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A series of amino acid-derived 1,2,3-triazoles presenting the amino acid residue and the benzazole fluorophore connected by a triazole-4-carboxylate spacer was studied for enantioselective recognition using only steady-state fluorescence spectroscopy in solution. In this investigation, the optical sensing was performed with D-(-) and L-(+)-Arabinose and (R)-(-) and (S)-(+)-Mandelic acid as chiral analytes. The optical sensors showed specific interactions with each pair of enantiomers, allowing photophysical responses, which were used for their enantioselective recognition. DFT calculations confirm the specific interaction between the fluorophores and the analytes corroborating the observed high enantioselectivity of these compounds with the studied enantiomers. Finally, this study investigated nontrivial sensors for chiral molecules by a mechanism different than turn-on fluorescence and has the potential to broad chiral compounds with fluorophoric units as optical sensors for enantioselective sensing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.

Background: Plants play an important role in cancer therapy. They are source of natural molecules which can induce apoptosis in cancer cells by affecting molecular mechanisms implicated in cancer progression. The MAP Kinase/ERK1/2 and PI3K/AKT signaling pathways are two classical signaling pathways implicated in cancer progression and constitute therapeutic targets against cancer. This study aimed to evaluate the effect of euphol on MAP Kinase/ERK1/2 and PI3K/AKT signaling pathways in glioblastoma and prostate cancer cells. Euphol is a tetracyclique triterpene alcohol isolated from Tapinanthus sp. which is a hemi parasitic plant belonging to Loranthaceae family., Methods: Plant powder was extracted by maceration and euphol was isolated and described using respectively column chromatography separation on silica gel and spectroscopic data. Cytotoxic effect of euphol was evaluated using XTT assay and its effect on MAP Kinase/ERK1/2 and PI3K/AKT protein expression was investigated by Western immunoblot analysis. Apotosis was analyzed by evaluating caspase-3/7 activity., Results: Our investigations demonstrated that this compound has an important cytotoxic effect on C6 and U87 MG glioblastoma (GBM) cells and PC-3 prostate cancer cells. Furthermore, euphol-induced apoptosis revealed by elevated caspase 3/7 activity, was correlated with a significant inhibition of MAP kinase/Erk 1/2 and PI3K/Akt signaling pathway in glioblastoma U87 MG cells. The reverse effect was observed in C6 glioblastoma cells, where apoptosis was correlated with a long-lasting activation of Erk 1/2.  In PC-3 cells, euphol had no or limited effect on Erk 1/2 and Akt activity., Conclusion: These results indicate that euphol induces cell death in glioblastoma and prostate cancer cells and regulates significantly Erk1/2 and Akt activity in glioblastoma cells.

The present work describes the isolation and anticancer activity of Tapinanthus sp. which is a hemi parasitic plant harvested on Combretum glutinosum , the host plant. Phytochemical study afforded a new flavonoid glycoside, tapinantoside ( 1 ) isolated for the first time from natural source, alongside six known compounds ( 2 - 7 ). Structure of compounds were elucidated by extensive spectroscopic analyses including 1 D and 2 D NMR, mass spectrometry and by comparison with literature data. The anticancer activity of extract and some isolated compounds were evaluated on glioblastoma (U87MG, C6) and prostate (PC-3) cancer cells. The methanol leaves extract showed good anticancer activity against U87 (IC 50 = 21.40 µg/mL) and PC-3 cells (IC 50 = 10.26 µg/mL). Compound 3 powerfully inhibits the proliferation of C6 (IC 50 = 38.84 µM) and PC-3 cells (IC 50 = 21.33 µM), while its effect was moderated on U87MG cells. Compound 1 and 7 were not active on all tested cancer cell lines.

Background: Increasingly, people are using social media (SM) to express grief, and researchers are using this data to investigate the phenomenon of mourning. As this research progresses, it is important to understand how studies are being conducted and how authors are approaching ethical challenges related to SM data., Objective: The aim of this review was to explore how SM data are being used to research experiences of mourning through the following questions: a) 'Which topics related to mourning are being studied?'; b) 'What study designs have been used to analyse SM data'; c) 'What type of data (natural or generated) have been used?'; and d) 'How are ethical decisions being considered?'., Methods: The JBI Scoping Review methodology guided this review. Eligibility criteria were determined using the PCC framework, and relevant key words and phrases derived from these criteria were used to search eight databases in September 2021 (CINAHL, Embase, LILACS, OpenGrey, ProQuest, PsycINFO, PubMed and Scopus). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines were used to report the results of this review., Results: Database searches resulted in 3418 records, of which, 89 met eligibility criteria. Four categories of grief and mourning were identified. Most records were qualitative in nature and used natural data. Only 20% of records reported ethics approval by an Institutional Review Board, with several including measures to protect participants, for example, using pseudonyms., Conclusions: This unique review mapped the diverse range of mourning-related topics that have been investigated using SM data and highlighted the variability in approaches to data analysis. Ethical concerns relating to SM data collection are identified and discussed. This is an emerging and rapidly changing field of research that offers new opportunities and challenges for exploring the phenomenon of mourning., Competing Interests: The authors have declared that no competing interests exist.

Increased focus towards food safety and quality is reshaping food purchasing decisions around the world. Although some food attributes are visible, many of the attributes that consumers seek and are willing to pay a price premium for are not. Consequently, consumers rely on trusted cues and information to help them verify the food quality and credence attributes they seek. In this study, we synthesise the findings from previous research to generate a framework illustrating the key trust influencing factors that are beyond visual and brand-related cues. Our framework identifies that consumer trust in food and the food system is established through the assurances related to individual food products and the actors of the food system. Specifically, product assurance builds consumer trust through food packaging labels communicating food attribute claims, certifications, country or region of origin, and food traceability information. In addition, producers, processors, and retailers provide consumers with food safety and quality assurances, while government agencies, third-party institutions, advocacy groups, and the mass media may modify how labelling information and food operators are perceived by consumers. We hope our framework will guide future research efforts to test these trust factors in various consumer and market settings.

Background: Cancer incidence has been growing in an alarming rate worldwide and new therapeutics are needed, particularly for intractable and chemoresistant cases. We evaluated the cytotoxic effects of Combretum fragrans F. Hoffm (Combretaceae) on glioblastoma (U87MG and C6) and prostate (PC-3) cancer cell lines., Methods: The cytotoxic effect of the methanolic extract of the stem bark of Combretum fragrans was assessed using XTT (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) test. Expressions of Akt and ERK1/2 were determined using Western blot technique, while Caspase-3/7 kits were used to evaluate caspase-3/7 activity., Results: C. fragrans extract inhibited the proliferation of U87 (IC50 = 20.13 µg/mL), C6 (IC50 = 12.17 µg/mL), and PC-3 (IC50 = 11.50 µg/mL) cells. Treatment with the extract resulted in lower levels (p < 0.001) of phospho-ERK1/2 and phospho-Akt in U87 cells, and instead, higher levels of phospho-ERK1/2 (p < 0.001) in C6 and PC-3 cells. An increase in caspase-3/7 activity was observed, mainly after 24 hours of treatment, indicating the activation of apoptotic processes., Conclusion: Altogether, these results suggest that C. fragrans have potent anticancer properties. This plant should be further investigated for developing new anticancer drugs.

Objective: To describe the use of a self-retaining thermoplastic polyurethane wound retractor for the management of hysterotomy during prenatal repair of myelomeningocele. Methods: The preliminary experience with 16 consecutive cases of open surgery for prenatal repair of myelomeningocele using a new technique is presented. Under general anesthesia, the gravid uterus was partially exteriorized through a low transverse abdominal incision and a high 3-4-cm midline vertical mini-hysterotomy was performed. After chorioamniotic membranes were opened with scissors, the internal ring of the retractor was placed into the amniotic cavity to compress the chorioamniotic membranes against the internal uterine wall and permit full retraction of the hysterotomy. Once the neurosurgical intervention was completed, the retractor was removed manually and uterine and abdominal incisions were closed using conventional techniques. Intra- and post-operative complications, as well as short-term pregnancy outcomes, were evaluated. Results: Intrauterine surgery was performed at a mean gestational age of 25.3 weeks and all except two of the interventions were completed within 3.0 h. When compared with the technique described in the Management of Myelomeningocele study (MOMS) trial, the use of the retractor was associated with a lower, although statistically nonsignificant, rate of chorioamniotic membrane separation (20/78 (26%) versus 2/16 (13%), respectively), preterm rupture of membranes (36/78 (46%) versus 4/16 (25%), respectively), and persistent oligohydramnios (16/78 (21%) versus 1/16 (6%), respectively) as well as higher gestational age at delivery (34.1 weeks ± 3.1 versus 36.0 weeks ± 1.93, respectively) and birthweight (2383 g ± 688 versus 2790 g ± 529, respectively). There were no intra- or post-operative complications associated with the use of the device. Only one (6%) of the hysterotomy scars was noted to be thin at the time of the cesarean delivery and no cases of dehiscence occurred. Conclusions: The use of a plastic wound retractor at the hysterotomy site provides a less traumatic approach than the conventional technique for the management of the uterine incision during open intrauterine surgery. Our experience with this technique was associated with short-term pregnancy outcomes that are similar and perhaps even superior to the technique reported in the MOMS trial. Because the device is inexpensive, easy to use, and widely available, its use during open intrauterine surgery should be considered. However, further clinical experience is required to reach a definitive conclusion regarding whether this technique should be incorporated into the protocol of prenatal repair of myelomeningocele.

This study investigates the effects of pH, H 2 O 2 concentration and reaction time of the UV/H 2 O 2 photochemical process on the removal of organic matter and ammonia from biologically pre-treated landfill leachates in anaerobic stabilization ponds. The results show that the concentration of H 2 O 2 and the initial pH are significant factors, with no significant interaction between them. A pH of 3 is the optimum value for the UV/H 2 O 2 process for the removal of organic matter, resulting in 51.63% chemical oxygen demand (COD) removal in addition to the removal of aromatic compounds. The N-NH 3 removal showed little variation between pH values of 1, 5, 7, 11 and 13; the removal was on the order of 16.43 ± 2.00%. The consumption of H 2 O 2 was elevated at pH 9, 11 and 13; at these pH values, the average removal was 94.56 ± 0.43%, compared to 43.07% at pH 3. First-order polynomial models and reaction times on the order of 15 min are sufficient for optimization studies and for evaluation of the effects of the studied parameters. The results of this study support the optimization of the UV/H 2 O 2 process for the removal of organic matter and ammonia from landfill leachates.

Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptides and their receptors, referred in this article as the "VIP-receptor system", has been reported to regulate proliferation, differentiation, and migration in a number of tumor cell types and more particularly in GBM cells. These neuropeptides are potent activators of the cAMP/PKA pathway. The present study aimed to investigate the cross-talks between the above cited signaling cascades. Regulation by VIP-related neuropeptides of GBM migration and invasion was evaluated ex vivo in rat brain slices explanted in culture. Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique. Quantification of nuclear GLI1, phospho-Akt, and phospho-PTEN was assessed by western-immunoblotting. The VIP-receptor system agonists VIP and PACAP-38 significantly reduced C6 cells invasion in the rat brain parenchyma ex vivo, and C6 and U87 migration in vitro. A VIP-receptor system antagonist, VIP 10-28 increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP 10-28 increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP 10-28 effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process.

Photogrammetric processing is available in various software solutions and can easily deliver 3D pointclouds as accurate as 1 pixel. Certain applications, e.g., very accurate shape reconstruction in industrial metrology or change detection for deformation studies in geosciences, require results of enhanced accuracy. The tie-point extraction step is the opening in the photogrammetric processing chain and therefore plays a key role in the quality of the subsequent image orientation, camera calibration and 3D reconstruction. Improving its precision will have an impact on the obtained 3D. In this research work we describe a method which aims at enhancing the accuracy of image orientation by adding a second iteration photogrammetric processing. The result from the classical processing is used as a priori information to guide the extraction of refined tie-points of better photogrammetric quality. Evaluated on indoor and UAV acquisitions, the proposed methodology shows a significant improvement on the obtained 3D point accuracy.

Objectives: To (1) characterize patients' medical experiences from initial injury until they become candidates for upper extremity reconstruction (UER); and (2) identify points in this medical context that may be most amenable to interventions designed to increase UER utilization., Design: A qualitative cross-sectional study using grounded theory methodology and constant comparative analysis of data collected through semistructured individual interviews., Setting: Community., Participants: A sample of individuals with C4 to C8 cervical spinal injuries (N=19) who sustained injuries at least 1 year before interview. Nine patients had undergone reconstruction, and 10 had not. The study sample was predominantly male (79%) and white (89%), and American Spinal Injury Association grades A through D were represented (A, 42%; B, 32%; C, 16%; D, 10%)., Interventions: Not applicable., Main Outcome Measures: Participants' self-report of their medical experiences from the time of injury through the early recovery period., Results: We identified 3 domains that formed patients' medical context before UER candidacy: (1) their ability to achieve and maintain health; (2) their relationship with health care providers; and (3) their expectations regarding clinicians' tetraplegia-specific expertise. Trust emerged as a major theme driving potential intervention targets. Patients transferred to referral centers had higher trust in tertiary providers relative to local physicians. In the outpatient setting, patients' trust correlated with the tetraplegia-specific expertise level they perceived the specialty to have (high for physical medicine and rehabilitation, intermediate for urology, low for primary care)., Conclusions: In appropriate candidates, UER produces substantial functional gains, but reconstruction remains underused in the tetraplegic population. By analyzing how patients achieve health and build trust in early recovery/injury, our study provides strategies to improve UER access. We propose that interventions targeting highly trusted points of care (transfer hospitals) and avoiding low-trust points (primary care physicians, home health) will be most effective. Urology may represent a novel entry point for UER interventions., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Patients with tetraplegia consistently rank better use of the upper extremity as their top functional priority. Multiple case series have demonstrated that upper extremity reconstruction (UER) is well-tolerated and can produce substantial functional improvements for appropriate candidates; however, UER remains critically underutilized. The mechanisms that drive differences in provider practice and referral patterns have been studied, but comprehensive examination of the patient factors that influence UER decisions has not been performed for American patients., Methods: Nineteen patients with C4-8 cervical spinal injuries were selected using purposive sampling: 9 patients had undergone UER, 10 had not undergone UER. Semistructured interviews were conducted and transcripts evaluated using grounded theory methodology., Results: Our study yielded a conceptual model that describes the characteristics common to all patients who undergo UER. Patients who selected reconstruction proceeded stepwise through a shared sequence of steps: (1) functional dissatisfaction, (2) awareness of UER, and (3) acceptance of surgery. Patients' ability to meet these criteria was determined by 3 checkpoints: how well they coped, their access to information, and the acceptability of surgery. Extremely positive or negative coping prevented patients from moving from the Coping to the Information Checkpoint; thus, they remained unaware of UER and did not undergo surgery. A lack of knowledge regarding reconstruction was the strongest barrier to surgery among our participants., Conclusions: We built a conceptual model that outlines how patients' personal and contextual factors drive their progression to UER. Moving from functional dissatisfaction to understanding that they were candidates for UER was a substantial barrier for participants, particularly those with very high and very low coping skills., Clinical Relevance: To improve utilization for all patients, interventions are needed to increase UER awareness. Standardizing introduction to UER during the rehabilitation process or improving e-content may represent key awareness access points., (Copyright © 2017 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Mesenchymal stromal cells (MSCs) are adult multipotent stem cells residing as pericytes in various tissues and organs where they can differentiate into specialized cells to replace dying cells and damaged tissues. These cells are commonly found at injury sites and in tumors that are known to behave like " wounds that do not heal." In this article, we discuss the mechanisms of MSCs in migrating, homing, and repairing injured tissues. We also review a number of reports showing that tumor microenvironment triggers plasticity mechanisms in MSCs to induce malignant neoplastic tissue formation, maintenance, and chemoresistance, as well as tumor growth. The antitumor properties and therapeutic potential of MSCs are also discussed.

Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death, motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pathways as particularly attractive targets for efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis is the worst feature of cancer development. This feature results from a cascade of events emerging from the hijacking of epithelial-mesenchymal transition, angiogenesis, migration, and invasion by transforming cells and is associated with poor survival, drug resistance, and tumor relapse. In the present review, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed.

Background and Objectives: Although lipid-based drug delivery systems have gained much importance in recent years due to their ability to improve the solubility and bioavailability of poorly soluble drugs, compartmental pharmacokinetic analyses have not been extensively explored. The oral pharmacokinetics of commercial liquid formulation and a developed semisolid system containing saquinavir mesylate (SQVM) were compared in Beagle dogs. A compartmental analysis after intravenous bolus administration of this drug (1 mg/kg) was also performed., Method: Pharmacokinetic profiles were analyzed using both non-compartmental and compartmental approaches. Plasma concentration of the drug was determined by high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS)., Results: The disposition curve of SQVM given intravenously was better described by a three-compartment model. In contrast, plasma profiles obtained following the oral administration were fitted to a two-compartment model with lag time due to the fact that the distribution phase was masked by the absorption phase in these formulations., Conclusion: The proposed semisolid lipid system was found to be a promising formulation for commercial purposes given the similarity of SQVM absorption rate to that from the commercial liquid formulation.

Introduction: Little is known about the costs of treating burn patients after a mass casualty event. A devastating Color Dust explosion that injured 499 patients occurred on June 27, 2015 in Taiwan. This study was performed to investigate the economic effects of treating burn patients at a single medical center after an explosion disaster., Methods: A detailed retrospective analysis on 48 patient expense records at Chang Gung Memorial Hospital after the Color Dust explosion was performed. Data were collected during the acute treatment period between June 27, 2015 and September 30, 2015. The distribution of cost drivers for the entire patient cohort (n=48), patients with a percent total body surface area burn (%TBSA)≥50 (n=20), and those with %TBSA <50 (n=28) were analyzed., Results: The total cost of 48 burn patients over the acute 3-month time period was $2,440,688, with a mean cost per patient of $50,848 ±36,438. Inpatient ward fees (30%), therapeutic treatment fees (22%), and medication fees (11%) were found to be the three highest cost drivers. The 20 patients with a %TBSA ≥50 consumed $1,559,300 (63.8%) of the total expenses, at an average cost of $77,965±34,226 per patient. The 28 patients with a %TBSA <50 consumed $881,387 (36.1%) of care expenses, at an average cost of $31,478±23,518 per patient., Conclusions: In response to this mass casualty event, inpatient ward fees represented the largest expense. Hospitals can reduce this fee by ensuring wound dressing and skin substitute materials are regionally stocked and accessible. Medication fees may be higher than expected when treating a mass burn cohort. In preparation for a future event, hospitals should anticipate patients with a %TBSA≥50 will contribute the majority of inpatient expenses., Competing Interests: Statement Research reported in this publication was supported in part by grants from the University of Michigan Medical School Student Biomedical Research Program (to John-Michael Muller), and by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 2 K24-AR053120-06 (to Dr. Kevin C. Chung). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All authors listed in this manuscript report no conflicts of interest., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Revisiting aggregation of extractant molecules into water-poor mixed reverse micelles, we propose in this paper to identify the thermodynamic origins of synergy in solvent extraction. Considering that synergistic extraction properties of a mixture of extractants is related to synergistic aggregation of this mixture, we identify here the elements at the origin of synergy by independently investigating the effect of water, acid, and extracted cations. Thermodynamic equations are proposed to describe synergistic aggregation in the peculiar case of synergistic solvent extraction by evaluating critical aggregation concentration (CAC) as well as specific interactions between extractants due to the presence of water, acid and cations. Distribution of two extractant molecules in the free extractants and in reverse micelles was assessed, leading to an estimation of the in-plane interaction parameter between extractants in the aggregates as introduced by Bergström and Eriksson ( Bergström, M.; Eriksson, J. C. A Theoretical Analysis of Synergistic Effects in Mixed Surfactant Systems . Langmuir 2000 , 16 , 7173 - 7181 ). Based on this model, we study the N,N'-dimethyl-N,N'-dioctylhexylethoxymalonamide (DMDOHEMA) and di(2-ethylexyl) phosphoric acid (HDEHP) mixture and show that adding nitric acid enhances synergistic aggregation at the equimolar ratio of the two extractants and that this configuration can be related to a favored enthalpy of mixing.

Mammalian infants vocalize when socially isolated. Vocalization guides the return of the caregiver and thereby maintains an environment critical to the infant's survival. Although the role of the periaqueductal gray area (PAG) in these vocalizations is established, other aspects of the relevant neural circuitry remain under-studied. Here we report that output from the nucleus accumbens (Acb) is necessary for isolation-induced vocalizations of infant rats aged postnatal days (PND) 11-13. Local inhibition via infusion of the GABA A agonist muscimol (.8 μg/side) of the Acb, but not the dorsolateral striatum, blocked isolation-induced vocalizations, independent of whether the isolation was at room temperature, followed a brief reunion with the dam, or occurred in a cool (10 °C) environment. These findings highlight a possible anatomical area mediating the mammalian infant response to social separation and, more generally, to the development of social attachment., (© 2016 Wiley Periodicals, Inc.)

The complexation of selected trivalent lanthanide ions with derivatives of the tetranitrogen donor ligands 6,6'-bis-1R,1H-1,2,3-triazol-4-yl-2,2'-bipyridines (BTzBPs, R = alkyl or aryl) was investigated in solid state and in solution. An anhydrous solid [Ce(Bn-BTzBP)(NO 3 ) 3 ] (Bn = benzene) complex was synthesized and characterized by single-crystal X-ray diffraction. Eu(III) complexes with the 2-ethyl(hexyl) derivative EH-BTzBP in methanol were studied by time-resolved fluorescence spectroscopy. Earlier studies have identified the EH-BTzBP as a potentially useful solvent extraction reagent for the separation of americium from lanthanide metal ions, a challenging component of advanced nuclear fuel cycles for actinide transmutation. To help identify species formed in the extraction process, the influence of 2-bromohexanoic acid (identified as an essential component of the separation system) on Eu(III) complexes was investigated. Comparison with an organic phase after extraction of Eu(III) by EH-BTzBP and 2-bromohexanoic acid showed that both 1:1 and 1:2 (Eu/EH-BTzBP) complexes are involved in the extraction. UV-visible spectrophotometry was used to compare Eu(III) stability constants with those of other Ln(III) complexes.

Purpose: This study evaluates the advantage of the quercetin encapsulation in nanosized emulsion (QU-NE) administered orally in rats in order to demonstrate its anti-oedematous and antioxidant effects as well as its toxicity., Methods: The nanocarriers were prepared using the hot solvent diffusion with the phase inversion temperature methods. The nanocarriers physicochemical properties were then investigated. The anti-edematous activity was tested using paw edema in rats. In addition, NF-kB expression in subcutaneous tissue of the paws was accessed by immunohistochemistry while the lipid peroxidation was analyzed in the liver by malondialdehyde reaction with thiobarbituric acid. Hematological, renal and hepatic toxicity as well as the genetic damage were also evaluated., Results: The results demonstrated that QU-NE exhibited pronounced anti-oedematous property comparable to drug diclofenac. This effect was associated with NF-κB pathway inhibition. The lipid peroxidation was also only reduced in rats treated with QU-NE. Besides this, no genetic damage, hematological, renal or hepatic toxicities were observed after administration of QU-NE., Conclusions: These results suggest that quercetin nanosized emulsion exhibits anti-oedematous and antioxidant properties and does not demonstrate toxic effects. This indicates that it has a potential application in the treatment of inflammatory diseases.

Neuroblastoma (NB) is a pediatric cancer. New therapies for high-risk NB aim to induce cell differentiation and to inhibit MYCN and ALK signaling in NB. The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP) are 2 related neuropeptides sharing common receptors. The level of VIP increases with NB differentiation. Here, the effects of VIP and PACAP analogs developed for therapeutic use were studied in MYCN-amplified NB SK-N-DZ and IMR-32 cells and in Kelly cells that in addition present the F1174L ALK mutation. As previously reported by our group in IMR-32 cells, VIP induced neuritogenesis in SK-N-DZ and Kelly cells and reduced MYCN expression in Kelly but not in SK-N-DZ cells. VIP decreased AKT activity in the ALK-mutated Kelly cells. These effects were PKA-dependent. IMR-32, SK-NDZ and Kelly cells expressed the genes encoding the 3 subtypes of VIP and PACAP receptors, VPAC1, VPAC2 and PAC1. In parallel to its effect on MYCN expression, VIP inhibited invasion in IMR-32 and Kelly cells. Among the 3 PACAP analogs tested, [Hyp(2)]PACAP-27 showed higher efficiency than VIP in Kelly cells. These results indicate that VIP and PACAP analogs act on molecular and cellular processes that could reduce aggressiveness of high-risk NB., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is a highly malignant and aggressive primary brain tumor. In spite of an arsenal of therapeutic interventions, the prognosis of glioblastoma remains very poor. Cisplatin-based therapy is one of the most important chemotherapy treatments for GBM, although its efficacy is limited by drug resistance and undesirable side effects. In the present study, we designed a chimera molecule containing the platinum binding moiety MBL-III-7 (1) attached N-terminal to the sequence of d-maurocalcine (D-MCa), a protease-resistant and highly efficient cell-penetrating peptide (CPP) derived from the Tunisian chactid scorpion toxin, L-MCa. The concept behind this design is that MCa, through its cell retention properties, should reduce cell expulsion of the platinum complex and increase its efficiency. The anti-cancer properties of the synthesized platinum analogue Pt-MBL-III&#95;7-D&#95;MCa (Pt-1-DMCa) were assessed in human glioblastoma cells (U87) by assaying cell viability and apoptosis. The new molecule exhibited enhanced anti-cancer efficacy compared to cisplatin, especially at low doses. By inducing intracellular oxidative stress, Pt-1-DMCa potentiated platinum-induced DNA damage and led to enhanced p53 phosphorylation, followed by increased activation of both mitochondrial and death receptor pathways. Decreased phosphorylated AKT and ERK levels were associated with the apoptosis induced by the novel synthesized cisplatin analogue. Our results suggested that a chimera between platinum and a maurocalcine-derived CPP is a highly successful anti-cancer compound that works by targeting the intracellular redox system. Pt-1-DMCa is an interesting candidate for a preclinical assessment of platinum-based therapy in GBM treatments and possibly other cancer types.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides acting through VPAC1, VPAC2 and PAC1 receptors (referred here as the VIP-receptor system). In the central nervous system, VIP and PACAP are involved in neurogenesis, cell differentiation and migration, suggesting that they could be implicated in the development of glioblastoma (GBM). The infiltrative nature of GBM remains a major problem for the therapy of these tumors. We previously demonstrated that the VIP-receptor system regulated cell migration of the human cell lines M059J and M059K, derived from a single human GBM. Here, we evaluated the involvement of the VIP-receptor system in GBM cell invasion. In Matrigel invasion assays, M059K cells that express more the VIP-receptor system than M059J cells were less invasive. Invasion assays performed in the presence of agonists, antagonists or anti-PACAP antibodies as well as experiments with transfected M059J cells overexpressing the VPAC1 receptor indicated that the more the VIP-receptor system was expressed and activated, the less the cells were able to invade. Western immunoblotting experiments revealed that the VIP-receptor system inactivated the signaling protein AKT. Invasion assays carried out in the presence of an AKT inhibitor demonstrated the involvement of this signaling kinase in the regulation of cell invasion by the VIP-receptor system in M059K cells. The inhibition by VIP of invasion and AKT was also observed in U87 cells. In conclusion, VIP and PACAP act as anti-invasive factors in different GBM cell lines, a function mediated by VPAC1 inhibition of AKT signaling in M059K cells.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non-tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of β-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of β-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of β-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue.

Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed.

Breast cancer is the most common cancer in women worldwide. Understanding the biology of this malignant disease is a prerequisite for selecting an appropriate treatment. Cell cycle alterations are seen in many cancers, including breast cancer. Newly popular targeted agents in breast cancer include cyclin dependent kinase inhibitors (CDKIs) which are agents inhibiting the function of cyclin dependent kinases (CDKs) and agents targeting proto-oncogenic signaling pathways like Notch, Wnt, and SHH (Sonic hedgehog). CDKIs are categorized as selective and non-selective inhibitors of CDK. CDKIs have been tried as monotherapy and combination therapy. The CDKI Palbocyclib is now a promising therapeutic in breast cancer. This drug recently entered phase III trial for estrogen receptor (ER) positive breast cancer after showing encouraging results in progression free survival in a phase II trials. The tumor microenvironment is now recognized as a significant factor in cancer treatment response. The tumor microenvironment is increasingly considered as a target for combination therapy of breast cancer. Recent findings in the signaling pathways in breast cancer are herein summarized and discussed. Furthermore, the therapeutic targeting of the microenvironment in breast cancer is also considered., (Copyright © 2014 Elsevier Inc. All rights reserved.)

An increasing number of G protein-coupled receptors, like receptors for vasoactive intestinal peptide (VIP), are found in cell nucleus. As VIP receptors are involved in the regulation of glioma cell proliferation and migration, we investigated the expression and the nuclear localization of the VIP receptors VPAC1 and VPAC2 in this cancer. First, by applying Western blot and immunofluorescence detection in three human glioblastoma (GBM) cell lines, we observed a strong nuclear staining for the VPAC1 receptor and a weak nuclear VPAC2 receptor staining. Second, immunohistochemical staining of VPAC1 and VPAC2 on tissue microarrays (TMA) showed that the two receptors were expressed in normal brain and glioma tissues. Expression in the non-nuclear compartment of the two receptors significantly increased with the grade of the tumors. Analysis of nuclear staining revealed a significant increase of VPAC1 staining with glioma grade, with up to 50% of GBM displaying strong VPAC1 nuclear staining, whereas nuclear VPAC2 staining remained marginal. The increase in VPAC receptor expression with glioma grades and the enhanced nuclear localization of the VPAC1 receptors in GBM might be of importance for glioma progression., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: It is not clearly known how frequently the recommendations given to travelers are followed, and what factors could encourage compliance with these recommended measures., Methods: Adults consulting at a Medical Department for International Travelers (International Travelers' Medical Services, ITMS) in October and November 2010 were asked to answer a questionnaire before their journey. They were also contacted for a post-travel telephone interview to determine whether they had followed the recommendations regarding vaccinations and malaria prevention, and the reasons for poor or noncompliance with these recommendations., Results: A total of 353 travelers were included, with post-travel data available for 321 of them. Complete compliance with all the recommendations (vaccinations and malaria chemoprophylaxis) was observed in 186/321 (57.9%) of the travelers. Only 55.6% (233/419) of the prescribed vaccinations were given, with huge variability according to the type of vaccine. Only 57.3% (184/321) of the patients used a mosquito net. Among the 287 prescriptions for antimalarial drugs, 219 (76.3%) were taken correctly, 37 (12.9%) were taken incorrectly (noncompliance with the duration and/or dosage), and 31 (10.8%) were not taken at all. Traveling to areas of mass tourism (Kenya/Senegal), consulting their general practitioner (GP), and being retired were significantly and independently associated with better overall compliance in univariate and multivariate analyses., Conclusions: Compliance could be improved by focusing on factors associated with poor compliance to improve the advice given to less compliant travelers, by providing clear information tailored to each traveler, with a focus on key messages, and by improving coordination between ITMS and GPs., (© 2012 International Society of Travel Medicine.)

Reasons for Performing Study: Appropriate management of atypical myopathy (AM) requires the establishment of an accurate diagnosis and prognosis. Furthermore, preventive measures to avoid AM need to be refined., Objectives: The aims of the study were as follows: 1) to improve the diagnosis of AM; 2) to identify prognostic predictors; and 3) to refine recommended preventive measures based on indicators of risk factors., Methods: An exploratory analysis of cases in Europe between 2006 and 2009 reported to the Atypical Myopathy Alert Group was conducted. Based on clinical data, reported cases were allocated into 2 groups: confirmed or highly probable AM (AM group; further divided into survivors and nonsurvivors); and cases with a low probability of having AM or with another final diagnosis (non-AM group). Using Welch's test and odds ratios corrected for multiple comparisons, the AM vs. non-AM groups were compared to identify indicators for diagnosis and risk factors, and survivors vs. nonsurvivors in the AM group were compared to identify prognostic factors. Sensitivity, specificity and positive and negative predictive values were calculated for specific clinical signs related to final diagnosis and outcome., Results: From 600 reported cases, 354 AM cases (survival rate of 26%) and 69 non-AM cases were identified, while there were insufficient data to categorise the remainder. Variables valuable for diagnosing AM compared with similar diseases were as follows: presence of dead leaves and wood and/or trees on pastures; sloping pastures; full-time pasture access; no food supplementation; normal body condition; pigmenturia; normothermia; and congested mucous membranes. Nonsurvival was associated with recumbency, sweating, anorexia, dyspnoea, tachypnoea and/or tachycardia. Survival was associated with remaining standing most of the time, normothermia, normal mucous membranes, defaecation and vitamin and antioxidant therapy., Conclusions and Potential Relevance: This study refines the list of risk factors for AM. Clinical signs valuable for diagnosis and prognosis have been identified, enabling clinicians to improve management of AM cases., (© 2012 EVJ Ltd.)

Reasons for Performing Study: Improved understanding of the epidemiology of atypical myopathy (AM) will help to define the environmental factors that permit or support the causal agent(s) to exert toxicity., Objectives: This European survey of AM aimed to describe spatiotemporal distribution, survival, clinical signs, circumstances in which AM develops and its different expressions between countries and over time., Methods: The spatiotemporal distribution, history and clinical features of AM cases reported to the Atypical Myopathy Alert Group from 2006 to 2009 were described. Comparisons of data from the most severely affected countries and from the large outbreaks were made with Fisher's exact and Welch's tests with Bonferroni correction., Results: Of 600 suspected cases, 354 met the diagnostic criteria for confirmed or highly probable AM. The largest outbreaks occurred during the autumns of 2006 and 2009 in Belgium, France and Germany. For the first time, donkeys, zebras and old horses were affected, and clinical signs such as gastrointestinal impaction, diarrhoea, penile prolapse, buccal ulceration and renal dysfunction were observed. Affected horses spent >6 h/day on pastures that almost always contained or were surrounded by trees. The latency period was estimated at up to 4 days. Overall survival rate was 26%. Although differences between countries in affected breeds, body condition, horse management and pasture characteristics were recognised, the common presenting clinical signs and mortality were similar between countries., Conclusions and Potential Relevance: This study describes new data on case details, history and clinical course of AM that is of preventive, diagnostic and therapeutic value. However, the true impact of the findings of this study on the development of or severity of AM should be tested with case-control studies., (© 2012 EVJ Ltd.)

Background: This paper presents the latest international descriptive epidemiological data for invasive breast cancer amongst women, including incidence, survival and mortality, as well as information on mammographic screening programmes., Results: Almost 1.4 million women were diagnosed with breast cancer worldwide in 2008 and approximately 459,000 deaths were recorded. Incidence rates were much higher in more developed countries compared to less developed countries (71.7/100,000 and 29.3/100,000 respectively, adjusted to the World 2000 Standard Population) whereas the corresponding mortality rates were 17.1/100,000 and 11.8/100,000. Five-year relative survival estimates range from 12% in parts of Africa to almost 90% in the United States, Australia and Canada, with the differential linked to a combination of early detection, access to treatment services and cultural barriers. Observed improvements in breast cancer survival in more developed parts of the world over recent decades have been attributed to the introduction of population-based screening using mammography and the systemic use of adjuvant therapies., Conclusion: The future worldwide breast cancer burden will be strongly influenced by large predicted rises in incidence throughout parts of Asia due to an increasingly "westernised" lifestyle. Efforts are underway to reduce the global disparities in survival for women with breast cancer using cost-effective interventions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We prepared a new glucuronide prodrug of cyclopamine designed to target selectively the Hedgehog signalling pathway of cancer cells. This prodrug includes a novel self-immolative linker bearing a hydrophilic side chain that can be easily introduced via"click chemistry". With this design, the prodrug exhibits reduced toxicity compared to the free drug on U87 glioblastoma cells. However, in the presence of β-glucuronidase, the prodrug conducts to the quick release of cyclopamine thereby restoring its antiproliferative activity.

Modulation of serotonin transporter (5-HTT) function causes changes in affective behavior, both in humans and rodents. Stressful life events likewise affect emotional behavior. In humans, a low-expressing genetic 5-htt variant, the s allele of the 5-htt linked promoter region, has been associated with increased risk for depression only where there was a history of stressful life events. To investigate this gene by environment interaction in mice, we compared the effects of inescapable shocks on the behavior of wild-type (5-htt+/+), heterozygote (5-htt+/-) and serotonin transporter deficient (5-htt-/-) mice. Inescapable shocks induce behavioral changes including a shock escape deficit, in a subsequent test when escape is possible. Confirming a gene by environment interaction, we found that stress increases escape latencies in a gene-dose dependent manner (5-htt-/->5-htt+/->5-htt +/+), where as there were no differences among the genotypes in the unstressed condition. The vulnerability to increased escape latency could not be accounted for by enhanced fear learning, as 5-htt-/- mice did not show heightened fear conditioning. The interaction of 5-htt genotype and stress appeared to produce a selective behavioral vulnerability, because no interaction of 5-htt genotype and stress was observed in other measures of anxiety and depression-linked behavior, including the open field, novelty suppressed feeding, and forced swim tests. We replicated prior findings that the 5-htt-/- displays heightened anxiety and depression-like behavior at baseline (unstressed condition). In conclusion, our data offer the possibility for future investigation of the neural basis underlying 5-htt genotype-by-stress interaction shown here., (© 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.)

We report a case of 31-year-old woman presented with a chronic pelvic pain and a 3-cm left ovarian cyst on ultrasonography. At the time of laparoscopy, we observed two blue peritoneal lesions at the pelvic insertion of left round ligament. Histopathological examination of a biopsy showed a pigmentation due to a decorative tattoo of the left thigh., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor in adults. This cancer has an infiltrative nature and the median survival of patients is about one year. Vasoactive intestinal peptide (VIP) belongs to a structurally related family of polypeptides and is a major regulatory factor in the central and peripheral nervous systems. VIP regulates proliferation of astrocytes and of numerous cancer cell lines and modulates migration in prostatic and colonic cancer cell lines. Little is known about the involvement of VIP and its receptors (VIP-receptor system) in proliferation or migration of GBM cells. The effects of VIP, PACAP and of synthetic VIP antagonists were tested in two human GBM cell lines, M059K and M059J, established from two different parts of a single tumor. In these cells, the data revealed that the VIP-receptor system did not affect proliferation but controlled cell migration. Indeed, in M059K cells which express components of the VIP receptor system, the VIP receptor antagonists and a PACAP antibody enhanced migration. The VIP receptor antagonists increased generation of typical migration-associated processes: filopodia and lamellipodia, and activation of Rac1 and Cdc42 GTPases. Reciprocally, in M059J cells which poorly express the VIP-receptor system, treatments with the agonists VIP and PACAP resulted in decreased cell migration. Furthermore, the peptides appeared to act through a subclass of binding sites displaying an uncommon very high affinity for these ligands. Taken together, these observations suggest that components of the VIP-receptor system negatively regulate cell migration, thus showing potential anti-oncogenic properties., (2010 Elsevier Ltd. All rights reserved.)

The first glucuronide prodrug of the hedgehog signaling inhibitor cyclopamine was synthesized. The carbamoyl derivatisation of cyclopamine significantly decreased its toxicity towards the U87 human glioblastoma cell line. However, when the prodrug was incubated with beta-glucuronidase in the culture media, the active drug was efficiently released thereby restoring its anti-proliferative activity., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

Mammalian infant behavior directed toward caregivers is critical to survival and may play a role in establishing social bonds. Most mammalian infants vocalize when isolated. Rat pups vocalize at a higher rate when isolated following an interaction with an adult female than after an interaction with littermates, a phenomenon termed maternal potentiation. We previously reported that the D2 receptor family agonist quinpirole disrupts maternal potentiation at a dose that does not alter vocalization rate following contact with littermates. Here we further examine the role of dopamine in maternal potentiation by testing effects of both D1 and D2 receptor family ligands, alone and in combination, on maternal potentiation. We tested the drugs' effects on isolation vocalization subsequent to littermate contact and then another isolation preceded by a brief "reunion" period of exposure either to the anesthetized dam or a handling-only "pickup" condition. D2 receptor stimulation blocked the increase in vocalizations following reunion with the dam. The D2 agonist effect in the dam-reunion condition was much larger than its small effect in the pickup condition, providing further evidence that D2 receptors exert a selective modulation of maternal potentiation. On the other hand, systemic administration of the D1 agonist SKF81297 reduced isolation vocalizations nonspecifically, across all the experimental conditions. Finally, the D1 and D2 receptor dual antagonist, alpha-flupenthixol, increased isolation vocalizations and disrupted potentiation, but at doses that also inhibited locomotion. We conclude that D2 receptor family activation has a more selective effect of disrupting maternal potentiation than D1 receptor family activation.

Rat pups' vocalization during social separation and the cessation of vocalization upon social reunion (contact quieting) model early life affiliative relationships. The present study examined the roles of dopamine (DA) receptors in regulating contact quieting. Contact quieting to the dam, but not to littermates, was disrupted by either blockade or exogenous stimulation of DA D1-like receptors. The D2 antagonist raclopride also prevented the quieting effect of reunion with the dam and had a lesser effect on the quieting properties of littermates. In contrast, the D2 agonist quinpirole permitted or enhanced contact quieting. Combined systemic and local striatal administration of D2 ligands showed that stimulation of striatal D2 receptors can enhance, but is not necessary for, contact quieting to the dam. These results are consistent with the literature linking the neural mechanisms of affiliation and reinforcement. This is also the first demonstration that the neurochemical substrates of an infant comfort response to dams differ from a behaviorally similar response to siblings.

Background: Social-ecological resilience refers to the dynamic process of adaptive learning, reorganization and meaning-making demonstrated in linked human, animal, and plant ecosystems often organized in formal and/or informal social institutions, as they anticipate, withstand and/or judiciously engage with adversity while maintaining function without fundamentally losing their identity., Objective: To present two sets of examples that illustrate the complex ways in which transformation and persistence, two key aspects of the adaptive cycle may work together to preserve established patterns of human and/or animal uses of water resources and food plant species, in rural East and West Africa, respectively around the Serengeti National Park (Tanzania), and "Park W" (Niger), with the aim of identifying possible indicators of social-ecological resilience., Methods: Selective combinations of ecological and anthropological, quantitative and qualitative methods, including participatory tools of investigation and analysis., Results and Discussion: Our preliminary results are presented with minimal commentary and discussion in order to avoid hasty and/or unwarranted interpretation of the ongoing purposely iterative processes of investigation and analysis in the two study sites. Nevertheless we have identified a number of possible indicators of social-ecological resilience that may be tested in other localities in Africa and elsewhere.

Neuroblastoma is a pediatric tumor which can spontaneously regress or differentiate into a benign tumor. MYCN oncogene amplification occurs in 22% of neuroblastomas and is associated with poor prognosis. Retinoic acid (RA), a molecule able to induce differentiation and to decrease MYCN expression, is used in the therapy of neuroblastomas. The neuropeptide vasoactive intestinal peptide (VIP) is known to control proliferation or differentiation of numerous cancer cells. In vitro, VIP induces differentiation of neuroblastoma cells. To determine whether VIP could modulate MYCN expression, we carried out real-time quantitative RT-PCR and Western immunoblot analyses in human neuroblastoma SH-SY5Y and IMR-32 cells. The results indicated that VIP reduced MYCN mRNA and protein expression, especially in the MYCN-amplified IMR-32 cells, with a maximal and transient decrease by approximately 50% after few hours of treatment with VIP at 10(-6) M. This effect was compared to that of RA at 10(-5) M, which induced a diminution of MYCN mRNA expression by approximately 25% after few days of treatment. This indicated that VIP and RA display complementary kinetics. Cotreatments showed that VIP and RA had synergistic effects on regulation of expression of MYCN proteins. VIP and RA cotreatments regulated also expression of two MYCN target genes, SKP2 and TP53INP1. These results suggest that VIP, in combination with RA may have a potential therapeutic benefit in neuroblastomas with MYCN amplification, a genetic abnormality associated with poor prognosis.

Vasoactive intestinal peptide (VIP) is a neuropeptide known to regulate proliferation and differentiation in normal and tumoral cells. We previously reported that VIP induced neuritogenesis in human neuroblastoma SH-SY5Y cells cultured in serum-free medium. This neuritogenesis was associated with a regulated expression of neuronal cytoskeleton markers. To further characterize the neuroblastic cell differentiation induced by VIP in human SH-SY5Y cells, we investigated expression of synaptosomal-associated protein of 25 kDa (SNAP-25), a protein implicated in exocytosis associated with different processes, including neurite outgrowth. Western immunoblotting and real-time RT-PCR analyses revealed that VIP increased expression of the SNAP-25 protein and the level of both SNAP-25a and SNAP-25b mRNA isoforms. Immunofluorescence experiments indicated that SNAP-25 was mainly located in neurites and at the plasma membrane in SH-SY5Y cells treated with VIP. RNA interference experiments demonstrated that SNAP-25 was involved in VIP-induced neuritogenesis. In conclusion, SNAP-25 is up-regulated and implicated in neuritogenesis in human neuroblastoma SH-SY5Y cells treated with the neuropeptide VIP.

The aims of this case-control study were to identify in vitamin K antagonist (VKA)-treated unselected patients, factors associated with international normalised ratio (INR) values: (i) greater than 6.0.; and (ii) ranging from 4.0 to 6.0 complicated with bleeding. We also assessed VKA-related morbidity in these patients. During a two-month period, 4,188 consecutive and unselected patients were referred to our Emergency Department. At admission, the medical records of each patient and two age- and sex-matched controls were reviewed for: both duration and indication of VKA therapy, previous medical history of VKA-related haemorrhage, underlying co-morbidities, concomitant medications other than VKA, duration of hospitalization and deaths' causes. Of these 4,188 subjects, 50 case-patients (1.19%) were identified; both case-patients and controls did not differ as regards indications and patterns of VKA therapy. Interestingly, two-thirds of case-patients were women, suggesting that female gender may be a risk factor of VKA over-coagulation onset. We identified the following risk factors of VKA over-coagulation: previous medical history of INR levels over therapeutic range, therapy with antibiotics, amiodarone and proton pump inhibitors, as well as fever. A total of 88% of case-patients were hospitalized; mean duration of patients' hospitalization was seven days [range: 1-56 days]; no patient died from major bleeding. Our study underscores that it is of utmost importance to consider the strength of indication before starting VKA therapy, as this therapy has been responsible for as high as 1.19% of admissions in unselected subjects referred to an Emergency Department. Our data therefore suggest that internists should be aware of VKA-related high morbidity, particularly in situations at risk of VKA over-coagulation.

The middle third of the clavicle is commonly involved in any injury and account for 5-10% of all fractures in adults. Although non-unions are rare, their treatment has not been well defined yet. This report describes the arterial supply of the clavicle to clarify the pathological mechanism and the surgical procedure of non-unions. This study was based on delineation of the thoraco-acromial and suprascapular arteries with colored latex on 17 specimens (ten cadavers). Observations were made after macroscopic dissection and maceration. The main blood supply to the middle third of the clavicle was the periosteal. This supply came from the two branches of the thoraco-acromial trunk that penetrated the pectoralis major muscle and the deltoid muscle. In 13 cases, these two periosteal branches were anastomosed between these two muscle attachments. Periosteal vascularization was always seen on the superior surface and the anterior border of the bone, but never on the inferior surface or the posterior border. The suprascapular artery contributed to supply the middle third of the clavicle by several periosteal branches and also by an independent branch. This branch was born proximally near the internal, middle thirds union and passed along the posterior face of the subclavius muscle and pierced the bone through the nutria foramina located near the external, middle thirds union. Nevertheless, intraosseous arteries were noted only in four cases. In these cases, they were never more than 2cm long. Our results showed that the periosteal blood supply located between the muscles insertions and the arterial supply from the suprascapular artery could be twice compromised in case of important displacement or severe fracture. If treatments of clavicular fractures or non-unions cannot preserve the periosteal blood supply, bone grafting should be indicated.