Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity

We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.     

Monitoring Change in Child Mortality through Household Surveys

Background

Most low- and middle-income countries lack fully functional civil registration systems. Measures of under-five mortality are typically derived from periodic household surveys collecting detailed information from women on births and child deaths. However, such surveys are expensive and are not appropriate for monitoring short-term changes in child mortality. We explored and tested the validity of two new analysis methods for less-expensive summary histories of births and child deaths for such monitoring in five African countries.

Methods and Findings

The first method we explored uses individual-level survey data on births and child deaths to impute full birth histories from an earlier survey onto summary histories from a more recent survey. The second method uses cohort changes between two surveys in the average number of children born and the number of children dead by single year of age to estimate under-five mortality for the inter-survey period. The first method produces acceptable annual estimates of under-five mortality for two out of six applications to available data sets; the second method produced an acceptable estimate in only one of five applications, though none of the applications used ideal data sets.

Conclusions

The methods we tested were not able to produce consistently good quality estimates of annual under-five mortality from summary birth history data. The key problem we identified was not with the methods themselves, but with the underlying quality of the summary birth histories. If summary birth histories are to be included in general household surveys, considerable emphasis must be placed on quality control.     

Depression, somatization and anxiety in female patients with temporomandibular disorders (TMD)

The aim of this research was to determine the possible differences in degrees of depression, somatization and anxiety between the acute and chronic female patients with temporomandibular disorders (TMD), and whether these differences exist in healthy female patients. Ninety female patients were involved in this research; 60 of them were TMD patients of the Dental Polyclinic, while other 30 females came for a routine recall visit and had no problem related to TMD. Patients were aged 22 to 67 years, the average age being 38.5 +/- 12 years. All patients were asked to fill in the RDC/TMD protocol and three psychological tests (Emotions Profile Index, Somatization Scale and life Events Scale). Following the analysis of the RDC/TMD protocol and psychological tests, it was determined that the chronic female patients had higher depression and somatization scores in comparison with the acute patients (p < 0.01); the acute patients self-perceive higher levels of anxiety in relation to the control group; furthermore, the patients reporting higher levels of depression were more inclined to somatization and had experienced a greater number of stress events in the past six months. It is beyond doubt that patients suffering from the TMD's exhibit higher levels of depression, somatization and anxiety compared to the healthy ones, which proves that physiological factors may play a predisposing role in combination with reduced level of body tolerance to pain, and a decreased tolerance to stress.     

Senile lentigo--cosmetic or medical issue of the elderly population

Senile lentigo or age spots are hyperpigmented macules of skin that occur in irregular shapes, appearing most commonly in the sun-exposed areas of the skin such as on the face and back of the hands. Senile lentigo is a common component of photoaged skin and is seen most commonly after the age of 50. There are many disscusions on whether senile lentigo represents a melanoma precursor, namely lentigo maligna melanoma and, if there is a need for a regular follow up in cases of multiple lesions. Clinical observations sometimes report that in the location of the newly diagnosed melanoma, such lesion preexsisted. On contrary, some authors believe that senile lentigo represents a precursor of seborrheic keratosis, which does not require a serious medical treatment. However, the observation of the possible association of senile lentigo with the melanoma development makes us cautious in the assessment of this lesion. Histologically, there are elongated rete ridges with increased melanin at the tips, and the number of melanocytes is not increased. The dermatoscopic features are also distinctive. If the lesion becomes inflammed it may evolve into benign lichenoid keratosis. Cryotherapy and laser treatment are common therapeutic approaches. Sun protection creams may be useful in early lesions.     

The role of apoptosis in the pathogenesis of malignant melanoma

Malignant melanoma genesis is a very complex process that involves a sequence of pathogenetic cellular events. Mutation of various genes and numerous other cellular mechanisms play an important role in the course of malignant melanocyte alteration and their malignant transformation from naevi into melanoma. Apoptosis is an active, genetically controlled process of programmed cell death, which leads to cell destruction and cell death without involvement of surrounding cells or inflammatory response. In this process, disrupted mechanisms of cell regulation and apoptosis take place in malignant melanoma cells, thus leading to their uncontrolled proliferation and melanocyte growth. Apoptosis is a process that involves two major pathways, the intrinsic and extrinsic apoptotic pathway, which interlace at certain points and ultimately result in apoptosis. It can be said that molecular events regulating cell survival, normal growth arrest, apoptosis and cell differentiation, contribute to the overall pathogenesis of malignant cell growth. It is presumed that in the future, understanding of molecular aberrations and cellular processes, such as cell signaling, cell cycle regulation and cell apoptosis, will be essential for better patient monitoring and rational design of effective treatment.     

Response to oxygen deficiency (depletion): Bivalve assemblages as an indicator of ecosystem instability in the northern Adriatic Sea

Benthic communities represent a powerful tool for the detection of natural and anthropogenic disturbances, as well as for the assessment of marine ecosystem stability. This paper shows that bivalve assemblages could serve as excellent indicators of disturbance and ecosystem instability. The goal of this study was to compare two sets of data in order to determine the differences between two different periods belonging to bivalve assemblage in the muddy detritic bottom of the northern Adriatic Sea in the post-anoxic period during December 1989, 1990, 1991 and quite a while later, during 2003, 2004 and 2005. Abundances of some indicator species such as Corbula gibba, Modiolarca subpicta and Timoclea ovata were detected during the post-anoxic period. Recruitment in the quality of bivalve assemblages was proved by the ecologic and biotic indexes during 2003, 2004 and 2005, during a period of relatively stable ecological conditions. Fluctuation in bivalve diversity due to the ecological quality of the marine ecosystem in the eastern part of the northern Adriatic Sea is also discussed.     

Standing at the Gateway to Europe - The Genetic Structure of Western Balkan Populations Based on Autosomal and Haploid Markers

Contemporary inhabitants of the Balkan Peninsula belong to several ethnic groups of diverse cultural background. In this study, three ethnic groups from Bosnia and Herzegovina - Bosniacs, Bosnian Croats and Bosnian Serbs - as well as the populations of Serbians, Croatians, Macedonians from the former Yugoslav Republic of Macedonia, Montenegrins and Kosovars have been characterized for the genetic variation of 660 000 genome-wide autosomal single nucleotide polymorphisms and for haploid markers. New autosomal data of the 70 individuals together with previously published data of 20 individuals from the populations of the Western Balkan region in a context of 695 samples of global range have been analysed. Comparison of the variation data of autosomal and haploid lineages of the studied Western Balkan populations reveals a concordance of the data in both sets and the genetic uniformity of the studied populations, especially of Western South-Slavic speakers. The genetic variation of Western Balkan populations reveals the continuity between the Middle East and Europe via the Balkan region and supports the scenario that one of the major routes of ancient gene flows and admixture went through the Balkan Peninsula.