Template induced conformational change of amyloid-β monomer.
Population of aggregation-prone conformers for the monomeric amyloid-β (Aβ) can dramatically speed up its fibrillar aggregation. In this work, we study the effect of preformed template on the conformational distributions of the monomeric Aβ by replica exchange molecular dynamics. Our results show that the template consisting of Aβ peptides with cross-β structure can induce the formation of β-rich conformations for the monomeric Aβ, which is the key feature of the aggregation-prone conformers. Similar effect is observed when the hIAPP peptides and poly alanine peptides were used as templates, suggesting that the template effect is insensitive to the sequence details of the template peptides. In comparison, the template with helical structure has no significant effects on the β-propensity of the monomeric Aβ. Analysis to the interaction details revealed that the template tends to disrupt the intrapeptide interactions of the monomeric Aβ, which are absent in the fibrillar state, suggesting that the preformed template can reorganize the intrapeptide interactions of the monomeric Aβ during the capturing stage and reduce the energy frustrations for the fibrillar aggregations.


Detection of ventilatory threshold using near infrared spectroscopy in men and women.
The onset of anaerobic (lactate) metabolism during incremental exercise, which may be a result of an imbalance between tissue oxygen supply and demand, has been associated with the gas exchange ventilatory threshold (VT). This study was designed to examine whether near infrared spectroscopy (NIRS) could be used to detect the VT in healthy subjects. Twenty-one men and 19 women completed incremental cycle ergometry during which NIRS measurements were obtained from the right vastus lateralis and gas exchange measurements were monitored simultaneously using a metabolic cart. The VT was identified from the metabolic data by the V-slope method and from NIRS data as the intensity at which tissue absorbency crossed the resting baseline value observed immediately prior to the initiation of exercise. Pearson correlations for the relative oxygen uptake and power output observed for the two methods of detecting VT were 0.90 and 0.88, respectively, in men and 0.89 and 0.86, respectively, in women (P < 0.01). No significant differences were observed between the two methods of detecting VT for any of the physiological responses (P > 0.05). No significant (P > 0.05) gender differences were observed in muscle oxygenation values at the VT, 32% in men and 38% in women. These results validate the use of NIRS as an alternate noninvasive method for detecting VT during cycle exercise in healthy subjects.


Agglomeration Behavior and Fate of Food-Grade Titanium Dioxide in Human Gastrointestinal Digestion and in the Lysosomal Environment.
In the present study, we addressed the knowledge gaps regarding the agglomeration behavior and fate of food-grade titanium dioxide (E 171) in human gastrointestinal digestion (GID). After thorough multi-technique physicochemical characterization including TEM, single-particle ICP-MS (spICP-MS), CLS, VSSA determination and ELS, the GI fate of E 171 was studied by applying the in vitro GID approach established for the regulatory risk assessment of nanomaterials in Europe, using a standardized international protocol. GI fate was investigated in fasted conditions, relevant to E 171 use in food supplements and medicines, and in fed conditions, with both a model food and E 171-containing food samples. TiO2 constituent particles were resistant to GI dissolution, and thus, their stability in lysosomal fluid was investigated. The biopersistence of the material in lysosomal fluid highlighted its potential for bioaccumulation. For characterizing the agglomeration degree in the small intestinal phase, spICP-MS represented an ideal analytical tool to overcome the limitations of earlier studies. We demonstrated that, after simulated GID, in the small intestine, E 171 (at concentrations reflecting human exposure) is present with a dispersion degree similar to that obtained when dispersing the material in water by means of high-energy sonication (i.e., ≥70% of particles <250 nm).


The zinc-finger antiviral protein recruits the RNA processing exosome to degrade the target mRNA.
Zinc-finger antiviral protein (ZAP) is a host antiviral factor that specifically inhibits the replication of Moloney murine leukemia virus (MLV) and Sindbis virus (SIN) by preventing accumulation of the viral mRNA in the cytoplasm. In previous studies, we demonstrated that ZAP directly binds to its specific target mRNAs. In this article, we provide evidence indicating that ZAP recruits the RNA processing exosome to degrade the target RNA. ZAP comigrated with the exosome in sucrose or glycerol velocity gradient centrifugation. Immunoprecipitation of ZAP coprecipitated the exosome components. In vitro pull-down assays indicated that ZAP directly interacted with the exosome component hRrp46p and that the binding region of ZAP was mapped to amino acids 224-254. Depletion of the exosome component hRrp41p or hRrp46p with small interfering RNA significantly reduced ZAP's destabilizing activity. These findings suggest that ZAP is a trans-acting factor that modulates mRNA stability.


Expression of alpha- and beta-human chorionic gonadotropin subunits in cultured human cells.
We surveyed several human cell lines for production of alpha- and beta-human chorionic gonadotropin (hCG) under a variety of conditions known to induce gene expression. alpha- and beta-hCG subunits were monitored in culture media by specific radioimmunoassays and were shown to be quite sensitive to serum refeeding and growth state of all cell types studied. The permanent line JEG-3 secreted both alpha- and beta-subunits whereas HeLa cells secreted only the alpha-subunit. Production of both subunits was augmented in these permanent cell lines, for each growth state, by pretreating cells with 5-azacytidine; in contrast, spontaneous beta-hCG production by normal human fibroblasts (four of six strains) was only rarely increased after 5-azacytidine treatment, and more often was suppressed by 30 to 40%. Three of five strains from inherited chromosomal breakage syndromes produced immunoassayable beta-hCG spontaneously, two of which increased secretion upon treatment with either UV or mitomycin C. Surprisingly, one normal cell strain of fetal origin was induced to secrete alpha-hCG, but not beta-hCG, after UV irradiation. JEG-3 and HeLa cells produced detectable cognate mRNA for alpha- or beta-hCG subunits or both by Northern and S1 nuclease protection analyses, whereas such transcripts from untransformed human fibroblasts were consistently below detectable levels. Quantitation of beta-hCG mRNA by RNA:RNA annealing kinetics indicates that even the fibroblast strain producing the highest secreted beta-hCG levels contained cognate mRNAs at only approximately 0.1 per cell. We conclude that hCG expression in human fibroblasts is strongly repressed at the transcriptional level, although a variety of conditions (growth state, serum refeeding, cell senescence, or DNA damage) can affect the level of "leaky" expression, at least in some responding fraction of cells.


Evaluation of overdiagnosis of breast cancer in screening with mammography: results of the Nijmegen programme.
After 12 years of screening for breast cancer in Nijmegen (1975-86), during which period six mammographic examination rounds were carried out, the extent of overdiagnosis was evaluated. Overdiagnosis is defined as a histologically established diagnosis of invasive or intraductal breast cancer that would never have developed into a clinically manifest tumour during the patient's normal life expectancy if no screening examination had been carried out. The whole 12-year period shows an excess of 11% of breast cancer cases in Nijmegen, compared with the neighbouring city of Arnhem, where no mass screening was performed. The incidence of breast cancers in Nijmegen in the period 1975-78 is higher, compared with the incidence rates in Arnhem; the rate ratio is 1.30. For the time-intervals 1979-82 and 1983-86 the rate ratios are 1.03 and 1.01 respectively with (0.89; 1.18) and (0.86; 1.16) as 95% confidence intervals. This leads to the conclusion that there is no evidence that screening programmes using modern mammography constitute a significant risk for overdiagnosis of breast cancers.


Characterization of industrial waste from a natural gas distribution company and management strategies: a case study of the East Azerbaijan Gas Company (Iran).
Although a fundamental prerequisite for the successful implementation of any waste management plan is the availability of sufficient and accurate data, there are few available studies regarding the characterization and management of gas distribution company waste (GDCW). This study aimed to characterize the industrial waste generated by the East Azerbaijan Gas Distribution Company (EAGDC) and to present environmental management strategies. The EAGDC serves 57 cities and 821 villages with a total population of more than 2.5 million as well as numerous industrial units. The methodology of this study was based on a checklist of data collected from each zone of the company, site visits (observation), and quantity and quality analysis according to the formal data available from different zones. The results indicate that more than 35 different kinds of industrial solid waste are generated in different industrial installations. The most important types of generated waste include empty barrels (including mercaptans, diesel fuel, deionized waters and oil), faulty gas meters and regulators, a variety of industrial oils, sleeves, filter elements and faulty pipes, valves and fittings. The results indicated that, currently, GDCW is generally handled and disposed of with domestic waste, deposited in companies' installation yards and stores or, sometimes, recycled through non-scientific approaches that can create health risks to the public and the environment, even though most of the GDCW was determined to be recyclable or reusable materials. This study concludes that gas distribution companies must pay more attention to source reduction, recycling and reusing of waste to preserve natural resources, landfill space and the environment.


Diversity and evolution of protein translocation.
Cells need to translocate proteins into and across hydrophobic membranes in order to interact with the extracellular environment. Although a subset of proteins are thought to spontaneously insert into lipid bilayers, translocation of most transported proteins requires additional cellular components. Such components catalyze efficient lateral transport into or across cellular membranes in prokaryotes and eukaryotes. These include, among others, the conserved YidC/Oxa1/Alb3 proteins as well as components of the Sec and the Tat pathways. Our current knowledge of the function and distribution of these components and their corresponding pathways in organisms of the three domains of life is reviewed. On the basis of this information, the evolution of protein translocation is discussed.


CD127+CCR5+CD38+++ CD4+ Th1 effector cells are an early component of the primary immune response to vaccinia virus and precede development of interleukin-2+ memory CD4+ T cells.
The stages of development of human antigen-specific CD4+ T cells responding to viral infection and their differentiation into long-term memory cells are not well understood. The inoculation of healthy adults with vaccinia virus presents an opportunity to study these events intensively. Between days 11 and 14 postinoculation, there was a peak of proliferating CCR5+CD38+++ CD4+ effector cells which contained the cytotoxic granule marker T-cell intracellular antigen 1 and included gamma interferon (IFN-gamma)-producing vaccinia virus-specific CD4+ T cells. The majority of these initial vaccinia virus-specific CD4+ T cells were CD127+ and produced interleukin-2 (IL-2) but not CTLA-4 in response to restimulation in vitro. Between days 14 and 21, there was a switch from IFN-gamma and IL-2 coexpression to IL-2 production only, coinciding with a resting phenotype and an increased in vitro proliferation response. The early CCR5+CD38+++ vaccinia virus-specific CD4+ T cells were similar to our previous observations of human immunodeficiency virus (HIV)-specific CD4+ T cells in primary HIV type 1 (HIV-1) infection, but the vaccinia virus-specific cells expressed much more CD127 and IL-2 than we previously found in their HIV-specific counterparts. The current study provides important information on the differentiation of IL-2+ vaccinia virus-specific memory cells, allowing further study of antiviral effector CD4+ T cells in healthy adults and their dysfunction in HIV-1 infection.


Resection of metastasis and local recurrences of renal cell carcinoma after presurgical targeted therapy: probability of complete local control and outcome.
To analyse probability of complete local control and outcome in patients with metastases and local recurrences who have a high probability of failure of local therapy and who were treated with presurgical targeted therapy with the intention to reconsider complete resection or other local therapies such as radiotherapy or ablation. From two institutional databases, patients with metastatic or locally recurrent RCC were retrospectively identified who received targeted therapy based on a multidisciplinary tumour board decision because of high probability of failure of local control. From January 2007 until November 2014, 34 patients were treated and included in the analysis. Five patients underwent no local therapy due to insufficient downsizing to attempt resection. The probability of proceeding to local therapy was 85.3 %. Median overall survival of 29 patients with local therapy after pretreatment was 67 months (range 9-173, 95 % CI 90.87) with a median disease-free survival of 12 months (range 0-147 months). The probability to achieve complete local therapy and discontinue targeted therapy was 73.5 % (25 of 34 patients). Median time without systemic therapy was 12 months. In a retrospective series of patients with a high probability of failure of local therapy, neoadjuvant targeted therapy was associated with successful complete local treatment in approximately 70 % of patients with a time off targeted therapy of ≥1 year in 50 %. Only number of metastatic sites and the disease-free interval after treatment were associated with outcome.


Healthcare financing systems for increasing the use of tobacco dependence treatment.
We hypothesized that provision of financial assistance for smokers trying to quit, or reimbursement of their care providers, could lead to an increased rate of successful quit attempts. The primary objective of this review was to assess the impact of reducing the costs of providing or using smoking cessation treatment through healthcare financing interventions on abstinence from smoking. The secondary objectives were to examine the effects of different levels of financial support on the use and/or prescription of smoking cessation treatment and on the number of smokers making a quit attempt. We searched the Cochrane Tobacco Addiction Group Specialized Register in April 2012. We considered randomised controlled trials (RCTs), controlled trials and interrupted time series studies involving financial benefit interventions to smokers or their healthcare providers or both. Two reviewers independently extracted data and assessed the quality of the included studies. Risk ratios (RR) were calculated for individual studies on an intention-to-treat basis and meta-analysis was performed using a random-effects model. We included economic evaluations when a study presented the costs and effects of two or more alternatives. We found eleven trials involving financial interventions directed at smokers and healthcare providers.Full financial interventions directed at smokers had a statistically significant favourable effect on abstinence at six months or greater when compared to no intervention (RR 2.45, 95% CI 1.17 to 5.12, I² = 59%, 4 studies). There was also a significant effect of full financial interventions when compared to no interventions on the number of participants making a quit attempt (RR 1.11, 95% CI 1.04 to 1.32, I² = 15%) and use of smoking cessation treatment (NRT: RR 1.83, 95% CI 1.55 to 2.15, I² = 43%; bupropion: RR 3.22, 95% CI 1.41 to 7.34, I² = 71%; behavioural therapy: RR 1.77, 95% CI 1.19 to 2.65). There was no evidence of an effect on smoking cessation when we pooled two trials of financial incentives directed at healthcare providers (RR 1.16, CI 0.98 to 1.37, I² = 0%). Comparisons of full coverage with partial coverage, partial coverage with no coverage, and partial coverage with another partial coverage intervention did not detect significant effects. Comparison of full coverage with partial or no coverage resulted in costs per additional quitter ranging from $119 to $6450. Full financial interventions directed at smokers when compared to no financial interventions increase the proportion of smokers who attempt to quit, use smoking cessation treatments, and succeed in quitting. The absolute differences are small but the costs per additional quitter are low to moderate. We did not detect an effect on smoking cessation from financial incentives directed at healthcare providers. The methodological qualities of the included studies need to be taken into consideration when interpreting the results.


Target detection in left and right hemispace: effects of positional pre-cuing and type of background.
The two experiments reported here examined the degree to which detection of targets by the right hemisphere can be characterized as occurring at the global level and detection by the left hemisphere can be characterized as occurring at the local level. Although the results provided some evidence for such a dichotomy, these hemispheric differences in processing were modified by the overall configuration in which the item is embedded, the nature of the background, and whether a precue indicates the probable location of the target. The findings are discussed in relation to current theories of hemispheric differences in spatial processing.


Neuropathologic and clinical features of Parkinson's disease in Alzheimer's disease patients.
While dementia in Parkinson's disease (PD) is well described, PD features in Alzheimer's disease (AD) are being increasingly recognized. In 20 neuropathologically confirmed AD brains, 11 cases (55%) showed PD changes (Lewy body formation, neuronal loss, and gliosis of pigmented nuclei), with no significant difference in age or symptom duration between those cases with and without PD pathology. A history of rigidity in the absence of neuroleptic medication was noted in 80% of those with PD pathology but only 14% of those without PD pathology. Tremor was not observed in either group. This suggests that extrapyramidal signs, especially rigidity, noted in many AD patients are related to coexistent PD pathology.


Generating properly weighted ensemble of conformations of proteins from sparse or indirect distance constraints.
Inferring three-dimensional structural information of biomacromolecules such as proteins from limited experimental data is an important and challenging task. Nuclear Overhauser effect measurements based on nucleic magnetic resonance, disulfide linking, and electron paramagnetic resonance labeling studies can all provide useful partial distance constraint characteristic of the conformations of proteins. In this study, we describe a general approach for reconstructing conformations of biomolecules that are consistent with given distance constraints. Such constraints can be in the form of upper bounds and lower bounds of distances between residue pairs, contact maps based on specific contact distance cutoff values, or indirect distance constraints such as experimental phi-value measurement. Our approach is based on the framework of sequential Monte Carlo method, a chain growth-based method. We have developed a novel growth potential function to guide the generation of conformations that satisfy given distance constraints. This potential function incorporates not only the distance information of current residue during growth but also the distance information of future residues by introducing global distance upper bounds between residue pairs and the placement of reference points. To obtain protein conformations from indirect distance constraints in the form of experimental phi-values, we first generate properly weighted contact maps satisfying phi-value constraints, we then generate conformations from these contact maps. We show that our approach can faithfully generate conformations that satisfy the given constraints, which approach the native structures when distance constraints for all residue pairs are given.


Binocular field configuration in owls: the role of foraging ecology.
The binocular field of vision differs widely in birds depending on ecological traits such as foraging. Owls (Strigiformes) have been considered to have a unique binocular field, but whether it is related to foraging has remained unknown. While taking into account allometry and phylogeny, we hypothesized that both daily activity cycle and diet determine the size and shape of the binocular field in owls. Here, we compared the binocular field configuration of 23 species of owls. While we found no effect of allometry and phylogeny, ecological traits strongly influence the binocular field shape and size. Binocular field shape of owls significantly differed from that of diurnal raptors. Among owls, binocular field shape was relatively conserved, but binocular field size differed among species depending on ecological traits, with larger binocular fields in species living in dense habitat and foraging on invertebrates. Our results suggest that (i) binocular field shape is associated with the time of foraging in the daily cycle (owls versus diurnal raptors) and (ii) that binocular field size differs between closely related owl species even though the general shape is conserved, possibly because the field of view is partially restricted by feathers, in a trade-off with auditory localization.


Metabolic Fate of β-Aspartyl-(14)C-glycine in Normal Young Rats.
The metabolic fate of α- and β-L-aspartyl-[U-(14)C]glycine was investigated in normal young rats in vivo and in vitro. The radioactive dipeptides were synthesized from L-aspartic acid and [U-(14)C]glycine in our laboratory. When labeled β-aspartylglycine was given intraperitoneally, about 66% of the dose was excreted in the urine and 8% was recovered in the expired carbon dioxide over a 24-hr period. More than 90% of the urinary radioactivity was present in the β-aspartylglycine fraction of the urine. When the labeled α-aspartylglycine was given, 3% and 22% of the dose were recovered, respectively, in the urine and expired carbon dioxide. In slice experiments with kidney, liver and small intestine from normal rats, α-aspartylglycine was rapidly and almost completely hydrolyzed, and a large amount of free (14)C-glycine was released. In contrast, β-aspartylglycine was hardly hydrolyzed to the corresponding amino acids in liver and small intestine, and only slightly in kidney. These results suggest that in normal young rats most β-aspartylglycine, which may originate from endogenous tissue proteins, is hardly hydrolyzed and rapidly excreted into the urine.


Hepatocyte nuclear factor (HNF)-4alpha induces expression of endothelial Fas ligand (FasL) to prevent cancer cell transmigration: a novel defense mechanism of endothelium against cancer metastasis.
Endothelial Fas ligand (FasL) contributes to the "immune privilege" of tissues such as testis and eye, in which apoptosis is induced in infiltrating Fas-positive activated T cells and results in the inhibition of leukocyte extravasation. In this study, we examined the role of endothelial FasL in controlling cancer cell transmigration using rat lung endothelial (RLE) cell line bearing a doxycycline-inducible hepatocyte nuclear factor (HNF)-4alpha expression system. We showed that a detectable level of FasL was expressed in RLE cells and that this expression was markedly up-regulated and well correlated to the degree of HNF-4alpha expression in a time-dependent manner. When various cancer cells were overlaid on an RLE monolayer sheet, we examined the ability of endothelial FasL to induce massive apoptosis in Fas-expressing cancer cells and found a causal link to inhibition of the transmigration. Finally, we showed that FasL was expressed in capillaries of the rat brain by immunohistochemical staining, suggesting that FasL serves its functions not only in vitro, but also in vivo. These results raise the possibility that HNF-4alpha is involved in regulating cancer cell transmigration by modulating the Fas-FasL system.


Hormone therapy for postmenopausal osteoporosis management.
Menopausal hormone therapy (MHT) has been used for prevention and treatment of postmenopausal osteoporosis for several decades. However, public concerns were raised over the safety of MHT after the initial report was published in 2002 by the Women's Health Initiative. We conducted a historical review on this subject, primarily focusing on level I evidence from randomized controlled trials, systematic reviews and meta-analyses, and summarized high-quality evidence on the efficacy and safety of MHT in management of postmenopausal osteoporosis. Clinical issues were also discussed on MHT initiation, identification of treatment candidates and treatment duration, as well as discontinuation of MHT.


Dysobinin, a tetranortriterpenoid.
The planar furan ring in the title compound (6beta-acetoxyazadirone, C(30)H(38)O(6)) is twisted with respect to the steroid D ring. The crystal structure is stabilized by C-H.O hydrogen bonds and van der Waals interactions.


Carbocysteine.
Carbocysteine is prescribed for conditions characterized by the accumulation of excessive mucus. Although often described as a mucolytic, its function is probably that of mucoregulation, which results in physical changes in accumulated secretions that are favorable in terms of clearance. The chemistry, pharmacology, pharmacokinetics, clinical applications, and toxicology of carbocysteine are reviewed.


Success of laser endoureterotomy of ureteral strictures associated with ureteral stones is related to stone impaction.
Since the holmium:yttrium-aluminum-garnet (Ho:YAG) laser is the flexible lithotrite of choice for ureteral stones, its application to ureteral strictures associated with ureteral calculi is convenient. The results of Ho:YAG laser endoureterotomy in this specific setting have not been defined. We report our experience with Ho:YAG laser endoureterotomy of ureteral strictures associated with ureteral stone treatment, with or without a history of stone impaction. We reviewed the medical records of 13 patients with ureteral stricture related to stone treatment, with (n = 9) or without (n = 4) a history of impacted ureteral stones, who were managed with Ho:YAG laser endoureterotomy. Follow-up was obtained with radiographic imaging and renal scans. The overall success rate was 62%, with a mean follow-up of 21 months in successful cases and a mean recurrence time of 1.6 months in failures. Outcome was not associated with length or location of the stricture. Among the nine strictures associated with impacted stones, treatment was successful in only 5 (56%). Of the four strictures that occurred after stone removal but without history of impaction, the success rate was 75%. Success was also greater for strictures managed with post-procedure stents >or=8 Fr (75%), compared to stents <or=7 Fr. (56%). Our results suggest that laser endoureterotomy of ureteral strictures due to ureteral stone treatment without a history of impaction is associated with a reasonable success rate (75%), but that laser endoureterotomy for strictures related to impacted stones is associated with a success rate of only 56%. Larger caliber stents might be preferred in this setting.


Recurrence of Japanese encephalitis epidemic in Wuhan, China, 2009-2010.
Japanese encephalitis (JE) was once epidemic in most areas of China, including Wuhan, a city located in the central part of China. The incidence of JE dramatically decreased due to nationwide immunization with the live attenuated JE virus (JEV) vaccine, and no JE cases were reported during 2005-2008 in Wuhan. In 2009 and 2010, 31 JE cases reoccurred in this area. In this study, we investigated the causes of JE recurrence. All JE cases were laboratory-confirmed by detecting the JEV-specific IgM antibody with an IgM-capture enzyme-linked immunosorbent assay (ELISA). All patients were children between 2 months and 9 years of age with a median age of 2 years. Of the 31 cases, 9 had received one or two doses of the JEV vaccine, 11 had not been immunized previously with the JEV vaccine, and 11 had an unclear immunization history. Through reverse transcription polymerase chain reaction (RT-PCR), sequencing, and phylogenetic analysis, two new strains of JEV were isolated from Culex tritaeniorhynchus and identified as genotype 1 JEV, rather than genotype 3, which circulated in this area previously. Vaccine failure or missed vaccination may have caused JE recurrence. Local centers for disease control and prevention need to improve immunization coverage, and the efficacy of the JE vaccine needs to be reevaluated in a population at risk for disease.


Building and Accessing Clausal Representations: The Advantage of First Mention versus the Advantage of Clause Recency.
We investigated two seemingly contradictory phenomena: the Advantage of the First-Mentioned Participant (participants mentioned first in a sentence are more accessible than participants mentioned second) and the Advantage of the Most Recent Clause (concepts mentioned in the most recent clause are more accessible than concepts mentioned in an earlier clause). We resolved this contradiction by measuring how quickly comprehenders accessed participants mentioned in the first versus second clauses of two-clause sentences. Our data supported the following hypotheses: Comprehenders represent each clause of a two-clause sentence in its own mental substructure. Comprehenders have greatest access to information in the substructure that they are currently developing; that is, they have greatest access to the most recent clause. However, at some point, the first clause becomes more accessible because the substructure representing the first clause of a two-clause sentence serves as a foundation for the whole sentence-level representation.


Potential role of recombinant factor VIIa as a hemostatic agent.
Recombinant factor VIIa (rFVIIa) has been shown to induce hemostasis in hemophilia patients with inhibitors against factor VIII or factor IX independent of factor VIII/factor IX. Factor VIIa binds to tissue factor (TF) exposed at the site of injury and generates, through factor X activation on the TF-bearing cells, enough thrombin to activate factors VIII, V, and XI, as well as platelets. The thrombin-activated platelets provided a perfect template for binding of activated factors VIII, IX, and V, further activation of factor X, and thrombin generation. Factor VIIa in high concentrations binds to thrombin-activated platelets and is capable of activating factor X, thereby generating thrombin independent of the presence of factor VIII or factor IX. Accordingly, rFVIIa has been shown to initiate hemostasis in severe hemophilila patients with inhibitors subjected to major surgery and suffering from serious limb- and life-threatening bleeding. Since rFVIIa enhances thrombin generation-thereby providing the formation of tight, stable fibrin hemostatic plugs resistance to premature lysis-it should be hemostatic in other situations characterized by impaired thrombin generation. A hemostatic effect has been reported in patients with various platelet disorders and factor XI deficiency. Further, a hemostatic effect of rFVIIa has been reported in patients subjected to trauma and extensive surgery who have developed profuse, excessive bleeding resulting in hemodilution and changes in coagulation patterns. rFVIIa was developed to treat bleeding in hemophilia patients with inhibitors against factor VIII or factor IX and has been shown to induce effective hemostasis in most such patients and also in life- and limb-threatening bleeding. It has also been used successfully to stop bleeding in patients who do not have hemophilia but who do have acquired antibodies against factor VIII (acquired hemophilia). rFVIIa initiates hemostasis by forming a complex with TF exposed as a result of vessel wall injury. Pharmacologic doses of rFVIIa can enhance thrombin generation on platelets that are already thrombin-activated, resulting in the formation of full thrombin burst. By enhancing thrombin generation, rFVIIa helps to form tight, stable, fibrin plugs resistant to premature fibrinolysis. This also maintains hemostasis in the absence of factor VIII or factor IX. Pharmacologic doses of rFVIIa may accordingly be of benefit in producing hemostasis in situations other than hemophilia characterized by profuse bleeding and impaired thrombin generation. There is now clinical experience indicating a hemostatic effect in patients with thrombocytopenia and functional platelet defects. rFVIIa has also been successfully used in acute trauma patients with profuse bleedings and in other bleeding situations.


Increase in intracellular Ca(2+) and calcitonin gene-related peptide release through metabotropic P2Y receptors in rat dorsal root ganglion neurons.
We examined the effects of the activation of metabotropic P2Y receptors on the intracellular Ca(2+) concentration and the release of neuropeptide calcitonin gene-related peptide (CGRP) in isolated adult rat dorsal root ganglion neurons. In small-sized dorsal root ganglion neurons (soma diameter<30 microm) loaded with fura-2, a bath application of ATP (100 microM) evoked an increase in intracellular Ca(2+) concentration, while the removal of extracellular Ca(2+) partly depressed the response to ATP, thus suggesting that the ATP-induced increase in intracellular Ca(2+) concentration is due to both the release of Ca(2+) from intracellular stores and the influx of extracellular Ca(2+). Bath application of uridine 5'-triphosphate (UTP; 100 microM) also caused an increase in intracellular Ca(2+) concentration in small-sized dorsal root ganglion neurons and the P2 receptor antagonists suramin (100 microM) and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 10 microM) virtually abolished the response, indicating that the intracellular Ca(2+) elevation in response to UTP is mediated through metabotropic P2Y receptors. This intracellular Ca(2+) increase was abolished by pretreating the neurons with thapsigargin (100 nM), suggesting that the UTP-induced increase in intracellular Ca(2+) is primarily due to the release of Ca(2+) from endoplasmic reticulum Ca(2+) stores. An enzyme-linked immunosorbent assay showed that an application of UTP (100 microM) significantly stimulated the release of CGRP and that suramin (100 microM) totally abolished the response, suggesting that P2Y receptor-mediated increase in intracellular Ca(2+) is accompanied by CGRP release from dorsal root ganglion neurons. These results suggest that metabotropic P2Y receptors contribute to extracellular ATP-induced increase in intracellular Ca(2+) concentration and subsequent release of neuropeptide CGRP in rat dorsal root ganglion neurons.


The role of androgens in the regulation of muscle oxidative capacity following aerobic exercise training.
Reduced production or bioavailability of androgens, termed hypogonadism, occurs in a variety of pathological conditions. While androgens target numerous tissues throughout the body, hypogonadism specifically reduces the ability of skeletal muscle to produce adenosine triphosphate aerobically, i.e., muscle oxidative capacity. This has important implications for overall health as muscle oxidative capacity impacts a number of metabolic processes. Although androgen replacement therapy is effective at restoring muscle oxidative capacity in hypogonadal individuals, this is not a viable therapeutic option for all who are experiencing hypogonadism. While aerobic exercise may be a viable alternative to increase muscle oxidative capacity, it is unknown whether androgen depletion affects this adaptation. To determine this, sham and castrated mice were randomized to remain sedentary or undergo 8 weeks of aerobic treadmill exercise training. All mice were fasted overnight prior to sacrifice. Though exercise increased markers of muscle oxidative capacity independent of castration (cytochrome c oxidase subunit IV and cytochrome c), these measures were lower in castrated mice. This reduction was not due to a difference in peroxisome proliferator activated receptor gamma coactivator 1 alpha protein content, as expression was increased to a similar absolute value in sham and castrated animals following exercise training. However, markers of BCL2/Adenovirus E1B 19 kDa Interacting Protein 3 (BNIP3)-mediated mitophagy were increased by castration independent of exercise. Together, these data show that exercise training can increase markers of muscle oxidative capacity following androgen depletion. However, these values are reduced by androgen depletion likely due in part to elevated BNIP3-mediated mitophagy.


G-protein-coupled receptor affinity prediction based on the use of a profiling dataset: QSAR design, synthesis, and experimental validation.
A QSAR model accounting for "average" G-protein-coupled receptor (GPCR) binding was built from a large set of experimental standardized binding data (1939 compounds systematically tested over 40 different GPCRs) and applied to the design of a library of "GPCR-predicted" compounds. Three hundred and sixty of these compounds were randomly selected and tested in 21 GPCR binding assays. Positives were defined by their ability to inhibit by more than 70% the binding of reference compounds at 10 microM. A 5.5-fold enrichment in positives was observed when comparing the "GPCR-predicted" compounds with 600 randomly selected compounds predicted as "non-GPCR" from a general collection. The model was efficient in predicting strongest binders, since enrichment was greater for higher cutoffs. Significant enrichment was also observed for peptidic GPCRs and receptors not included to develop the QSAR model, suggesting the usefulness of the model to design ligands binding with newly identified GPCRs, including orphan ones.


LPS activates neuroinflammatory pathways to induce depression in Parkinson's disease-like condition.
Aim: This study aimed to observe the effects of lipopolysaccharide (LPS) intraperitoneal (i.p.) injection on rats and investigate how neuroinflammation contributes to the pathogenesis of depression in Parkinson's disease (dPD). Methods: Rats were administered LPS (0.5 mg/kg, i.p.) for either 1, 2, or 4 consecutive days to establish a rat model of dPD. The sucrose preference test (SPT), the open field test (OFT), and the rotarod test evaluated depression-like and motor behaviors. Magnetic resonance imaging was used to detect alterations in the intrinsic activity and the integrity of white matter fibers in the brain. The expression of c-Fos, ionized calcium-binding adapter molecule (Iba-1), and tyrosine hydroxylase (TH) was evaluated using immunohistochemistry. The concentration of interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and interleukin-10 (IL-10) was measured using Luminex technology. Results: LPS i.p. injections decreased sucrose preference in the SPT, horizontal and center distance in the OFT, and standing time in the rotarod test. The intrinsic activities in the hippocampus (HIP) were significantly reduced in the LPS-4 d group. The integrity of white matter fibers was greatly destroyed within 4 days of LPS treatment. The expression of c-Fos and Iba-1 in the prefrontal cortex, HIP, and substantia nigra increased dramatically, and the number of TH+ neurons in the substantia nigra decreased considerably after LPS injection. The levels of IL-6, TNF-α, and IL-10 were higher in the LPS-4 d group than those in the control group. Conclusion: Injection of LPS (0.5 mg/kg, i.p.) for 4 consecutive days can activate microglia, cause the release of inflammatory cytokines, reduce intrinsic activities in the HIP, destroy the integrity of white matter fibers, induce anhedonia and behavioral despair, and finally lead to dPD. This study proved that LPS injection (0.5 mg/kg, i.p.) for 4 consecutive days could be used to successfully create a rat model of dPD.


Naso- or Orbitocutaneous Fistulas after Free Flap Reconstruction of Orbital Exenteration Defects: Retrospective Study, Systematic Review, and Meta-Analysis.
Objective Naso- or orbitocutaneous fistula (NOF) is a challenging complication of orbital exenteration, and it often requires surgical repair. We sought to identify the incidence and risk factors for NOF after orbital exenteration. Study Design Retrospective chart review, systematic review, meta-analysis. Setting Tertiary care center. Participants Patients undergoing free flap reconstruction following orbital exenteration. Records were reviewed for clinicopathologic data, operative details, and outcomes. Main Outcome Measures Univariate analysis was used to assess risk factors for incidence of postoperative NOF. PubMed and Cochrane databases were searched for published reports on NOF after orbital exenteration. Rates of fistula and odds ratios for predictive factors were compared in a meta-analysis. Results Total 7 of 77 patients (9.1%) developed NOF; fistula formation was associated with ethmoid sinus involvement ( p < 0.05) and minor wound break down ( p < 0.05). On meta-analysis, pooled rates of fistula formation were 5.8% for free flap patients and 12.5% for patients receiving no reconstruction. Conclusion Immediate postoperative wound complications and medial orbital wall resection increased the risk for NOF. On review and meta-analysis, reconstruction of orbital exenteration defects decreased the risk for fistula formation, but published series did not demonstrate a significant decrease in risk with free flaps compared with other methods of reconstruction.


[Acupuncture at "seven acupoints on neck" for cervical spondylosis of vertebral artery type].
To compare the efficacy difference among acupuncture at "seven acupoints on neck", acupuncture at regular acupoints and betahistine mesilate tablet for cervical spondylosis of vertebral artery type, and to explore the effective treatment for cervical spondylosis of vertebral artery type. Ninety patients were randomly divided into a regular acupuncture group, a medication group and a neck-seven-acupoint group, 30 cases in each group. According to the acupoints prescription for vertigo in "11th Five-Year" Nation Textbook Acupuncture and Moxibustion, the patients in the regular acupuncture group were treated with acupuncture at Fengchi (GB 20) and Baihui (GV 20), etc.; the patients in the neck-seven-acupoint group were treated with Fengfu (GV 16), Fengchi (GB 20), Tianzhu (BL 10) and Wangu (GB 12); the two groups were treated once a day, 6 treatments were taken as one course; there was an interval of 1 day between course and totally two course were given. The patients in the medication group were treated with betahistine mesilate tablets, 1 tablet each time, 3 times a day, for 2 weeks. The vertigo symptom and function score, mean blood flow velocity of left vertebral artery (LVA), right vertebral artery (RVA), basilar artery (BA) as well as pulsatile index (PI) and resistance index (RI) were observed, and the clinical efficacy of the three groups was compared. The total effective rate was 93.3% (28/30) in the neck-seven-acupoint group, which was superior to 76.7% (23/30) in the regular acupuncture group and 70.0% (21/30) in the medication group (both P<0.05). The vertigo symptom and function score were all improved after treatment in the three groups (all P<0.05), and the improvement in the neck-seven-acupoint group was superior to those in the regular acupuncture group and medication group (both P<0.05). The mean blood flow velocity of LVA, RVA and BA was all improved after treatment in the neck-seven-acupoint group and regular acupuncture group (all P<0.05), which was not significant in the medication group (all P>0.05). The improvement of mean blood flow velocity in the neck-seven-acupoint group was superior to those in the medication group and regular acupuncture group (all P<0.05); the improvement in the regular acupuncture group was superior to that in the medication group (all P<0.05). PI and RI were all reduced after treatment in the three groups (all P<0.05); the reduction in the neck-seven-acupoint group was more significant those those in the medication group and regular acupuncture group (all P<0.05), and the reduction in the regular acupuncture group was superior to that in the medication group (all P<0.05). Acupuncture at "seven acupoints on neck" has better clinical efficacy than regular acupuncture and betahistine mesilate tablets, which could obviously improve vertigo and brain blood supply.


Panmixia in a fragmented and unstable environment: the hydrothermal shrimp Rimicaris exoculata disperses extensively along the Mid-Atlantic Ridge.
Dispersal plays a fundamental role in the evolution and persistence of species, and especially for species inhabiting extreme, ephemeral and highly fragmented habitats as hydrothermal vents. The Mid-Atlantic Ridge endemic shrimp species Rimicaris exoculata was studied using microsatellite markers to infer connectivity along the 7100-Km range encompassing the sampled sites. Astonishingly, no genetic differentiation was found between individuals from the different geographic origins, supporting a scenario of widespread large-scale dispersal despite the habitat distance and fragmentation. We hypothesize that delayed metamorphosis associated to temperature differences or even active directed migration dependent on physical and/or chemical stimuli could explain these results and warrant further studies on adaptation and dispersal mechanisms.


Pylephlebitis Caused by Fusobacterium nucleatum in a Septuagenarian Healthy Caucasian Male: Atypical Presentation of Lemierre's Syndrome.
Lemierre's syndrome (LS) is characterized by thrombophlebitis of the internal jugular vein caused primarily by Fusobacterium necrophorum. LS is usually suspected in fit young adults with prolonged or prior pharyngeal infection. Atypical Lemierre's syndrome is commonly defined as Fusobacterium-associated thrombophlebitis outside the head-neck veins and usually occurs in older patients than typical Lemierre's syndrome. Here we present a case of atypical LS in a septuagenarian healthy Caucasian male with no prior history of pharyngitis and in whom both computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated partial portal vein thrombosis associated with Fusobacterium nucleatum. This case report confirms previous reports of Fusobacterium nucleatum-associated LS variants presenting with abdominal vein thrombosis and illustrates clinical recovery after a combination of anticoagulation and antibiotic therapy.


Oral Candidiasis in children and adolescents with cancer. Identification of Candida spp.
Oral candidiasis represents a serious problem for children with cancer. The mortality rate of this infection has increased due to fungal septicemia, associated with a primary buccal infection. Identify the Candida spp. in buccal lesions of patients with cancer, establish the predominant species and correlate them to age and sex of the patient, clinical presentation, type of neoplasic disease and cytostatic therapy received. 62 patients, between 0-16 years, were investigated in a cross sectional study. SAMPLE INCLUSION CRITERIA: Patients with malignant neoplasic disease that were receiving cytostatic treatment and had suspicious lesions of oral candidiasis. Patients with antifungal therapy, active caries, calculus or intraoral appliances were excluded. A clinical evaluation was carried out. The lesion sample was taken and studied by direct exam and culture in CHROMagar-Candida and Sabouraud-Dextrose Agar with chloramphenicol. The identification of the isolated yeast was done by the filamentation test, carbohydrate fermentation and assimilation. Most of the cases (69.35%) were positive to oral candidiasis, C. albicans was the most frequent species found, followed by C. parapsilosis (14.89%), C. tropicalis (12.77%), C. krusei (4.26%), C. glabrata (2.13%) and C. lusitaniae (2.13%). In some cases more than one specie were isolated (9.30%). The most frequent location of the lesion was in the tongue (72.70%). The pseudomembranous candidiasis was the most frequent clinical presentation found (78.71%). There were not significant statistically differences with regard to sex and age of the patient, type of neoplasic disease and cytostatic agent received. The results suggest that oral candidiasis is a frequent complication in the pediatric oncological population, being C. albicans the main etiological agent, however, there is an important participation of other Candida species.


Key factors for successful en bloc endoscopic submucosal dissection of early stage gastric cancer using an insulation-tipped diathermic knife.
En bloc endoscopic mucosal resection (EMR) is presently considered to be the treatment of choice for endoscopically resectable early stage gastric cancer (EGC). Although a new EMR technique using an insulation-tipped diathermic knife (endoscopic submucosal dissection using an IT knife: IT knife-ESD) is reportedly suitable for en bloc resection, a failure in en bloc resection (piecemeal resection) can occur. We retrospectively analyzed factors affecting the success rate of en bloc resection by IT knife-ESD. A total of 71 gastric lesions were treated by IT knife-ESD. En bloc/piecemeal resection rates were investigated. Twelve potential factors associated with clinicopathological characteristics or procedures were analyzed univariately and multivariately. IT knife-ESD was successfully performed in all 71 lesions. En bloc resection was achieved in 63 lesions (91%), while eight lesions (9%) were removed as two or more fragments (piecemeal resection). The multivariate analysis identified only one independent factor affecting the success rate of en bloc resection: the second-half period of procedure application. The en bloc resection rate was not associated with the tumor location/site, tumor size, specimen size, and ulceration within the tumor. Much experience with IT knife-ESD may resolve the tumor-related technical difficulties. It is true for this advanced procedure that endoscopist experience is highly likely to be a critical factor for treatment success. We consider that IT knife-ESD for EGC is feasible and safe when performed by experienced endoscopists.


The Potential Impact of Radix Paeoniae Alba in Embryonic Development of Mice.
Although Radix Paeoniae Alba (RPA) has been ranked as one of the top 6 herbs used frequently to prevent and treat miscarriages clinically, there is no clear evidence regarding its safety in embryonic development. This study aims to evaluate the potential impacts of RPA on embryonic stem cells (ESCs) and pregnant mice. Cytotoxicity assays of the extract were performed in ESCs and 3T3 cells. Pregnant ICR mice were orally treated with RPA extracts at dosages of 0 (G1 group as negative controls), 2, 8 and 32 g/kg/day (G2, G3 and G4 groups) respectively from the gestation day (Gd) 6-15. On Gd 18, there was no significant difference in the IC50 values between ESCs and 3T3 cells (p > 0.05). There was no significant difference in the maternal and fetal evaluations among four groups (p > 0.05). Fetal IL-2, IL-2r, TNF-α, TNF-αr, IL-4, IL-4r, IL-10r, IL-17 and IL-17r of G4 group were significantly lower than G1 group (p < 0.05). In conclusion, RPA at dosage of 32 g/kg/day (16-folds of human daily dosage) did not cause adverse impact in cultured ESCs and pregnant mice. RPA might down-regulate fetal Th1/Th2/Th17 cytokines and receptors maybe beneficial to embryonic survival and development. Copyright © 2017 John Wiley & Sons, Ltd.


Mapping cell cortex rheology to tissue rheology and vice versa.
The mechanics of biological tissues mainly proceeds from the cell cortex rheology. A direct, explicit link between cortex rheology and tissue rheology remains lacking, yet would be instrumental in understanding how modulations of cortical mechanics may impact tissue mechanical behavior. Using an ordered geometry built on 3D hexagonal, incompressible cells, we build a mapping relating the cortical rheology to the monolayer tissue rheology. Our approach shows that the tissue low-frequency elastic modulus is proportional to the rest tension of the cortex, as expected from the physics of liquid foams as well as of tensegrity structures. A fractional visco-contractile cortex rheology is predicted to yield a high-frequency fractional visco-elastic monolayer rheology, where such a fractional behavior has been recently observed experimentally at each scale separately. In particular cases, the mapping may be inverted, allowing to derive from a given tissue rheology the underlying cortex rheology. Interestingly, applying the same approach to a 2D hexagonal tiling fails, which suggests that the 2D character of planar cell cortex-based models may be unsuitable to account for realistic monolayer rheologies. We provide quantitative predictions, amenable to experimental tests through standard perturbation assays of cortex constituents, and hope to foster new, challenging mechanical experiments on cell monolayers.


Alternative reconstruction of donor defect of free radial forearm flap in head and neck cancer.
We report our method of restoration of the radial artery in the use of the anterolateral thigh (ALT) flap to overcome the important drawback of sacrificing the radial artery in cases of free radial forearm flap (FRFF), which is indicated for reconstruction of the tongue and other intraoral defects. There were 12 patients in our series, but only seven completed their postoperative evaluations. We harvested FRFF and ALT flaps simultaneously. The former was used for palatal or lip reconstruction and the latter was anastomosed as a flow-through flap to salvage the radial artery. All major donor site problems of the FRFF were solved by coverage by the ALT flap, except for abnormal sensation on the radial side of the donor hand. The FRFF is a proper choice for small tongue or lip defects. When it is chosen for its unique merits, the ALT flap can also serve as an alternative in reconstructing the donor site with least morbidity, including the restoration of patency to the radial artery.


Interleukin 17A rs2275913 polymorphism is associated with susceptibility to systemic lupus erythematosus: A meta and trial sequential analysis.
The role of cytokines in the development of systemic lupus erythematosus (SLE) has received much attention. Interleukin-17 A upregulates several inflammation-related genes and is thought to have a crucial role in SLE development. The susceptibility to SLE development has been linked to functional genetic variations of the IL-17A gene; nevertheless, the findings have been conflicting. We conducted a meta-analysis that included previously published reports to establish a definitive conclusion on the role of the IL-17A rs2275913 polymorphism in SLE propensity. The PubMed, Google Scholar, and Scopus databases were used to find eligible published articles. All analyses were conducted using Comprehensive Meta-analysis V3.1. Funnel plots and Egger's regression analysis were used to assess publication bias. Q statistics and I2 test explored the heterogeneity among the included studies. Combined odds ratio, 95% confidence interval were calculated for each comparison model. Based on the inclusion and exclusion criteria, a total of four reports, comprising of 608 SLE patients and 815 healthy controls, were considered for the present meta-analysis. The homozygous comparison (AA vs. GG: combined odds ratio= 2.046, p = 0.005) and recessive genetic model (AA vs. GG+GA: combined odds ratio=1.901, p = 0.010) analysis revealed a significant association of rs2275913 with susceptibility to the development of SLE. However, other genetic comparisons (A vs. G, GA vs. GG, AA+GA vs. GG) failed to demonstrate such association. Furthermore, trial sequential analysis revealed a sufficient number of studies, including enough cases and controls that have already been considered to conclude the role of IL17-A rs2275913 polymorphism in SLE. IL-17A rs2275913 polymorphism is associated with susceptibility to SLE development.


Gliquidone.
The title compound {systematic name: N-cyclo-hexyl-carba-moyl-4-[2-(7-meth-oxy-4,4-dimethyl-1,3-dioxo-1,2,3,4-tetra-hydro-isoquinolin-2-yl)eth-yl]benzene-sulfonamide}, C(27)H(33)N(3)O(6)S, displays an intra-molecular N-H⋯O=S inter-action, as well as inter-molecular N-H⋯O=C hydrogen bonds. The latter inter-actions lead to the formation of hydrogen-bonded chains parallel to the c axis. The conformation of the sulfonyl-urea fragment is in agreement with a recent theoretical study [Kasetti et al. (2010 ▶). J. Phys. Chem. B, 114, 11603-11610].


PRISMA: Program of Research to Integrate the Services for the Maintenance of Autonomy. A system-level integration model in Quebec.
The Program of Research to Integrate the Services for the Maintenance of Autonomy (PRISMA) began in Quebec in 1999. Evaluation results indicated that the PRISMA Project improved the system of care for the frail elderly at no additional cost. In 2001, the Quebec Ministry of Health and Social Services made implementing the six features of the PRISMA approach a province-wide goal in the programme now known as RSIPA (French acronym). Extensive Province-wide progress has been made since then, but ongoing challenges include reducing unmet need for case management and home care services, creating incentives for increased physician participation in care planning and improving the computerized client chart, among others. PRISMA is the only evaluated international model of a coordination approach to integration and one of the few, if not the only, integration model to have been adopted at the system level by policy-makers.


[Acid secretion inhibition with new mechanisms of action: substituted benzimidazole].
Omeprazole and other substituted benzimidazoles produce a marked inhibition of gastric acid secretion with a long duration of action. Any kind of stimulated acid secretion is inhibited by the substituted benzimidazoles. The inhibitory mechanism of action is very selective. The substituted benzimidazoles inhibit the parietal cell H+, K+-ATPase, an enzyme which is the proton pump in the secretory membrane of the parietal cell. An oral daily dose of 15 mg omeprazole in humans produced about 80% acid inhibition just after dosage and about 40% 24 hours later. Preliminary results in duodenal ulcer patients show that a daily dose of 20-60 mg omeprazole produces fast ulcer healing in almost all patients.


Aggressive and malignant pituitary tumours: state-of-the-art
Pituitary adenomas are unique in multiple ways. They are rarely malignant in terms of metastases; yet, they may be aggressive. Their cancerous potential is defined in a classic oncological way by the ability to metastasise, and therefore, it has been crucial to differentiate this process from aggressive behaviour, characterised as a particularly invasive and/or recurrent behaviour and resistance to common modalities of therapy. Recently, however, important changes have been introduced to the diagnosis and management of aggressive and malignant pituitary tumours including the 4th edition of the World Health Organization (WHO) classification for endocrine tumours (2017) as well as ESE Clinical Guidelines (2018), although an attempt to establish predictive and/or prognostic markers of clinical aggressiveness remains difficult. In this review, we focus on a group of pituitary tumours causing significant problems in clinical practice and requiring multidisciplinary input. We summarise updates in definitions of tumour invasiveness, aggressiveness and malignant transformation, as well as histological classification, and emphasise the new considerations regarding aggressive and malignant potential and its relationship to therapeutic strategies.


Clinical Usefulness of PRECISE-DAPT Score for Predicting Bleeding Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: An Analysis From the SMART-DATE Randomized Trial.
Although the current guidelines endorse the PRECISE-DAPT score (Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy) to inform clinical decisions regarding duration of DAPT in patients undergoing percutaneous coronary intervention, use of the PRECISE-DAPT score to guide duration of DAPT has not been properly validated by randomized trials focused on the population with acute coronary syndrome. This study aimed to evaluate the usefulness of the PRECISE-DAPT score for predicting future bleeding and ischemic events and to compare clinical outcomes of short-term and long-term DAPT duration according to the PRECISE-DAPT score in patients with acute coronary syndrome. This was a substudy of the SMART-DATE trial (6- Versus 12-Month or Longer Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome), in which patients with acute coronary syndrome undergoing percutaneous coronary intervention were randomly assigned to either 6- (n=1357) or 12-month or longer DAPT (n=1355). Major bleeding (Bleeding Academic Research Consortium type 3-5) and ischemic (myocardial infarction, stent thrombosis, or ischemic stroke) events at 18 months after the index procedure were compared between the 6- and 12-month or longer DAPT groups, according to PRECISE-DAPT score. The PRECISE-DAPT score was moderately effective at predicting bleeding events (area under the curve, 0.754 [95% CI, 0.655-0.854]; P<0.001). In patients with nonhigh PRECISE-DAPT score (<25, n=1967 [72.5%]), 6-month DAPT was associated with higher ischemic risk (2.7% versus 1.3%; HR, 2.01 [95% CI, 1.03-3.91]; P=0.040; absolute risk difference, +1.3%; P=0.035) with similar bleeding risk (0.4% versus 0.3%; HR, 2.00 [95% CI, 0.37-10.94]; P=0.422; absolute risk difference, +0.2%; P=0.498), compared with 12-month or longer DAPT. Among patients with high PRECISE-DAPT score (≥25, n=745 [27.5%]), 6-month DAPT presented a similar ischemic risk (4.8% versus 3.4%; HR, 1.43 [95% CI, 0.68-2.98], P=0.348; absolute risk difference, +1.5%; P=0.327) but significantly reduced major bleeding risk (0.6% versus 2.3%; HR, 0.25 [95% CI, 0.05-1.17]; P=0.079; absolute risk difference, -1.7%; P=0.045). Consistent with current guidelines, determination of the duration of DAPT according to PRECISE-DAPT score could improve the clinical outcomes in patients with acute coronary syndrome after percutaneous coronary intervention with current-generation drug-eluting stents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01701453.


Beneficial effects of ursodeoxycholic acid via inhibition of airway remodelling, apoptosis of airway epithelial cells, and Th2 immune response in murine model of chronic asthma.
In previous studies, anti-inflammatory, anti-apoptotic and immunomodulatory effects of ursodeoxycholic acid (UDCA) on liver diseases have been shown. In this study, we aimed to investigate the effects of UDCA on airway remodelling, epithelial apoptosis, and T Helper (Th)-2 derived cytokine levels in a murine model of chronic asthma. Twenty-seven BALB/c mice were divided into five groups; PBS-Control, OVA-Placebo, OVA-50mg/kg UDCA, OVA-150mg/kg UDCA, OVA-Dexamethasone. Mice in groups OVA-50mg/kg UDCA, OVA-150mg/kg UDCA, OVA-Dexamethasone received the UDCA (50mg/kg), UDCA (150mg/kg), and dexamethasone, respectively. Epithelium thickness, sub-epithelial smooth muscle thickness, number of mast and goblet cells of samples isolated from the lung were measured. Immunohistochemical scorings of the lung tissue for matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEG-F), transforming growth factor-beta (TGF-β), terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) and cysteine-dependent aspartate-specific proteases (caspase)-3 were determined. IL-4, IL-5, IL-13, Nitric oxide, ovalbumin-specific immunoglobulin (Ig) E levels were quantified. The dose of 150mg/kg UDCA treatment led to lower epithelial thickness, sub-epithelial smooth muscle thickness, goblet and mast cell numbers compared to placebo. Except for MMP-9 and TUNEL all immunohistochemical scores were similar in both UDCA treated groups and the placebo. All cytokine levels were significantly lower in group IV compared to the placebo. These findings suggested that the dose of 150mg/kg UDCA improved all histopathological changes of airway remodelling and its beneficial effects might be related to modulating Th-2 derived cytokines and the inhibition of apoptosis of airway epithelial cells.


Cyst formation and faecal-oral transmission of Dientamoeba fragilis--the missing link in the life cycle of an emerging pathogen.
Dientamoeba fragilis is a protozoan parasite emerging as a cause of diarrhoea and "irritable-bowel-like" gastrointestinal disease in humans with a propensity for establishing long-term, chronic infections in humans. Although Dientamoeba was discovered over a century ago its life cycle and mode of transmission is not known. No cyst stage has been described and no animal models are presently available for the study of this parasite. Here we describe the establishment of an animal model using laboratory rodents, the fulfilling of Koch's postulates, and the discovery of a new cyst stage in the life cycle of D. fragilis. Our demonstration of long-term parasite carriage by rodents and prolonged shedding of cysts, together with elevated levels of calprotectin in the stool, confirms the capacity of this organism to cause disease and indicates dientamoebiasis should be considered in the differential diagnosis of gastrointestinal diseases such as Inflammatory Bowel Syndrome (IBS). Finally, we suggest that the cyst stage described here is the vehicle that mediates faecal-oral transmission of D. fragilis between hosts.


Diverticulum of the midthoracic esophagus: pathogenesis and surgical treatment.
Midthoracic esophageal diverticula represent 15% of all esophageal diverticula. Gastrointestinal endoscopy, barium swallow, esophageal manometry (indispensable for detecting any motor alterations often at the root of the pathogenesis of the diverticulum and for selecting the best surgical option), and 24-h pHmetry are the correct examinations to perform. Simple diverticulectomy performed via thoracoscopy can be sufficient for small diverticula without associated motor alterations. In other cases, it is best to combine diverticulectomy with a longitudinal extramucous myotomy extending at least 3 or 4 cm above and below the neck of the diverticulum or to the entire esophageal body for diffuse esophageal spasm. We report the case of a 67-year-old male patient with a sacciform diverticulum at the mid-third on the anterior wall of the thoracic esophagus. Manometric examination showed peristaltic waves with an amplitude and duration that were above normal at the inferior third of the esophagus. Lower esophageal sphincter (LES) and upper esophageal sphincter (UES) were essentially normal. The diagnosis was pulsion-type midthoracic esophageal diverticulum. We performed a diverticulectomy with endoGIA via right thoracoscopy and extramucous myotomy extended from the upper margin of the diverticulum to the esophageal inlet in the hiatus, corresponding to the area showing motor alteration. After 3 months, the patient reported complete remission of symptoms and had gained 4 kg. Radiography of the digestive tube showed a normal transit at the distal esophagus. Manometric follow-up revealed the presence of peristaltic waves with a normal amplitude and duration along the entire esophagus.


Expression and characterization of the fourth repeat of Xenopus interphotoreceptor retinoid-binding protein in E. coli.
Interphotoreceptor retinoid-binding protein (IRBP) is an extracellular glycolipoprotein which in higher vertebrates has a 4-repeat structure and carries endogenous vitamin A and fatty acids. The location of IRBP's 1-2 binding sites for retinol is unknown. To begin to understand which repeat(s) are responsible for ligand-binding, we expressed the fourth repeat of Xenopus IRBP in E. coli to determine if it could by itself bind all-trans retinol. Our expression studies used a polyhistidine fusion domain to purify the recombinant protein directly from inclusion bodies. The fusion protein could be renatured without aggregation if refolded at a sufficiently dilute concentration (< 3 microM). The recombinant fourth repeat of Xenopus IRBP binds [3H]all-trans retinol and the fluorescence of this ligand increases 8-fold upon binding. The binding is saturable with a Kd = 0.4 microM. The expression of recombinant IRBP fragments as fusion proteins in prokaryotes will be useful for defining the structural requirements for ligand binding by this interesting protein.


Vacuum sealing drainage in the treatment of migrated polyacrylamide hydrogel after breast augmentation: a case report.
Polyacrylamide hydrogel (PAAG) injection for breast augmentation can result in a variety of complications, including implant migration. The migrated PAAG can become colonized by pathogens, resulting in secondary infections which can be extremely difficult to treat. We report the case of a 43-year-old female patient who underwent PAAG injection for breast augmentation. Implant migration was diagnosed 8 years after the initial injection. Here, we report the first use of vacuum sealing drainage as a convenient and effective alternative to manage the complications of extensive PAAG migration after breast augmentation.


Developing empathy in nursing students: a cohort longitudinal study.
To determine whether a specific training course will enhance empathic skills in student nurses during a 3-year degree course. The study considers levels of empathy in student nurses and assesses whether these can be increased. Empathy is accepted as a critical component of supportive relationships. Many scholars have argued that empathy provides health professionals with the capacity to improve the health of patients, so it should ideally be taught to make health professionals more responsive to patient needs. Cohort longitudinal study. Data were collected using the Italian version of the Balanced Emotional Empathy Scale (BEES). The study was designed to guarantee repeated measurements of levels of emotional empathy in the pre- and postintervention phases. This allowed us to evaluate the development and improvement of empathy and to measure the effects of extra training on the students' empathy skills. Two groups took part in the study: the Intervention and the Control Groups. Students in the Intervention Group attended additional seminars and laboratories in small groups with tutors to learn and develop communicative and empathic abilities. One hundred and three participants (76% women) completed the study. Data showed that the training course was effective, especially for women: BEES scores 31.60 at pre-intervention phase and 42.91 at the end of the academic course. Results regarding men were less clear, and the study discusses these unexpected, anomalous findings. According to literature, men and women have different empathic traits, and we found that they show disparate empathic tendencies. More women than men took advantage of the training course. In any case, our data show that specific training courses are effective. As our study shows, empathy is a skill that may be taught. So it would be advisable to introduce these into the traditional nursing curriculum.


[Spontaneous rupture of giant subcapsular hemangioma of the liver with hemoperitoneum and hemorrhagic shock: a case report].
Cavernous hemangioma is the most common benign tumour of the liver and is found quite commonly during abdominal ultrasonography performed for other diseases. It is often asymptomatic and undergoes enlargement in fewer than 10% of cases. Spontaneous rupture of a giant hepatic hemangioma (diameter > 4 cm) with hemoperitoneum occurs very rarely. Only 32 cases have been reported in a recent review of the medical literature, with an operative mortality of more than 35%. We describe a new case of a giant subcapsular hemangioma localised in hepatic segments II and III in an 84-year-old woman, which ruptured spontaneously into the abdominal cavity and presented with hemoperitoneum and hypovolaemic shock. The hemangioma was diagnosed preoperatively by spiral CAT and treated successfully with emergency hepatic bisegmentectomy.


HIF-1α regulated tongue squamous cell carcinoma cell growth via regulating VEGF expression in a xenograft model.
We aimed to study the mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) regulating the cell proliferation of tongue squamous cell carcinoma (TSCC) via vascular endothelial growth factor (VEGF). We used RNA interference (RNAi) technique, transfected chemically synthesized siRNA against HIF-1α into CAL-27 cells, and detected the expression of HIF-1α and VEGF by real time-PCR and Western blotting in order to find out if HIF-1α regulated the expression of VEGF. A xenograft experiment was carried out to observe the role of HIF-1α on the tumor growth of tongue squamous cell carcinoma. HIF-1α and VEGF mRNA expression was significantly downregulated 36 and 48 h after transfection (P<0.05); the protein expression of HIF-1α and VEGF was also significantly suppressed by siRNA against HIF-1α. Furthermore, intratumoraly injection of HIF-1α targeting siRNA suppressed tumor growth in nude mice. HIF-1α regulated VEGF expression, and they may contribute to TSCC cell tumor growth.


A Randomized Phase 4 Study of Immunogenicity and Safety After Monovalent Oral Type 2 Sabin Poliovirus Vaccine Challenge in Children Vaccinated with Inactivated Poliovirus Vaccine in Lithuania.
Understanding immunogenicity and safety of monovalent type 2 oral poliovirus vaccine (mOPV2) in inactivated poliovirus vaccine (IPV)-immunized children is of major importance in informing global policy to control circulating vaccine-derived poliovirus outbreaks. In this open-label, phase 4 study (NCT02582255) in 100 IPV-vaccinated Lithuanian 1-5-year-olds, we measured humoral and intestinal type 2 polio neutralizing antibodies before and 28 days after 1 or 2 mOPV2 doses given 28 days apart and measured stool viral shedding after each dose. Parents recorded solicited adverse events (AEs) for 7 days after each dose and unsolicited AEs for 6 weeks after vaccination. After 1 mOPV2 challenge, the type 2 seroprotection rate increased from 98% to 100%. Approximately 28 days after mOPV2 challenge 34 of 68 children (50%; 95% confidence interval, 38%-62%) were shedding virus; 9 of 37 (24%; 12%-41%) were shedding 28 days after a second challenge. Before challenge, type 2 intestinal immunity was undetectable in IPV-primed children, but 28 of 87 (32%) had intestinal neutralizing titers ≥32 after 1 mOPV2 dose. No vaccine-related serious or severe AEs were reported. High viral excretion after mOPV2 among exclusively IPV-vaccinated children was substantially lower after a subsequent dose, indicating induction of intestinal immunity against type 2 poliovirus.


Pro-osteoclastic in vitro effect of Polyethylene-like nanoparticles: Involvement in the pathogenesis of implant aseptic loosening.
Polyethylene micro-sized wear particles released from orthopedic implants promote inflammation and osteolysis; however, less is known about the bioactivity of polyethylene nanosized wear particles released from the last generation of polymer-bearing surfaces. We aim to assess the internalization of fluorescent polyethylene-like nanoparticles by both human macrophages and osteoclasts and also, to determine their effects in osteoclastogenesis in vitro. Human macrophages and osteoclasts were incubated with several ratios of fluorescent polyethylene-like nanoparticles between 1 and 72 h, and 4 h, 2, 4, 6, and 9 days, respectively. The internalization of nanoparticles was quantified by flow cytometry and followed by both confocal and video time-lapse microscopy. Osteoclast differentiation and activity was semiquantified by tartrate-resistant acid phosphatase (TRAP) staining, TRAP mRNA relative expression, and pit resorption assay, respectively. Macrophages, osteoclast precursors and mature osteoclasts internalized nanoparticles in a dose- and time-dependent manner and maintained their resorptive activity. In addition, nanoparticles significantly increased the osteoclastogenesis as shown by upregulation of the TRAP expressing cell number. We conclude that polyethylene-like nanosized wear particles promote osteoclast differentiation without alteration of bone resorptive activity of mature osteoclasts and they could be considered as important actors in periprosthetic osteolysis of the last new generation of polymer-bearing surfaces. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2649-2657, 2016.


Missing data in substance abuse research? Researchers' reporting practices of sexual orientation and gender identity.
Lesbian, gay, bisexual, and transgender individuals are at higher risk for substance use and substance use disorders than heterosexual individuals and are more likely to seek substance use treatment, yet sexual orientation and gender identity are frequently not reported in the research literature. The purpose of this study was to identify if sexual orientation and gender identity are being reported in the recent substance use literature, and if this has changed over time. The PsycINFO and PubMed databases were searched for articles released in 2007 and 2012 using the term "substance abuse" and 200 articles were randomly selected from each time period and database. Articles were coded for the presence or absence of sexual orientation and gender identity information. Participants' sexual orientation was reported in 3.0% and 4.9% of the 2007 and 2.3% and 6.5% of the 2012 sample, in PsycINFO and PubMed sample articles, respectively, while non-binary gender identity was reported in 0% and 1.0% of the 2007 sample and 2.3% and 1.9% of the 2012 PsycINFO and PubMed sample articles. There were no differences in rates of reporting over time. Sexual orientation and gender identity are rarely reported in the substance abuse literature, and there has not been a change in reporting practices between 2007 and 2012. Recommendations for future investigators in reporting sexual orientation and gender identity are included.


Bathing effects of east saline groundwater concentrates on allergic (atopic) dermatitis-like skin lesions induced by 2,4-dinitrochlorobenzene in hairless mice.
In the present study, it was evaluated whether east saline groundwater concentration solution (ESGWc) exerted a favorable inhibitory effect on 2,4-dinitrochlorobenzene (DNCB)-induced allergic/atopic-like dermatitis (AD). AD was induced and boosted by sensitization with DNCB via topical application on the dorsal back skins. Mice with DNCB-induced AD were bathed in 100-, 200- and 400-fold diluted ESGWc. After 6 weeks bathing, changes to body weight, clinical skin severity scores, scratching behavior, serum total immunoglobulin (Ig)E levels, submandibular lymph node and spleen weights, splenic cytokine levels, skin cytokine mRNA expressions, antioxidant defense systems and superoxide anion productions were recorded to determine the effects of bathing on the histopathology of dorsal back skin tissues. All DNCB-induced mice demonstrated that the induction of AD through IgE-mediated hypersensitivities, oxidative stresses, activation of MMP and apoptosis of keratinocytes resulted in no significant differences in body weight between the different groups at each time point following initial sensitization. However, markers of DNCB-induced AD were significantly inhibited (P<0.05) in a concentration-dependent manner following bathing in all concentrations of ESGWc. The results obtained in the present study suggest that bathing in ESGWc may have favorable protective effects against DNCB-induced AD due to favorable systemic and local immunomodulatory effects, active cytoprotective anti-apoptotic effects, inhibitory effects of matrix metalloproteinase activity, and anti-inflammatory and antioxidative effects.


A simple, two-step, site-specific preparation of fluorinated naphthalene and phenanthrene derivatives from fluorobromo-substituted alkenes.
A facile two-step procedure for the site-specific preparation of fluorinated naphthalene and phenanthrene derivatives is described. The Sonogashira reaction of bromofluoro-substituted alkenes with terminal alkynes, followed by base-catalyzed cyclization in refluxing N-methyl-2-pyrrolidinone (NMP), affords the corresponding fluorinated naphthalene and phenanthrene derivatives in good yields.


Prognostic significance of POLE proofreading mutations in endometrial cancer.
Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.


Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats, dogs and monkeys.
1. This study examined the pharmacokinetics, distribution, metabolism and excretion of the selective prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-33679). The compounds were investigated following oral and/or intravenous administration to intact rats, dogs and monkeys, and bile-duct-cannulated rats and dogs. 2. After oral administration of [14C]selexipag, selexipag was well absorbed in rats and dogs with total recoveries of over 90% of the dose, mainly in the faeces. Biliary excretion was the major elimination pathway for [14C]MRE-269 as well as [14C]selexipag, while renal elimination was of little importance. [14C]Selexipag-related radioactivity was secreted into the milk in lactating rats. 3. Plasma was analysed for total radioactivity, selexipag and MRE-269 in rats and monkeys. Selexipag was negligible in rat plasma due to extensive metabolism, and MRE-269 was present in rat and monkey plasma. A species difference was clearly evident when selexipag was incubated in rat, dog and monkey plasma. 4. Total radioactivity was rapidly distributed to tissues. The highest concentrations were found in the bile duct and liver without significant accumulation or persistence, while there was limited melanin-associated binding, penetration of the blood-brain barrier and placental transfer of drug-related materials.


Transport of fatty acid is obligatory coupled with H+ entry in spheroplasts of Escherichia coli K12.
Transport of palmitate by spheroplasts of Escherichia coli K12 was studied. [14C]Palmitate was accumulated in spheroplasts approximately 1700-fold over the extracellular concentration of unbound [14C]palmitate. Uptake of [14C]palmitate was inhibited to 13% by addition of H+ uncoupler carbonyl cyanide-m-chlorophenylhydrazone (CCCP). Spheroplasts exhibited the uptake of 9-aminoacridine depending on the addition of palmitate to the incubation mixture. The rate of [14C]palmitate uptake by the spheroplasts pre-equilibrated in a buffer at pH 7.5 or 8.0 significantly increased in comparison with the spheroplasts pre-equilibrated in a buffer at pH 7.0 when the spheroplasts were incubated at an external pH of 7.0.


[Involvement of AKT/eNOS in brain derived neurotrophic factor-induced angiogenesis].
To investigate the signaling pathways involved in brain derived neurotrophic factor (BDNF) -induced angiogenesis and to provide a novel pathway to anti-angiogenesis in multiple myeloma. The phosphorylation of AKT and endothelial NO synthase (eNOS) in human umbilical venous epithelial cells (HUVEC) were detected by Western blot. The angiogenic activity in vitro was evaluated by transwell migration assay and tube formation assay. BDNF-induced in vivo angiogenic activity was evaluated by Matrigel plug assay. The concentration of NO was detected by nitric acid deoxidizase assay. Cell apoptosis was detected by FITC-Annexin V/PI double staining and flow cytometry. BDNF activated the phosphatidylinositol-3-kinase (PI3K)/AKT/eNOS pathway in HUVEC in a time- and dose-dependent manner. BDNF-stimulated NO production was blocked by LY294002, a PI3K inhibitor. In vitro, BDNF induced HUVEC migration and tube formation on Matrigel, which could be significantly blocked by LY294002 and N(G)-nitro-L-arginine methyl ester (L-NAME) respectively; but BDNF induced HUVEC apoptosis could be blocked only by LY294002. In vivo, BDNF increased capillary ingrowth into subcutaneously implanted Matrigel plugs in mice, which could be significantly reduced in L-NAME treated mice. BDNF induces angiogenesis through the AKT/eNOS signaling kinase pathway. It may be a novel target for the anti-angiogenesis therapy for multiple myeloma.


Postoperative chemotherapy with S-1 plus oxaliplatin versus S-1 alone in locally advanced gastric cancer (RESCUE-GC study): a protocol for a phase III randomized controlled trial.
The ACTS-GC study had shown postoperative adjuvant therapy with S-1 improved survival of patients with locally advanced gastric cancer. Addition of oxaliplatin to S-1 is considered to be acceptable as one of the treatment options for gastric cancer patients after radical gastrectomy with D2 lymph node excision. We have commenced a randomized phase III trial in December 2016 to evaluate S-1 plus oxaliplatin compared with S-1 alone in the adjuvant setting for locally advanced gastric cancer. A total of 564 patients will be accrued from 13 Chinese institutions in two years. The primary endpoint is 3-year relapse-free survival. The secondary endpoints are 5-year overall survival, proportion of patients who complete the postoperative chemotherapy and incidence of adverse events. The trial has been approved by the institutional review board of each participating institution and it was activated on December, 2016. The enrollment will be finished in December, 2018. Patient's follow-up will be ended until December, 2023. ClinicalTrials.gov, identifier: NCT02867839. Registered on August 4, 2016.


Material girls and Material love: Consuming femininity and the contradictions of post-girl power among Kenyan schoolgirls.
In this paper, I use qualitative data to explore the practices engaged in by Kenyan schoolgirls to participate in modern consuming womanhood, as well as the contradictory implications of these practices for thinking about globalized mediated femininities and their enactment in resource-poor settings. The paper examines the centrality of consumption to valued modern femininity among young women around the world, as well as the structural reality of gendered access to income. I show how the cooptation of the materiality of romantic love and normative expectations of male provision in romantic relationships bridge the gap between consumption desires and economic realities among Kenyan schoolgirls in both powerful and problematic ways. The paper ends with a reflection of the implications of these findings for post-girl power, the post-feminist age and the re-inscription of patriarchy.


Do motivation deficits in schizophrenia-spectrum disorders promote cannabis use? An investigation of behavioural response to natural rewards and drug cues.
Deficits in incentive motivation are often present in both Schizophrenia Spectrum Disorders (SSD) and substance-use disorders. The current study aims to test whether the presence of such deficits confers vulnerability to cannabis use in individuals with SSD. SSD patients (n=35) and healthy controls (n=35) were each divided into a group with (n=20) and a group without (n=15) current cannabis use disorder. Subjects performed a behavioural task designed for schizophrenia patients in which they could seek exposure to pleasant and cannabis visual stimuli on the basis of internal representations of these stimuli. Intensity of cannabis use was assessed by self-report. SSD patients were significantly less likely than controls to exert effort to try to re-view pleasant stimuli but were not significantly less likely to work to avoid unpleasant stimuli. Lack of response to re-view pleasant stimuli significantly predicted higher subsequent cannabis self-administration in patients but not controls, after controlling for degree of prior exposure to cannabis. Deficits in incentive motivation may be an aspect of SSD which promotes cannabis use in this population.


[Pneumothorax in pregnancy. A review of 16 cases including one of the authors'].
Pneumothorax in pregnancy raises several problems especially of therapy. In the present study we report a case observed in our Institution and literature data on 15 further cases. Pneumothorax occurred in 9 cases in the course of pregnancy, in 6 cases during delivery and in 1 case in the post-partum period. Immediate treatment was insertion of pleural drain in 13 patients and bed rest in 3 patients. Surgery was required in 8 cases and was performed after delivery in 5 cases and during pregnancy in 3 cases, 6 thoracotomies, 1 bilateral thoracotomy and 1 sternotomy for bilateral pneumothorax were carried out. Actually a videothoracoscopic treatment, requiring general anaesthesia, is also possible. In all observed cases pneumothorax didn't represent a serious risk for both mother and foetus, for the timely therapeutic measures. Pneumothorax represents an uncommon pathology, usually underestimated in literature, that must be taken into account whenever during pregnancy or the post-partum period a progressive respiratory failure arises.


The association between serum chloride levels and chronic kidney disease progression: a cohort study.
Limited data suggest serum chloride levels associate with mortality in heart failure, chronic kidney disease (CKD), and pulmonary arterial hypertension. Randomized trials have also shown that administration of crystalloid intravenous fluids with lower chloride concentration may have better renal outcomes. However, chloride has not been studied longitudinally for CKD progression. We used a prospective cohort of subjects with stage 3 and 4 CKD recruited from a nephrology clinic at a single medical center. Linear regression, linear regression with generalized estimating equations, and Cox proportional hazards models were created for outcomes of overall change in estimated glomerular filtration rate (eGFR), longitudinal changes in eGFR, and time to > 30% decline in eGFR, respectively. Baseline chloride was modeled continuously and categorically, and models were adjusted for potential confounders. Median follow-up was 1.7 years. Baseline median age was 72 years and median eGFR was 35.7 mL/min/1.73m2. In multivariable analysis, higher serum chloride associated with worsened eGFR decline. Every 1 mEq/L increase in chloride associated with an overall eGFR decline of 0.32 mL/min/1.73m2 (p = 0.003), while the difference in eGFR decline in the highest quartile of chloride was 3.4 mL/min/1.73m2 compared to the lowest quartile (p = 0.004). No association between serum chloride and time to 30% decline in eGFR was observed in multivariable analysis (hazard ratio 1.05 per 1 mEq/L increase in serum chloride, p = 0.103). In CKD patients, higher serum chloride associated with a modestly steeper rate of eGFR decline, and may be a useful biomarker to predict CKD progression. Further studies are needed to determine causality.


Liquid chromatography/time-of-flight mass spectrometry analysis of postmortem blood samples for targeted toxicological screening.
A liquid chromatography/time-of-flight mass spectrometry (LC-TOF-MS) method for targeted toxicological screening in human postmortem blood samples from forensic autopsy cases has been developed, validated and compared with a previously used method using gas chromatography with nitrogen-phosphorus detection (GC-NPD). Separation was achieved within 12 min by high-resolution gradient chromatography. Ions were generated in positive and negative electrospray ionization mode and were detected in 2-GHz single mass spectrometry mode, m/z range 50-1,000. Before injection, 0.25 g blood was prepared by protein precipitation with 500 μL of a mixture of acetonitrile and ethanol containing deuterated internal standards. An in-house database comprising 240 drugs and metabolites was built by analysing solutions from certified standards or other documented reference material available. Identification was based on scoring of retention time, accurate mass measurement and isotopic pattern. Validation was performed on spiked blood samples and authentic postmortem blood samples. The thresholds defined as minimum required performance levels were for most compounds in the range from 0.01 to 0.10 μg/g. Typically, a mass error of less than 2 ppm and a precision of area measurements of less than 5 % coefficient of variation were achieved. Positive identification was confirmed at concentrations up to 500 μg/g. Most compounds were determined in positive ionization mode, but for a limited number of compounds (fewer than 4 %) negative ionization was needed and a few early-eluted compounds could not be identified owing to substantial influence of interferences from the matrix and were thus not included in the screening. A robust and valid toxicological screening by LC-TOF-MS for postmortem blood samples, covering 50 % more compounds, and with higher precision and sensitivity than the previously used screening by GC-NPD was achieved.


Prudential Use of the Morally Controversial COVID-19 Vaccines.
In recent months, there has been a lot of debate surrounding the use of those COVID-19 vaccines that have been either tested or manufactured with cell lines that were isolated from the remains of an aborted fetal child. Most faithful and orthodox Catholic moral theologians, among whom I count myself, have concluded that their use is not intrinsically evil. Therefore, like every other decision that falls into the category of actions that are not intrinsically evil, the decision to be vaccinated with these morally controversial vaccines has to be governed by the virtue of prudence. It is a decision that calls for a wisdom that properly sees this action within the constellation of actions that propels the human agent to the heights of holiness. This is why prayer is so essential for authentic moral judgment. With prayer, we ask the Holy Spirit who is the all-prudent one to guide our actions so that we can choose and act well not only for our only well-being but for the well-being of all. Acts that are not themselves intrinsically evil are deemed virtuous or not within the narrative of the individual person's life.