Heritability of Caffeine Metabolism: Environmental Effects Masking Genetic Effects on CYP1A2 Activity but Not on NAT2.

Heritability of caffeine pharmacokinetics and cytochrome P450 1A2 (CYP1A2) activity is controversial. Here, we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic (MZ) and dizygotic (DZ) twins. In the entire group, common and unique environmental effects explained most variation in caffeine area under the curve (AUC). Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and, even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893). In contrast, nearly all of the variations (99%) of NAT2 activity were explained by genetic effects. This study illustrates two very different situations in pharmacogenetics from an almost exclusively genetic determination of NAT2 activity with no environmental modulation to only moderate genetic effects on CYP1A2 activity with strong environmental modulation.

Heritability of metoprolol and torsemide pharmacokinetics.

Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated.

Validation of a new imaging device for telemedical ulcer monitoring.

PURPOSE: To clarify whether a new portable imaging device (PID) providing 3D images for telemedical use constitutes a more correct expression of the clinical situation compared to standard telemedical equipment in this case iPhone 4s. METHOD: We investigated intra- and interindividual variability between the new portable camera and the iPhone images vs. clinical assessment as the 'gold standard'. The study included 36 foot ulcers. Four specialists rated the ulcers and filled out a questionnaire, which formed the basis of the evaluation. RESULTS: We found fair to very good intra-rater agreement for the new PID and iPhone, respectively. The gold standard was evaluated by assessing the ulcer twice by two different specialists. Kappa values were moderate to very good with respect to inter-rater agreement except for two variables. The agreement between standard and new equipment compared to the gold standard showed highest agreement with the new PID. CONCLUSION: The new PID is more in accordance with the clinical assessment compared to standard images. It opens for the possibility of using more advanced techniques in a telemedical approach to ulcer treatment and care, including volume measurements.

Small volume resuscitation with hypertonic sodium chloride solution in cattle undergoing surgical correction of abomasal volvulus.

A randomized clinical trial was conducted to compare the efficacy of rapid intravenous (IV) infusion of a 7.2% hypertonic saline solution with that of continuous application of an isotonic solution in stabilizing the circulation of cows with abomasal volvulus. Cattle treated with hypertonic saline had a significantly greater reduction in volume deficit within the first 10 min of therapy than cows treated with isotonic saline (from 5.9 ± 4.8 to 2.1 ± 4.4 L/100 kg vs. 7.0 ± 4.5 to 4.9 ± 3.8 L/100 kg, respectively). The central venous pressure (CVP) of the cows given the hypertonic saline rose within the first 10 min of therapy from 7.3 ± 3.5 to 10.8 ± 3.4 cm H2O, while the CVP of the cattle treated with isotonic saline did not increase significantly during this time. Sixty minutes after the start of the infusion, the CVP of the isotonic group was still significantly lower than that of the hypertonic group (9.5 ± 2.1 vs. 10.3 ± 3.3 cm H2O, respectively). Within the first 60 min, the base excess decreased from 5.5 ± 6.9 to 4.7 ± 6.2 mmol/L in the hypertonic group whereas it increased from 5.6 ± 5.7 to 6.8 ± 5.4 mmol/L in the isotonic group. These results suggest that for cows with abomasal volvulus, IV therapy with hypertonic saline may improve the haemodynamic and circulatory situation considerably faster and more effectively than continuous infusion with isotonic saline.

Is it really organic?--multi-isotopic analysis as a tool to discriminate between organic and conventional plants.

Novel procedures for analytical authentication of organic plant products are urgently needed. Here we present the first study encompassing stable isotopes of hydrogen, carbon, nitrogen, oxygen, magnesium and sulphur as well as compound-specific nitrogen and oxygen isotope analysis of nitrate for discrimination of organically and conventionally grown plants. The study was based on wheat, barley, faba bean and potato produced in rigorously controlled long-term field trials comprising 144 experimental plots. Nitrogen isotope analysis revealed the use of animal manure, but was unable to discriminate between plants that were fertilised with synthetic nitrogen fertilisers or green manures from atmospheric nitrogen fixing legumes. This limitation was bypassed using oxygen isotope analysis of nitrate in potato tubers, while hydrogen isotope analysis allowed complete discrimination of organic and conventional wheat and barley grains. It is concluded, that multi-isotopic analysis has the potential to disclose fraudulent substitutions of organic with conventionally cultivated plants.

The effects of social contact and milk allowance on responses to handling, play, and social behavior in young dairy calves.

The aim of this study was to investigate the effects of social contact and milk allowance on social behavior, play behavior, and responses to handling in dairy calves. Forty test calves and 16 companion calves were allocated to 1 of 5 treatments from birth to 4 wk of age: (1) housed singly and fed 5 L of milk/d; (2) housed singly and fed 9 L of milk/d; (3) housed in pairs and fed 5 L of milk/d; (4) housed in pairs and fed 9 L of milk/d; or (5) kept with the dam and fed 9 L of milk/d. From 4 to 6 wk of age, all calves were offered 5 L of milk/d to promote intake of solid feed before weaning. At 6 wk of age, all calves were weaned, and at 7 wk of age, they were grouped (7 calves/group: 1 test calf from each treatment and 2 companion calves). The response to restraint during blood sampling was recorded weekly; singly housed calves struggled more during restraint than did calves kept with the dam, and pair-housed calves struggled at an intermediate level. Play behavior was recorded for 20 min/wk after the provision of fresh straw; calves housed singly and fed a low milk allowance spent less time playing than did calves in all other treatments. Three days after grouping, calves were subjected to a feed competition test; calves receiving the high milk allowance and housed in pairs spent more time feeding than did those receiving the high milk allowance and housed singly, with all other treatments showing intermediate responses. These results indicate that social contact decreased responses to restraint and increased play and competitive success. The high milk allowance increased play but reduced competitive success after grouping. Lower responses to restraint indicated less responsiveness to stress. Play is considered an indicator of positive welfare, and competitive success helps calves succeed in a group environment.

Brief report: biomarkers of aortic vascular prosthetic graft infection in a porcine model with Staphylococcus aureus.

Aortic vascular prosthetic graft infection (AVPGI) with Staphylococcus aureus is a feared post-operative complication. This study was conducted to evaluate the clinical signs and potential biomarkers of infection in a porcine AVPGI model. The biomarkers evaluated were: C-reactive protein (CRP), fibrinogen, white blood cells (WBC), major histocompatibility complex II (MHC II) density, lymphocyte CD4:CD8 ratio and tumour necrosis factor-alpha (TNF-α) in vitro responsiveness. Sixteen pigs were included in the study, and randomly assigned into four groups (n = 4): "SHAM" pigs had their infra-renal aorta exposed by laparotomy; "CLEAN" pigs had an aortic graft inserted; "LOW" and "HIGH" pigs had an aortic graft inserted and, subsequently, S. aureus were inoculated on the graft material (5 × 10(4) colony-forming units [CFU] and 1 × 10(6) CFU, respectively). Biomarkers were evaluated prior to surgery and on day 2, 5, 7, and 14 post-operatively in blood samples. Of all biomarkers evaluated, CRP was superior for diagnosing S. aureus AVPGI in pigs, with a sensitivity of 0.86 and a specificity of 0.75.

Reproductive performance and bone status markers of gilts and lactating sows supplemented with two different forms of vitamin D.

In swine nutrition, little is known about the vitamin D requirements for reproductive processes and bone health. Consequently, the vitamin D recommendation for sows during gestation and lactation is not based on scientific reports. The current study was undertaken to obtain information on the dose-response pattern of 2 vitamin D sources, the commonly used cholecalciferol, called vitamin D(3), and a newly developed Hy.D product (25-hydroxycholecalciferol). In Exp. 1, a total of 160 gilts were randomly assigned from the first estrus until d 28 of gestation to dietary treatments containing 4 concentrations of 1 of the 2 different vitamin D sources [200, 800, 1,400, and 2,000 IU/kg of vitamin D from cholecalciferol or corresponding doses of 5, 20, 35, and 50 microg/kg of feed from 25(OH)D(3) (Hy.D)]. In a concurrent experiment, the same 8 dietary treatments were provided to 160 multiparous sows from the first day of mating until weaning. Plasma concentrations of 25(OH)D(3) were influenced by a dose x form interaction (P < 0.001); furthermore, plasma 25(OH)D(3) concentrations were influenced by the lactation state of the sows. Irrespective of the dietary dose and form of vitamin D provided to the sows, very little vitamin D was transferred to the progeny. Reproductive performance was not influenced by dietary vitamin D treatments, except for a decreased number of stillborn piglets (P = 0.03, SE = 0.40) with the larger doses of vitamin D (1,400 and 2,000 IU of vitamin D, resulting in 1.17 and 1.13 stillborn piglets per litter, respectively) compared with the smaller doses of vitamin D (200 and 800 IU of vitamin D, resulting in 1.98 and 1.99 stillborn piglets per litter, respectively). In the gilt trial, the ultimate strength of the bones (P = 0.01) and their content of ash (P = 0.02) were greater when vitamin D(3) was supplemented in doses larger than 800 IU, compared with the same amount of Hy.D supplementation. In the sow experiment, lactation day (P < 0.001), rather than dietary vitamin D, influenced the concentrations of osteocalcin and Ca as well as the activities of total alkaline phosphatase and bone alkaline phosphatase in plasma. Age of the suckling piglets affected their plasma bone health markers. In conclusion, at doses greater than 200 IU, Hy.D was more bioavailable than vitamin D(3) and, as such, could be considered an equivalent or even more advantageous source of vitamin D. In addition, a dietary dose of approximately 1,400 IU of vitamin D is recommended for reproducing swine. Irrespective of the dietary dose and form of vitamin D provided to the sows, very little vitamin D was transferred to the progeny.

No effect of the plant growth regulator, chlormequat, on boar fertility.

Chlormequat is a commonly used plant growth regulator in agriculture. Defined levels of chlormequat residue are allowed in food and an acceptable daily intake is defined for humans. However, there are results in the literature suggesting that a daily intake below the acceptable level for human is detrimental for mammalian reproduction. In the present experiment we investigated the effect of chlormequat at levels up to that acceptable for humans on reproduction in male pigs. Chlormequat (also known as chlorocholine chloride (CCC)) was mixed into the diet and given to the experimental animals at three levels (three treatment groups), i.e. 0 mg CCC/kg BW per day (Control), 0.025 mg CCC/kg BW per day and 0.05 mg CCC/kg BW per day. Eight mother sows per treatment group were used in the experiment. From the day of insemination, the mother sows received the experimental diets. The piglets were weaned at 4 weeks of age and two boar littermates continued on the same treatment as the dam until maturity and delivery of semen for in vitro fertilization (IVF) and in vivo fertilization. Semen volume, sperm concentration and fraction of live sperms were not (P 0.46) detrimentally affected by chlormequat intake. The fraction of oocytes developing to more than the one-cell stage at day 5 after IVF was not (P = 0.88) detrimentally affected by chlormequat intake. Chlormequat intake did not detrimentally affect the fraction of gilts being pregnant after one insemination (P = 0.65) or the number of embryos in the pregnant gilts (P = 0.36). Serum chlormequat concentration was 0.9 µg/kg in the 0.025 mg CCC/kg BW per day group and 1.8 µg/kg in the 0.05 mg CCC/kg BW per day group, but was below the detection limit in control animals. In conclusion, the plant growth regulator chlormequat could not be proven to be detrimental to the selected reproduction traits in male pigs. This is in contrast to existing results from the male mouse.