Effect of a commercial product containing canthaxanthin for in ovo feeding to broiler embryos on hatchability, chick quality, oxidation status, and performance.

In ovo feeding has been indicated to improve hatchability, newly hatched chick quality, and broiler performance. The aim of this study was to investigate the effect of in ovo feeding of a commercial canthaxanthin product (CCX) containing lignosulphonate, corn starch, canthaxanthin, dextrin (yellow), and ethoxyquin through assessing incubation results, newly hatched quality and oxidation status and broiler performance at 1 to 14 d of age. A total of 780 egg were distributed in a randomized complete block design with 5 treatments (levels of CCX: 0.0, 0.35, 0.45, 0.55, and 0.65 mg/0.5 mL of sterilized and distilled water) and 156 eggs per treatment. The blocking factor was setters. At 17.5 d of embryo development, in ovo injected treatments were applied, using a manual needle. The in ovo feeding of CCX resulted in lower hatching rates (P < 0.05) and a longer hatching window (P < 0.05) as compared with noninjected CCX treatment. The CCX injection did not affect the bursa and spleen percentage of newly hatched chick (P > 0.05). In addition, a higher percentage of chicks with poor physical quality score (<71.0 points) was obtained among the chicks from eggs injected with 0.55 and 0.65 mg of CCX (P < 0.05). There were higher total proteins and catalase activity in the livers of the chicks injected with CCX. Broiler chicks in the control group (0.0 mg of CCX) presented higher BW and BW gain during 1 to 7 and 7 to 14 d of after hatch (P < 0.05). The viability (%) of chicks at 1 to 14 d of after hatch decreased with inoculation greater than 0.45 mg of CCX in ovo (P < 0.05). Although the CCX shown an improvement in oxidation status of chicks, the hatchability and performance of broilers decreased. We concluded that a commercial CCX is not recommended for injection in ovo, and furthers studies should carried out to elucidate the use of pure canthaxanthin.

Physical, histological, endocrinological and steroidogenical evaluation of male cats postnatally exposed to sexual steroids.

To test the hypothesis that postnatal sexual steroids induce an impairment of domestic male cat reproductive function, this study describes the physical, endocrine, steroidogenical and histological effects of a single, high dose of a postnatal sexual steroid in this species. Twenty male kittens were randomly assigned within the first 24 h of birth to: Testosterone enanthate 12.5 mg sc (TE; n = 8), medroxyprogesterone acetate 10 mg sc (MA; n = 6), or Placebo sc (PL; n = 6). The cats were followed until puberty when they were castrated. Kittens achieved puberty without age differences among groups (P > 0.05). Two MA cats presented abnormal testicular descent. Histological evaluation of the MA (P < 0.01), but not of TE testes revealed decreased diameter (P < 0.01) and epithelial height (P < 0.01) of the seminiferous tubules. Leydig cell nuclear area was also reduced in this group. Conversely, tubular/intertubular ratio was increased in TE animals (P < 0.01). Quantitative real-time PCR analysis of mRNA expression of testicular tissue revealed no significant differences among groups for StAR, CYP17A1 and androgen receptors. TE animals showed decreased CYP19A1 mRNA expression (P < 0.05). In the first 4 postnatal weeks, fecal testosterone (T) values were high, basal and intermediate in TE, MA and PL (P < 0.05), respectively. These differences progressively diminished and the three groups presented basal T concentrations from the 7th week on (P > 0.05). It was concluded that the postnatal progestagen initially suppressed the gonadal axis and caused an impairment of spermatogenesis and testicular descent at puberty. Androgen treatment caused downregulation of the final steroidogenic cascade.

Importance of body condition score and ovarian activity on determining the fertility in beef cows supplemented with long-acting progesterone after timed-AI.

The working hypothesis was that supplementation with progesterone (iP4) at early diestrus increases pregnancy rates of suckled beef cows with poor body condition score (BCS) and/or in anestrus when cows are submitted to timed insemination (TAI). The time of ovulation among suckled multiparous (n = 1270) and primiparous (n = 303) Nelore cows was synchronized using an estradiol/P4-based protocol for TAI (D0). At Day ‒10, visual evaluation of BCS was performed (scale = 1-5) and animals were classified according to an ovarian activity (OA) score: (OA1) absence of CL and presence of follicles ≥ 8 mm, (OA2) absence of CL and presence of follicles < 8 mm and (OA3) presence of corpus luteum (CL). On Day 4, animals were assigned randomly to receive 150 mg of injectable, long-acting P4 (iP4, n = 786) or non-iP4 (n = 787). Further, ultrasonic evaluations were performed on D0 and D4 for measurements of the largest follicle diameter (DF) and CL area, respectively. The BCS affected positively DF, CL area and OA. Supplementation with iP4 did not affect (P = 0.49) pregnancy rates and there was no significant interaction (P > 0.1) of P4 treatment with BCS or OA was detected for conception and pregnancy rates. Regardless of iP4, pregnancy rates of cows with moderate (2.75-3.25) (59.1%) and high (≥ 3.5) (57.8%) BCS were greater than those of cows with low (2.0-2.5) BCS (41.5%). Cows in OA2 had a greater P/AI (51.3%) than cows in OA1 (41.7%) or OA3 (41.9%). In conclusion, P4 supplementation after TAI did not improve P/AI and did not enhance the response to treatment of cows with a low BCS, regardless of OA.

Does heavy metal exposure affect the condition of Whitethroat (Sylvia communis) nestlings?

Anthropogenic pollution results in high concentrations of heavy metals in the environment. Due to their persistence and a high potential for bioaccumulation, metals are a real threat for birds breeding in industrial areas. The aim of the present study has been to explore the contents of heavy metals (arsenic As, cadmium Cd, chromium Cr, copper Cu, iron Fe, nickel Ni, lead Pb and zinc Zn) in the excreta of Whitethroat (Sylvia communis) nestlings living in polluted environment and to investigate the relationship between these contents and the nestlings' condition. Excrement samples contained all the studied elements. The contents of arsenic, cadmium, copper and zinc in the excreta of nestlings from nests located close to a slag dump were several times higher than in the soil near the dump, which suggested accumulation in food consumed by the birds. Condition parameters (body mass and haemoglobin concentration) were not related to heavy metal concentrations in the nestlings' excreta, except of Zn. It is possible that Whitethroats are able to detoxicate heavy metals to a certain extent. Detailed, multi-element analysis of the environment, food and bird tissues or excreta should be performed to explore relations between different chemicals and bird condition.

Meal replacements followed by topiramate for the treatment of adolescent severe obesity: A pilot randomized controlled trial.

OBJECTIVE: To assess the safety and efficacy of short-term meal replacement therapy followed by topiramate for body mass index (BMI) reduction in adolescents with severe obesity. METHODS: Adolescents (ages 12-18 years) with severe obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2 ) were recruited for this double-blind, randomized, placebo-controlled trial. Participants completed 4 weeks of meal replacement therapy followed by randomization (1:1) to either 24 weeks of topiramate 75 mg/day or placebo. Mean changes were compared between groups. RESULTS: Thirty adolescents (mean age 15.2 ± 1.7 years, mean BMI 40.3 ± 4.6 kg/m2 ) completed the meal replacement phase and were randomized; 21 completed the study. The difference in mean percent change in BMI between the topiramate and placebo groups was not significant (-1.9%; 95% CI: -5.2% to +1.5%; P = 0.291). Significant improvements in visceral fat and very-low-density lipoprotein cholesterol were observed in the topiramate compared with the placebo group. There were no concerning changes in neurocognitive function or bone health. CONCLUSIONS: In this pilot study, 4 weeks of meal replacement therapy followed by 24 weeks of low-dose topiramate compared with meal replacement therapy alone did not result in significant BMI reduction for adolescents with severe obesity.

Immunocontraception for managing feral cattle in Hong Kong.

Conflicts between human interests and feral cattle in Hong Kong derive from growing numbers of free-roaming cattle. Public antipathy towards lethal population control led the local authorities to consider fertility control to reduce cattle numbers. This study assessed the potential side effects of the immunocontraceptive GonaCon on individual female cattle and established the effectiveness of GonaCon to induce infertility. We evaluated GonaCon in 34 captive cattle assigned to four groups: Control administered a sham solution; Webbed (surgically sterilized through removal of the oviducts), administered one dose of GonaCon; Webbed, administered one dose of GonaCon and a booster dose three months later, and Treated, administered one dose of GonaCon. The side effects of GonaCon were assessed by monitoring injection site, body weight, body condition, size of lymph nodes, body temperature, and feeding behaviour 1 week and 1, 3, 6, 9 and 12 months after vaccination and by haematological and biochemical variables at vaccination and three months post-vaccination. The effectiveness of GonaCon to cause infertility was monitored by quantifying anti-GnRH antibody titres and by using kits to detect cycling and pregnancy. GonaCon-treated cattle showed no injection site reaction, limping, or abnormal behaviour. No differences were observed in all physiological and welfare indicators between control and vaccinated cattle. All control cattle and 4 of the 12 cattle in the Treated group became pregnant. Cattle administered a booster dose had higher anti-GnRH antibody titres than cattle that received one dose. We concluded that GonaCon does not compromise the animals' welfare and is effective in reducing fertility in cattle. A booster dose is likely to increase the duration of infertility. Further studies are required to assess the feasibility and costs of immunocontraception for controlling free-roaming cattle populations.

Effects of dietary supplementation of organic chromium (picolinate) on physical and biochemical characteristics of semen and carcass traits of male turkeys.

This experiment investigated the effect of dietary chromium (Cr as picolinate) on physical and biochemical characteristics of semen and carcass traits of adult male turkey. Seventy-two (72) male turkeys (16 weeks old) were randomly distributed into four dietary treatment groups (4×3×6) for a period of 24 weeks. Three experimental diets were supplemented with 250, 500 and 750µg Cr/kg (T2, T3 and T4 respectively) in basal diet (T1 considered as control). Semen physical characteristics viz. sperm concentration, progressive motility, live and dead count of spermatozoa and fertility differed significantly (P<0.05). Sperm concentration, progressive motility and fertility were higher and dead count was lower in T4 (750µg) group than control (T1) or other dietary treatments (T2 or T3) group. Semen biochemical parameters like creatinine, acid phosphatase (ACP) and alkaline phosphatase (ALP) concentration did not differ significantly among the dietary treatment groups, whereas, total protein, glucose, malondialdehyde (MAD) and cholesterol concentration differed significantly (P<0.05) amongst the treatment groups. Protein and MAD were higher while glucose and cholesterol concentrations were lower in T3 and T4 group than control or T1 group. The shrinkage loss, eviscerated yield, relative weight (as percent of body weight) of breast, thigh and liver improved on supplementation of Cr leading to significantly higher in T4 group in comparison to control. From this study, it could be concluded that supplementation of chromium as chromium picolinate, at 750µg/kg level in diet was beneficial for improving physical characteristics of semen, carcass yield and breast yield of adult male turkeys. However, Cr levels of 500 or 750µg/kg in diet were beneficial for semen biochemical parameters of adult male turkeys.

What are carotenoids signaling? Immunostimulatory effects of dietary vitamin E, but not of carotenoids, in Iberian green lizards.

In spite that carotenoid-based sexual ornaments are one of the most popular research topics in sexual selection of animals, the antioxidant and immunostimulatory role of carotenoids, presumably signaled by these colorful ornaments, is still controversial. It has been suggested that the function of carotenoids might not be as an antioxidant per se, but that colorful carotenoids may indirectly reflect the levels of nonpigmentary antioxidants, such as melatonin or vitamin E. We experimentally fed male Iberian green lizards (Lacerta schreiberi) additional carotenoids or vitamin E alone, or a combination of carotenoids and vitamin E dissolved in soybean oil, whereas a control group only received soybean oil. We examined the effects of the dietary supplementations on phytohaemagglutinin (PHA)-induced skin-swelling immune response and body condition. Lizards that were supplemented with vitamin E alone or a combination of vitamin E and carotenoids had greater immune responses than control lizards, but animals supplemented with carotenoids alone had lower immune responses than lizards supplemented with vitamin E and did not differ from control lizards. These results support the hypothesis that carotenoids in green lizards are not effective as immunostimulants, but that they may be visually signaling the immunostimulatory effects of non-pigmentary vitamin E. In contrast, lizards supplemented with carotenoids alone have higher body condition gains than lizards in the other experimental groups, suggesting that carotenoids may be still important to improve condition.

The role of canine distemper virus and persistent organic pollutants in mortality patterns of Caspian seals (Pusa caspica).

Persistent organic pollutants are a concern for species occupying high trophic levels since they can cause immunosuppression and impair reproduction. Mass mortalities due to canine distemper virus (CDV) occurred in Caspian seals (Pusa caspica), in spring of 1997, 2000 and 2001, but the potential role of organochlorine exposure in these epizootics remains undetermined. Here we integrate Caspian seal mortality data spanning 1971-2008, with data on age, body condition, pathology and blubber organochlorine concentration for carcases stranded between 1997 and 2002. We test the hypothesis that summed PCB and DDT concentrations contributed to CDV associated mortality during epizootics. We show that age is the primary factor explaining variation in blubber organochlorine concentrations, and that organochlorine burden, age, sex, and body condition do not account for CDV infection status (positive/negative) of animals dying in epizootics. Most animals (57%, n = 67) had PCB concentrations below proposed thresholds for toxic effects in marine mammals (17 µg/g lipid weight), and only 3 of 67 animals had predicted TEQ values exceeding levels seen to be associated with immune suppression in harbour seals (200 pg/g lipid weight). Mean organonchlorine levels were higher in CDV-negative animals indicating that organochlorines did not contribute significantly to CDV mortality in epizootics. Mortality monitoring in Azerbaijan 1971-2008 revealed bi-annual stranding peaks in late spring, following the annual moult and during autumn migrations northwards. Mortality peaks comparable to epizootic years were also recorded in the 1970s-1980s, consistent with previous undocumented CDV outbreaks. Gompertz growth curves show that Caspian seals achieve an asymptotic standard body length of 126-129 cm (n = 111). Males may continue to grow slowly throughout life. Mortality during epizootics may exceed the potential biological removal level (PBR) for the population, but the low frequency of epizootics suggest they are of secondary importance compared to anthropogenic sources of mortality such as fishing by-catch.

Effect of dietary supplementation with flaxseed oil or vitamin E on sheep experimentally infected with Fasciola hepatica.

The effects of two diets supplemented with flaxseed oil (FO) or vitamin E (VE) were studied in sheep infected with Fasciola hepatica. The control group (CO), not supplemented, had higher weight gain and faecal egg count (P < 0.05) at the end of the study. At necropsy, the number (71.2 ± 26.5) and size of flukes were lower in the FO group (P < 0.01), probably due to the higher levels of white blood cells and lymphocytes (P < 0.01). This group also had higher red blood cell and haematocrit values (P < 0.01). The CO group had more severe hypoproteinaemia and hypoalbuminaemia, due to having the highest fluke burden (123.0 ± 35.2), and also the highest IgG1 titre (P < 0.01). The diet did not affect production or gene expression levels of IFN-γ and IL-4. On the other hand, the supplementation with VE led to a reduction in adult fluke burden (97.7 ± 39.9) and lower lipid oxidation in the liver (P < 0.001).

Responses to capture stress and exogenous corticosterone vary with body condition in female red-sided garter snakes (Thamnophis sirtalis parietalis).

This study examined whether hormonal and behavioral responses to capture stress and exogenous corticosterone (CORT) vary with body condition in female red-sided garter snakes (Thamnophis sirtalis parietalis). Female snakes were collected during the spring mating season and treated with 4 h of capture stress. We measured plasma CORT and estradiol before, during and after capture stress treatment followed by latency to copulate, a measure of female receptivity. Body condition was determined as the residual from a regression of body mass on snout-vent-length. Baseline CORT did not differ between females in positive and negative body condition, but females in negative body condition showed a significantly larger increase in plasma CORT in response to capture stress. Estradiol, which is generally low during the mating season in this population, did not change in response to capture stress. Body condition, but not capture stress, influenced latency to copulate, suggesting that females are resistant to the behavioral effects of capture stress during the spring mating season. In a second experiment, only females in negative body condition increased latency to copulate in response to injection of a physiological (15 µg) dose of exogenous CORT, while all females responded to a pharmacological (60 µg) dose. These results indicate that behavioral responses to exogenous CORT vary with female body condition during the short mating season. Taken together, our data suggest that variation in body condition may be associated with differences in HPA axis sensitivity and/or glucocorticoid receptor density in the brain.

Dietary galactooligosaccharide affects intestinal microbiota, stress resistance, and performance of Caspian roach (Rutilus rutilus) fry.

The aim of this study was to assess the effects of galactooligosaccharide (GOS), on the growth performance, stress resistance and intestinal microbiota of Caspian roach (Rutilus rutilus) fry. Specimens (1.36 ± 0.03 g) were fed either a basal control diet (0% GOS, non-supplemented) or the basal diet supplemented with 1% and 2% of GOS. After 7 weeks of the feeding trials, growth factors (final weight, weight gain, specific growth rate, condition factor and food conversion ratio) as well as body composition, resistance to salinity stress and autochthonous intestinal microbiota were assessed. Results demonstrated that at the end of the trial growth factors (final weight, weight gain, SGR, FCR) were significantly higher in 2% GOS fed fish (P < 0.05). In addition, supplementation of GOS significantly increased both survival rate (P < 0.05), and resistance to a salinity stress challenge of prebiotic fed groups (P < 0.05). However, body composition and the total autochthonous intestinal heterotrophic bacteria counts remained unaffected in different treatments (P > 0.05). Nevertheless, autochthonous lactic acid bacteria levels were significantly elevated in fish fed 2% dietary GOS (P < 0.05). These results confirm that GOS improves growth performance, stress resistance and modulates intestinal microbiota by increasing lactic acid bacteria of Caspian roach fry, a very important fish species in the Caspian Sea.

Effects of post-partum administration of ketoprofen on sow health and piglet growth.

The effect of the non-steroidal anti-inflammatory drug ketoprofen on the post farrowing phase of sows was studied in a randomized, blinded, placebo-controlled trial. Ketoprofen (3mg/kg) was administered intramuscularly to 20 healthy sows for 3 days post-partum (p.p.). The control group (n=20) received a saline placebo. Backfat, number of days of constipation and days before feed refusal were measured. Body condition (BCS) and shoulder sores were scored for 1 week p.p. Changes in BCS, backfat and shoulder sore scores were analysed with ANOVA. Blood was collected on days -1, 0, 5 and 14 with respect to medication. Aspartate aminotransferase (AST), creatinine kinase (CK), haptoglobin and serum amyloid A (SAA) were quantified and analysed with a Mann-Whitney U test. BCS and backfat decreased less following ketoprofen administration than with the placebo (-0.08 ± 0.2 vs. -0.8 ± 0.2, 1.0 ± 0.8mm vs. -2.0 ± 0.9 mm, respectively; P<0.05 for both) during the first 2 weeks of lactation. The shoulder sore score deterioration was milder during days 4-6 p.p. with ketoprofen than placebo (P<0.05). Duration of constipation was shorter with ketoprofen than placebo (5.5 ± 0.3 vs. 6.4 ± 0.3 days p.p.; P<0.05). Incidences of feed refusal occurred later in the ketoprofen group than in the placebos (9.6 ± 0.9 vs. 3.8 ± 0.8 days p.p.; P<0.05). AST and SAA values were higher after ketoprofen administration than placebo on day 5 p.p. (P<0.05). It was concluded that ketoprofen appeared to benefit sows during the first 2 weeks post farrowing, but caused some tissue irritation.

High- and low-purity glycerine supplementation to dairy cows in early lactation: effects on silage intake, milk production and metabolism.

This study evaluated the effects of supplemental low- and high-purity glycerine on silage intake, milk yield and composition, plasma metabolites and body condition score (BCS) in dairy cows. A total of 42 cows of the Swedish Red Breed, housed in individual tie stalls, were fed 0.25 kg of low- or high-purity glycerine on top of concentrate, twice daily, during the first 4 weeks of lactation. One-third of the cows acted as controls, receiving no glycerine. Silage was fed for ad libitum intake and concentrate was fed at restricted level of intake, about 6 kg/day for primiparous cows and 7 kg/day for multiparous cows. Feed refusals were weighed daily. Cows were milked twice daily, milk yield was recorded on four occasions per week and milk samples were collected simultaneously. Blood samples were drawn from the coccygeal vessel once a week. Low- and high-purity glycerine had no effect on silage or total dry matter intake (P = 0.38 and P = 0.75, respectively) or on BCS (P = 0.45). Cows fed high-purity glycerine tended to have higher milk yield than control cows (P = 0.06). Milk composition tended to differ among treatments. No main effects of treatment on concentration of glycerine (P = 0.44), glucose (P = 0.78), insulin (P = 0.33), non-esterified fatty acids (P = 0.33) and ß-hydroxybutyrate (P = 0.15) in plasma. These data indicate that high-purity glycerine has the potential to increase milk yield, as well as enhance the milk protein concentration and milk fat + protein yield.

The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo-controlled, clinical trial.

IMPORTANCE: Medical treatment options for pediatric obesity remain limited. Glucagon-like peptide-1 (GLP-1) receptor agonists induce weight loss by suppressing appetite and increasing satiety, but few studies have evaluated this therapy as a treatment for obesity. OBJECTIVE: To evaluate the effects of exenatide on body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and cardiometabolic risk factors in adolescents with severe obesity. DESIGN: Three-month, randomized, double-blind, placebo-controlled, multicenter clinical trial followed by a 3-month open-label extension. SETTING: An academic medical center and an outpatient pediatric endocrinology clinic. PATIENTS: A total of 26 adolescents (12-19 years of age) with severe obesity (BMI ≥ 1.2 times the 95th percentile or BMI ≥ 35). INTERVENTION: All patients received lifestyle modification counseling and were equally randomized to exenatide or placebo injection, twice per day. MAIN OUTCOME MEASURES: The primary end point was the mean percent change in BMI measured at baseline and 3 months. Secondary end points included absolute change in BMI, body weight, body fat, blood pressure, hemoglobin A1c, fasting glucose, fasting insulin, and lipids at 3 months. RESULTS: Twenty-two patients completed the trial. Exenatide elicited a greater reduction in percent change in BMI compared with placebo (-2.70% [95% CI, -5.02% to -0.37%]; P = .03). Similar findings were observed for absolute change in BMI (-1.13 [95% CI, -2.03 to -0.24]; P = .02) and body weight (-3.26 kg [95% CI, -5.87 to -0.66 kg]; P = .02). Although not reaching the level of statistical significance, reduction in systolic blood pressure was observed with exenatide. During the open-label extension, BMI was further reduced in those initially randomized to exenatide (cumulative BMI reduction of 4%). CONCLUSIONS AND RELEVANCE: These results provide preliminary evidence supporting the feasibility, safety, and efficacy of GLP-1 receptor agonist therapy for the treatment of severe obesity in adolescents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01237197.

Effects of the anti-thyroidal compound potassium-perchlorate on the thyroid system of the zebrafish.

The increasing pollution of aquatic habitats with anthropogenic compounds has led to various test strategies to detect hazardous chemicals. However, information on effects of pollutants in the thyroid system in fish, which is essential for growth, development and parts of reproduction, is still scarce. Other vertebrate groups such as amphibians or mammals are well-studied; so the need for further knowledge especially in fish as a favored vertebrate model test organism is evident. Modified early life-stage tests were carried out with zebrafish exposed to the known thyroid inhibitor potassium perchlorate (0, 62.5, 125, 250, 500 and 5000 µg/L) to identify adverse effects on the hypothalamic-pituitary-thyroid axis. Especially higher perchlorate concentrations led to conspicuous alterations in thyroidal tissue architecture and to effects in the pituitary. In the thyroid, severe hyperplasia at concentrations ≥ 500 µg/L together with an increase in follicle number could be detected. The most sensitive endpoint was the colloid, which showed alterations at ≥ 250 µg/L. The tinctorial properties and the texture of the colloid changed dramatically. Interestingly, effects on epithelial cell height were minor. The pituitary revealed significant proliferations of TSH-producing cells resulting in alterations in the ratio of adeno- to neurohypophysis. The liver as the main site of T4 deiodination showed severe glycogen depletion at concentrations ≥ 250 µg/L. In summary, the thyroid system in zebrafish showed effects by perchlorate from concentrations ≥ 250 µg/L, thus documenting a high sensitivity of the zebrafish thyroid gland for goitrogens. In the future, such distinct alterations could lead to a better understanding and identification of potential thyroid-disrupting chemicals.

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors.

BACKGROUND: Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet. AIMS: To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy. METHODS: Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. RESULTS: Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2). CONCLUSIONS: Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.

Estrogenic effects of water from the Yangtze River (Nanjing section) on goldfish (Carassius auratus) after an early life stage exposure.

Effects of river water from the Yangtze River (Nanjing section) on fish development, vitellogenin (VTG) induction, gonado-somatic index (GSI) and sex ratio were investigated by exposing goldfish (Carassius auratus) in the early life stage (from fertilization to 28 days post-hatch) to water samples (25%, 50% and 100%) collected from three representative sections. The results showed that there was no significant effect on hatching success for any of the exposure groups, but survival was significantly reduced when compared with the control (P < 0.05). Body lengths, weights of all treated fish did not differ significantly from those of the control. Condition factors (CF) of larval fish exposed to 50% and 100% river water from the Jiangxinzhou section and 100% river water from the Daqiao section were significantly lower than that of the control (P < 0.05). VTG inductions were significant in larval fish exposed to all the dilution series of river water. No significant difference in CF value was observed in any exposure group after 150 days of depuration. VTG was fully eliminated after 75 days of depuration. For both female and male, GSI did not significantly differ between exposure groups and the control after 150 days of convalescence. The highest female:male ratios were observed in response to the treatment with 50% or 100% river water from the Jiangxinzhou section and 100% river water from the Daqiao section (53:47, 56:44 and 54:46, respectively), but no significant difference in sex ratio was observed in any treated group when compared to the control. The results showed that early life stage exposure of river water from the Yangtze River (Nanjing section) had adverse effects on goldfish development and reproductive health, and the effects on CF and VTG were reversible after depuration in clean water.

Preliminary evidence of the contribution of the intestinal microflora to biotin supply in zebrafish Danio rerio (Hamilton-Buchanan).

A study was conducted to preliminarily assess the contribution of the intestinal microflora to biotin supply in zebrafish. Biotin and avidin were added to three isonitrogenous and isocaloric purified diets to provide molar avidin: biotin ratios of 0:0 (basal diet), 0:1 (biotin-supplemented diet), and 120:0. Another diet was made by supplementing the antibiotic succinylsulfathiazole (1%, wt/wt) to the basal diet. A fifth diet was the Zeigler commercial diet for zebrafish. Each diet was fed to a triplicate group of fish (mean initial mass 0.266 g) for 8 weeks. The condition factor, feed conversion ratio (FCR), percentage weight gain, and survival were similar in fish groups fed the commercial and the biotin-supplemented diets, but energy conversion efficiency and whole-body biotin content were highest in the fish fed the commercial diet (p<0.05). Reduced growth and survival, and increased FCR were noted in fish fed basal diet compared with those fed biotin-supplemented diet. The supplementation of avidin in diet led to lower survival and condition factor, and higher FCR than that observed with basal diet. Intestinal microbial synthesis is assumed to be a significant source of biotin to the zebrafish, as fish fed the antibiotic-supplemented diet showed the lowest growth, health condition, and feed utilization.