Metabolomic phenotyping of a cloned pig model

<p>Abstract</p> <p>Background</p> <p>Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal outbred pigs.</p> <p>Results</p> <p>The metabolic phenotype of cloned pigs (n = 5) was for the first time elucidated by nuclear magnetic resonance (NMR)-based metabolomic analysis of multiple bio-fluids including plasma, bile and urine. The metabolic phenotype of the cloned pigs was compared with normal outbred pigs (n = 6) by multivariate data analysis, which revealed differences in the metabolic phenotypes. Plasma lactate was higher for cloned vs control pigs, while multiple metabolites were altered in the bile. However a lower inter-individual variability for cloned pigs compared with control pigs could not be established.</p> <p>Conclusions</p> <p>From the present study we conclude that cloned and normal outbred pigs are phenotypically different. However, it cannot be concluded that the use of cloned animals will reduce the inter-individual variation in intervention studies, though this is based on a limited number of animals.</p

Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer

Although ovarian cancer is a rare disease, it constitutes the fifth leading cause of cancer death among women. It is of major importance to develop new therapeutic strategies to improve survival. Combining P8-D6, a novel dual topoisomerase inhibitor with exceptional anti-tumoral properties in ovarian cancer and compounds in preclinical research, and olaparib, a PARP inhibitor targeting DNA damage repair, is a promising approach. P8-D6 induces DNA damage that can be repaired by base excision repair or homologous recombination in which PARP plays a major role. This study analyzed benefits of combining P8-D6 and olaparib treatment in 2D and 3D cultures with ovarian cancer cells. Measurement of viability, cytotoxicity and caspase activity were used to assess therapy efficacy and to calculate the combination index (CI). Further DNA damage was quantified using the biomarkers RAD51 and γH2A.X. The combinational treatment led to an increased caspase activity and reduced viability. CI values partially show synergisms in combinations at 100 nM and 500 nM P8-D6. More DNA damage accumulated, and spheroids lost their membrane integrity due to the combinational treatment. While maintaining the same therapy efficacy as single-drug therapy, doses of P8-D6 and olaparib can be reduced in combinational treatments. Synergisms can be seen in some tested combinations. In summary, the combination therapy indicates benefits and acts synergistic at 100 nM and 500 nM P8-D6

Aspects of gastrointestinal motility in relation to the development of digestive function in neonates

Abstract Gastrointestinal motility is responsible for mixing and transport of digesta and elimination of undigested residues. The basis for the motility is the electrical activity of the gastrointestinal smooth muscle, which has a recurring pattern. In the small intestine of mature animals, this pattern is associated with periodic fluctuations of mesenteric blood flow, and gastric, pancreatic and biliary secretion, and with intestinal absorption. In general, feeding disrupts the cyclic pattern in the stomach and small intestine, replacing it with a continuous post-feeding pattern, and the duration of the post-feeding pattern is dependent on animal species, composition of the diet and feeding regime. The perinatal and weaning periods manifest drastic changes in digestive function and, thus, in gastrointestinal motility. Due to difficulties in performing studies in perinatal and neonatal animals, only few data on the development of gastrointestinal motility, and its synchronisation with other digestive functions, are available. Whereas some studies in the literature indicate that the development of gastrointestinal motility follows the maturation of the regulatory mechanisms, recent data also suggest that changes in gastrointestinal motility around birth and weaning reflect changes in nutrient supply. This paper deals with some aspects of gastrointestinal motility, primarily in the gastric antrum and small intestine, of neonatal animals. Certainly, changes in gastrointestinal motility in early life could be of paramount importance for proper digestive function and this research area requires further attention

Effects of fructooligosaccharides on cecum polyamine concentration and gut maturation in early-weaned piglets

Polyamines are molecules involved in cell growth and differentiation and are produced by bacterial metabolism. However, their production and effects by the microbiota selected by fructooligosaccharides consumption are controversial. In this study, we investigated the influence of supplementation of fructooligosaccharides on the cecal polyamine production by the microflora selected, and its effect on gut maturation in newborn piglets. Twenty piglets were fed a control formula (n = 10) or a formula supplemented with fructooligosaccharides (8 g/l) (n = 10) for 13 days. Colony-forming unit’s count of cecal content was done in different media. Several intestinal development parameters were measured as well as the polyamine concentration in the cecal mucosa and cecal content. A dose-dependent study on in vitro polyamine production by fructooligosaccharides addition to the isolated cecal content was performed. Bifidogenic activity of fructooligosaccharides increased polyamine concentration in the cecal content, mainly putrescine, with no beneficial effect on gut maturation. Bifidobacterium spp. were able to produce polyamines, but they were not the most significant bacterial producer of polyamines in the cecum of piglets fed fructooligosaccharides. Bifidogenic activity of fructooligosaccharides did not lead to an increase in gut maturation in piglets of 15 days of age although polyamines were increased in the cecal content

A Problem with the Individual Approach in the WHO Health Inequality Measurement

BACKGROUND: In the World Health Report 2000, the World Health Organization made the controversial choice to measure inequality across individuals rather than across groups, the standard in the field. This choice has been widely discussed and criticized. DISCUSSION: We look at the three questions: (1) is the World Health Organization's health inequality measure value-free as it claims? (2) if it is not, what is the normative position implied by its approach when measuring health inequality? and (3) is the individual approach a logically consistent methodological choice for that normative position? SUMMARY: We argue that the World Health Organization's health inequality measure is not value-free. If it was, the health inequality information that the measurement collected could not reasonably be included in its ranking of how well national health systems performed. The World Health Organization's normative position can be interpreted as a quite expansive view of justice, in which health distributions that have causes amenable to human intervention are considered to be matters of justice. Our conclusion is that if the World Health Organization's health inequality measure is to be interpreted meaningfully in a policy context, its conceptual underpinning must be re-evaluated