Evaluating digestibility and toxicity of native warm-season grasses for equines.

Introduced cool-season grasses are dominant in Virginia's grasslands, but their high digestible energy and nonstructural carbohydrate (NSC) levels pose a risk for horses prone to obesity and laminitis. Native warm-season grasses (NWSGs) have lower digestible energy and NSC levels that may be more suitable for horses susceptible to laminitis. Although NWSGs have desirable characteristics, they are novel forages for horses. Little is known about NWSG intake or potential toxicity to horses or how grazing by horses may affect NWSG swards. The overall objectives of this research were to 1) assess voluntary intake, toxicological response, and apparent digestibility of NWSG hays fed to horses; and 2) evaluate the characteristics of three NWSG species under equine grazing. For the first objective, a hay feeding trial using indiangrass (IG) (Sorghastrum nutans) and big bluestem (BB) (Andropogon gerardii) was conducted with nine Thoroughbred geldings in a replicated 3 × 3 Latin square design. Voluntary dry matter intake of IG and BB hays by horses were 1.3% and 1.1% of BW/d, lower than orchardgrass (Dactylis glomerata), an introduced cool-season grass, at 1.7% of BW/d (P = 0.0020). Biomarkers for hepatotoxicity remained within acceptable ranges for all treatments. Apparent dry matter digestibility (DMD) did not differ among hays, ranging from 39% to 43%. NSC levels ranged from 4.4% to 5.4%, below maximum recommended concentrations for horses susceptible to laminitis. For the second objective, a grazing trial was conducted comparing IG, BB, and eastern gamagrass (EG) (Tripsacum dactyloides) yields, forage losses, changes in vegetative composition, and effects on equine bodyweight. Nine, 0.1-ha plots were seeded with one of the three native grass treatments, and each plot was grazed by one Thoroughbred gelding in two grazing bouts, one in July and another in September 2019. IG had the greatest available forage, at 4,340 kg/ha, compared with 3,590 kg/ha from BB (P < 0.0001). EG plots established poorly, and had only 650 kg/ha available forage during the experiment. Grazing reduced standing cover of native grasses in IG and BB treatments by about 30%. Horses lost 0.5-1.5 kg BW/d on all treatments. Findings suggest IG and BB merit further consideration as forages for horses susceptible to obesity and pasture-associated laminitis.

Z chromosome divergence, polymorphism and relative effective population size in a genus of lekking birds.

Sex chromosomes contribute disproportionately to species boundaries as they diverge faster than autosomes and often have reduced diversity. Their hemizygous nature contributes to faster divergence and reduced diversity, as do some types of selection. In birds, other factors (mating system and bottlenecks) can further decrease the effective population size of Z-linked loci and accelerate divergence (Fast-Z). We assessed Z-linked divergence and effective population sizes for two polygynous sage-grouse species and compared them to estimates from birds with various mating systems. We found lower diversity and higher FST for Z-linked loci than for autosomes, as expected. The π(Z)/π(A) ratio was 0.38 in Centrocercus minimus, 0.48 in Centrocercus urophasianus and 0.59 in a diverged, parapatric population of C. urophasianus, a broad range given the mating system among these groups is presumably equivalent. The full data set had unequal males and females across groups, so we compared an equally balanced reduced set of C. minimus and individuals pooled from both C. urophasianus subgroups recovering similar estimates: 0.54 for C. urophasianus and 0.38 for C. minimus. We provide further evidence that N(eZ)/N(eA) in birds is often lower than expected under random mating or monogamy. The lower ratio in C. minimus could be a consequence of stronger selection or drift acting on Z loci during speciation, as this species differs strongly from C. urophasianus in sexually selected characters with minimal mitochondrial divergence. As C. minimus also exhibited lower genomic diversity, it is possible that a more severe demographic history may contribute to its lower ratio.

Physiopathology of radiation-induced neurotoxicity.

Ionizing irradiation for the treatment of malignant brain tumors has associated with it a risk of inducing serious morphologic and functional deficits. While obvious tissue damage generally occurs after relatively high radiation doses, cognitive impairment can be seen after lower exposures. The mechanisms responsible for cognitive injury are not well understood, but may involve neurogenesis, a process that is affected by microenvironmental factors including oxidative stress and inflammation. In addition, damage to neurons, either directly or through environmental influences may have a profound impact on cognition. The relationships between cellular response, environmental factors and behavior are complex and difficult to study. However, understanding such issues should provide critical information relevant to the development of strategies and approaches to ameliorate or treat radiation-induced injuries that are associated with behavioral performance.

Grazing management and supplementation effects on forage and dairy cow performance on cool-season pastures in the southeastern United States.

Cool-season annual forages provide high-quality herbage for up to 5 mo in the US Gulf Coast states, but their management in pasture-based dairy systems has received little attention. Objectives of this study were to evaluate pasture and animal responses when lactating Holstein cows (n=32, mean DIM=184±21) grazed either N-fertilized rye (Secale cereale L.)-annual ryegrass (Lolium multiflorum Lam.) mixed pastures or rye-annual ryegrass-crimson clover (Trifolium incarnatum L.)-red clover (Trifolium pratense L.) pastures at 2 stocking rates (5 vs. 2.5 cows/ha) and 2 rates of concentrate supplementation [0.29 or 0.40 kg of supplement (as is)/kg of daily milk production]. Two cows paired by parity (one multiparous and one primiparous) were assigned randomly to each pasture. The 2 × 2 × 2 factorial arrangement of treatments was replicated twice in a completely randomized design. Forage mixture and supplementation rate did not affect milk production during three 28-d periods. Greater milk production occurred at the low (19.7 kg/d) than the high (14.7 kg/d) stocking rate during periods 2 and 3, but production was similar during period 1. Despite lower production per cow, milk production per hectare was generally greater at the high stocking rate (81.6 vs. 49.5 kg/ha). Generally, greater pregraze herbage mass on pastures at the lower stocking rate (1,400 vs. 1,150 kg/ha) accounted for greater herbage allowance. Both forage (8.0 vs. 5.9 kg/d) and total (14.1 vs. 11.6) organic matter intake were greater at the low stocking rate. Cows fed less supplement had greater forage organic matter intake (8.0 vs. 6.1 kg/d). Greater herbage mass was associated with the greater intake and subsequent greater milk production. Differences in forage nutritive value, blood metabolites and milk composition, although showing some response to treatments, may not be of sufficient magnitude to affect choice of pasture species or other management practices. Animal performance was not improved by adding clovers to mixed cool-season grass pastures like those in this study. Stocking rate had a major effect on pasture and animal performance. During the cool season, supplementation with concentrates should be planned based on estimated energy intake from forages to achieve optimum milk production and ensure maintenance of body condition.

Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine.

Understanding how the hippocampus processes episodic memory information during neuropathological conditions is important for treatment and prevention applications. Previous data have shown that during chronic neuroinflammation the expression of the plasticity related behaviourally-induced immediate early gene Arc is altered within the CA3 and the dentate gyrus; both of these hippocampal regions show a pronounced increase in activated microglia. Low doses of memantine, a low to moderate affinity open channel uncompetitive N-Methyl-d-aspartate receptor antagonist, reduce neuroinflammation, return Arc expression to control levels and attenuate cognitive deficits induced by lipopolysaccharide. Here we investigate whether neuroinflammation affects the accuracy of information processing in the CA3 and CA1 hippocampal regions and if this is modified by memantine treatment. Using the immediate early gene-based brain-imaging method called cellular analysis of temporal activity by fluorescence in situ hybridization, it is possible to detect primary transcripts at the genomic alleles; this provides exceptional temporal and cellular resolution and facilitates the mapping of neuronal activity. Here, we use this method to compare the neuronal populations activated by two separate experiences in CA1 and CA3 and evaluate the accuracy of information processing during chronic neuroinflammation. Our results show that the CA3 pyramidal neuron activity is not stable between two exposures to the same environment context or two different contexts. CA1 networks, however, do not differ from control conditions. These data suggest that during chronic neuroinflammation, the CA3 networks show a disrupted ability to encode spatial information, and that CA1 neurons can work independently of CA3. Importantly, memantine treatment is able to partially normalize information processing in the hippocampus, suggesting that when given early during the development of the pathology memantine confers neuronal and cognitive protection while indirectly prevents pathological microglial activation.

Forage systems for cow-calf production in the Appalachian region.

Small cow-calf operations are common in the Appalachian region. Tall fescue [Lolium arundinaceum (Schreb.) S. J. Darbyshire] is the dominant forage in these systems for direct grazing as well as for stockpiling. The present study was conducted from 2001 to 2005. A total of 108 Angus and Angus crossbred cows were allotted randomly to 6 forage systems and then to 3 replicates within each system. In brief, system 1 had a stocking rate of 0.91 ha/cow in a Middleburg 3-paddock (A, B, and C) system. System 2 was similar to system 1 except for a stocking rate of 0.71 ha/cow. A stocking rate of 0.71 ha/cow also was used in systems 3 through 6. All A paddocks had tall fescue, whereas B paddocks had tall fescue/white clover (Trifolium repens L.) except in system 6, which had tall fescue/lespedeza [Lespedeza cuneata (Dum. Cours.) G. Don]. System 3 evaluated a 2-paddock (A and B) rotational grazing system, and system 4 evaluated a 3-paddock (A, B, and C) rotational grazing system, with paddock C containing orchardgrass (Dactylis glomerata L.) and alfalfa (Medicago sativa L.). Systems 5 and 6 differed from system 2 in the areas of paddocks B and C as well as in the forage mixtures used. In paddock C, system 5 had switchgrass (Panicum virgatum L.) and system 6 had tall fescue and birdsfoot trefoil (Lotus corniculatus L.). System 1 had the greatest average herbage availability from weaning until breeding (P < 0.05) with the least amount of hay fed (P = 0.03) when compared with the remainder of the systems. Differences (P > 0.05) in percentage of ground cover were not detected among systems. There was no year x system interaction effect on the cow or calf performance variables evaluated and no treatment effect on cow performance variables. There was a treatment effect on calf performance variables. System 2 produced the greatest adjusted weaning weight, kilograms of calf weaned per hectare, and kilograms of calf per kilograms of cow at weaning (P < 0.05). Numerical ranking for total calf production per hectare from the greatest to least was system 2, 6, 3, 5, 4, and 1. Systems evaluated did not affect cow performance although differences in calf performance and overall productivity of the systems were observed.

Redox changes induced in hippocampal precursor cells by heavy ion irradiation.

Hippocampal precursors retain the capacity to proliferate and differentiate throughout life, and their progeny, immature neurons, can undergo neurogenesis, a process believed to be important in maintaining the cognitive health of an organism. A variety of stresses including irradiation have been shown to deplete neural precursor cells, an effect that inhibits neurogenesis and is associated with the onset of cognitive impairments. Our past work has shown that neural precursor cells exposed to X-rays or protons exhibit a prolonged increase in oxidative stress, a factor we hypothesize to be critical in regulating the function of these cells after irradiation and other stresses. Here we report that irradiation of hippocampal precursor cells with high-linear energy transfer (LET) 1 GeV/nucleon 56Fe ions leads to significantly higher levels of oxidative stress when compared to lower LET radiations (X-rays, protons). Irradiation with 1 Gy of 56Fe ions elicits twofold to fivefold higher levels of reactive oxygen species (ROS) compared to unirradiated controls, and at lower doses (

Using superoxide dismutase/catalase mimetics to manipulate the redox environment of neural precursor cells.

Past work has shown that neural precursor cells are predisposed to redox sensitive changes, and that oxidative stress plays a critical role in the acute and persistent changes that occur within the irradiated CNS. Irradiation leads to a marked rise in reactive oxygen species (ROS) that correlates with oxidative endpoints in vivo and reductions in neurogenesis. To better understand the impact of oxidative stress on neural precursor cells, and to determine if radiation-induced oxidative damage and precursor cell loss after irradiation could be reduced, a series of antioxidant compounds (EUK-134, EUK-163, EUK-172, EUK-189) were tested, three of which possess both superoxide dismutase (SOD) and catalase activities and one (EUK-163) whose only significant activity is SOD. Our results show that these SOD/catalase mimetics apparently increase the oxidation of a ROS-sensitive fluorescent indicator dye, particularly after short (12 h) treatments, but that longer treatments (24 h) decrease oxidation attributable to radiation-induced ROS. Similarly, other studies found that cells incubated with CuZnSOD showed some increase in intracellular ROS levels. Subsequent data suggested that the dye-oxidising capabilities of the EUK compounds were linked to differences in their catalase activity and, most likely, their ability to catalyse peroxidative pathways. In unirradiated mice, the EUK-134 analogue induced some decrease of proliferating precursor cells and immature neurons 48 h after radiation, an effect that may be attributable to cytotoxicity and/or inhibition of precursor proliferation. In irradiated mice, a single injection of EUK-134 was not found to be an effective radioprotector at acute times (48 h). The present results support continued development of our in vitro model as a tool for predicting certain in vivo responses, and suggest that in some biological systems the capability to scavenge superoxide but produce excess H(2)O(2), as is known for CuZnSOD, may be potentially deleterious. Our results also show that the ability of catalase mimetics, like true catalases, to catalyse peroxidase reactions can complicate the interpretation of data obtained with certain fluorescent ROS-indicator dyes.

Brown seaweed- (Tasco) treated conserved forage enhances antioxidant status and immune function in heat-stressed wether lambs.

Twenty-seven wether lambs were utilized to evaluate select innate immunity and oxidative stress in response to diet and heat stress. Dietary treatments were: (i) control (tall fescue) hay = no Tasco (tradename for the extract of the brown seaweed, Ascophyllum nodosum, Acadian Sealants Ltd, Nova Scotia, Canada); (ii) pre-harvest Tasco-Forage-treated hay and (iii) control hay + post-harvest Tasco-EX. Tasco-Forage and Tasco-EX are two forms of the Tasco extract that are either applied to foliage or used for direct feeding, respectively. All lambs were supplemented with soyabean meal and trace mineralized salt. Heat stress was applied for 10 days with measurements obtained at days 0, 4 and 10. A heat x treatment interaction indicated hay with Tasco enhanced monocyte oxidative burst through short duration (p < 0.05) and long duration (p < 0.10) heat stress. Phagocytic activity was influenced by days of heat stress (p < 0.001) and treatment (p = 0.02) with post-harvest Tasco lambs exhibiting the greatest immune enhancement (p < 0.05). Red and white blood cell glutathione peroxidase increased by heat stress day 10 in Tasco lambs. Superoxide dismutase activity was increased and lipid hydroperoxide metabolites minimized (p < 0.01) through long duration heat stress in the pre-harvest Tasco group. Tasco treatment of tall fescue hay prior to harvest appears to provide residual effects on animal antioxidant availability in short-duration heat stress. Tasco supplementation to post-harvest fescue hay enhances immune function and protects against prolonged heat-induced oxidative stress.

Comparison of three techniques for estimating the forage intake of lactating dairy cows on pasture.

Quantifying DMI is necessary for estimation of nutrient consumption by ruminants, but it is inherently difficult on grazed pastures and even more so when supplements are fed. Our objectives were to compare three methods of estimating forage DMI (inference from animal performance, evaluation from fecal output using a pulse-dose marker, and estimation from herbage disappearance methods) and to identify the most useful approach or combination of approaches for estimating pasture intake by lactating dairy cows. During three continuous 28-d periods in the winter season, Holstein cows (Bos taurus; n = 32) grazed a cool-season grass or a cool-season grass-clover mixture at two stocking rates (SR; 5 vs. 2.5 cows/ha) and were fed two rates of concentrate supplementation (CS; 1 kg of concentrate [as-fed] per 2.5 or 3.5 kg of milk produced). Animal response data used in computations for the animal performance method were obtained from the latter 14 d of each period. For the pulse-dose marker method, chromium-mordanted fiber was used. Pasture sampling to determine herbage disappearance was done weekly throughout the study. Forage DMI estimated by the animal performance method was different among periods (P < 0.001; 6.5, 6.4, and 9.6 kg/d for Periods 1, 2, and 3, respectively), between SR (P < 0.001; 8.7 [low SR] vs. 6.3 kg/d [high SR]) and between CS (P < 0.01; 8.4 [low CS] vs. 6.6 kg/d [high CS]). The period and SR effect seemed to be related to forage mass. The pulse-dose marker method generally provided greater estimates of forage DMI (as much as 11.0 kg/d more than the animal performance method) and was not correlated with the other methods. Estimates of forage DMI by the herbage disappearance method were correlated with the animal performance method. The difference between estimates from these two methods, ranging from -4.7 to 5.4 kg/d, were much lower than their difference from pulse-dose marker estimates. The results of this study suggest that, when appropriate for the research objectives, the animal performance or herbage disappearance methods may be useful and less costly alternatives to using the pulse-dose method.

Pasture forages, supplementation rate, and stocking rate effects on dairy cow performance.

Objectives were to evaluate effects of forage species, stocking rate, and supplementation rate on performance and physiology of grazing lactating Holstein cows under intensive rotational stocking management during summer. Eight treatments were arranged in a 2 x 2 x 2 factorial design. Animals (n = 62) grazed pastures of Tifton 85 bermudagrass or Florigraze rhizoma peanut, a tropical legume. Low and high stocking rates were 7.5 and 10.0 cows/ha for bermudagrass and 5.0 and 7.5 cows/ha for rhizoma peanut. Within each forage-stocking rate combination, cows were fed supplement at 0.33 or 0.5 kg of supplement (as-fed basis)/kg daily milk production. Cows grazing rhizoma peanut pastures produced more milk (16.9 vs. 15.4 kg/d) but had higher rectal temperatures (39.4 vs. 39.1 degrees C). Milk production per cow was improved at the higher stocking rate for bermudagrass but was reduced at the higher stocking rate for peanuts. Increasing supplementation rate boosted plasma glucose, milk production, and milk protein percent. Increased supplementation rate had a greater positive impact on milk production of cows grazing bermudagrass compared to rhizoma peanut (21.9 vs. 10.6% increase) due to a lower substitution of grain for forage intake. Organic matter intakes of forage, supplement, and total diet were greatest by cows grazing rhizoma peanut pastures and averaged 12.4, 6.1, and 18.5 kg/d compared to 9.2, 5.4, and 14.6 kg/d for cows grazing bermudagrass. Despite lower individual feed intake and performance, production per unit land area was 29% greater (112 vs. 90 kg of milk/ha per d) for cows grazing bermudagrass due to the greater stocking rate possible with that forage. Only cows supplemented at the high rate and kept at the high stocking rate on bermudagrass maintained body weight. Cows on other treatments lost body weight. Tifton 85 bermudagrass appears to be an excellent summer forage for dairy cows grazing in the southeastern U.S. given its nutritive value characteristics and high yields. Optimum stocking rate may be as high as 10 cows/ha during times of peak growth of forage for low-to-moderately producing cows fed supplement. Furthermore, the positive milk production response to additional supplement when cows grazed Tifton 85 pastures (0.8 kg/kg of supplement), indicates the value of providing supplement to cows grazing this moderate quality forage.

Southeastern pasture-based dairy systems: housing, posilac, and supplemental silage effects on cow performance.

This experiment tested performance and physiological responses to evaporative cooling, bovine somatotropin (bST), and supplemental silage of lactating cows grazing bermudagrass (Tifton 85; Cynodon dactylon x C. nlemfuensis cv.) pastures. Multiparous (n = 32) cows (196 d in milk) were assigned one of five treatments arranged in two replicates. Treatments were 1) cows maintained continuously on pasture with access to shade, 2) treatment 1 + bST, 3) night housing on pasture, then free-stall housing with fans and misters from 0730 to 1630 h, 4) treatment 3 + bST, and 5) treatment 4 + corn silage fed at 0.5% of body weight (dry matter basis) in the barn. A grain supplement was fed at a rate of 0.5 kg/kg of milk produced. Time spent grazing ranged from 4 to 7.2 h/d, with cows fed corn silage spending the least amount of time. Cows given bST grazed 45 min/d longer than controls, but intake of bermudagrass was unchanged. Intake of bermudagrass ranged from 7.4 to 9.5 kg/d of organic matter, with the lowest intake by cows fed corn silage. With the exception of cows fed corn silage, cows kept in a cooling barn during the day ate equivalent amounts of pasture as those given unlimited access to pasture. Production of 4% fat-corrected milk was greater by cows injected with bST (17.7 vs. 15.8 kg/d) compared with controls and tended to be greater for cows given daytime cooling compared with cows on pasture continuously (17.2 vs. 16.3 kg/d). Cows provided evaporative cooling did not lose weight compared with continually pastured cows (6.3 vs. -10.9 kg/24 d). Cows injected with bST compared with controls maintained their body weight better (2.5 vs. -7.1 kg/24 d). Cows given bST had increased concentration of plasma insulin-like growth factor-I (142 vs. 89 ng/ml), insulin (0.60 vs. 0.56 ng/ml), and nonesterified fatty acids (318 vs. 239 mEq/L). Cows given bST and those continually on pasture had greater diurnal body temperatures. Use of barn cooling systems and bST treatments as management tools provided limited improvement in performance of midlactation cows managed in pasture-based systems.

Tasco-Forage: I. Influence of a seaweed extract on antioxidant activity in tall fescue and in ruminants.

Seaweed (Ascophyllum nodosum) is a known source of plant growth regulators, and application to turfgrasses has increased activity of the antioxidant superoxide dismutase (SOD) and specific vitamin precursors. Increased antioxidant activity in both plants and animals diminishes oxidative stress. Two pasture experiments investigated effects of Tasco-Forage (a proprietary seaweed-based product) applied to tall fescue (Festuca arundinacea) on antioxidant activity in plants and in ruminants that grazed the forage. In Exp. 1, fescue was 70 to 100% infected with the endophyte fungus Neotyphodium coenophialum ([Morgan-Jones and Gams] Glenn, Bacon, and Hanlin). Twenty-four wether lambs (initial BW 41 kg; SD = 5) grazed fescue treated with 0, 1.7, or 3.4 kg Tasco/ha applied in April and July, 1994, with four replications per treatment. Grazing occurred for 26 d beginning April 21 and for 22 d beginning July 19. In July, there was a linear increase in daily gains (P < 0.05), and serum vitamin A (P < 0.13) and whole-blood Se (P < 0.10) tended to increase in lambs grazing Tasco-treated fescue. In Exp. 2,48 Angus and Angus x Hereford steers (initial BW 245 kg; SD = 20) grazed infected or uninfected tall fescue in Virginia that was treated (3.4 kg/ ha) or untreated with Tasco in April and July, 1995. Steers that grazed infected tall fescue had lower (P < 0.02) serum vitamin A and E and tended (P < 0.07) to have lower whole-blood Se in September compared with steers that grazed uninfected tall fescue. Tasco decreased (P < 0.06) serum vitamin E but tended to increase whole-blood Se (P < 0.10) in September and serum vitamin A in July (P < 0.12). During 1996 and 1997, the experiment was repeated in Virginia with Angus steers and was replicated at Prairie, MS, where 1/4 Brahman x 3/4 Angus steers were used. Forty-eight steers were included at each location in each year (n = 192 total steers for 1996 and 1997). Steers that grazed infected tall fescue in Mississippi had lower (P < 0.05) serum vitamin E by the end of the grazing season. At both locations Tasco increased (P < 0.05) activity of superoxide dismutase in both infected and uninfected fescue. The endophyte in tall fescue seemed to decrease antioxidant activity in grazing steers, whereas Tasco seemed to increase antioxidant activity in both the forage and the grazing ruminant. Tasco may provide opportunities to reduce oxidative stress in plants and animals.

X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats.

The effects of X-irradiation on proliferating cells in the dentate subgranular zone were assessed in young adult Fisher 344 rats exposed to a range of X-ray doses and followed for up to 120 days. Apoptosis was quantified using morphology and end-labeling immunohistochemistry, and cell proliferation was detected using antibodies against the thymidine analog BrdU and the cyclin-dependent kinase p34(cdc2). Radiation-induced apoptosis occurred rapidly, with maximum morphological and end-labeling changes observed 3-6h after irradiation. Twenty-four hours after irradiation cell proliferation was significantly reduced relative to sham-irradiated controls. The number of apoptotic nuclei increased rapidly with radiation dose, reaching a plateau at about 3Gy. The maximum number of apoptotic nuclei was substantially higher than the number of proliferating cells, suggesting that non-proliferating as well as proliferating cells in the subgranular zone were sensitive to irradiation. Subgranular zone cell proliferation was significantly reduced relative to age-matched controls 120 days after doses of 5Gy or higher. These findings suggest that neural precursor cells of the dentate gyrus are very sensitive to irradiation and are not capable of repopulating the subgranular zone at least up to 120 days after irradiation. This may help explain, in part, how ionizing irradiation induces cognitive impairments in animals and humans.

The radioresponse of the central nervous system: a dynamic process.

Radiation continues to be a major treatment modality for tumors located within and close to the central nervous system (CNS). Consequently, alleviating or protecting against radiation-induced CNS injury would be of benefit in cancer treatment. However, the rational development of such interventional strategies will depend on a more complete understand-ing of the mechanisms responsible for the development of this form of normal tissue injury. Whereas the vasculature and the oligodendrocyte lineage have traditionally been considered the primary radiation targets in the CNS, in this review we suggest that other phenotypes as well as critical cellular interactions may also be involved in determining the radio-response of the CNS. Furthermore, based on the assumption that the CNS has a limited repertoire of responses to injury, the reaction of the CNS to other types of insults is used as a framework for modeling the pathogenesis of radiation-induced damage. Evidence is then provided suggesting that, in addition to acute cell death, radiation induces an intrinsic recovery/repair response in the form of specific cytokines and may

Plasma pharmacokinetics and tissue biodistribution of boron following administration of a boronated porphyrin in dogs.

This study was undertaken to determine the plasma pharmacokinetics and tissue biodistribution of boron in dogs following the administration of a boronated porphyrin (BOPP) compound, a potential sensitizing agent for binary therapies of cancer. An intravenous dose of 35 mg/kg of BOPP was administered to a total of sixteen dogs and plasma samples obtained at multiple time points for up to 28 days after administration. Groups of four dogs each were studied for 25, 79, 240, and 672 h. At the end of each study period, subjects were sacrificed and tissue samples obtained. Boron concentrations were determined for all tissue and plasma samples, and pharmacokinetic parameters were determined using mixed effects modeling. Plasma boron levels displayed triexponential kinetics with a long terminal half-life and small volume of distribution. Liver, lymph node, adrenal, and kidney tissues accumulated the highest levels of boron, with very low levels associated with most tissues of the head. We conclude that BOPP has pharmacokinetic and tissue distribution properties that suggest that it may be a suitable compound for use as a sensitizing agent in binary therapy of cancer.

Toxicology of a boronated porphyrin in dogs.

Among the most important characteristics of any therapeutic agent are efficacy and an acceptable toxicity. Prior to human use, toxicity studies are performed in both small and large animal models. Our laboratory has developed a new binary therapy agent, a boronated porphyrin (BOPP), with excellent potential efficacy. The purpose of this study is to examine the toxicology of this compound in dogs. Sixteen dogs were given 35 mg/kg of BOPP intravenously and evaluated for up to 28 days following administration. Clinical and pathologic responses were measured. BOPP was clinically well tolerated with some cases of weight loss, vomiting and mild photosensitivity. Adverse effects were limited primarily to thrombosis at the administration site in several subjects and three cases of mild, possibly transient, liver injury. Clinical pathologic tests found reversible changes in white blood cell counts and platelets, with neither change being clinically significant. The low toxicity associated with BOPP as shown in this study provides valuable evidence supporting the use of BOPP in binary therapy.

Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat.

Aberrant reorganization of dentate granule cell axons, the mossy fibers, occurs in human temporal lobe epilepsy and rodent epilepsy models. Whether this plasticity results from the remodeling of preexisting mossy fibers or instead reflects an abnormality of developing dentate granule cells is unknown. Because these neurons continue to be generated in the adult rodent and their production increases after seizures, mossy fibers that arise from either developing or mature granule cells are potential substrates for this network plasticity. Therefore, to determine whether seizure-induced, mossy fiber synaptic reorganization arises from either developing or mature granule cell populations, we used low-dose, whole-brain x-irradiation to eliminate proliferating dentate granule cell progenitors in adult rats. A single dose of 5 Gy irradiation blocked cell proliferation and eliminated putative progenitor cells in the dentate subgranular proliferative zone. Irradiation 1 d before pilocarpine-induced status epilepticus significantly attenuated dentate granule cell neurogenesis after seizures. Two irradiations, 1 d before and 4 d after status epilepticus, essentially abolished dentate granule cell neurogenesis but failed to prevent mossy fiber reorganization in the dentate molecular layer. These results indicate that dentate granule cell neurogenesis in the mature hippocampal formation is vulnerable to the effects of low-dose ionizing irradiation. Furthermore, the development of aberrant mossy fiber remodeling in the absence of neurogenesis suggests that mature dentate granule cells contribute substantially to seizure-induced network reorganization.

Long-term impairment of subependymal repopulation following damage by ionizing irradiation.

In the mammalian brain, the subependyma (SE) contains stem cells capable of producing neurons and glia. In normal brain these stem cells are responsible, in part, for maintaining the morphologic and functional integrity of the SE; what role the cells of the SE play in brain injury has not yet been elucidated. The present study was designed to determine the long-term regenerative potential of the rat SE after significant depletion of stem cells. Ionizing irradiation was used to deplete cells of the SE and subsequent cellular responses were quantified using immunohistochemical analyses on formalin-fixed, paraffin-embedded tissues. A histomorphometric approach was used to quantify total cell number, number of proliferating cells, number of immature neurons, astrocytes, and undifferentiated components of the SE. Because there are no markers specific for stem cells, we used a repopulation assay as an indirect measure of stem cell response after injury. Our data showed clear radiation dose-dependencies in our quantitative endpoints, implying that there was progressively more stem cell damage with increasing radiation dose. Repopulation of the SE in terms of total cell number, number of proliferating cells and numbers of immature neurons was impaired in a dose-dependent fashion up to 180 days after treatment. These data suggest that after irradiation, surviving stem cells are unable to regenerate the SE. This inability to regenerate after stem cell damage/depletion could have important implications with respect to the normal function of the SE and the function of the SE after brain injury.

Cerebrovascular effects of the bradykinin analog RMP-7 in normal and irradiated dog brain.

The effects of an intravenous (i.v.) injection of the bradykinin analog RMP-7 (100 ng/kg) were assessed in normal dogs and dogs with focal, radiation-induced brain lesions. A dose of 20 Gy was delivered to a point 0.75 cm from a removable interstitial 125I source; parameters relating to blood flow and permeability were quantified using computed tomography 2-8 weeks after irradiation. Blood flow-related endpoints included regional cerebral blood flow (rCBF), mean transit time of blood and vascular volume, while endpoints related to permeability included blood-to-brain transfer constant (Ki), brain-to-blood transfer constant and plasma volume. In unirradiated brain, an i.v. bolus of RMP-7 administered through the left cephalic vein induced a rapid and transient hypotension and a statistically significant increase in vascular volume; no alterations in any parameter related to permeability were observed. After irradiation, changes in rCBF after RMP-7 depended upon time after exposure, effects presumably due to changing morphology in the irradiated tissues. In the radiation lesions, significant increases in Ki were observed 5 minutes after injection of RMP-7, but those increases were not related to time after irradiation or alteration in blood flow-related parameters. Our results showed that RMP-7 selectively increased permeability in already damaged vasculature without affecting the extent or volume of radiation-induced vasogenic edema. These data suggest that RMP-7 may provide an effective means to enhance the delivery of compounds to an already compromised brain while not exacerbating the potential adverse effects of pre-existing vasogenic edema.