv) at both harvest times, statistically significant increases in the N/L ratio in groups of mice exposed to 0.5 Gy only. Our findings suggested that depletion in pGSN levels reflects not only the responses to 28Si-ion exposure at both harvest times but also early and late-occurring damage.

Pathogenesis of extra efferent vessel development in diabetic glomeruli.

The development of extra efferent vessels (EEV) is a little-known feature of diabetic glomerulopathy. The only previous large study [Min W, Yamanaka N. Three-dimensional analysis of increased vasculature around the glomerular vascular pole in diabetic nephropathy. Virchows Archiv A Pathol Anat 1993; 423:201-7] known to us found that up to 5 EEV per glomerulus (glom) each drained a separate lobule. Most EEV connected to the second- and third-order branches of the afferent arteriole (AA), and drained into peritubular capillaries. Although not so stated, the illustrations suggested that some EEV could be shunts, and thus detrimental to glom function, and possibly glom health. There was no correlation between the unquantitated presence of increased EEV at the vascular pole (VP) and the severity of the major diabetic glomerular (glom) lesions. The authors opined that efferent arteriole (EA) stenosis by insudative lesions (IL) stimulated the formation of EEV. To confirm and extend these findings, we have repeated the study in 18 diabetic cases with mild to severe, but not end-stage, diffuse and nodular lesions (DL and NL), 8 controls, and the 2 normal traumatic nephrectomy cases. Up to 18 EEV per glom were found in diabetic cases along with occasional EEV in controls. EEV contained muscle and were almost identical to the EA in structure. Nearly all EEV connected with efferent glom capillaries at the VP, where they exited the glom through apparently preexisting gaps in the Bowman's capsule and/or glomerular capillary basement membranes (BCBM/GCBM). The EA exited through a similar gap, so the exit of EEV was accomplished without altering the anatomical relationships between the exiting vessels and the components of the VP thought to be important in the control of glom outflow. The largest number of EEV occurred in long-standing T2DM cases with mild to moderate DL and NL. Complete photographic glom reconstructions revealed numerous anastomoses among efferent glom capillaries in normal and diabetic gloms with mild to moderate DL and NL. No disproportionately dilated EEV were seen. The findings just cited confirm that EEV are common and surprisingly numerous in diabetic gloms. They suggest that EEV formation served to preserve glom function, and that EEV could neither shunt nor restrict glom outflow locally. In our opinion, the formation of EEV represents a significant, possibly hemodynamically induced, remodeling of the glom that should be added to the list of changes that occur in diabetes. It is hypothesized that EEV develop because of increased glom inflow, and that the latter may be attributable to AA muscle damage that impairs its contractile ability.

Induction of Chronic Inflammation and Altered Levels of DNA Hydroxymethylation in Somatic and Germinal Tissues of CBA/CaJ Mice Exposed to (48)Ti Ions.

Although the lung is one of the target organs at risk for cancer induction from exposure to heavy ions found in space, information is insufficient on cellular/molecular responses linked to increased cancer risk. Knowledge of such events may aid in the development of new preventive measures. Furthermore, although it is known that germinal cells are sensitive to X- or γ-rays, there is little information on the effects of heavy ions on germinal cells. Our goal was to investigate in vivo effects of 1 GeV/n (48)Ti ions (one of the important heavy ions found in the space environment) on somatic (lung) and germinal (testis) tissues collected at various times after a whole body irradiation of CBA/CaJ mice (0, 0.1, 0.25, or 0.5 Gy, delivered at 1 cGy/min). We hypothesized that (48)Ti-ion-exposure induced damage in both tissues. Lung tissue was collected from each mouse from each treatment group at 1 week, 1 month, and 6 months postirradiation. For the testis, we collected samples at 6 months postirradiation. Hence, only late-occurring effects of (48)Ti ions in the testis were studied. There were five mice per treatment group at each harvest time. We investigated inflammatory responses after exposure to (48)Ti ions by measuring the levels of activated nuclear factor kappa B and selected pro-inflammatory cytokines in both tissues of the same mouse. These measurements were coupled with the quantitation of the levels of global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Our data clearly showed the induction of chronic inflammation in both tissues of exposed mice. A dose-dependent reduction in global 5hmC was found in the lung at all time-points and in testes collected at 6 months postirradiation. In contrast, significant increases in global 5mC were found only in lung and testes collected at 6 months postirradiation from mice exposed to 0.5 Gy of 1 GeV/n (48)Ti ions. Overall, our data showed that (48)Ti ions may create health risks in both lung and testicular tissues.

Protective effect of apigenin on radiation-induced chromosomal damage in human lymphocytes.

The potential use of flavonoids as a radioprotector is of increasing interest because of their high antioxidant activity and abundance in the diet. The aim of this study is to examine genotoxic and radioprotective effects of one of the most common flavonoids, apigenin, on radiation-induced chromosome aberrations in human lymphocytes. The cytokinesis-block micronucleus (CBMN) assay was used to evaluate such effects of apigenin. Blood samples were collected from two non-smoking healthy male volunteers who had no history of previous exposure to other clastogenic agents. Isolated lymphocytes were cultured. There were two tubes per concentration for all treatments. To evaluate the genotoxicity of apigenin, cells were first treated with different concentrations of apigenin (0, 2.5, 5, 10 and 25 microg/mL) at 24 h after culture initiation, followed by cytochalasin-B (Cyt-B) treatment (3 microg/mL) and cell harvest at 44 and 72 h, respectively. Secondly, to investigate the radioprotective effect, cell cultures were exposed to different concentrations of apigenin as described above for 30 min before being irradiated to 2 Gy of 137Cs gamma rays (at a dose rate of 0.75 Gy/min). In all instances, the frequency of MN was scored in binucleated (BN) cells. The nuclear proliferation index also was calculated. We did not detect an increase in the frequency of MN in non-irradiated human lymphocyte cultures treated with 2.5, 5.0 or 10 microg/mL apigenin; although, we did observe an increase in cultures treated with 25 microg/mL apigenin (the highest concentration of apigenin used in our study). We also observed a significant increase in the frequency of MN in irradiated cells overall; however, the frequency was decreased as the concentration of apigenin increased, suggesting a radioprotective effect. These findings provide a basis for additional studies to help clarify the potential use and benefit of apigenin as a radioprotector.

Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon ((28)Si) ions.

Although myeloid leukemia (ML) is one of the major health concerns from exposure to space radiation, the risk prediction for developing ML is unsatisfactory. To increase the reliability of predicting ML risk, a much improved understanding of space radiation-induced changes in the target cells, i.e. hematopoietic stem/progenitor cells (HSPCs), is important. We focused on the in vivo induction of late-occurring damage in HSPCs of mice exposed to (28)Si ions since such damage is associated with radiation-induced genomic instability (a key event of carcinogenesis). We gave adult male CBA/CaJ mice, known to be sensitive to radiation-induced ML, a whole-body exposure (2 fractionated exposures, 15 days apart, that totaled each selected dose, delivered at the dose-rate of 1 cGy/min) to various doses of 300 MeV/n (28)Si ions, i.e. 0 (sham controls), 0.1, 0.25, or 0.5 Gy. At 6 months post-irradiation, we collected bone marrow cells from each mouse (five mice per treatment-group) for obtaining the myeloid-lineage of HSPC-derived clones for analyses. We measured the frequencies of late-occurring chromosome aberrations (CAs), using the genome-wide multicolor fluorescence in situ hybridization method. The measurement of CAs was coupled with the characterization of the global DNA methylation patterns, i.e. 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC). A dose-dependent increase in the frequencies of CAs was detected (Analysis of Variance or ANOVA, p<0.01), indicating the induction of genomic instability after exposure of mice to 300 MeV/n (28)Si ions. Slight increases in the levels of 5 mC were observed in all treatment groups, as compared to the sham-control level. In contrast, there was a significant reduction in levels of 5 hmC (ANOVA, p<0.01). Since these endpoints were evaluated in the same mouse, our data suggested for the first time a link between a reduction in 5 hmC and genomic instability in HSPC-derived myeloid colonies of CBA/CaJ mice exposed to 300 MeV/n (28)Si ions.

No Evidence for the In Vivo Induction of Genomic Instability by Low Doses of CS Gamma Rays in Bone Marrow Cells of BALB/CJ and C57BL/6J Mice.

In spite of extensive research, assessment of potential health risks associated with exposure to low-dose (≤ 0.1 Gy) radiation is still challenging. We evaluated the in vivo induction of genomic instability, expressed as late-occurring chromosome aberrations, in bone-marrow cells of two strains of mouse with different genetic background, i.e. the radiosensitive BALB/cJ and the radioresistant C57BL/6J strains following a whole-body exposure to varying doses of (137)Cs gamma rays (0, 0.05, 0.1, and 1.0 Gy). A total of five mice per dose per strain were sacrificed at various times post-irradiation up to 6 months for sample collections. Three-color fluorescence in situ hybridization for mouse chromosomes 1, 2, and 3 was used for the analysis of stable-aberrations in metaphase-cells. All other visible gross structural-abnormalities involving non-painted-chromosomes were also evaluated on the same metaphase-cells used for scoring the stable-aberrations of painted-chromosomes. Our new data demonstrated in bone-marrow cells from both strains that low doses of low LET-radiation (as low as 0.05 Gy) are incapable of inducing genomic instability but are capable of reducing specific aberration-types below the spontaneous rate with time post-irradiation. However, the results showed the induction of genomic instability by 1.0 Gy of (137)Cs gamma rays in the radiosensitive strain only.

Hemodynamic effects of anthrax toxins in the rabbit model and the cardiac pathology induced by lethal toxin.

Anthrax lethal toxin (LeTx) and edema toxin (EdTx) have been shown to alter hemodynamics in the rodent model, while LeTx primarily is reported to induce extensive tissue pathology. However, the rodent model has limitations when used for comparison to higher organisms such as humans. The rabbit model, on the other hand, has gained recognition as a useful model for studying anthrax infection and its pathophysiological effects. In this study, we assessed the hemodynamic effects of lethal toxin (LeTx) and edema toxin (EdTx) in the rabbit model using physiologically relevant amounts of the toxins. Moreover, we further examine the pathological effects of LeTx on cardiac tissue. We intravenously injected Dutch-belted rabbits with either low-dose and high-dose recombinant LeTx or a single dose of EdTx. The animals' heart rate and mean arterial pressure were continuously monitored via telemetry until either 48 or 72 h post-challenge. Additional animals challenged with LeTx were used for cardiac troponin I (cTnI) quantitation, cardiac histopathology, and echocardiography. LeTx depressed heart rate at the lower dose and mean arterial pressure (MAP) at the higher dose. EdTx, on the other hand, temporarily intensified heart rate while lowering MAP. Both doses of LeTx caused cardiac pathology with the higher dose having a more profound effect. Lastly, left-ventricular dilation due to LeTx was not apparent at the given time-points. Our study demonstrates the hemodynamic effects of anthrax toxins, as well as the pathological effects of LeTx on the heart in the rabbit model, and it provides further evidence for the toxins' direct impact on the heart.

Beneficial effect of a hydrogen sulphide donor (sodium sulphide) in an ovine model of burn- and smoke-induced acute lung injury.

BACKGROUND AND PURPOSE: The present study investigated whether the pathophysiological changes induced by burn and smoke inhalation are modulated by parenteral administration of Na(2)S, a H(2)S donor. EXPERIMENTAL APPROACH: The study used a total of 16 chronically instrumented, adult female sheep. Na(2)S was administered 1 h post injury, as a bolus injection at a dose of 0.5 mg.kg(-1) and subsequently, as a continuous infusion at a rate of 0.2 mg.kg(-1).h(-1) for 24 h. Cardiopulmonary variables (mean arterial and pulmonary arterial blood pressure, cardiac output, ventricular stroke work index, vascular resistance) and arterial and mixed venous blood gases were measured. Lung wet-to-dry ratio and myeloperoxidase content and protein oxidation and nitration were also measured. In addition, lung inducible nitric oxide synthase expression and cytochrome c were measured in lung homogenates via Western blotting and enzyme-linked immunosorbent assay (elisa) respectively. KEY RESULTS: The H(2)S donor decreased mortality during the 96 h experimental period, improved pulmonary gas exchange and lowered further increase in inspiratory pressure and fluid accumulation associated with burn- and smoke-induced acute lung injury. Further, the H(2)S donor treatment reduced the presence of protein oxidation and 3-nitrotyrosine formation following burn and smoke inhalation injury. CONCLUSIONS AND IMPLICATIONS: Parenteral administration of the H(2)S donor ameliorated the pulmonary pathophysiological changes associated with burn- and smoke-induced acute lung injury. Based on the effect of H(2)S observed in this clinically relevant model of disease, we propose that treatment with H(2)S or its donors may represent a potential therapeutic strategy in managing patients with acute lung injury.