Adiponectin stimulates glucose uptake in mouse blastocysts and embryonic carcinoma cells.

Preimplantation embryos are sensitive to maternal hormones affecting embryonic signal transduction and metabolic functions. We examined whether adiponectin, the most abundantly secreted adipokine, can influence glucose transport in mouse embryonic cells. In mouse blastocysts full-length adiponectin stimulated glucose uptake, while no effect of globular adiponectin was found. Full-length adiponectin stimulated translocation of GLUT8 glucose transporter to the cell membrane; we did not detect significant changes in the intracellular localization of GLUT4 glucose transporter in adiponectin-treated blastocysts. To study adiponectin signaling in detail, we used embryoid bodies formed from mouse embryonic carcinoma cell (ECC) line P19. We confirmed the expression of adiponectin receptors in these cells. Similar to mouse blastocysts, full-length adiponectin, but not globular adiponectin, stimulated glucose uptake in ECC P19 embryoid bodies. Moreover, full-length adiponectin stimulated AMPK and p38 MAPK phosphorylation. These results indicate that besides AMPK, p38 MAPK is a potential target of adiponectin in mouse embryonic cells. AMPK inhibitor did not influence the adiponectin-stimulated p38 MAPK phosphorylation, indicating independent action of these two signaling pathways. In mouse embryos adiponectin acts as a hormonal regulator of glucose uptake, which becomes especially important in phases with reduced levels of circulating insulin. Our results suggest that adiponectin maintains the glucose supply for early embryos under hypoinsulinaemic conditions, for example, in mothers suffering from type 1 diabetes mellitus.

[Multihospital use of imaging techniques in decentralized trauma care]. / Multihospitale Nutzung bildgebender Verfahren in der dezentralen Traumaversorgung.

BACKGROUND: Decentralized trauma care in the Wald and Weinviertel region in the north of lower Austria comprises five hospitals for primary care including one regional trauma center. Due to the geographical position and adverse weather conditions a web-based teleradiology system was established to ensure the best possible treatment and joint access to the results of radiological investigations. OBJECTIVE: The article describes a new picture archiving and communication system (PACS), which provides an online teleradiological workflow between the central trauma care unit and peripheral departments in a local trauma network as well as the advantages and disadvantages. MATERIAL AND METHODS: A corporately used PACS enables streaming-based full access to studies which are created within the system. Radiological studies can be obtained on request from all subscribers within the network. RESULTS: Teleradiological networks can essentially contribute to a suitable treatment pathway in an association of hospitals and therefore lead to a rapid initiation of treatment. CONCLUSION: Especially in rural areas with decentralized trauma care, the joint use of teleradiological resources can lead to a better treatment quality.

How well are Swiss French physicians prepared for future practice in primary care?

BACKGROUND: Moving from postgraduate training into independent practice represents a major transition in physicians' professional life. Little is known about how Swiss primary care graduates experience such a transition. The aim of this study was to explore the extent to which primary care physicians who recently set up private practice felt prepared to work as independent practitioners. METHODS: We conducted 7 focus groups among recently established (≤ 5 years) primary care physicians in Switzerland. Questions focused on positive and negative aspects of setting up a practice, and degree of preparedness. Transcripts were analysed according to organisational socialisation and work role transition frameworks. RESULTS: Participants felt relatively well prepared for most medical tasks except for some rheumatologic, minor traumatology, ENR, skin and psychiatric aspects. They felt unprepared for non clinical tasks such as office, insurance and medico-legal management issues and did not anticipate that the professional networking outside the hospital would be so important to their daily work. They faced dilemmas opposing professional values to the reality of practice which forced them to clarify their professional roles and expectations. Adjustment strategies were mainly informal. CONCLUSION: Although the postgraduate primary care curriculum is longer in Switzerland than in most European countries, it remains insufficiently connected with the reality of transitioning into independent practice, especially regarding role development and management tasks. A greater proportion of postgraduate training, with special emphasis on these issues, should take place directly in primary care.

[Efficacy of epidural steroid injections for chronic lumbar pain syndromes without neurological deficits. A randomized, double blind study as part of a multimodal treatment concept]. / Wirksamkeit periduraler Steroidinjektionen in der Therapie von nichtradikulären chronischen Rückenschmerzen. Eine randomisierte, doppelverblindete Vergleichsstudie im Rahmen eines multimodalen Behandlungskonzeptes.

BACKGROUND: Chronic lumbar pain syndromes without neurological deficits are generated by a multitude of causes. Functional, morphological and psychosocial factors are discussed. In many cases a diseased intervertebral disc is found on radiological examination but the clinical relevance of these findings is not clear. For this study it was postulated that a diseased disc results in a local inflammatory reaction therefore causing pain and impairing treatability of patients. An epidural injection of steroids can reduce inflammation and therefore improve treatability and ultimately treatment outcome. METHODS: A double blind randomized prospective trial was carried out. Patients treated in hospital for a chronic lumbar pain syndrome without neurological deficits within a multimodal treatment program were screened for indications for an epidural steroid injection (e.g. diseased lumbar disc and intention to treat). Patients eligible for the study were randomized into two groups. The treatment group received an epidural injection of 80 mg triamcinolone and 8 ml bupivacaine 0.25 %. The control group received only an epidural injection of 8 ml bupivacaine 0.25 %. RESULTS: In both groups pain intensity and treatability showed a statistically significant improvement after the epidural injection. The differences between the control and treatment groups were small and not clinically relevant. A small subgroup might profit from the steroid injection. In addition the treatability was dependent on psychometric values and the long-term outcome from a reduction of muscular skeletal dysfunctions. DISCUSSION: After the epidural injection the decrease in pain and increase in treatability was statistically significant. The mechanism of the improvement is not clear and should be examined further. The epidural injection of a steroid in this subgroup of patients did not lead to a clinical improvement in the outcome.

Gastrointestinal hormonal responses on GPR119 activation in lean and diseased rodent models of type 2 diabetes.

BACKGROUND: G protein-coupled receptor 119 (GPR119) has emerged as a potential target for the treatment of type 2 diabetes (T2D) and tool compounds have been critical in the evaluation of GPR119 functions. METHODS: We synthesised a novel small-molecule GPR119 agonist, PSN-GPR119, to study GPR119 signalling activities in cells overexpressing GPR119. We measured GPR119-stimulated peptide hormone release from intestinal loops and oral glucose tolerance in vivo from lean (C57BL/6J mouse or Sprague-Dawley (SD) rat) and diabetic (ob/ob mouse or ZDF rat) models. To evaluate the direct effects of GPR119 agonism on gastrointestinal (GI) tissue, we measured vectorial ion transport (measured as ISC; short-circuit current) across rodent GI mucosae and from normal human colon specimens. RESULTS: GPR119 activation by PSN-GPR119 increased cAMP accumulation in hGPR119-overexpressing HEK293 cells (EC50, 5.5 nM), stimulated glucagon-like peptide 1 (GLP-1) release from GLUTag cells (EC50, 75 nM) and insulin release from HIT-15 cells (EC50, 90 nM). In vivo, PSN-GPR119 improved glucose tolerance by ~50% in lean mice or rats and ~60% in the diabetic ob/ob mouse or ZDF rat models. Luminal addition of PSN-GPR119 to isolated loops of lean rat small intestine stimulated GLP-1, glucose insulinotropic peptide (GIP) and peptide YY (PYY) release under basal (5 mM) and high glucose (25 mM) conditions. Activation of GPR119 also reduced intestinal ion transport. Apical or basolateral PSN-GPR119 addition (1 µM) to lean or T2D rodent colon mucosae reduced ISC levels via PYY-mediated Y1 receptor agonism. The GPR119 response was glucose sensitive and was abolished by Y1 receptor antagonism. Similarly, in human colon, mucosa PSN-GPR119 acted via a Y1-specific mechanism. CONCLUSIONS: Our results show that functional GPR119 responses are similar in lean and diabetic rodent, and human colon; that GPR119 stimulation can result in glucose lowering through release of intestinal peptide hormones and that PSN-GPR119 is a useful tool compound for future studies.

[Athletic pubalgia and hip impingement]. / Pubalgie et confit fémoro-acétabulaire.

Athletic pubalgia is a painful and complex syndrom encountered by athletes involved in pivoting and cutting sports such as hockey and soccer. To date, there is no real consensus on the criteria for a reliable diagnostic, the different investigations, and the appropriate therapy. Current literature underlines intrinsic and extrinsic factors contributing to athletic pubalgia. This review article reports upon two novelties related to the issue: the importance and efficience of prevention program and the association of femoro-acetabular impingement with the pubalgia.

In situ X-ray study of the structural evolution of gold nano-domains by spray deposition on thin conductive P3HT films.

Gold (Au) nanoparticles are deposited from aqueous solution onto one of the most used conductive polymers, namely poly(3-hexylthiophene) (P3HT), using airbrush deposition. We report on the structure formation and packing of the Au nanoparticles after a 5 s spray cycle. In situ grazing incidence small-angle X-ray scattering (GISAXS) measurements with 20 ms time resolution allow a real-time observation of the emergence and evolution of the microstructure during a spray cycle and subsequent solvent evaporation. The results reveal multistage nanoscale ordering of the Au nanoparticles during the spray cycle. Further ex situ atomic force microscopy measurements of the sprayed films showed the formation of Au monolayer islands on top of the polymer film. Our study suggests that the solvent-substrate interaction as well as solvent evaporation kinetics are important factors that need to be taken into consideration in order to grow a compact uniform monolayer film for the fabrication of ultrathin films using airbrush deposition.

Vaccination against seasonal flu in Switzerland: The indecision of pregnant women encouraged by healthcare professionals.

BACKGROUND: The recommendation for seasonal flu immunization from the second trimester of pregnancy, adopted in summer 2010 in Switzerland, is situated within a social context characterized by reluctance toward some vaccinations, a relatively low vaccination coverage against flu in the general population, and still heated debates fuelled by vaccination campaigns organized around the A(H1N1)pdm09 flu pandemic in winter 2009 to 2010. This study examines Swiss pregnant women's representations of the risks associated with seasonal flu and its vaccination. METHODS: Semi-structured interviews were conducted with 29 women, while in the maternity unit in March 2011, 3 to 5 days after giving birth. The interviews addressed the risks associated with flu, modes of protection, motivations for, and obstacles to vaccination. RESULTS: The interviewees did not show major preoccupations regarding seasonal flu and they tended to distance themselves from the at-risk status. They did not directly challenge seasonal flu immunization; however, they were reluctant to do it. Their attitudes were supported by their personal experience and the experience of their social networks. Healthcare professionals, particularly medical doctors, gave very little direction, or even did not raise the issue with them. CONCLUSIONS: Between the rather moderate positions of those who are against vaccination and those who support it, an intermediate grey zone, characterized by hesitation, was observed. Furthermore, the indecision of pregnant women is reinforced by doubts among the persons they are close to and also among the professionals they met during their pregnancy.

Anisotropic elasticity in confocal studies of colloidal crystals.

We consider the theory of fluctuations of a colloidal solid observed in a confocal slice. For a cubic crystal we study the evolution of the projected elastic properties as a function of the anisotropy of the crystal using numerical methods based on the fast Fourier transform. In certain situations of high symmetry we find exact analytic results for the projected fluctuations.

Fish early life stage toxicity prediction from acute daphnid toxicity and quantum chemistry.

One step towards reduced animal testing is the use of in silico screening methods to predict toxicity of chemicals, which requires high-quality data to develop models that are reliable and clearly interpretable. We compiled a large data set of fish early life stage no observed effect concentration endpoints (FELS NOEC) based on published data sources and internal studies, containing data for 338 molecules. Furthermore, we developed a new quantitative structure-activity-activity relationship (QSAAR) model to inform estimation of this endpoint using a combination of dimensionality reduction, regularization, and domain knowledge. In particular, we made use of a sparse partial least squares algorithm (sPLS) to select relevant variables from a huge number of molecular descriptors ranging from topological to quantum chemical properties. The final QSAAR model is of low complexity, consisting of 2 latent variables based on 8 molecular descriptors and experimental Daphnia magna acute data (EC50, 48 h). We provide a mechanistic interpretation of each model parameter. The model performs well, with a coefficient of determination r 2 of 0.723 on the training set (cross-validated q 2 = 0.686) and comparable predictivity on a test data set of chemically related molecules with experimental Daphnia magna data (r 2 test = 0.687, RMSE = 0.793 log units).

Antidiabetic and hypolipidemic potential of Campomanesia xanthocarpa seed extract obtained by supercritical CO2.

Campomanesia xanthocarpa, a plant belonging to the Myrtaceae family, is popularly known as gabiroba. Leaves of gabiroba has been popularly used to treat various diseases, including inflammatory, renal, and digestive, among others. Additionally, studies have shown an effect to reduce blood cholesterol levels. The aim of this study was to evaluate the antihyperglycemic and hypolipidemic effects of Campomanesia xanthocarpa seed extract in hyperglycemic rats. The results showed that 400 mg/kg of seed extract was able to decrease blood glucose levels and to increase the muscular and hepatic glycogen content as well as to inhibit the sucrase and maltase activity. At doses of 200 mg/kg and 800 mg/kg, the activity of these enzymes was also reduced. In the lipid profile 400 mg/kg produced a decrease in total and LDL cholesterol serum levels; and with 200 mg/kg there was an increase in HDL cholesterol levels. The extract did not present hepatic and renal toxic effects at the different doses tested. The results suggest that the treatment with Campomanesia xanthocarpa seeds extract is useful in reducing glycemia, total cholesterol and LDL levels with potential adjuvant therapeutic in the treatment of diabetes and hypercholesterolemia, however, additional pharmacological and toxicological studies are still required.

Antioxidant activity, antibacterial and inhibitory effect of intestinal disaccharidases of extracts obtained from Eugenia uniflora L. Seeds.

The use of medicinal plants for disease prevention, treatment and cure is an ancient practice used by humanity, and many plants species are used in bioprospecting research. In this context, its stands out Eugenia uniflora L., populary known as pitangueira and belongs to the Myrtaceae family, with a wide geographic distribution and native of Brazil. In view of the therapeutic qualities of the plant and the lack of the studies on its seeds, the present study had as objective to evaluate the phytochemical profile of the extracts of Eugenia uniflora L. seeds, from different solvents, as well as their antibacterial activity, antioxidant and its inhibitory effect of intestinal disaccharidases. Results showed a high content of phenolic compounds and total flavonoids, thus characterizing antioxidant activity, also highlighting the best bacteriostatic action for the Gram positive strain of Staphylococcus aureus in the ethanolic fraction. Regarding the disaccharidases, a strong inhibitory action was observed for all concentrations, evidencing a antihyperglycemic potential. The present research allowed to concluded that Eugenia uniflora L. seeds have promising biological activities for the industrial sector, but a more detailed investigation is needed regarding their bioactive compounds.

Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial.

The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. "Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.

Trimer stability of YadA is critical for virulence of Yersinia enterocolitica.

Yersinia adhesin A (YadA) is a trimeric autotransporter adhesin with multiple functions in host-pathogen interactions. The aim of this study was to dissect the virulence functions promoted by YadA in vitro and in vivo. To accomplish this, we generated Yersinia enterocolitica O:8 mutants expressing point mutations in YadA G389, a highly conserved residue in the membrane anchor of YadA, and analyzed their impact on YadA expression and virulence functions. We found that point mutations of YadA G389 led to impaired transport, stability, and surface display of YadA. YadA G389A and G389S mutants showed comparable YadA surface expression, autoagglutination, and adhesion to those of wild-type YadA but displayed reduced trimer stability and complement resistance in vitro and were 10- to 1,000-fold attenuated in experimental Y. enterocolitica infection in mice. The G389T, G389N, and G389H mutants lost trimer stability, exhibited strongly reduced surface display, autoagglutination, adhesion properties, and complement resistance, and were avirulent (>10,000-fold attenuation) in mice. Our data demonstrate that G389 is a critical residue of YadA, required for optimal trimer stability, transport, surface display, and serum resistance. We also show that stable trimeric YadA protein is essential for virulence of Y. enterocolitica.

Defective acidification in human breast tumor cells and implications for chemotherapy.

Multidrug resistance (MDR) is a significant problem in the treatment of cancer. Chemotherapeutic drugs distribute through the cyto- and nucleoplasm of drug-sensitive cells but are excluded from the nucleus in drug-resistant cells, concentrating in cytoplasmic organelles. Weak base chemotherapeutic drugs (e.g., anthracyclines and vinca alkaloids) should concentrate in acidic organelles. This report presents a quantification of the pH for identified compartments of the MCF-7 human breast tumor cell line and demonstrates that (a) the chemotherapeutic Adriamycin concentrates in acidified organelles of drug-resistant but not drug-sensitive cells; (b) the lysosomes and recycling endosomes are not acidified in drug-sensitive cells; (c) the cytosol of drug-sensitive cells is 0.4 pH units more acidic than the cytosol of resistant cells; and (d) disrupting the acidification of the organelles of resistant cells with monensin, bafilomycin A1, or concanamycin A is sufficient to change the Adriamycin distribution to that found in drug-sensitive cells, rendering the cell vulnerable once again to chemotherapy. These results suggest that acidification of organelles is causally related to drug resistance and is consistent with the hypothesis that sequestration of drugs in acidic organelles and subsequent extrusion from the cell through the secretory pathways contribute to chemotherapeutic resistance.

Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.

Nuclear transport in 3T3 fibroblasts: effects of growth factors, transformation, and cell shape.

Nucleocytoplasmic transport of fluorescent-labeled macromolecules was investigated in transformed and nontransformed 3T3 fibroblasts. Insulin and epidermal growth factor enhanced transport three-fold after 1-2-h incubation with nontransformed adhering fibroblasts; no enhancement of transport was observed for spherical unattached fibroblasts. The concentration of growth factor for maximal enhancement was 3-10 nM. Nuclear transport for Kirsten murine sarcoma virus-transformed BALB/c 3T3 fibroblasts, however, was maximally enhanced before addition of growth factors; addition of insulin or epidermal growth factor causes no additional transport enhancement. Transformation also minimizes cell shape effects on macromolecular nuclear transport. These results provide evidence that protein growth factors and oncogenic transformation may use a similar mechanism for activation of nuclear transport.

Epidermal growth factor and insulin stimulate nuclear pore-mediated macromolecular transport in isolated rat liver nuclei.

Fluorescence photobleaching was used to measure the effect of epidermal growth factor (EGF), insulin, and glucagon on the nuclear transport of fluorescent-labeled dextrans across the nuclear pore complex. EGF and insulin were found to stimulate transport approximately 200%, while boiling these polypeptide growth factors greatly diminished this enhancement activity. Glucagon demonstrated no enhancement effect. The nuclear transport enhancement effects were observed at EGF and insulin concentrations that elicit the various physiological responses, e.g., nanomolar range.

Chemical modification of matrix porin from Escherichia coli: probing the pore topology of a transmembrane protein.

Chemical modification of amino groups in matrix porin solubilized and purified from outer membranes of Escherichia coli in beta-octylglucoside was performed with eosin isothiocyanate and citraconic anhydride. At pH 7 8.5, the former reagent labeled a single amino group in the native protein, while more extensive derivatization was observed with increasing pH or upon denaturation. Citraconic anhydride modified approximately 12-14 residues in native porin and 15-16 of the total of 19 amino groups in the denatured state. Fluorescamine, another amine-specific reagent of intermediate size, derivatized 3 and 16 residues in the native and denatured states, respectively. These results indicate that reactive probes of various sizes may serve as indicators for the surface accessibility of reactive residues in matrix porin. The increased derivatization of lysyl residues at high pH (or in phosphate buffer) suggests the method's sensitivity to different conformational states of the protein. The extent of tyrosine modification (1-2 residues in the native, and approximately 22 in the denatured porin) depended on the state of protein folding, even with reagents of small size. The approach of using various probes with differing properties and specificities thus appears useful for the determination of membrane protein asymmetry, pore topology, and conformational states of transmembrane proteins.