Effects of a two-hour early awakening and of bright light exposure on plasma patterns of cortisol, melatonin, prolactin and testosterone in man.

Bright light is a synchronizing agent that entrains human circadian rhythms and modifies various endocrine and neuroendocrine functions. The aim of the present study was to determine whether and how the exposure to a bright light stimulus during the 2 h following a 2 h earlier awakening could modify the disturbance induced by the the sleep deprivation on the plasma patterns of hormones whose secretion is sensitive to light and/or sleep, namely melatonin, prolactin, cortisol and testosterone. Six healthy and synchronized (lights on: 07.00-23.00) male students (22.5 +/- 1.1 years) with normal psychological profiles volunteered for the study in winter. The protocol consisted of a baseline control night (customary sleep schedule) followed by three shortened nights with a rising at 05.00 and a 2 h exposure to either dim light (50 lux; one week) or bright light (2000 lux; other week). Our study showed a phase advance of the circadian rhythm of plasma cortisol without significant modifications of the hormone mean or peak concentration. Plasma melatonin concentration decreased following bright light exposure, whereas no obvious modifications of plasma testosterone or prolactin patterns could be observed in this protocol.     

Attempt to eliminate health inequalities in Poland arising at the time of political and economic transformation: Polish 400 Cities Project.

AIM: Epidemiological data show that citizens of small towns and villages have presented worse trends in cardiovascular mortality during the political, social and economic transformation in Poland during past 15 years than citizens of large towns. To try to eliminate these inequalities the Polish 400 Cities Project (P400CP), a large educational and interventional project, was prepared. The project consists of two arms: medical and social interventions. MATERIAL AND METHODS: The main aim of the medical screening intervention in P400CP is to increase detection and control of cardiovascular risk factors in inhabitants of 418 small cities (<8000 inhabitants) and surrounding villages, particularly in men and people of lower education. In 2003 and 2004 the P400CP covered 123 cities. All together, 36 696 subjects aged between 18 and 98 years were examined. In all participants, blood pressure (BP), anthropometric measurements, laboratory tests and questionnaire interviews were performed. The social arm of P400CP is one of multi-level educational intervention. Modern techniques of social psychology and marketing were involved to increase participation in interventions. RESULTS: Only 12.5% of all subjects had normal BP, cholesterol (<190 mg/dl) and glucose (<100 mg/dl in whole capillary blood) levels. During the first screening visit 65.5% of all examined subjects had BP>/=140 mmHg or >/=90 mmHg. The fasting glucose level was increased in 19% of women and 26% of men. Almost two-third of all subjects had a total cholesterol level above the norm. CONCLUSIONS: The prevalence of cardiovascular risk factors in participants of the screening programme P400CP in small towns in Poland was very high. High prevalence and low control of risk factors in participants of the P400CP confirm the decision to target this programme at citizens of small towns and villages.     

Central and peripheral serotonergic influences on viscerovisceral inhibitory reflex during duodenal distension in sheep

The effects of duodenal distension on forestomach and abomasal motility were investigated in conscious sheep chronically fitted with intraparietal electrodes, a duodenal cannula, and an intracerebroventricular cannula. Duodenal distensions with a balloon inflated with 40 ml (DD40) of water reduced the frequency of forestomach and abomasal contractions by 45 and 32%, respectively, while distension with 80 ml (DD80) induced a total inhibition. Methysergide, a mixed 5HT₁-5HT₂ antagonist administered intravenously (200 g/kg) or intracerebroventricularly (20 g/kg) suppressed the DD40-induced inhibition and reduced that induced by DD80. Sprioxatrine, a selective 5HT_1A antagonist, intravenously (100 g/kg) or intracerebroventricularly (10 g/kg), suppressed the DD40 and DD80-induced inhibition, which was also attenuated by the 5HT₂ antagonist ritanserin given intravenously (200 g/kg) or intracerebroventricularly (20 g/kg). Granisetron, a 5HT₃ antagonist, injected intravenously (150 g/kg), abolished the effects of DD40 and DD80 while it had no antagonistic action on DD40 and DD80 when given intracerebroventricularly (15 g/kg). It is concluded that in sheep, duodenal distension inhibits forestomach and abomasal motility through 5HT_1A and 5HT₂ receptors at the level of the central nervous system and 5HT₃ receptors located peripherally.This work was presented in part at the First United European Gastroenterology Week, September 25–30, 1992, Athens, Greece.     

Interstitial Outburst of Angiogenic Factors During Skeletal Muscle Regeneration After Acute Mechanical Trauma

Angiogenesis is a key event during tissue regeneration, but the intimate mechanisms controlling this process are still largely unclear. Therefore, the cellular and molecular interplay along normal tissue regeneration should be carefully unveiled. To this matter, we investigated by xMAP assay the dynamics of some angiogenic factors known to be involved in tissue repair, such as follistatin (FST), Placental Growth Factor‐2 (PLGF‐2), epidermal growth factor (EGF), betacellulin (BTC), and amphiregulin (AREG) using an animal model that mimics acute muscle contusion injuries. In situ immunofluorescence was used for the evaluation and tissue distribution of their cellular sources. Tissue levels of explored factors increased significantly during degeneration and inflammatory stage of regeneration, peaking first week postinjury. However, except for PLGF‐2 and EGF, their levels remained significantly elevated after the inflammatory process started to fade. Serum levels were significantly increased only after 24 h for AREG and EGF. Though, for all factors except FST, the levels in injured samples did not correlate with serum or contralateral tissue levels, excluding the systemic influence. We found significant correlations between the levels of EGF and AREG, BTC, FST and FST and AREG in injured samples. Interstitial cells expressing these factors were highlighted by in situ immunolabeling and their number correlated with measured levels dynamics. Our study provides evidence of a dynamic level variation along the regeneration process and a potential interplay between selected angiogenic factors. They are synthesized, at least partially, by cell populations residing in skeletal muscle interstitium during regeneration after acute muscle trauma. Anat Rec, 298:1864–1879, 2015. © 2015 Wiley Periodicals, Inc.     

Salecan-Clay Based Polymer Nanocomposites for Chemotherapeutic Drug Delivery Systems; Characterization and In Vitro Biocompatibility Studies

Salecan is a microbial polysaccharide suitable to obtain hydrogel for biomedical applications due to the excellent hydrophilicity and biocompatibility properties. In this work, Salecan of different concentrations was introduced into polymethacrylic acid (PMAA) in the presence of clay to form novel semi synthetic hydrogel nanocomposites systems and loaded afterwards with doxorubicin (DOX). The physical–chemical characteristics of the nanocomposites systems and their effect on the viability, and morphology of MDBK (Madin–Darby bovine kidney), HT-29 human colorectal adenocarcinoma and Colo 205 human colon adenocarcinoma cell lines were investigated. DOX release from the nanocomposite systems, cell up-take and subsequent effect on cell proliferation was also analyzed. It was found that Salecan concentration determined the swelling behavior, structural parameters and morphological features of the nanocomposite systems. The hydrogen bonds strongly influenced the formation of PMAA–Salecan–clay systems, each component bringing its own contribution, thus demonstrating the achievement of an advanced crosslinked network and a more compacted hydrogel nanocomposite morphology. All the synthesized nanocomposites had negligible toxicity to normal MDBK cells and chemoresistent HT-29 cell line, whereas in the case of Colo 205 cells a decrease by 40% of the cell viability was obtained for the sample containing the highest amount of Salecan. This effect was correlated with the lowest pore size distribution leading to highest available specific surface area and entrapped amount of DOX which was further released from the nanocomposite sample. Corroborating all the data it can be suggested that the synthesized nanocomposites with Salecan and clay could be good candidates as vehicles for chemotherapeutic agents.     

A case of atlas assimilation: description of bony and soft structures

A case of atlas assimilation revealed during serial study of suboccipital region is presented. The specimen was harvested from the body of 31-year-old woman. Images of the computed tomography scans are correlated with classic dissection. Asymmetrical bony assimilation is accompanied by asymmetrical development of the suboccipital musculature. In the presented case, the atlantic segments of both vertebral arteries preserved their usual course between bony elements derived from the atlas and proatlas. Development of the soft tissues must be influenced by similar factors as development of the skeleton. Detailed radiologic studies, possibly with volumetric reconstructions, are necessary in cases of atlas assimilation before surgical interventions in the region of craniovertebral junction.     

In vivo anticancer activity of rhomboidal Pt(II) metallacycles

The development of novel antitumor agents that have high efficacy in suppressing tumor growth, have low toxicity to nontumor tissues, and exhibit rapid localization in the targeted tumor sites is an ongoing avenue of research at the interface of chemistry, cancer biology, and pharmacology. Supramolecular metal-based coordination complexes (SCCs) have well-defined shapes and geometries, and upon their internalization, SCCs could affect multiple oncogenic signaling pathways in cells and tissues. We investigated the uptake, intracellular localization, and antitumor activity of two rhomboidal Pt(II)-based SCCs. Laser-scanning confocal microscopy in A549 and HeLa cells was used to determine the uptake and localization of the assemblies within cells and their effect on tumor growth was investigated in mouse s.c. tumor xenograft models. The SCCs are soluble in cell culture media within the entire range of studied concentrations (1 nM–5 µM), are nontoxic, and showed efficacy in reducing the rate of tumor growth in s.c. mouse tumor xenografts. These properties reveal the potential of Pt(II)-based SCCs for future biomedical applications as therapeutic agents.Molecular assemblies of nanoscale-size and well-defined geometries have recently emerged as an interesting new paradigm in drug design and drug delivery. To date, liposomes, the self-assembled lipid nanoparticles held together by weak interactions, are among the most widely studied and clinically successful nanoparticle-based drug carriers. Their use allows the drug to achieve sustained plasma levels while encapsulated, with the size preventing the fast clearance by the kidneys that often occurs with the free drug. However, liposomes themselves do not produce a therapeutic effect and their application as drug carriers for medical purposes has often been hindered by poor loading capacity (<5 wt %) and the inability to pass through biological barriers (1, 2). Inorganic and hybrid porous materials, such as molecular organic frameworks (MOFs), have also shown promise due to their higher loading capacities (>25 wt %) (3–5), but MOFs have poor hydrolytic stability (6, 7). Recent studies on materials from Institut Lavoisier (MIL)-100(Cr) and MIL-100(Fe), however, suggest that MOFs can persist in biologically relevant environments and can act as vehicles for some anticancer and antiviral agents (8–10). These early findings have prompted further investigations into the biomedical applications of supramolecular coordination complexes (SCCs) (11–24). SCCs preserve the attractive properties of MOFs, such as building block modularity (22, 23, 25), yet afford an increased solubility in the biological milieu and lend themselves to small-molecule characterization techniques due to their well-defined structure.Although development of SCCs for biomedical applications is in its infancy, some SCCs, such as trigonal prisms self-assembled from p-cymene and ruthenium-based metal fragments with pyridyl donors, have shown the ability to act as effective carriers of some chemotherapeutic agents (26–28). Moreover, a library of cytotoxic to cancer cells p-cymene ruthenium-based polygons and cages has also been developed (11). For biomedical applications, the information about the cellular uptake, delivery of a guest, and metabolism of the drug delivery vehicle is critical, although currently the fate of SCCs in biological environments is not well understood. In a rare report, a systematic investigation of the structural stability of a water-soluble, hexacationic ruthenium-based trigonal prism was performed; however, it was determined that the ruthenium-based trigonal prisms decompose in the presence of amino acids histidine, lysine, and arginine (29).An intriguing approach is the design of tumor-targeted modalities that combine detection and treatment through the self-assembly of emissive, metal-based coordination complexes. Such modalities can be especially valuable as they often do not require photoexcitation to elicit cytotoxicity. Recently Gray, Gross, and Medina-Kauwe and coworkers reported HerGa, a self-assembled tumor-targeted particle that bears the Ga(III)-metalated derivative of the sulfonated corrole (30, 31). The particle, which contained Ga(III)-corrole noncovalently bound to the tumor-targeting cell penetration protein HerPBK10, provided both tumor detection and elimination. Systemic injection of this protein–corrole complex resulted in tumor accumulation, which can be visualized in vivo due to the red corrole fluorescence. Cytotoxic and cytostatic properties of these targeted Ga(III) corroles were found to be cell-line dependent, with the ability to induce late M-phase arrest in several cancer cell lines (32).Despite the well-known cytotoxic properties of mono- and multinuclear platinum complexes (33–35), studies of the antitumor properties of platinum-based SCCs are rare (17, 36). Moreover, recent reports have demonstrated that platinum-based SCCs can act as effective hosts for guests and have interesting photophysical properties (37–42). In particular, highly emissive rhomboids based on aniline-containing donors and Pt-based metal acceptors have been developed that display different photophysical properties from those of their constituent subunits (40). These assemblies are interesting targets to investigate the cytotoxicity of organoplatinum SCCs, whereas their emission spectra could be used for interrogating the structural integrity in vitro. Here, for the first time to our knowledge, we report the uptake of SCCs in vitro in cell-based assays, determined by using laser-scanning confocal microscopy, and an in vivo assessment of the anticancer activity of SCCs in mouse s.c. tumor xenograft models.