Furosemide kinetics and dynamics in rats and humans.

1. Increasing doses of furosemide (F) were given intravenously to rats and humans and initial pharmacokinetics and pharmacodynamics were compared. 2. Weight-related initial renal excretion rate of F was twice as high in rats and serum concentration at 30 min was twice as high in humans (P less than 0.01). 3. Volume of distribution for F was 44% larger in rats (P less than 0.01). 4. Maximal weight-related diuretic and natriuretic responses were, like the theoretical maximal efficiency, 5-6 times higher in the rat. The potency was 230 times lower in the rats. 5. On a molecular basis species differences in kinetics disappeared when standardization was based on ERPF and species differences in dynamics disappeared when standardization was based on GFR.     

The effect of protein supplement source or supply pattern on the intake,digestibility, rumen kinetics,nitrogen utilisation and growth of Ethiopian Menz sheep fed teff straw

A series of trials were conducted to study the effect of either nitrogen source or supply pattern on the growth, rumen fermentation pattern and utilisation of straw by Ethiopian Menz sheep. All experimental sheep were given teff straw basal diet (CON). Irrespective of the trial, treatment sheep were offered either cottonseed cake (CSC), leucaena (LEU) and sesbania (SESM) in the morning prior to teff straw. Additional treatments with sesbaia were offered either in the evening (SESE) or morning and evening (SESME). Measurements included roughage intake, digestibility, kinetics, rumen fermentation patterns, nitrogen utilisation, microbial protein supply and growth of sheep.Rate of degradation was highest (P < 0.05) when sesbania was offered once a day compared with twice a day, while supplementation produced higher (P < 0.05) liquid passage rates. Diets with sesbania produced higher (P < 0.05) roughage intake compared with leucaena. Microbial protein supply as well as N economy were similar (P > 0.05) among the foliage diets irrespective of source, time or frequency of feeding. Supplementation enhanced (P < 0.001) growth rates in sheep, while cottonseed cake (CSC) diet was superior (P < 0.01) to the fodder trees. Growth rates declined across treatments during the second phase (6–10 weeks) compared with the initial period (1–6 weeks). It is also possible for farmers to feed sesbania supplements in the morning or evening or twice daily without any detrimental effects.     

Genetic analysis of an F2 intercross between two strains of Japanese quail provided evidence for quantitative trait loci affecting carcass composition and internal organs

The purpose of this study was to identify genomic regions, quantitative trait loci (QTL), affecting carcass traits on chromosome 1 in an F2 population of Japanese quail. For this purpose, two white and wild strains of Japanese quail (16 birds) were crossed reciprocally and F1 generation (34 birds) was created. The F2 generation was produced by intercrossing of the F1 birds. Phenotypic data including carcass weight, internal organs and carcass parts were collected on F2 animals (422 birds). The total mapping population (472 birds) was genotyped for 8 microsatellite markers on chromosome 1. QTL analysis was performed with interval mapping method applying the line-cross model. Significant QTL were identified for breast weight at 0 (P < 0.01), 172 (P < 0.05) and 206 (P < 0.01), carcass weight at 91 (P < 0.05), carcass fatness at 0 (P < 0.01), pre-stomach weight at 206 (P < 0.01) and uropygial weight gland at 197 (P < 0.01) cM on chromosome 1. There was also evidence for imprinted QTL affecting breast weight (P < 0.01) on chromosome 1. The proportion of the F2 phenotypic variation explained by the significant additive, dominance and imprinted QTL effects ranged from 1.0 to 7.3 %, 1.2 to 3.3 % and 1.4 to 2.2 %, respectively.     

Biological mechanisms related to differences in residual feed intake in dairy cows

Residual feed intake (RFI), defined as the difference between an animal’s actual feed intake and expected feed intake over a specific period, is an inheritable character of feed conversion efficiency in dairy cows. Research has shown that a lower RFI could improve the profitability of milk production. This study explored variation in RFI by comparing the differences in body size, milk performance, feeding behavior, and serum metabolites in 29 Holstein cows in mid lactation. The cows were selected from a total of 84 animals based on their RFI following feedlot tests. Selected cows were ranked into high RFI (RFI >1 SD above the mean, n=14) and low RFI (RFI<1 SD below the mean, n=15). The low RFI cows (more efficient) consumed 1.59 kg/day less dry matter than the high RFI group (P<0.01), while they produced nearly equal 4% fat-corrected milk. The milk : feed ratio was higher for the low RFI group than for the high RFI group (P<0.05). The levels of milk protein (P<0.01), total solids (P<0.05), and nonfat solids (P<0.05) were also higher for the low RFI group, whereas milk urea nitrogen was lower (P<0.01). The daily feeding duration was shorter for the low RFI group than for the high RFI group (P<0.01). No significant differences were found in levels of glucose, β-hydroxybutyrate, prolactin, insulin, IGF-1, growth hormone or ghrelin, but the level of neuropeptide Y was higher (P<0.01) and levels of leptin and non-esterified fatty acid (P<0.05) were lower for the low RFI group than for the high RFI group. There were substantial differences between cows with different RFI, which might affect the efficiency of milk protein metabolism and fat mobilization.     

The influence of handling by humans on the behaviour,reproduction and corticosteroids of male and female pigs

The influence of three handling treatments on the behaviour, reproduction and free corticosteroid concentrations was studied in 15 male and 30 female pigs. Two handling treatments, considered as pleasant and unpleasant, were imposed for 5 min, three times per week from 11 weeks of age. The third handling treatment involved minimal contact with humans from 11 weeks of age. In a 3-min test at 18 weeks, pigs in the pleasant treatment were quicker (P<0.01) to enter an area within 0.5 m of the experimenter and had more interactions (P<0.05) with the experimenter than pigs in the unpleasant and minimal treatments. Gilts in the unpleasant treatment had a lower (P<0.05) pregnancy rate at the second oestrus when mated to non-experimental boars than gilts in the pleasant treatment (33.3 and 87.5%, respectively). Boars in the unpleasant treatment had smaller (P<0.05) testicles at 23 weeks of age and attained a coordinated mating response at a later age (P<0.05) than boars in the pleasant treatment (53.2 and 63.3 cm², and 192 and 161 days, respectively). In addition, pigs in the unpleasant treatment had higher (P<0.05) free corticosteroid concentrations in the absence of humans at 20 weeks (gilts) and 27 weeks (boars) than pigs in the pleasant treatment (boars and gilts combined, 2.4 and 1.7 ng ml⁻¹, respectively). For many of the reproductive parameters, the effect of the minimal handling treatment was intermediate to that of the other two treatments. It was concluded that the unpleasant handling treatment resulted in a chronic stress response, with consequent adverse effects on reproduction.     

Generation of reactive oxygen species during cryopreservation may improve Lilium × siberia pollen viability

During biotic and abiotic stress in plants, reactive oxygen species (ROS) may play two very different roles: high ROS concentrations can exacerbate damage, whereas low concentrations can activate defense responses. The aim of this study was to investigate the relationship between ROS generation and pollen viability after cryopreservation. ROS generation was detected from ‘Siberia’ (Lilium?×?siberia) pollen using flow cytometry with 2′,7′-dichlorodihydrofluorescein diacetate as a fluorescent probe. Pollen viability was determined by 2,3,5-triphenyltetrazolium chloride staining. ROS generation was slightly increased by rapid cooling (26.13?±?4.74 vs. 15.80?±?2.30 for fresh pollen) and significantly increased by vitrification (49.74?±?1.43; P?<?0.01). Pollen viabilities after rapid cooling and vitrification were significantly increased (58.88?±?3.76% and 70.35?±?2.90%, respectively) over that of fresh pollen (46.65?±?1.61%; P?<?0.01). No significant differences in ROS generation were associated with cold acclimation at different temperatures before rapid cooling. However, sharp decreases in viability were observed with cold acclimation at 4°C and ?20°C relative to rapid cooling without acclimation (P?<?0.01). We observed nonsignificant decreases in ROS generation among vitrification treatments that omitted different steps and a significant decrease when the unloading step was omitted (P?<?0.05). Pollen viabilities were significantly reduced when the loading or dehydration steps were omitted (P?<?0.01). No significant differences were observed in ROS generation or pollen viability among the treatments when 200 U/ml catalase was added to different solutions used in the vitrification process. Comprehensive analysis of all data indicated a positive correlation between ROS generation and pollen viability (r?=?0.651, P?<?0.001). Therefore, increasing ROS generation during cryopreservation may improve the viability of ‘Siberia’ pollen.     

Anti-diabetic effects of sodium 4-amino-2,6-dipicolinatodioxovanadium(V) dihydrate in streptozotocin-induced diabetic rats

The evaluation of the anti-diabetic effects of an organic vanadium(V) complex in streptozotocin (STZ)-induced diabetic rats was investigated. The STZ-induced diabetic rats were orally administrated with sodium 4-amino-2,6-dipicolinatodioxovanadium(V) dihydrate (V5dipic-NH₂), a vanadium(V) coordination compound. The compound was administered through drinking water at a concentration of 0.1 mg/mL for 20 days, and then the concentration was increased to 0.3 mg/mL for the following 20 days. At the end of the experiment, V5dipic-NH₂ statistically significantly reduced the levels of blood glucose (P < 0.01), serum total cholesterol (P < 0.01), triglycerides (P < 0.01) and the activities of serum aspartate amino transferase (P < 0.05) and alkaline phosphatase (P < 0.01) compared to untreated diabetic animals. After treatment with 0.3 mg/mL V5dipic-NH₂, the oral glucose tolerance was improved in diabetic animals (P < 0.01). In addition, the daily intake of elemental vanadium was markedly decreased in V5dipic-NH₂-treated diabetic rats compared to vanadyl sulfate (VOSO₄)-treated diabetic rats, which suggested that the anti-diabetic activity of the element vanadium was elevated after being modified with an organic ligand. These results suggested that V5dipic-NH₂, as an organic vanadium compound, is more effective than inorganic vanadium salt at alleviating the symptoms of diabetes.     

Sex steroid regulation of urinary excretion of carnitine in rats

The concentration of acid soluble carnitine was determined in several body tissues and fluids in rats under various conditions of sex steroid regulation. Intact female rats had significantly greater liver carnitine concentrations and urinary excretion rates, and lower blood plasma and heart carnitine concentrations than intact male rats. Ovariectomy increased blood plasma carnitine concentrations (P < 0.01) and the excretion of carnitine in the urine (P < 0.05). The administration of either estradiol or testosterone to ovariectomized rats did not alter blood plasma concentrations or urinary excretion of carnitine. Orchidectomized rats had similar blood plasma carnitine concentrations when compared to intact males but excreted significantly (P < 0.01) greater quantities of carnitine in their urine. Administration of testosterone to orchidectomized rats reduced (P < 0.01), whereas estradiol stimulated (P < 0.05) the excretion rate of carnitine in the urine; however, blood plasma carnitine concentrations were not affected by these hormones. These data suggest that a major site for modulation of body carnitine concentration in the male resides in the control of kidney excretion by androgens. Liver, heart and skeletal muscle carnitine concentrations were not altered by the administration of either estradiol or testosterone to orchidectomized or ovariectomized rats.     

Nutrient digestibility and fecal characteristics are different among captive exotic felids fed a beef‐based raw diet

Nutrient digestibility has not been well characterized in exotic felids. The objective of this experiment was to evaluate differences in nutrient digestibility and fecal characteristics in five large exotic captive felid species, including bobcats, jaguars, cheetahs, Indochinese tigers, and Siberian tigers. All animals were individually housed and adapted to a beef‐based raw diet (Nebraska Brand^® Special Beef Feline, North Platte, NE) for 16 d. Total fecal collections were conducted from days 17 to 20. Fecal samples were weighed and scored on collection. Diet and fecal samples were evaluated for dry matter, organic matter, protein, fat, and energy to determine total tract digestibility. Fresh fecal samples were collected to determine fecal pH, ammonia, phenol, indole, short‐chain fatty acid, and branched‐chain fatty acid concentrations. Fecal scores were greater (P<0.01) in Indochinese tigers when compared with all other species, and cheetahs had greater (P<0.01) fecal scores than jaguars and bobcats. Fat digestibility was greater (P<0.01) in Siberian tigers, Indochinese tigers, and bobcats (96%) compared with cheetahs and jaguars (94%). Digestible energy was greater (P<0.05) in bobcats and Indochinese tigers at 93.5 and 92.9%, respectively, compared with cheetahs and jaguars, 91.6%. Fecal pH was greater (P<0.01) in bobcats compared with all other species evaluated. Indole concentrations were greater (P<0.05) in cheetahs and jaguars compared with bobcats and Indochinese tigers. Fecal ammonia concentrations were increased (P<0.05) in cheetahs compared with all other species. The beef‐based raw diet was highly digestible; however, differences in fat and digestible energy suggest that species should be considered when determining caloric needs of exotic felids. Zoo Biol 27:126–136, 2008. © 2008 Wiley‐Liss, Inc.     

Effects of allopurinol on uric acid concentrations,xanthine oxidoreductase activity and oxidative stress in broiler chickens

The purpose of this study was to determine the effects of allopurinol (AL) on xanthine oxidoreductase (XOR) activity and uric acid (UA) levels in chickens. Thirty 5-week-old broilers were divided into three groups and fed 0 (control), 25 (AL25) or 50 (AL50) mg AL per kg of body mass for 5 weeks. Chicks were weighed twice weekly and leukocyte oxidative activity (LOA) and plasma purine levels were determined weekly in five birds per group. Chicks were sacrificed after 2 or 5 weeks, and samples from tissues were taken for analysis of XOR activity. Plasma UA concentrations were lower (P < 0.001) and xanthine and hypoxanthine concentrations were greater (P < 0.001) in AL25 and AL50 birds compared to controls, whereas no differences (P = 0.904) were detected in allantoin concentrations. By week 5, body mass was reduced (P < 0.001) to 84.0 and 65.1% of that in controls for AL25 and AL50 broilers, respectively, and LOA was 4.1 times greater (P < 0.05) in AL25 compared to control birds. Liver XOR activity was increased by 1.1 and 1.2 times in AL25 and AL50 birds, but there was no change (P > 0.05) in XOR activity in the pancreas and intestine. These results suggest that AL effect on XOR activity is tissue dependent.     

Interspecies differences in the empty body chemical composition of domestic animals

Domestication of animals has resulted in phenotypic changes by means of natural and human-directed selection. Body composition is important for farm animals because it reflects the status of energy reserves. Thus, there is the possibility that farm animals as providers of food have been more affected by human-directed selection for body composition than laboratory animals. In this study, an analysis was conducted to determine what similarities and differences in body composition occur between farm and laboratory animals using literature data obtained from seven comparative slaughter studies (n = 136 observations). Farm animals from four species (cattle, goats, pigs and sheep) were all castrated males, whereas laboratory animals from three species (dogs, mice and rats) comprised males and/or females. All animals were fed ad libitum. The allometric equation, Y = aX^b, was used to determine the influence of species on the accretion rates of chemical components (Y, kg) relative to the growth of the empty body, fat-free empty body or protein weights (X, kg). There were differences between farm and laboratory animals in terms of the allometric growth coefficients for chemical components relative to the empty BW and fat-free empty BW (P < 0.01); farm animals had more rapid accretion rates of fat (P < 0.01) but laboratory animals had more rapid accretion rates of protein, water and ash (P < 0.01). In contrast, there was no difference in terms of the allometric growth coefficients for protein and water within farm animals (P > 0.2). The allometric growth coefficients for ash weight relative to protein weight for six species except sheep were not different from a value of 1 (P > 0.1), whereas that of sheep was smaller than 1 (P < 0.01). When compared at the same fat content of the empty body, the rate of change in water content (%) per unit change in fat content (%) was not different (P > 0.05) across farm animal species and similar ash-to-protein ratios were obtained except for dogs. The fraction of empty body energy gain retained as fat increased in a curvilinear manner, and there was little variation among farm animals at the same fat content of the empty body. These findings may provide the opportunity to develop a general model to predict empty body composition across farm animal species. In contrast, there were considerable differences of chemical body composition between farm and laboratory animals.     

Does the effect of pelleting depend on the wheat sample when fed to chickens?

Experimental comparisons of the nutritional value of different wheat cultivars commonly use feeds in meal form even though the large-scale broiler producers use steam pelleted feeds. The aim of this experiment was to examine the effect of steam pelleting on the performance, dietary N-corrected apparent metabolisable energy (AMEn), total tract dry matter retention (DMR), nitrogen retention (NR) and fat digestibility (FD) coefficients, and digestive tract development of broilers fed four different wheat samples in complete diets. Four European wheat samples, with different chemical composition and endosperm characteristics, were used in a broiler experiment. The wheat samples were milled through a 5 mm screen and four basal feeds containing 670 g/kg of each selected wheat sample were mixed. The basal feeds were then split into two batches and one of them was steam pelleted resulting in eight experimental diets. Each diet was fed ad libitum to eight pens of two male Ross 308 broilers from 10 to 24 days of age. Feeding pelleted diets improved (P<0.001) feed intake and weight gain, and daily water intake of the birds. Pelleting also improved dietary AMEn and FD (P<0.001) and DMR (P<0.05). An interaction (P<0.05) was observed between wheat samples and steam pelleting for NR. Steam pelleting improved (P<0.05) NR in the wheat sample with high starch and protein and hard endosperm but not in the rest of the wheat samples. Similar interactions (P<0.05) were also observed between wheat sample and steam pelleting for gain to feed (G : F) and water to feed (W : F) ratios. Pelleting improved G : F ratio the greatest in the wheat sample with high starch and protein and hard endosperm. Feeding the same wheat sample also decreased (P<0.05) W : F but only in the mash diets. Regardless of the wheat sample the values of dietary AMEn did not differ (P>0.05). Feeding different wheat types and pelleting did not (P>0.05) change the development of the gastrointestinal tract of the birds. The study showed that there were differences between four wheat samples when they were fed in pelleted complete feed, but no differences were observed when fed in mash form complete diets. Research on the interaction between pelleting and wheat chemical and quality characteristics is warranted.     

Effects of season and feeding level on reproductive activity and semen quality in Payoya buck goats

The aim of this study was to determine if there is a seasonal pattern of reproductive activity in male Payoya goats and if this seasonality can be modulated by a higher level of nutrition. For a period of 16 months, 10 adult bucks were divided into two experimental groups that differed in their feeding level. The high nutrition group (H, n = 5) received 1.6 times their maintenance food requirements. The control nutrition group (C, n = 5) received a diet that supported 1.1 times their maintenance requirements. Body weight and testosterone concentrations were determined weekly, and testicular weight was determined every 2 weeks. Sexual behaviour and semen characteristics were determined monthly. Feeding level did not affect the onset or the end of the reproductive activity as measured by testosterone concentrations, with high testosterone concentrations between July and November. Ejaculation latency was positively influenced by feeding level: 43.2 ± 2.2 s vs. 61.6 ± 3.2 s for H and C group, respectively (P < 0.001). The percentage of males that ejaculated or that were sexually active was higher in the H group (P < 0.01). No differences between feeding levels were observed in the different semen characteristics studied. However, major differences between months were observed for all studied variables. These results lead us to conclude that Payoya bucks exhibit large seasonal variation in their reproductive activity. Higher feeding level allowed a better sexual behaviour in bucks in late spring, when male effect is used on the local livestock to breed females.     

Does soil nutrient availability influence night-time water flux of aspen saplings?

Previous investigations have been demonstrated that night-time water flux may increase or remain unchanged at low mineral nutrient availability. At the same time, it is a well-known fact that night-time water flux is relatively high in fast-growing species, which typically grow in fertile soil. To test the impact of soil nutrient deficiency on night-time water flux and fine-root acclimation in saplings of hybrid aspen (Populus tremula L. × Populus tremuloides Michx.), a growth chamber experiment was carried out. We set up a hypothesis that night-time sap flux density (F) and night-time water use percentage from daytime water use (NWU) are more intense in fertile conditions, in order to enhance or sustain the high intrinsic growth potential of hybrid aspen. The main limiting element in the low nutrient availability treatment (low-n) was nitrogen. The nitrogen concentrations of leaves and fine-roots exhibited the strongest (R² = 0.95; P < 0.001) positive relationship with NWU and foliar biomass. Both the night-time F and NWU were several times higher in the case of fertilized soil (high-n treatment) compared to low-n treatment (P < 0.01). The differences in nocturnal (and in diurnal) F disappeared at the end of the period of sap flow measurements, when the foliage area of trees was almost full-grown. Endogenous increase in water flux during predawn hours was observable only in the high-n treatment. Significantly greater NWU (P < 0.01) and specific fine-root length (P < 0.05), but smaller fine-root biomass (P < 0.05) in saplings of the high-n treatment potentially allow plants to use mass flow in soil more efficiently for transportation nutrients towards roots and to decrease construction costs for fine-root biomass production. Our results suggest that decreased night-time water flux as a result of strong nutrient (especially nitrogen) deficit could be characteristic to fast-growing tree species, which are adapted to grow in fertile soil.     

Ruminal large and small particle kinetics in dairy cows fed red clover and grass silages harvested at two stages of growth

Passage, comminution and digestion rates of large and small particles were estimated using a rumen evacuation technique and total faecal collection with five lactating dairy cows in a 5 × 5 Latin square experiment. Two grass and two red clover silages harvested at early and late primary growth stages and a 1:1 mixture of late harvest grass and early harvest red clover were the dietary treatments. Cows received 9.0 kg supplementary concentrate per day. Ruminal contents and faeces were divided into large (>1.25 mm) and small (1.25–0.038 mm) particles by wet sieving. Indigestible neutral detergent fibre (iNDF) was determined by 12 days ruminal in situ incubation followed by neutral detergent extraction. Plant species did not affect ruminal particle size distribution, whereas advancing forage maturity decreased the proportion of large particles for both grass and red clover silage diets. Ruminal pool size of iNDF was higher (P<0.001) with red clover compared to grass silage diets. Ruminal passage rates of iNDF and potentially digestible NDF (pdNDF) increased with decreasing particle size (P<0.01). Passage rate of iNDF for small particles was slower (P<0.01) when red clover compared to grass silage diets were fed. Particle comminution rate in the rumen was slower (P<0.001) with red clover compared to grass silage diets and it increased (P<0.01) with advancing forage maturity. The contribution of particle comminution to ruminal mean retention time of iNDF in the ruminal large particle pool was smaller (P<0.01) in red clover compared to grass silage diets and it increased (P<0.05) with the mixed silage compared to the separate silages. Passage rate of pdNDF for both large and small particles was not affected by dietary treatments. Digestion rate of pdNDF for large particles was faster (P<0.001) with red clover compared to grass silage diets. Differences in ruminal passage and digestion rates of the large and small particles, in addition to differences in the passage and digestion rates of red clover compared to grass silage diets, emphasize the need to consider particle size and forage type in metabolic models predicting feed intake and fibre digestibility in ruminants.     

Sympathetic nervous activity and cardiovascular variability after a 3-day tail suspension in rats

The effects of a 3-day tail suspension on central and peripheral sympathetic activity were studied in rats by determining the in vivo noradrenaline (NA) turnover in the brain cell groups involved in central blood pressure control (A1, A2, A5 and A6) and in two peripheral organs, heart and kidneys. In addition, cardiovascular parameters and their variabilities were investigated by recording blood pressure (BP) and heart rate (HR) before and after suspension. These measurements were processed by spectrum analysis to assess the influence of tail suspension on autonomic balance. The NA turnover in the suspended rats was markedly reduced in A2 (–49%, P<0.01) and A5 (–38%, P<0.01) nuclei but unchanged in A1 and A6 cell groups compared with the control rats. Peripheral NA turnover was decreased in cardiac atria (–44%, P<0.001) and ventricles (–27%, P<0.01) while it was unchanged in kidneys after suspension. The BP, HR and their variabilities were similar in both groups of animals and showed no changes after suspension compared with baseline values. Spectrum analysis of BP and HR in our conscious suspended rats revealed no changes in power spectrum density or in peak frequencies. The discrepancy between the decrease in central sympathetic activity and the absence of changes in cardiovascular parameters after tail suspension raises the question of the validity of the tail suspended rat model when studying the cardiovascular deconditioning observed in humans after an exposure to actual or simulated weightlessness.     

Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.     

Inhaled radon-induced genotoxicity in Wistar rat,Syrian hamster,and Chinese hamster deep-lung fibroblasts in vivo

This study was performed (1) to provide a comparison of the genotoxin effects of inhaled radon and radon progeny, referred to as radon in this paper, among three species of rodents: Wistar rats, Syrian hamsters, and Chinese hamsters; (2) to determine if initial chromosome damage was related to the risk of induction of lung cancer; and (3) to evaluate the tissue repair and long-term presence of cytogenetic damage in respiratory tract cells. These species were selected because Syrian hamsters are very resistant to radon induction of lung cancer and Wistar rats are sensitive; no literature is available on the in vivo effects of radon in the Chinese hamster. Exposure-response relationships were established for the rats and Syrian hamsters while the Chinese hamsters received a single exposure of radon. At 4 h (0.2 days), 15 days, and 30 days after the highest WLM exposure to radon, Wistar rats, Chinese hamsters, and Syrian hamsters were killed, and lung fibroblasts were isolated and grown in culture to determine the frequency of induced micronuclei. Animals at each level of exposure showed an increase in the frequency of micronuclei relative to that in controls (P < 0.05). The exposure-response relationship data for rats and Syrian hamsters killed 0.2 days after the end of exposure were fit to linear equations (micronuclei/1000 binucleated cells = 15.5±14.4+0.53±0.06 WLM and 38.3±15.1+0.80±0.08 WLM, respectively). For the single exposure level used (496 WLM) in Chinese hamsters killed at 0.2 days after exposure, the frequency of micronuclei/1000 binucleated cells/WLM was 1.83±0.02. A comparison of the sensitivity for induction of micronuclei/WLM illustrated that Chinese hamsters were three times more sensitive than rats. The Syrian hamsters also showed a significantly elevated response (P < 0.05) relative to rats. These data suggest that initial chromosome damage is not the major factor responsible for the high rate of radon-induced cancer in rats relative to Syrian hamsters. The frequency of micronuclei in radon-exposed rats, Syrian hamsters, and Chinese hamsters significantly decreased (P < 0.05) as a function of time after the exposure. The rate of loss of damaged cells from the lung was greatest in the Chinese hamsters, followed by Wistar rats and Syrian hamsters, respectively. Our experiments demonstrated that the mammalian lung fibroblast/micronucleus method has the potential to (1) detect species differences in the induction of in vivo genotoxic damage in the lungs by inhaled environmentalal agents; (2) evaluate exposure-response relationships for in vivo induction of genetic damage; and (3) determine the persistence in vivo of preclastogenic and premutagenic lesions in cell populations.     

Active immunization against GnRH in pre-pubertal domestic mammals: testicular morphometry,histopathology and endocrine responses in rabbits,guinea pigs and ram lambs

Effective tools for male contraception are important in the control of reproduction in animal populations. The aim of the present study was to evaluate the effects of active immunization against gonadotropin-releasing hormone (GnRH) on male reproductive function assessing testicular morphological changes and serum-gonadotropin levels in pre-pubertal rabbits, guinea pigs and ram lambs. An anti-GnRH vaccine was developed by linking a GnRH-homologous molecule to a tetanus clostridial toxoid (Al(OH)₃ coadjuvant). After vaccination protocols testicular morphometry, histopathological alterations and endocrine responses (FSH, LH, testosterone and cortisol serum levels) were evaluated. Testicular volume was significantly reduced in vaccinated animals with respect to the control group in rabbits, guinea pigs and ram lambs (P<0.05 to P<0.001). The anti-GnRH vaccine generated a reduction in testicular volume of 15-, 27- and 11-fold, respectively. Tubule diameters decreased in the vaccinated group with respect to the control ~2.0-, 1.2- and 3.5-fold, respectively (P<0.001). Tubule, intertubular and lumen volumes significantly decreased in vaccinated rabbits (P<0.05), guinea pigs and ram lambs (P<0.01). Vaccinated animals of the three species showed significant reductions in spermatogonial numbers (10- to 40-fold; P<0.01). Sperm was absent in all seminiferous tubules of all rabbits, and most individuals of guinea pigs (80%) and ram lambs (60%). No significant differences were observed between vaccinated and control groups regarding FSH and LH during the experiments in the three experimental species/models used. Testosterone, however, was only significantly lower (~22-fold, P<0.01) in vaccinated rabbits. In conclusion, the present study demonstrated that pre-pubertal active immunization against GnRH leads to endocrine disruption and marked differences on testicular morphometry, development and activity among lagomorphs, hystricomorphs and ovine species with species-specific sensitivity regarding the anti-GnRH immune response.