Functions of peroxisome proliferator-activated receptors (PPAR) in skin homeostasis.

The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the nuclear hormone receptor family. Three isotypes (PPAR alpha, PPAR beta or delta, and PPAR gamma) with distinct tissue distributions and cellular functions have been found in vertebrates. All three PPAR isotypes are expressed in rodent and human skin. They were initially investigated for a possible function in the establishment of the permeability barrier in skin because of their known function in lipid metabolism in other cell types. In vitro studies using specific PPAR agonists and in vivo gene disruption approaches in mice indeed suggest an important contribution of PPAR alpha in the formation of the epidermal barrier and in sebocyte differentiation. The PPAR gamma isotype plays a role in stimulating sebocyte development and lipogenesis, but does not appear to contribute to epidermal tissue differentiation. The third isotype, PPAR beta, regulates the late stages of sebaceous cell differentiation, and is the most effective isotype in stimulating lipid production in these cells, both in rodents and in humans. In addition, PPAR beta activation has pro-differentiating effects in keratinocytes under normal and inflammatory conditions. Finally, preliminary studies also point to a potential role of PPAR in hair follicle growth and in melanocyte differentiation. By their diverse biological effects on cell proliferation and differentiation in the skin, PPAR agonists or antagonists may offer interesting opportunities for the treatment of various skin disorders characterized by inflammation, cell hyperproliferation, and aberrant differentiation.

Generalized canonical correlation analysis of matrices with different row and column orders

A Method is offered that makes it possible to apply generalized canonicalcorrelations analysis (CANCOR) to two or more matrices of different row and column order. The new method optimizes the generalized canonical correlationanalysis objective by considering only the observed values. This is achieved byemploying selection matrices. We present and discuss fit measures to assessthe quality of the solutions. In a simulation study we assess the performance of our new method and compare it to an existing procedure called GENCOM,proposed by Green and Carroll. We find that our new method outperforms the GENCOM algorithm both with respect to model fit and recovery of the truestructure. Moreover, as our new method does not require any type of iteration itis easier to implement and requires less computation. We illustrate the methodby means of an example concerning the relative positions of the political parties inthe Netherlands based on provincial data.

Exact tests for correlation and for the slope in simple linear regressions without making assumptions

We present an exact test for whether two random variables that have known bounds on their support are negatively correlated. The alternative hypothesis is that they are not negatively correlated. No assumptions are made on the underlying distributions. We show by example that the Spearman rank correlation test as the competing exact test of correlation in nonparametric settings rests on an additional assumption on the data generating process without which it is not valid as a test for correlation.We then show how to test for the significance of the slope in a linear regression analysis that invovles a single independent variable and where outcomes of the dependent variable belong to a known bounded set.

Riesz-Nágy singular functions revisited

In 1952 F. Riesz and Sz.Nágy published an example of a monotonic continuous function whose derivative is zero almost everywhere, that is to say, a singular function. Besides, the function was strictly increasing. Their example was built as the limit of a sequence of deformations of the identity function. As an easy consequence of the definition, the derivative, when it existed and was finite, was found to be zero. In this paper we revisit the Riesz-N´agy family of functions and we relate it to a system for real numberrepresentation which we call (t, t-1) expansions. With the help of these real number expansions we generalize the family. The singularity of the functions is proved through some metrical properties of the expansions used in their definition which also allows us to give a more precise way of determining when the derivative is 0 or infinity.

Finance versus costs for teaching hospitals in Spain

In this paper we analyse the observed systematic differences incosts for teaching hospitals (THhenceforth) in Spain. Concernhas been voiced regarding the existence of a bias in thefinancing of TH s has been raised once prospective budgets arein the arena for hospital finance, and claims for adjusting totake into account the legitimate extra costs of teaching onhospital expenditure are well grounded. We focus on theestimation of the impact of teaching status on average cost. Weused a version of a multiproduct hospital cost function takinginto account some relevant factors from which to derive theobserved differences. We assume that the relationship betweenthe explanatory and the dependent variables follows a flexibleform for each of the explanatory variables. We also model theunderlying covariance structure of the data. We assumed twoqualitatively different sources of variation: random effects andserial correlation. Random variation refers to both general levelvariation (through the random intercept) and the variationspecifically related to teaching status. We postulate that theimpact of the random effects is predominant over the impact ofthe serial correlation effects. The model is estimated byrestricted maximum likelihood. Our results show that costs are 9%higher (15% in the case of median costs) in teaching than innon-teaching hospitals. That is, teaching status legitimatelyexplains no more than half of the observed difference in actualcosts. The impact on costs of the teaching factor depends on thenumber of residents, with an increase of 51.11% per resident forhospitals with fewer than 204 residents (third quartile of thenumber of residents) and 41.84% for hospitals with more than 204residents. In addition, the estimated dispersion is higher amongteaching hospitals. As a result, due to the considerable observedheterogeneity, results should be interpreted with caution. From apolicy making point of view, we conclude that since a higherrelative burden for medical training is under public hospitalcommand, an explicit adjustment to the extra costs that theteaching factor imposes on hospital finance is needed, beforehospital competition for inpatient services takes place.

Unique and conserved functions of B cell-activating factor of the TNF family (BAFF) in the chicken.

The chicken represents the best-characterized animal model for B cell development in the so-called gut-associated lymphoid tissue (GALT) and the molecular processes leading to B cell receptor diversification in this species are well investigated. However, the mechanisms regulating B cell development and homeostasis in GALT species are largely unknown. Here we investigate the role played by the avian homologue of B cell-activating factor of the tumor necrosis factor family (BAFF). Flow cytometric analysis showed that the receptor for chicken B cell-activating factor of the tumor necrosis factor family (chBAFF) is expressed by mature and immature B cells. Unlike murine and human BAFF, chBAFF is primarily produced by B cells both in peripheral lymphoid organs and in the bursa of Fabricius, the chicken's unique primary lymphoid organ. In vitro and in vivo studies revealed that chBAFF is required for mature B cell survival. In addition, in vivo neutralization with a decoy receptor led to a reduction of the size and number of B cell follicles in the bursa, demonstrating that, in contrast to humans and mice, in chickens BAFF is also required for the development of immature B cells. Collectively, we show that chBAFF has phylogenetically conserved functions in mature B cell homeostasis but displays unique and thus far unknown properties in the regulation of B cell development in birds.

Location of multiple server common service centers or public facilities for minimizing general congestion and travel cost functions

We propose a model and solution methods, for locating a fixed number ofmultiple-server, congestible common service centers or congestible publicfacilities. Locations are chosen so to minimize consumers congestion (orqueuing) and travel costs, considering that all the demand must be served.Customers choose the facilities to which they travel in order to receiveservice at minimum travel and congestion cost. As a proxy for thiscriterion, total travel and waiting costs are minimized. The travel costis a general function of the origin and destination of the demand, whilethe congestion cost is a general function of the number of customers inqueue at the facilities.

The domain and interpretation of utility functions: An exploration

This paper proposes an exploration of the methodology of utilityfunctions that distinguishes interpretation from representation. Whilerepresentation univocally assigns numbers to the entities of the domainof utility functions, interpretation relates these entities withempirically observable objects of choice. This allows us to makeexplicit the standard interpretation of utility functions which assumesthat two objects have the same utility if and only if the individual isindifferent among them. We explore the underlying assumptions of suchan hypothesis and propose a non-standard interpretation according towhich objects of choice have a well-defined utility although individualsmay vary in the way they treat these objects in a specific context.We provide examples of such a methodological approach that may explainsome reversal of preferences and suggest possible mathematicalformulations for further research.

Exploiting fitness distance correlation of set covering problems

The set covering problem is an NP-hard combinatorial optimization problemthat arises in applications ranging from crew scheduling in airlines todriver scheduling in public mass transport. In this paper we analyze searchspace characteristics of a widely used set of benchmark instances throughan analysis of the fitness-distance correlation. This analysis shows thatthere exist several classes of set covering instances that have a largelydifferent behavior. For instances with high fitness distance correlation,we propose new ways of generating core problems and analyze the performanceof algorithms exploiting these core problems.

Correlation between placental bacterial culture results and histological chorioamnionitis: a prospective study on 376 placentas.

OBJECTIVE: To study the correlation between the bacteriological and histopathological findings in placentas from women with suspected or proven chorioamnionitis (CA). METHODS: Over a 1-year period, 376 placentas were prospectively collected and processed for bacteriological and pathological studies in cases of confirmed or suspected maternal or neonatal infection. RESULTS: Histological CA was diagnosed in 26.9% of placentas (101/376), and 27.7% (28/101) of these placentas had positive bacteriological cultures. A monomicrobial culture, mainly represented by Gram-positive cocci and Gram-negative bacilli, was identified in 27% of the positive bacterial cultures. The proportion of positive cultures was higher (p=0.03) when CA was associated with funisitis, as compared with placental samples with early CA. In placentas without histological CA, bacteriological cultures were mostly negative (230/275), although pathogenic bacteria were identified in 16.3% of them (45/275). CONCLUSIONS: The histological and bacteriological results were concordant in about 70% of the examined placentas, with 61.1% negative cases (CA absent and negative bacterial cultures), and only 7.4% placentas with positive histological and bacteriological results. Discordant results (positive histology with negative bacteriology) were obtained in placentas with early CA documented by histology although possibly in relation with antibiotic prophylaxis and the presence of fastidious bacteria. Conversely, negative histology with positive bacteriology could be explained by the presence of an early-stage bacterial infection that has not yet led to detectable microscopic lesions.

Expression of the proto-oncogene c-fos in three-dimensional fetal brain cell cultures and the lack of correlation with maturation-inducing stimuli.

Previous work has shown that aggregating fetal brain cell cultures are able to attain a highly differentiated state, and that their development is greatly enhanced by growth and/or differentiation factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and the protein kinase C-activating tumor promoter mezerein. The present study shows that in these 3-dimensional cultures the peptide growth factors EGF and bFGF as well as mezerein are able to induce the expression of the proto-oncogene c-fos. This induction was rapid and transient, in good agreement with observations reported from a wide variety of cell types in vitro. The maximal levels of c-fos mRNA found after stimulation were low in immature cultures and increased greatly as maturation progressed. Of the three factors tested, mezerein was the most potent inducer of c-fos. In contrast to the peptide growth factors EGF and bFGF which were found to induce c-fos only in glial cells, mezerein was stimulatory in glial cells as well as in neurons. A similar cell type specificity has been observed previously for the maturation-enhancing response in immature aggregate cultures. However, in the present study no correlation was found between the degree of c-fos induction and the extent of the maturation-enhancing stimulation. Immature cultures known to be most sensitive and responsive to these maturation-enhancing agents required relatively high doses of peptide growth factors for the induction of c-fos, and the maximal levels of c-fos mRNA elicited were much lower than those in differentiated cultures which did not show any long-term response to these stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Systematic study of the static electrical properties of the CO molecule: influence of the basis set size and correlation energy

The influence of the basis set size and the correlation energy in the static electrical properties of the CO molecule is assessed. In particular, we have studied both the nuclear relaxation and the vibrational contributions to the static molecular electrical properties, the vibrational Stark effect (VSE) and the vibrational intensity effect (VIE). From a mathematical point of view, when a static and uniform electric field is applied to a molecule, the energy of this system can be expressed in terms of a double power series with respect to the bond length and to the field strength. From the power series expansion of the potential energy, field-dependent expressions for the equilibrium geometry, for the potential energy and for the force constant are obtained. The nuclear relaxation and vibrational contributions to the molecular electrical properties are analyzed in terms of the derivatives of the electronic molecular properties. In general, the results presented show that accurate inclusion of the correlation energy and large basis sets are needed to calculate the molecular electrical properties and their derivatives with respect to either nuclear displacements or/and field strength. With respect to experimental data, the calculated power series coefficients are overestimated by the SCF, CISD, and QCISD methods. On the contrary, perturbation methods (MP2 and MP4) tend to underestimate them. In average and using the 6-311 + G(3df) basis set and for the CO molecule, the nuclear relaxation and the vibrational contributions to the molecular electrical properties amount to 11.7%, 3.3%, and 69.7% of the purely electronic μ, α, and β values, respectively

MACROPHAGES FROM CROHN'S DISEASE PATIENTS EXHIBIT DEFICIENT REPAIR FUNCTIONS

AbstractBackground: Mucosal healing is becoming a major goal in the treatment of Crohn's disease. It has been previously reported that myeloid cells induce mucosal healing in a mouse model of acute colitis. The aim in this study is to investigate the pro-repair function of myeloid cells in healthy donors (HD) and Crohn's disease patients (CD).Methods: Peripheral blood mononuclear cells (PBMC) from HD and CD patients were isolated from blood samples and tested either directly or after differentiation ex-vivo into macrophages (Μφ). Intestinal macrophages (IMACs) were isolated from the bowel mucosa of patients undergoing intestinal surgical resections. Through an in vitro wound healing assay the repairing ability of these various human myeloid cells and the mechanisms responsible of wound healing were evaluated.Results: PBMC and myeloid CD14+ cells from HD and CD were not able to repair at any tested cell concentration. Μφ from HD and ulcerative colitis (UC) patients were able to induce wound healing and this capacity was partially mediated by Hepatocyte Growth Factor (HGF). Remarkably, CD Μφ were unable to promote wound healing and produced lower levels of HGF as compared to Μφ from HD or UC patients. In particular, Μφ from CD in active phase (ACD) exhibited the weakest repair function, but this defect was rescued if rh- GM-CSF was added during the differentiation of PBMCs. Interestingly, IMACs from HD promoted wound healing and produced HGF.Conclusion: We demonstrated that CD Μφ, unlike HD or UC Μφ, were defective in promoting wound healing, in particular if coming from an ACD. This deficient pro-repair function was related to a lower production of HGF. IMACs from HD colonic mucosa induced wound healing, confirming the results obtained with Μφ. Our results are in keeping with the current theory of CD as an innate immunodeficiency. In this context, Μφ may be responsible for the mucosal repair defects observed in CD patients and for the subsequent chronic activation of the adaptive immune response.

Female-biased dispersal in the monogamous mammal Crocidura russula: evidence from field data and microsatellite patterns.

We investigated dispersal patterns in the monogamous Crocidura russula, based both on direct field observations (mark-recapture data) and on genetic analyses (microsatellite loci). Natal dispersal was found to be low. Most juveniles settled within their natal territory or one immediately adjacent. Migration rate was estimated to two individuals per year and per population. The correlation between genetic and geographical distances over a 16 km transect implies that migration occurs over short ranges. Natal dispersal was restricted to first-litter juveniles weaned in early May; this result suggests a direct dependence of dispersal on reproductive opportunities. Natal dispersal was highly female biased, a pattern unusual among mammals. Its association with monogamy provides support for the resource-competition model of dispersal. Our results demonstrate that a state-biased dispersal can be directly inferred from microsatellite genotype distributions, which opens new perspectives for empirical studies in this area.