Trends in qualifying biomarkers in drug safety. Consensus of the 2011 meeting of the spanish society of clinical pharmacology.

In this paper we discuss the consensus view on the use of qualifying biomarkers in drug safety, raised within the frame of the XXIV meeting of the Spanish Society of Clinical Pharmacology held in Málaga (Spain) in October, 2011. The widespread use of biomarkers as surrogate endpoints is a goal that scientists have long been pursuing. Thirty years ago, when molecular pharmacogenomics evolved, we anticipated that these genetic biomarkers would soon obviate the routine use of drug therapies in a way that patients should adapt to the therapy rather than the opposite. This expected revolution in routine clinical practice never took place as quickly nor with the intensity as initially expected. The concerted action of operating multicenter networks holds great promise for future studies to identify biomarkers related to drug toxicity and to provide better insight into the underlying pathogenesis. Today some pharmacogenomic advances are already widely accepted, but pharmacogenomics still needs further development to elaborate more precise algorithms and many barriers to implementing individualized medicine exist. We briefly discuss our view about these barriers and we provide suggestions and areas of focus to advance in the field.

Condition-dependent genetic benefits of extrapair fertilization in female blue tits Cyanistes caeruleus.

In many socially monogamous birds, both partners perform extrapair copulations (EPC). As this behaviour potentially inflicts direct costs on females, they are currently hypothesized to search for genetic benefits for descendants, either as 'good' or 'complementary' genes. Although these hypotheses have found some support, several studies failed to find any beneficial consequence of EPC, and whether this behaviour is adaptive to females is subject to discussion. Here, we test these two hypotheses in a natural population of blue tits by accounting for the effect of most parameters known to potentially affect extrapair fertilization. Results suggest that female body mass affected the type of extrapair genetic benefits obtained. Heavy females obtained extrapair fertilizations when their social male was of low quality (as reflected by sexual display) and produced larger extrapair than within-pair chicks. Lean females obtained extrapair fertilizations when their social mate was genetically similar, thereby producing more heterozygous extrapair chicks. Our results suggest that mating patterns may be condition-dependent.

Early maternal investment in mice: no evidence for compatible-genes sexual selection despite hybrid vigor.

Confronting a recently mated female with a strange male can induce a pregnancy block ('Bruce effect'). The physiology of this effect is well studied, but its functional significance is still not fully understood. The 'anticipated infanticide hypothesis' suggests that the pregnancy block serves to avoid the cost of embryogenesis and giving birth to offspring that are likely to be killed by a new territory holder. Some 'compatible-genes sexual selection hypotheses' suggest that the likelihood of a pregnancy block is also dependent on the female's perception of the stud's and the stimulus male's genetic quality. We used two inbred strains of mice (C57BL/6 and BALB/c) to test all possible combinations of female strain, stud strain, and stimulus strain under experimental conditions (N(total) = 241 mated females). As predicted from previous studies, we found increased rates of pregnancy blocks if stud and stimulus strains differed, and we found evidence for hybrid vigour in offspring of between-strain mating. Despite the observed heterosis, pregnancies of within-strain matings were not more likely to be blocked than pregnancies of between-strain matings. A power analysis revealed that if we missed an existing effect (type-II error), the effect must be very small. If a female gave birth, the number and weight of newborns were not significantly influenced by the stimulus males. In conclusion, we found no support for the 'compatible-genes sexual selection hypotheses'.

Molecular basis for changes in behavioral state in ant social behaviors.

A hallmark of behavior is that animals respond to environmental change by switching from one behavioral state to another. However, information on the molecular underpinnings of these behavioral shifts and how they are mediated by the environment is lacking. The ant Pheidole pallidula with its morphologically and behaviorally distinct major and minor workers is an ideal system to investigate behavioral shifts. The physically larger majors are predisposed to defend the ant nest, whereas the smaller minors are the foragers. Despite this predisposition, majors are able to shift to foraging according to the needs of the colony. We show that the ant foraging (ppfor) gene, which encodes a cGMP-dependent protein kinase (PKG), mediates this shift. Majors have higher brain PKG activities than minors, and the spatial distribution of the PPFOR protein differs in these workers. Specifically, majors express the PPFOR protein in 5 cells in the anterior face of the ant brain, whereas minors do not. Environmental manipulations show that PKG is lower in the presence of a foraging stimulus and higher when defense is required. Finally, pharmacological activation of PKG increases defense and reduces foraging behavior. Thus, PKG signaling plays a critical role in P. pallidula behavioral shifts.

Implementing an interfaculty series of courses on interprofessional collaboration in prelicensure health science curriculums.

Introduction: Interprofessional collaborative practices are increasingly recognized as an effective way to deal with complex health problems. However, health sciences students continue to be trained in specialized programs and have little occasion for learning in interdisciplinary contexts. Program Development: The project's purpose was to develop content and an educational design for new prelicensure interfaculty courses on interprofessional collaboration in patient and family-centered care which embedded interprofessional education principles where participants learn with, from and about each other. Implementation: Intensive training was part of a 45-hour program, offered each semester, which was divided into three 15-hour courses given on weekends, to enhance accessibility. Evaluation: A total of 215 students completed questionnaires following the courses, to assess their satisfaction with the educational content. Pre/post measures assessed perception of skills acquisition and perceived benefits of interprofessional collaboration training. Results showed a significant increase from the students' point of view in the knowledge and benefits to be gained from interprofessional collaboration training.

Morphology, testes development and behaviour of unusual triploid males in microchromosome-carrying clones of Poecilia formosa.

In a microchromosome-carrying laboratory stock of the normally all-female Amazon molly Poecilia formosa triploid individuals were obtained, all of which spontaneously developed into males. A comparison of morphology of the external and internal insemination apparatus and the gonads, sperm ploidy and behaviour, to laboratory-bred F(1) hybrids revealed that the triploid P. formosa males, though producing mostly aneuploid sperm, are partly functional males that differ mainly in sperm maturation and sexual motivation from gonochoristic P. formosa males.

Cycle length of spermatogenesis in shrews (mammalia: soricidae) with high and low metabolic rates and different mating systems.

The aim of the present study was to establish and compare the durations of the seminiferous epithelium cycles of the common shrew Sorex araneus, which is characterized by a high metabolic rate and multiple paternity, and the greater white-toothed shrew Crocidura russula, which is characterized by a low metabolic rate and a monogamous mating system. Twelve S. araneus males and fifteen C. russula males were injected intraperitoneally with 5-bromodeoxyuridine, and the testes were collected. For cycle length determinations, we applied the classical method of estimation and linear regression as a new method. With regard to variance, and even with a relatively small sample size, the new method seems to be more precise. In addition, the regression method allows the inference of information for every animal tested, enabling comparisons of different factors with cycle lengths. Our results show that not only increased testis size leads to increased sperm production, but it also reduces the duration of spermatogenesis. The calculated cycle lengths were 8.35 days for S. araneus and 12.12 days for C. russula. The data obtained in the present study provide the basis for future investigations into the effects of metabolic rate and mating systems on the speed of spermatogenesis.

The anti-apoptotic role of PPARbeta contributes to efficient skin wound healing.

PPARalpha and PPARbeta are expressed in the mouse epidermis during fetal development, but their expression progressively disappears after birth. However, the expression of PPARbeta is reactivated in adult mice upon proliferative stimuli, such as cutaneous injury. We show here that PPARbeta protects keratinocytes from growth factor deprivation, anoikis and TNF-alpha-induced apoptosis, by modulating both early and late apoptotic events via the Akt1 signaling pathway and DNA fragmentation, respectively. The control mechanisms involve direct transcriptional upregulation of ILK, PDK1, and ICAD-L. In accordance with the anti-apoptotic role of PPARbeta observed in vitro, the balance between proliferation and apoptosis is altered in the epidermis of wounded PPARbeta mutant mice, with increased keratinocyte proliferation and apoptosis. In addition, primary keratinocytes deleted for PPARbeta show defects in both cell-matrix and cell-cell contacts, and impaired cell migration. Together, these results suggest that the delayed wound closure observed in PPARbeta mutant mice involves the alteration of several key processes. Finally, comparison of PPARbeta and Akt1 knock-out mice reveals many similarities, and suggests that the ability of PPARbeta to modulate the Akt1 pathway has significant impact during skin wound healing.

Social evolution: the smell of cheating.

Coercion is a powerful means to enforce altruism and promote social cohesion in animal groups, but it requires the reliable identification of selfish individuals. Experiments in a desert ant provide the first direct proof that a single cuticular hydrocarbon elicits the policing of reproductive workers by other colony members.

Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.

The Na(+)-independent alanine-serine-cysteine transporter 1 (Asc-1) is exclusively expressed in neuronal structures throughout the central nervous system (CNS). Asc-1 transports small neutral amino acids with high affinity especially for D-serine and glycine (K(i): 8-12 microM), two endogenous glutamate co-agonists that activate N-methyl-D-aspartate (NMDA) receptors through interacting with the strychnine-insensitive glycine binding-site. By regulating D-serine (and possibly glycine) levels in the synaptic cleft, Asc-1 may play an important role in controlling neuronal excitability. We generated asc-1 gene knockout (asc-1(-/-)) mice to test this hypothesis. Behavioral phenotyping combined with electroencephalogram (EEG) recordings revealed that asc-1(-/-) mice developed tremors, ataxia, and seizures that resulted in early postnatal death. Both tremors and seizures were reduced by the NMDA receptor antagonist MK-801. Extracellular recordings from asc-1(-/-) brain slices indicated that the spontaneous seizure activity did not originate in the hippocampus, although, in this region, a relative increase in evoked synaptic responses was observed under nominal Mg(2+)-free conditions. Taken together with the known neurochemistry and neuronal distribution of the Asc-1 transporter, these results indicate that the mechanism underlying the behavioral hyperexcitability in mutant mice is likely due to overactivation of NMDA receptors, presumably resulting from elevated extracellular D-serine. Our study provides the first evidence to support the notion that Asc-1 transporter plays a critical role in regulating neuronal excitability, and indicate that the transporter is vital for normal CNS function and essential to postnatal survival of mice.

Parental investment and its sensitivity to corticosterone is linked to melanin-based coloration in barn owls.

Behavioral and physiological responses to unpredictable changes in environmental conditions are, in part, mediated by glucocorticoids (corticosterone in birds). In polymorphic species, individuals of the same sex and age display different heritable melanin-based color morphs, associated with physiological and reproductive parameters and possibly alternative strategies to cope with variation in environmental conditions. We examined whether the role of corticosterone in resolving the trade-off between self-maintenance and reproductive activities covaries with the size of melanin-based spots displayed on the ventral body side of male barn owls. Administration of corticosterone to simulate physiological stress in males revealed pronounced changes in their food-provisioning rates to nestlings compared to control males. Corticosterone-treated males with small eumelanic spots reduced nestling provisioning rates as compared to controls, and also to a greater degree than did corticosterone-treated males with large spots. Large-spotted males generally exhibited lower parental provisioning and appear insensitive to exogenous corticosterone suggesting that the size of the black spots on the breast feathers predicts the ability to cope with stressful situations. The reduced provisioning rate of corticosterone-treated males caused a temporary reduction in nestling growth rates but, did not affect fledgling success. This suggests that moderately elevated corticosterone levels are not inhibitory to current reproduction but rather trigger behavioral responses to maximize lifetime reproductive success.

Why Mathematics is essential in Biomedical Sciences degree?

Improvement of mathematical education and motivation of students in the mathematics" area is needed. What can be done? We introduce some ideas to generate the student"s interest for mathematics, because they often present difficulties in appreciating the relevance of mathematics and its role in the health sciences. We consider that a cornerstone in the strategy to attract the students" interest is linking the mathematics with real biomedical situations. We proceed in the following manner: We first present a real biomedical situation to produce interest and to generate curiosity. Second, we ask thought-provoking questions to students as: Which is the biomedical problem presented? Which is my knowledge on this situation? What could I do to solve this biomedical situation? Do I need some new mathematical concepts and procedures? Thereupon, the teacher explains the mathematical concepts necessary to solve the case presented, providing definitions, properties and tools for graphical display and/or mathematical calculations. In this learning methodology, ICTs were cornerstones for reaching the proposed competences. Furthermore, ICTs can also be used in the evaluative task in its two possible aspects: formative and for obtaining a qualification. Comments from students about this new mathematics teaching method indicate that the use of real biomedical case studies kept the lessons in mathematics interesting.