Differentiation of Rat Mesenchymal Stem Cells toward Osteogenic Lineage on Extracellular Matrix Protein Gradients.
This report addresses the issue of optimizing extracellular matrix protein density required to support osteogenic lineage differentiation of mesenchymal stem cells (MSCs) by culturing MSCs on surface-bound density gradients of immobilized collagen type I (COL1) and osteopontin (OPN). A chemical surface gradient is prepared by tailoring the surface chemical composition from high hydroxyl groups to aldehyde groups using a diffusion-controlled plasma polymerization technique. Osteogenesis on the gradient surface is determined by immunofluorescence staining against Runx2 as an early marker and by staining of calcium phosphate deposits as a late stage differentiation marker. The Runx2 intensity and calcified area increase with increasing COL1 density up to a critical value corresponding to 124.2 ng cm-2 , above which cell attachment and differentiation do not rise further, while this critical value for OPN is 19.0 ng cm-2 . This gradient approach may facilitate the screening of an optimal biomolecule surface density on tissue-engineered scaffolds, implants, or tissue culture ware to obtain the desired cell response, and may generate opportunities for more cost-effective regenerative medicine.


SIRT1 performs a balancing act on the tight-rope toward longevity.
Our recent study defined a new role for SIRT1 as a regulator of hepatic lipid metabolism. In the liver a major target of this sirtuin is the PPARalpha/PGC-1alpha signaling axis. Ablation of SIRT1 in the liver results in disrupted fatty acid oxidation, increased cellular stress, and elevations in proinflammatory cytokines. However, contrary to previous studies, we observed no changes in glucose production in the absence of SIRT1, despite impaired PGC-1alpha signaling. These findings point toward the involvement of other players in SIRT1-regulated hepatic metabolism. Here we discuss our findings, and comment on some of the controversy surrounding this protein in the current literature.


Impaired copper transport in schizophrenia results in a copper-deficient brain state: A new side to the dysbindin story.
Objectives: Several schizophrenia brain regions exhibit decreased dysbindin. Dysbindin modulates copper transport crucial for myelination, monoamine metabolism and cellular homeostasis. Schizophrenia patients (SZP) exhibit increased plasma copper, while copper-decreasing agents produce schizophrenia-like behavioural and pathological abnormalities. Therefore, we sought to determine dysbindin and copper transporter protein expression and copper content in SZP.Methods: We studied the copper-rich substantia nigra (SN) using Western blot and inductively-coupled plasma mass spectrometry. We characterised specific protein domains of copper transporters ATP7A, CTR1, ATP7B and dysbindin isoforms 1 A and 1B/C in SZP (n = 15) and matched controls (n = 11), and SN copper content in SZP (n = 14) and matched controls (n = 11). As a preliminary investigation, we compared medicated (ON; n = 11) versus unmedicated SZP (OFF; n = 4).Results: SZP exhibited increased C terminus, but not N terminus, ATP7A. SZP expressed less transmembrane CTR1 and dysbindin 1B/C than controls. ON exhibited increased C terminus ATP7A protein versus controls. OFF exhibited less N terminus ATP7A protein than controls and ON, suggesting medication-induced rescue of the ATP7A N terminus. SZP exhibited less SN copper content than controls.Conclusions: These results provide the first evidence of disrupted copper transport in schizophrenia SN that appears to result in a copper-deficient state. Furthermore, copper homeostasis may be modulated by specific dysbindin isoforms and antipsychotic treatment.


Molecular analysis of impaired urinary diluting capacity in glucocorticoid deficiency.
Urinary diluting ability and protein abundance of renal aquaporins (AQPs) and ion transporters in glucocorticoid-deficient (GD) rats were examined at baseline and in response to oral water loading. Rats underwent bilateral adrenalectomy followed by aldosterone (GD) or aldosterone + dexamethasone (CTL) replacement. Before oral water loading, urinary output was significantly decreased and urinary osmolality (U(osm)) was increased in GD compared with CTL rats. Protein abundance of inner medullary AQP2 (148 +/- 18%), phosphorylated AQP2 (pAQP2, 156 +/- 13%), and AQP3 (145 +/- 8%) was significantly upregulated in GD compared with CTL rats (all P < 0.05). GD rats also demonstrated a marked reduction in urinary Na(+) excretion compared with pair-fed CTL rats. Na(+)-K(+)-2Cl(-) cotransporter, Na(+)/H(+) exchanger type 3, and cortical beta- and gamma-subunits of the epithelial Na(+) channel were significantly upregulated in GD rats. At 1 h after an acute water load (40 ml/kg by oral gavage), GD rats demonstrated a decrease in percent water excretion (5 +/- 1 vs. 33 +/- 9%, P < 0.01) and urinary output (33 +/- 12 vs. 250 +/- 65 microl x kg(-1) x min(-1), P < 0.05) and an increase in U(osm) (1,894 +/- 292 vs. 316 +/- 92 mosmol/kgH(2)O, P < 0.001) compared with CTL rats. Plasma AVP was increased (1.6 +/- 0.2 vs. 0.9 +/- 0.2 pg/ml, P < 0.05), as was protein expression of inner medullary AQP2 (149 +/- 5%) and pAQP2 (177 +/- 9%, P < 0.01), in GD compared with CTL rats; apical expression of AQP2 was maintained in GD rats. The vasopressin V(2) receptor antagonist OPC-31260 increased percent water excretion and urinary output and reduced U(osm) compared with vehicle-treated GD rats. OPC-31260 also reversed the increased abundance and apical trafficking of inner medullary AQP2 and pAQP2 protein in GD rats. In conclusion, enhanced protein abundance of Na(+) transporters and Na(+) channels with Na(+) retention occurred with GD. OPC-31260 reversed upregulation and apical trafficking of AQP2 and pAQP2 in association with improved urinary diluting capacity and increased water excretion after oral water loading.


Inflammatory Bowel Disease: Role of Vagus Nerve Stimulation.
Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of refractory forms of epilepsy and depression. The brain-gut axis is increasingly being studied as a possible etiological factor of chronic inflammatory diseases, including inflammatory bowel diseases (IBD). A significant percentage of IBD patients lose response to treatments or experience side effects. In this perspective, VNS has shown the first efficacy data. The aim of this narrative review is to underline the biological plausibility of the use of VNS in patients affected by IBD, collect all clinical data in the literature, and hypothesize a target IBD population on which to focus the next clinical study.


[Pain syndrome correction after teeth whitening].
Was to develop an algorithm for the correction of pain syndrome using the drug Ketorol Express depending on the level of situational and personal anxiety of patients during office teeth whitening. The study involved 60 people (mean age 25±0.85 years), who were divided into three groups depending on the level of personal and situational anxiety according to the Spielberger scale modified by Yu. L. Khanin. In the first group of patients with a high level of anxiety Ketorol Express was prescribed as a preventive analgesia before the whitening procedure, then the drug was used in case of pain. In the second group, patients with an average level of anxiety the drug was prescribed immediately after the whitening procedure, and then used in the event of a pain syndrome. The third group of patients with a low level of anxiety took the drug only in case of pain. To assess the severity of pain, the general well-being by the patient and the general well-being by the doctor, visual analogue scales were used. The study showed that the occurrence and correction of pain syndrome during teeth whitening depends on the patient's psycho-emotional state (both personal and situational anxiety). The developed regimen for prescribing Ketorol Express can significantly reduce pain in patients with different levels of anxiety.


Exchange transfusion with fluorocarbon for studying synaptically evoked optical signal in rat cortex.
Optical imaging of intrinsic signal is a powerful technique for studying the functional organization of the brain [T. Bonhoeffer, D. S. Kim, D. Malonek, D. Shoham, A. Grinvald, Optical imaging of the layout of functional domains in area 17 and across the area 17/18 border in cat visual cortex, Eur. J. Neurosci. 7 (1995) 1973-1988; M. Hubener, D. Shoham, A. Grinvald, T. Bonhoeffer, Spatial relationships among three columnar systems in cat area 17, J. Neurosci. 17 (1997) 9270-9284; D. Malonek, A. Grinvald, Interactions between electrical activity and cortical microcirculation revealed by imaging spectroscopy: implications for functional brain mapping, Science 272 (1996) 551-554; A. Shmuel, A. Grinvald, Functional organization for direction of motion and its relationship to orientation maps in cat area 18, J. Neurosci. 16 (1996) 6945-6964] [1] [10] [14] [22]. Three components of intrinsic optical signal can be distinguished. Two of these components can be attributed either to changes in blood volume or to changes in oxygen consumption [R.D. Frostig, E.E. Lieke, D.Y. Ts'o, A. Grinvald, Cortical functional architecture and local coupling between neuronal activity and the microcirculation revealed by in vivo high resolution optical imaging of intrinsic signals, Proc. Natl. Acad. Sci. U. S. A. 87 (1990) 6082-6086] [7]. The origin of the third component is not yet clear but the component seems to be based on scattered light [H.U. Dodt, G. D'Arcangelo, E. Pestel, W. Zieglgansberger, The spread of excitation in neocortical columns visualized with infrared-dark field videomicroscopy, NeuroReport 7 (1996) 1553-1558; K. Holthoff, O.W. Witte, Intrinsic optical signals in rat neocortical slices measured with near-infrared dark-field microscopy reveal changes in extracellular space, J. Neurosci. 16 (1996) 2740-2749; B.A. MacVicar, D. Hochman, Imaging of synaptically evoked intrinsic optical signals in hippocampal slices, J. Neurosci. 11 (1991) 1458-1469; L. Trachsel, H.U. Dodt, W. Zieglgansberger, The intrinsic optical signal evoked by chiasm stimulation in the rat suprachiasmatic nuclei exhibits GABAergic day-night variation, Eur. J. Neurosci. 8 (1996) 319-328] [3] [9] [13] [24]. A spectral fitting method with three components is used for the analysis of intrinsic optical signal [M. Nemoto, Y. Nomura, C. Sato, M. Tamura, K. Houkin, I. Koyanagi, H. Abe, Analysis of optical signals evoked by peripheral nerve stimulation in rat somatosensory cortex: dynamic changes in hemoglobin concentration and oxygenation, J. Cereb. Blood Flow Metab. 19 (1999) 246-259] [17]. In order to validate the analysis, we need the knowledge on contribution of signal resulted from hemoglobin to total intrinsic optical signal. The exchange transfusion with fluorocarbon has the advantage that can change the spectral contribution of hemoglobin [M. Ferrari, M.A. Williams, D.A. Wilson, N.V. Thakor, R.J. Traystman, D.F. Hanley, Cat brain cytochrome-c oxidase redox changes induced by hypoxia after blood-fluorocarbon exchange transfusion, Am. J. Physiol. 269 (1995) H417-H424; A.L. Sylvia, C.A. Piantadosi, O(2) dependence of in vivo brain cytochrome redox responses and energy metabolism in bloodless rats, J. Cereb. Blood Flow Metab. 8 (1988) 163-172] [6] [23]. Here we describe a new method of the reduction of hemoglobin signal from somatosensory evoked optical intrinsic signal in rat cortex by the combination of exchange transfusion with fluorocarbon and imaging system of thinned skull cranial window. The method allows for the study of the synaptically evoked changes in light scattering as well as fluorescence of calcium indicator or voltage-sensitive dye without absorption of hemoglobin.


Radiobiological modeling of radiation-induced acute mucosal toxicity (oral mucositis and pharyngeal mucositis): A single-institutional study of head-and-neck carcinoma.
This study aimed to estimate the fitting parameters of sigmoidal dose-response (SDR) curve of radiation-induced acute oral and pharyngeal mucositis in head-and-neck (H and N) cancer patients treated with Intensity Modulated Radiation Therapy (IMRT) for the calculation of normal tissue complication probability (NTCP). Thirty H-and-N cancer patients were enrolled to model the SDR curve for oral and pharyngeal mucositis. The patients were evaluated weekly for acute radiation-induced (ARI) oral and pharyngeal mucositis toxicity, and their scoring was performed as per the common terminology criteria adverse events version 5.0. The radiobiological parameters, namely n, m, TD50, and γ50 were calculated from the fitted SDR curve obtained from the clinical data of H-and-N cancer patients. ARI toxicity for oral and pharyngeal mucosa in carcinoma of H-and-N cancer patients was calculated for the endpoint oral mucositis and pharyngeal mucositis. The n, m, TD50, and γ50 parameters from the SDR curve of Grade 1 and Grade 2 oral mucositis were found to be [0.10, 0.32, 12.35 ± 3.90 (confidence interval [CI] 95%) and 1.26] and [0.06, 0.33, 20.70 ± 6.95 (CI 95%) and 1.19] respectively. Similarly for pharyngeal mucositis, n, m, TD50, and γ50 parameters for Grade 1 and Grade 2 were found to be [0.07, 0.34, 15.93 ± 5.48 (CI. 95%) and 1.16 ] and [0.04, 0.25, 39.02 ± 9.98(CI. 95%) and 1.56] respectively. This study presents the fitting parameters for NTCP calculation of Grade 1 and Grade 2 ARI toxicity for the endpoint of oral and pharyngeal mucositis. The provided nomograms of volume versus complication and dose versus complication for different grades of oral mucositis and pharyngeal mucositis help radiation oncologists to decide the limiting dose to reduce the acute toxicities.


Novel molecular insights into the anti-oxidative stress response and structure-function of a salt-inducible cyanobacterial Mn-catalase.
KatB, a salt-inducible Mn-catalase, protects the cyanobacterium Anabaena from salinity/oxidative stress. In this report, we provide distinctive insights into the biological-biochemical function of KatB at the molecular level. Anabaena overexpressing the wild-type KatB protein (KatBWT) detoxified H2 O2 efficiently, showing reduced burden of reactive oxygen species compared with the strain overproducing KatBF2V (wherein F-2 is replaced by V). Correspondingly, the KatBWT protein also displayed several folds more activity than KatBF2V. Interestingly, the KatB variants with large hydrophobic amino acids (F/W/Y) were more compact, showed enhanced activity, and were resistant to thermal/chemical denaturation than variants with smaller residues (G/A/V) at the second position. X-ray crystallography-based analysis showed that F-2 was required for appropriate interactions between two subunits. These contacts provided stability to the hexamer, making it more compact. F-2, through its interaction with F-66 and W-43, formed the proper hydrophobic pocket that held the active site together. Consequently, only residues that supported activity (i.e., F/Y/W) were selected at the second position in Mn-catalases during evolution. This study (a) demonstrates that modification of nonactive site residues can alter the response of catalases to environmental stress and (b) has expanded the scope of amino acids that can be targeted for rational protein engineering in plants.


Structure and genome ejection mechanism of Staphylococcus aureus phage P68.
Phages infecting Staphylococcus aureus can be used as therapeutics against antibiotic-resistant bacterial infections. However, there is limited information about the mechanism of genome delivery of phages that infect Gram-positive bacteria. Here, we present the structures of native S. aureus phage P68, genome ejection intermediate, and empty particle. The P68 head contains 72 subunits of inner core protein, 15 of which bind to and alter the structure of adjacent major capsid proteins and thus specify attachment sites for head fibers. Unlike in the previously studied phages, the head fibers of P68 enable its virion to position itself at the cell surface for genome delivery. The unique interaction of one end of P68 DNA with one of the 12 portal protein subunits is disrupted before the genome ejection. The inner core proteins are released together with the DNA and enable the translocation of phage genome across the bacterial membrane into the cytoplasm.


Surprisal analysis of genome-wide transcript profiling identifies differentially expressed genes and pathways associated with four growth conditions in the microalga Chlamydomonas.
The usual cultivation mode of the green microalga Chlamydomonas is liquid medium and light. However, the microalga can also be grown on agar plates and in darkness. Our aim is to analyze and compare gene expression of cells cultivated in these different conditions. For that purpose, RNA-seq data are obtained from Chlamydomonas samples of two different labs grown in four environmental conditions (agar@light, agar@dark, liquid@light, liquid@dark). The RNA seq data are analyzed by surprisal analysis, which allows the simultaneous meta-analysis of all the samples. First we identify a balance state, which defines a state where the expression levels are similar in all the samples irrespectively of their growth conditions, or lab origin. In addition our analysis identifies additional constraints needed to quantify the deviation with respect to the balance state. The first constraint differentiates the agar samples versus the liquid ones; the second constraint the dark samples versus the light ones. The two constraints are almost of equal importance. Pathways involved in stress responses are found in the agar phenotype while the liquid phenotype comprises ATP and NADH production pathways. Remodeling of membrane is suggested in the dark phenotype while photosynthetic pathways characterize the light phenotype. The same trends are also present when performing purely statistical analysis such as K-means clustering and differentially expressed genes.


Application of tomographic methods in the diagnosis of pathological changes of the jaw.
The aim of this study was to evaluate the frequency of specific diagnostic methods used for diagnosis of oral pathologies. The sample consisted of 198 patients (98 man and 100 women) with formulated diagnosis, confirmed postoperatively by histopathological verification. In 74.7% of subjects only X-ray diagnostic examination was used. Both X-ray and computed tomography (CT) examinations were used in 18.7% of subjects. Magnetic resonance imaging (MRI) wasn't performed in any subject. In 6.6% of subjects neither X-ray nor CT was performed. The study reported on statistically significant differences in the distribution of specific diagnostic methods according to age groups (p = 0.026). Also, there was statistically significant differences in the distribution of diagnostic methods according to diagnostic groups (p = 0.053). In the group of 37 subjects, in whom both X-ray and computed tomography were used, the majority had carcinomas, followed by fractures and inflammatory cysts.


Synthesis of Phosphonated Carbon Nanotubes: New Insight into Carbon Nanotubes Functionalization.
Carbon nanotubes were successfully functionalized for the first time in a free radical phosphonylation reaction. Three synthetic protocols were proposed. Carbon nanotubes and diethylphosphite reacted in the presence of known radical initiator, such as azobisisobutyronitrile, single electron oxidant-Mn(OAc)3, or under UV radiation. The functionalized material was fully characterized by means of spectroscopic methods, together with microscopic, surface area and thermogravimetric analyses. UV-illumination was found to be the most effective approach for introducing phosphonates onto carbon nanotubes. X-ray photoelectron spectroscopy analysis showed 6% phosphorus in this sample. Moreover, the method was performed at room temperature for only one hour, using diethylphosphite as a reactant and as a solvent. The functionalized carbon nanotubes showed an improved thermal stability, with a decomposition onset temperature increase of more than 130 °C. This makes it very promising material for flame retarding applications.


Systematic review of the safety of regular preventive asthma medications during pregnancy.
To review the safety of regular preventive asthma medications during pregnancy. The following databases were searched from inception to February 2011: Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL Plus. The search was limited to human studies published in the English language. Titles of all articles were screened for relevance. Abstracts of relevant articles were scrutinized to confirm relevance before obtaining full text. Selected articles were read by 2 authors and the accuracy of the data extracted was confirmed. Thirty-three articles were included in the final review. Small sample size, missing data, inadequate control for confounding factors, and poor documentation of dosage range were common limitations of the studies reviewed. The use of inhaled corticosteroids, cromolyns, and long-acting β(2) agonists during pregnancy was not associated with any particular adverse event, although the fluticasone/salmeterol combination has been associated with poor outcomes in postmarketing studies. Congenital malformations have been reported with leukotriene receptor antagonist exposure during pregnancy, but those women also had exposure to other medications, including oral corticosteroids. Some negative outcomes of preventive asthma medications have been reported, although their direct link with medication use is inconclusive. Selection of preventive medications for asthma management during pregnancy should be based on an assessment of the risks and benefits of medication use versus the risks of poorly controlled asthma.


In-Hospital and One-Year Outcomes of Patients after Early and Late Resuscitated Cardiac Arrest Complicating Acute Myocardial Infarction-Data from a Nationwide Database.
The prognostic role of early (less than 48 h) resuscitated cardiac arrest (ErCA) complicating acute myocardial infarction (AMI) is still controversial. The present study aimed to analyse the short-term and one-year outcomes of patients after ErCA and late resuscitated cardiac arrest (LrCA) compared to patients without cardiac arrest (CA) complicating AMI. Data from the prospective nationwide Polish Registry of Acute Coronary Syndromes (PL-ACS) were used to assess patients with resuscitated cardiac arrest (rCA) after AMI. Baseline clinical characteristics and the predictors of all-cause death were assessed. The all-cause mortality rate, complications, performed procedures, and re-hospitalisations were assessed for the in-hospital period, 30 days after discharge, and 6- and 12-month follow-ups. Among 167,621 cases of AMI, CA occurred in 3564 (2.1%) patients, that is, 3100 (87%) and 464 (13%) patients with ErCA and LrCA, respectively. The mortality rates in the ErCA vs. LrCA and CA vs. non-CA groups were as follows: in-hospital: 32.1% vs. 59.1% (p < 0.0001) and 35.6% vs. 6.0% (p < 0.0001); 30-day: 2.2% vs. 3.2% (p = 0.42) and 9.9% vs. 5.2% (p < 0.0001); 6-month: 9.2% vs. 17.9% (p = 0.0001) and 12.3% vs. 21.1% (p < 0.0001); and 12-month: 12.3% vs. 21.1% (p = 0.001) and 13% vs. 7.7% (p < 0.0001), respectively. ErCA (hazard ratio (HR): 1.54, confidence interval (CI):1.28-1.89; p < 0.0001) and LrCA (HR: 2.34, CI: 1.39-3.93; p = 0.001) increased the risk of 12-month mortality. During the 12-month follow-up, patients after LrCA more frequently required hospitalisation due to heart failure compared to patients after ErCA. ErCA was related to a higher hospitalisation rate due to coronary-related causes and a higher rate of percutaneous coronary intervention. An episode of LrCA was associated with higher in-hospital and long-term mortality compared to ErCA. ErCA and LrCA were independent risk factors for one-year mortality.


The long non-coding RNA HOTAIR is transcriptionally activated by HOXA9 and is an independent prognostic marker in patients with malignant glioma.
The lncRNA HOTAIR has been implicated in several human cancers. Here, we evaluated the molecular alterations and upstream regulatory mechanisms of HOTAIR in glioma, the most common primary brain tumors, and its clinical relevance. HOTAIR gene expression, methylation, copy-number and prognostic value were investigated in human gliomas integrating data from online datasets and our cohorts. High levels of HOTAIR were associated with higher grades of glioma, particularly IDH wild-type cases. Mechanistically, HOTAIR was overexpressed in a gene dosage-independent manner, while DNA methylation levels of particular CpGs in HOTAIR locus were associated with HOTAIR expression levels in GBM clinical specimens and cell lines. Concordantly, the demethylating agent 5-Aza-2'-deoxycytidine affected HOTAIR transcriptional levels in a cell line-dependent manner. Importantly, HOTAIR was frequently co-expressed with HOXA9 in high-grade gliomas from TCGA, Oncomine, and our Portuguese and French datasets. Integrated in silico analyses, chromatin immunoprecipitation, and qPCR data showed that HOXA9 binds directly to the promoter of HOTAIR. Clinically, GBM patients with high HOTAIR expression had a significantly reduced overall survival, independently of other prognostic variables. In summary, this work reveals HOXA9 as a novel direct regulator of HOTAIR, and establishes HOTAIR as an independent prognostic marker, providing new therapeutic opportunities to treat this highly aggressive cancer.


Toward Understanding the Child's Experience in the Process of Parentification: Young Adults' Reflections on Growing up With a Depressed Parent.
This article reports on a qualitative study with 21 young adults who grew up with a depressed parent. We examined how young adults make sense of their childhood experiences of parental depression and how their retrospective reflections help us to understand the experiences of children and the processes of parentification. Participants recounted that their childhood consisted mainly of actions in the service of family well-being. At that time, they reflected on their own experiences only rarely. In adolescence, there was an evolution toward a greater consideration for oneself and a repositioning within the family. In the discussion, we explore the therapeutic implications of this study--and in particular--the meaningfulness of silence in the family process of parentification.


The clinical characteristic and prognostic factors of leptomeningeal metastasis in patients with non-small-cell lung cancer-a retrospective study from one single cancer institute.
Leptomeningeal metastasis (LM) is a detrimental complication of advanced non-small-cell lung cancer (NSCLC), and the optimal therapeutic approach for LM patients is in shortage. This retrospective study aimed to investigate the clinical features and prognostic factors of NSCLC patients with LM. We retrospectively reviewed the medical records of NSCLC patients with LM at the Shandong Cancer Hospital and Institute between July 2014 and March 2018. Identified cases had pathology-proven NSCLC with either positive cerebrospinal fluid cytology or leptomeningeal enhancement by MRI. One hundred and thirty-six NSCLC patients (58 men, 78 women) with LM were enrolled in the retrospective study; median age was 55 years (range, 29-89 years). Fifty-one patients harbored EGFR mutations, ALK rearrangement was detected in 6 patients. Treatment for LM consisted of EGFR-TKIs alone in 11 patients, whole brain radiotherapy (WBRT) alone in 19 patients, Chemotherapy (ChT) alone in 12 patients, EGFR-TKIs plus WBRT in 30 patients, WBRT plus ChT in 25 patients, and EGFR-TKIs plus ChT in 24 patients. The median progression-free survival was 3.9 months (95% confidence interval [CI]: 3.178-4.622), and the median overall survival (OSLM ) was 9.8 months (95% CI:7.5-12.1). Thirty patients who received WBRT plus EGFR-TKIs achieved longer survival than those who only received WBRT (median 13.6 vs 8.8 months; P = 0.027), but did not add any survival benefit than those only received EGFR-TKIs (median 13.6 vs 13.9 months; P = 0.352). A multivariate analysis indicated that KPS ≥ 80 (hazard ratio [HR] = 0.592, 95% CI:0.369-0.95; P = 0.03) and EGFR-TKIs (HR = 0.507, 95% CI:0.283-0.908; P = 0.022) after LM diagnosis were independent favourable predictors of survival, whereas smoking (HR = 1.181, 95% CI:1.009-3.246; P = 0.047) was an independent predictor of poor survival. Our results suggest that patients with good performance statuses, non-smoking patients, and the administration of EGFR-TKIs might improve clinical outcomes in NSCLC patients with LM.


Functional interaction between neuropeptide Y receptors and modulation of calcium channels in the rat hippocampus.
We investigated the functional interaction between neuropeptide Y (NPY) receptors using nerve terminals and cultured rat hippocampal neurons, and we evaluated the involvement of voltage-gated Ca(2+) channels (VGCCs) in NPY receptors-induced inhibition of Ca(2+) influx and glutamate release. The KCl-evoked release of glutamate from hippocampal synaptosomes was inhibited by 1 microM NPY and this effect was insensitive to either BIBP3226 (Y1 receptor antagonist) or L-152,804 (Y5 receptor antagonist), but was sensitive to BIIE0246 (Y2 receptor antagonist). We could also pharmacologically dissect the NPY receptors activity by using Y1, Y2 and Y5 receptor agonists ([Leu(31),Pro(34)]NPY, NPY13-36, NPY (19-23)-(Gly(1),Ser(3),Gln(4),Thr(6),Ala(31),Aib(32),Gln(34))-pancreatic polypeptide (PP), respectively), and in all the cases we observed that these agonists could inhibited the KCl-induced release of glutamate. However, the selective and specific co-activation of both Y1 and Y2 or Y2 and Y5 receptors resulted in non-additive inhibition, and this effect was prevented in the presence of the Y2 antagonist, but was insensitive to the Y1 or Y5 receptor antagonist. Moreover, as we previously showed for Y1 receptors, we also observed that the activation of Y5 receptors inhibited the glutamate release in the dentate gyrus and CA3 subregion, without significant effect in the CA1 subregion of the hippocampus. The same qualitative results were obtained when we investigated the role of NPY Y1 and Y2 receptors in modulating the changes in [Ca(2+)](i) due to KCl depolarisation in cultured hippocampal neurons. The inhibitory effect of nitrendipine (L-type VGCC blocker) or omega-conotoxin GVIA (omega-CgTx; N-type VGCC blocker) was not potentiated by the simultaneous activation of Y1 or Y2 receptors. Moreover, the exocytotic release of glutamate was inhibited by omega-agatoxin IVA (omega-Aga; P-/Q-type VGCC blocker), and this VGCC blocker did not potentiate Y1, Y2 or Y5 receptor-mediated inhibition of glutamate release. Also, the effect of ionomycin in inducing the exocytotic release of glutamate from hippocampal synaptosomes was insensitive to the activation of NPY receptors. In the present paper, we identified a role for NPY Y1, Y2 and Y5 receptors in modulating the exocytotic release of glutamate and the [Ca(2+)](i) changes in the rat hippocampus. In conditions of co-activation, there appears to exist a physiological cross-talk between Y1 and Y2 and also between Y2 and Y5 receptors, in which Y2 receptors play a predominant role. Moreover, we also show that Y1 and Y2 receptors exert their inhibitory action by directly modulating L-, N-, and P-/Q-type VGCCs, whereas the inhibition of glutamate release mediated by the Y5 receptors seems to involve P-/Q-type VGCCs.


Comparing clinical effects of marbofloxacin and gamithromycin in goat kids with pneumonia.
The aim of this study was to compare the clinical efficacy of a single-dose of gamithromycin (GM) or marbofloxacin (MR) in kids with naturally occurring pneumonia. Thirty-six kids, aged 2-2.5 months, with body weight ranging from 12 kg to 18 kg were presented with clinical signs of pneumonia. The most prominent clinical findings were an increase in the respiratory rate, crackling lung sounds on auscultation, coughing, nasal discharge and an increased rectal temperature. Mannheimia haemolytica and Mycoplasma spp. colonies were isolated from microbiological examination of six transtracheal washes and lung tissues of one necropsied kid. The severity of pneumonia was evaluated by using cumulative clinical score (CCS). The CCS of the 36 kids used in the study were four and above. Kids were randomly divided into two equal groups; the GM group received a single subcutaneous dose of GM at a dosage of 6 mg/kg and the MR group received MR intramuscularly at a dosage of 8 mg/kg as a single-dose. No side effects related to the drugs were detected in either group. All 36 kids were clinically examined 3 weeks after the initiation of the treatment. Clinical signs in both groups were almost completely absent at the end of the study. A single administration of GM or MR was successfully used in the treatment of kids with pneumonia.


Poly(ethylene glycol) hydrogels cross-linked by hydrolyzable polyrotaxane containing hydroxyapatite particles as scaffolds for bone regeneration.
Poly(ethylene glycol) (PEG) hydrogels cross-linked by a hydrolyzable polyrotaxane containing hydroxyapatite particles (PRX-HAp) were developed as scaffolds for bone regeneration. Five scaffolds with various composition of the polyrotaxane, PEG and HAp particles were prepared to examine cell adhesion in vitro using rat primary cultured osteoblast. Cells were observed to attach well on a PRX-HAp that have the same weight ratio of the polyrotaxane and HAp particles at 7 days after seeding. These results indicate that HAp particles are necessary for cell adhesion and survival, but a higher ratio of the particles is not suitable for cell adhesion. The composites of rat osteoblast and the PRX-HAp were implanted subcutaneously in syngeneic rats and harvested at 5 weeks after implantation. In histological analysis, osteoblast-like cells became arrayed along the surface of the PRX-HAp, and osteoid-like tissues were observed in the region between a queue of osteoblast-like cells and PRX-HAp. These images are similar to intramembranous ossification, and it is expected that bone regeneration occurs on the surface of the PRX-HAp. This study strongly suggests the great potential of the PRX-HAp as scaffolds for bone regeneration.


Successful catheter ablation of atrial tachycardia and atrial fibrillation in persistent left superior vena cava.
Atrial tachycardia (AT) and atrial fibrillation (AF) were observed in a 21-year old male who had a history of patch closure for an atrial septal defect (ASD) at the age of 5 and a persistent left superior vena cava (LSVC). During electrophysiologic study, atrial extrastimuli reproducibly induced AT which spontaneously terminated or changed into AF. Electroanatomical mapping revealed focal AT arising from the floor of the proximal LSVC. Radio- frequency applications within LSVC targeted to the earliest activation site of AT as well as the complex fractionated potential eliminated both AT and AF without trans-septal puncture.


[Barrett's oesophagus: place of antireflux surgery].
The aim of this study was to review the literature about the effect of antireflux surgery on the metaplasia-dysplasia-adenocarcinoma sequence in patients with Barrett's oesophagus. Antireflux operations (by laparotomy or laparoscopy) can alter the natural history of Barrett's oesophagus, allowing disease stabilization in a substantial proportion of patients without high grade dysplasia at time of surgery. It also may induce complete or partial regression of Barrett's epithelium, especially for short segment of Barrett's oesophagus, but in unpredictable manner. While regression of low-grade dysplasia is commonly observed, histologic progression is rarely observed after effective antireflux surgery. However, ineffective antireflux surgery expose to histologic progression to high-grade dysplasia or adenocarcinoma. These data support the need for a long-term clinical, endoscopic, and histologic follow-up program after antireflux surgery in patients with Barrett's oesophagus.


Implementation of a Sulfide-Air Fuel Cell Coupled to a Sulfate-Reducing Biocathode for Elemental Sulfur Recovery.
Bio-electrochemical systems (BES) are a flexible biotechnological platform that can be employed to treat several types of wastewaters and recover valuable products concomitantly. Sulfate-rich wastewaters usually lack an electron donor; for this reason, implementing BES to treat the sulfate and the possibility of recovering the elemental sulfur (S0) offers a solution to this kind of wastewater. This study proposes a novel BES configuration that combines bio-electrochemical sulfate reduction in a biocathode with a sulfide-air fuel cell (FC) to recover S0. The proposed system achieved high elemental sulfur production rates (up to 386 mg S0-S L-1 d-1) with 65% of the sulfate removed recovered as S0 and a 12% lower energy consumption per kg of S0 produced (16.50 ± 0.19 kWh kg-1 S0-S) than a conventional electrochemical S0 recovery system.


Quantitative optical coherence microscopy of neuron morphology in human entorhinal cortex.
The size and shape of neurons are important features indicating aging and the pathology of neurodegenerative diseases. Despite the significant advances of optical microscopy, quantitative analysis of the neuronal features in the human brain remains largely incomplete. Traditional histology on thin slices bears tremendous distortions in three-dimensional reconstruction, the magnitude of which are often greater than the structure of interest. Recently development of tissue clearing techniques enable the whole brain to be analyzed in small animals; however, the application in the human remains challenging. In this study, we present a label-free quantitative optical coherence microscopy (OCM) technique to obtain the morphological parameters of neurons in human entorhinal cortex (EC). OCM uses the intrinsic back-scattering property of tissue to identify individual neurons in 3D. The area, length, width, and orientation of individual neurons are quantified and compared between layer II and III in EC. The high-resolution mapping of neuron size, shape, and orientation shows significant differences between layer II and III neurons in EC. The results are validated by standard Nissl staining of the same samples. The quantitative OCM technique in our study offers a new solution to analyze variety of neurons and their organizations in the human brain, which opens new insights in advancing our understanding of neurodegenerative diseases.


Polytriarylamines with on-chain crystal violet moieties.
A novel polytriarylamine (PTAA)-type alternating copolymer with on-chain crystal violet moieties has been generated which shows the expected strong dependence of its UV-Vis absorption spectrum from the pH value of the surrounding medium. Starting from the colorless leucocrystal violet form subsequent protonation/water elimination (by trifluoroacetic acid) leads to the formation of a blue colored, cationic copolymer with on-chain crystal violet units that displays a characteristic Vis absorption band peaking at 627 nm. Further protonation leads to the generation of the corresponding dicationic species which is accompanied by a red shift of the long wavelength absorption maximum to 713 nm. The novel pH-sensitive polytriarylamine derivatives will be investigated as potential p-type semiconductors for OFET (gas) sensors.


Efficacy of the Benznidazole+Posaconazole combination therapy in parasitemia reduction: An experimental murine model of acute Chagas.
Benznidazole (BZL) and Nifurtimox (NFX) are the pharmacological treatment for acute phase Chagas Disease (CD); however, therapy resistance and residual mortality development remain important unresolved issues. Posaconazole (POS) has shown a trypanocidal effect in vivo and in vitro. Thus, this study aimed at comparing the T. Cruzi parasitic load-reducing effect of the combination of BZL+POS against that of monotherapy with either, during acute phase CD, in an experimental murine model. Nineteen Wistar rats were randomly allocated to four groups and inoculated with the trypomastigotes of T. cruzi strain´s JChVcl1. The rats were administered anti-parasites from day 20-29 post-infection. The Pizzi and Brener method was used for parasitemia measurement. Longitudinal data analysis for the continuous outcome of repeated measures was performed using parasitemia as the outcome measured at days 20, 22, 24, 27, and 29 post-infection. All four groups had similar parasitic loads (p=0.143) prior to therapy initiation. Among the three treatment groups, the BZL+POS (n=5) group showed the highest mean parasitic load reduction (p=0.000) compared with the control group. Likewise, the BZL+POS group rats showed an earlier therapeutic effect and were the only ones without parasites in their myocardial samples. Treatment of acute phase CD with BZL+POS was more efficacious at parasitemia and myocardial injury reduction, compared with monotherapy with either.


Scoring System to Predict pt2 in Gallbladder Cancer Based on Carcinoembryonic Antigen and Tumor Diameter.
T2 gallbladder cancer requires lymph node dissection for curative resection, whereas simple cholecystectomy is adequate to treat T1 gallbladder cancer. Hence, this study aimed to develop an accurate scoring system to preoperatively predict pT2 in gallbladder cancer. We retrospectively assessed data from 57 patients with suspected gallbladder cancer who underwent curative resection between September 2003 and May 2017. Six with apparent invasion of adjacent organs on preoperative images were excluded. We evaluated preoperative computed tomography, magnetic resonance and endoscopic ultrasonographic images, blood biochemistry, and the maximum standard uptake value in fluorodeoxyglucose-positron emission tomography images. We analyzed whether correlations between preoperative findings and the depth of tumor invasion could predict pT2. The pathological diagnosis was gallbladder cancer in 30 (58.8%) patients, of whom 21 (69.9%) had pT2 or worse. Multivariate analyses selected carcinoembryonic antigen and tumor diameter as independent predictors of pT2 or worse (odds ratios = 1.741 and 1.098, respectively; 95% confidence intervals = 1.004-3.020 and 1.008-1.197, respectively). A regression formula was created using carcinoembryonic antigen and tumor diameter to calculate pT2 predictive scores. The area under the receiver operating characteristics curve of the pT2 predictive score was 0.873. We created a scoring system to predict pT2 in gallbladder cancer using carcinoembryonic antigen and tumor diameter. The present findings suggested that carcinoembryonic antigen is important for the preoperative evaluation of gallbladder cancer.


Working memory consolidation: insights from studies on attention and working memory.
Working memory, the system that maintains a limited set of representations for immediate use in cognition, is a central part of human cognition. Three processes have recently been proposed to govern information storage in working memory: consolidation, refreshing, and removal. Here, we discuss in detail the theoretical construct of working memory consolidation, a process critical to the creation of a stable working memory representation. We present a brief overview of the research that indicated the need for a construct such as working memory consolidation and the subsequent research that has helped to define the parameters of the construct. We then move on to explicitly state the points of agreement as to what processes are involved in working memory consolidation.


[Gastrointestinal carcinoid tumors: a multi-technique diagnostic approach].
Carcinoid tumors account for less than 1% of all malignancies. The majority arise in the gastrointestinal system (GI carcinoids). The diagnosis of GI carcinoids is often made late, the protean symptoms are easy to overlook. Diagnosis, prognosis and treatment options are based on biochemical markers and imaging investigations. A high concentration of urinary 5-HIAA or an elevated serotonin level in plasma help to establish the diagnosis of GI carcinoid. Plasma chromogranin A has poor specificity (68%); its level depends on disease involvement and therapeutic response. Octreoscan is the best imaging technique to detect GI carcinoids, but CT scan and MRI are superior for the detection of metastasis. 18F-DOPA or 11C-5-HTP/PET, imaging fusion as of octreoscan or PET scan with CT or MRI, improve the results of metabolic imaging. Coronal contrast-enhanced CT or MRI angiogram can evaluate mesenteric vessel spread before surgery. Upper endoscopy or colonoscopy, can be performed to detect foregut carcinoid in MEN, or hindgut carcinoid. Echoendoscopy visualizes abdominal wall and local node involvement. Enteroscopy and capsule endoscopy localize 66% of midgut carcinoids. Although there have been considerable advances in diagnostic modalities, the diagnosis of carcinoid tumors is still, all too often, late.


Integration of biologic agents with cytotoxic chemotherapy in metastatic colorectal cancer.
Colorectal cancer (CRC) remains a leading cause of cancer death in the developed world. Metastatic disease eventually develops in nearly 50% of patients with CRC. Chemotherapy is the mainstay of treatment in metastatic CRC (mCRC); however the majority of patients remain incurable with current therapeutic options. Progress made in the field of surgery, locoregional treatment for low-volume metastatic disease, and systemic chemotherapy has created new treatment paradigms and improved survival in mCRC. Development of new cytotoxic drugs and the advent of targeted agents over the past decade have seen the median overall survival (OS) for mCRC increase from 9 months to > 2 years. Data from trials integrating targeted therapies appear to indicate that not all have efficacy as single agents and the choice of chemotherapy used in combination with these agents may impact results. Ongoing research is leading to identification of new biomarkers of response, further defining the subpopulations who achieve greatest benefit. Hence optimizing treatment for this group of patients has become increasingly complex, requiring a multidisciplinary approach not only to identify those who are curable with resectable disease but also to determine when it is best to incorporate targeted drugs, with which chemotherapy, and in whom. Currently bevacizumab, cetuximab, and panitumumab are the only approved biologic agents for use in mCRC. In this article we discuss the evidence supporting the use of biologic agents with chemotherapy and suggested strategies for their integration into the treatment armamentarium of mCRC.


Population genetic structure of the sugar beet cyst nematode Heterodera schachtii: a gonochoristic and amphimictic species with highly inbred but weakly differentiated populations.
The sugar beet cyst nematode Heterodera schachtii is a soil-dwelling phytoparasitic nematode that feeds on beet roots. It is an important pest in most sugar beet growing areas, and better knowledge of its genetic variability is an important step to preserve the durability of resistant sugar beet varieties. The population genetic structure of this species in northern France was studied using five microsatellite markers. A hierarchical sampling design was used to investigate spatial structuring at the scale of the region, the field and the plant. Multilocus genotypes were obtained for single individual second-stage larvae, using only one individual per cyst in order to avoid the analysis of closely allied individuals (larvae from the same cyst share at least the same mother). A consistent trend of heterozygote deficit at all loci was observed at all spatial scales. Heterozygote deficit at the level of individual plants argues against its generation through a Wahlund effect. Inbreeding could be due to very limited active dispersal of larvae in the soil, favouring mating between siblings, such as larvae emerging from the same cyst. Such behaviour could have important consequences for the evolution of virulence in increasing the production of homozygous virulent individuals. Moreover, an analysis of molecular variance (amova) reveals that only 1.6% of the genetic variability is observed among regions, 3.7% among fields of the same region and 94.6% within fields. The very low level of genetic differentiation among fields is also indicated by low values of FST (</= 0.105) even for fields 150 km apart. We suggest that long-distance gene flows occur due to passive transport of cysts by human activities, water or wind. As such mechanisms of gene flow would involve cysts and not larvae, the strong signals of inbreeding observed at the local scale should not be disrupted. To our knowledge, this study constitutes the first investigation of the genetic structure of a phytoparasitic nematode based on neutral codominant genetic markers scored in single individuals.


The Transition from Gastric Intestinal Metaplasia to Gastric Cancer Involves POPDC1 and POPDC3 Downregulation.
Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell-cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.


Molecular Elucidation of a Urate Oxidase from Deinococcus radiodurans for Hyperuricemia and Gout Therapy.
Urate oxidase initiates the uric acid degradation pathways and is extensively used for protein drug development for gout therapy and serum uric acid diagnosis. We first present the biochemical and structural elucidation of a urate oxidase from the extremophile microorganism Deinococcus radiodurans (DrUox). From enzyme characterization, DrUox showed optimal catalytic ability at 30 °C and pH 9.0 with high stability under physiological conditions. Only the Mg2+ ion moderately elevated its activity, which indicates the characteristic of the cofactor-free urate oxidase family. Of note, DrUox is thermostable in mesophilic conditions. It retains almost 100% activity when incubated at 25 °C and 37 °C for 24 h. In this study, we characterized a thermostable urate oxidase, DrUox with high catalytic efficiency and thermal stability, which strengthens its potential for medical applications.


Pharmacokinetic evaluation of intravenous artesunate in adults with uncomplicated falciparum malaria in Kenya: a phase II study.
Alternatives to treatment for malaria treatment of travellers are needed in the USA and in Europe for travellers who return with severe malaria infections. The objective of this study is to show the pharmacokinetic (PK) profile of intravenous artesunate (AS), which was manufactured under good manufacturing practice (GMP) conditions, in adults with uncomplicated falciparum malaria in Kenya. The PK parameters of intravenous AS manufactured under current cGMP were evaluated after a single dose of drug at 2.4 mg/kg infused over 2 min in 28 adults with uncomplicated Plasmodium falciparum malaria. Plasma concentrations of AS and dihydroartemisinin (DHA) were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) methodology. Pharmacokinetic data were analysed with a compartmental analysis for AS and DHA. The results suggest there were no drug-related adverse events in any of the patients. After intravenous infusion, the concentration of the parent drug rapidly declined, and the AS was converted to DHA. AS and DHA showed mean elimination half-lives of 0.17 hours and 1.30 hours, respectively. The high mean peak concentration (Cmax) of AS was shown to be 28,558 ng/mL while the Cmax of DHA was determined to be 2,932 ng/mL. Significant variability was noted in the PK profiles of the 28 patients tested. For example, Cmax values of AS were calculated to range from 3,362 to 55,873 ng/mL, and the Cmax value of DHA was noted to vary from 1,493 to 5,569 ng/mL. The mean area under the curve (AUC) of AS was shown to be approximately half that of DHA (1,878 ng · h/mL vs 3,543 ng · h/mL). The DHA/AS ratio observed was 1.94 during the one-day single treatment, and the AUC and half- life measured for DHA were significantly larger and longer than for AS. Intravenous AS can provide much higher peak concentrations of AS when compared to concentrations achieved with oral therapy; this may be crucial for the rapid elimination of parasites in patients with severe malaria. Given the much longer half-life of DHA compared to the short half-life of AS, DHA also plays a significant role in treatment of severe malaria.


Expression of peroxisome proliferator-activated receptor (PPAR)-gamma in human lung cancer.
The peroxisome proliferator-activated receptor (PPAR)-gamma is a member of the steroid nuclear receptors. Recent studies have demonstrated that PPAR-gamma is expressed in several cancer cells. We examined the PPAR-gamma expression in both normal lung and major types of human lung cancer. The expression of PPAR-gamma mRNA was detected in 2 out of 3 normal lung tissues and its protein was detected in 3 out of 5 normal lung tissues. In contrast, a small cell carcinoma cell line and all other types of lung cancer tissues expressed PPAR-gamma mRNA and its protein. Immunoreactive PPAR-gamma is strongly expressed in cancer cells and moderately in mononuclear cells, endothelial cells and fibroblasts of lung cancer tissues. Our results suggest that PPAR-gamma may play an important role in the pathogenesis and/or progression of lung cancer, and may be a novel therapeutical target for therapy of lung cancer.


Stability mechanisms for plate-like nanoparticles immersed in a macroion dispersion.
An integral equation theory and Monte Carlo simulations are applied to study a model macroion solution confined between two parallel plates immersed in a 1:1 electrolyte and the macroions' counterions. We analyze the cases in which plates are: (a) uncharged; (b) when they are like-charged to the macroions; (c) when they are oppositely charged to the macroions. For all cases a long range oscillatory behavior of the induced charge density between the plates is found (implying an overcompensation/undercompensation of the plates' charge density) and a correlation between the confined and outside fluids. The behavior of the force is discussed in terms of the macroion and ion structure inside and outside the plates. A good agreement is found between theoretical and simulation results.


Contrast-enhanced endoscopic ultrasound features of tubercular lymphadenopathy.
There is lack of data on the contrast-enhanced endoscopic ultrasound features of tubercular lymph node; our retrospective analysis of 37 patients with enlarged mediastinal and abdominal lymph nodes showed heterogeneous enhancement in the great majority (70%).


Development of a swirling double counterflow.
This numerical study of an axisymmetric motion of a viscous incompressible fluid in an elongated cylindrical container explains how a swirling inflow develops the global meridional circulation and two U-shaped throughflows (TFs). For moderate values of the Reynolds (Re) number, there is a single U-shaped TF: The fluid moves from the peripheral annular inlet near the sidewall to the dead end, turns around, goes back near the axis, and leaves the container through the central exhaust. As Re increases, vortex breakdown occurs near the dead end. If the exhaust orifice is wide, the ambient fluid is sucked into the container near its axis, reaches the dead-end vicinity, merges with the U-shaped TF, and goes back inside an annular region. Thus, a double counterflow develops, where the fluid moves to the dead end near both the sidewall and the axis and goes back in between. The physical mechanism of the double counterflow is a swirl decay combined with the focused flow convergence near the dead end. This double counterflow is beneficial for combustion applications.


Regulation of PCNA and cyclin D1 expression and epithelial morphogenesis by the ZO-1-regulated transcription factor ZONAB/DbpA.
The tight junction protein ZO-1 inhibits G1/S-phase transition by cytoplasmic sequestration of a complex formed by CDK4 and the transcription factor ZONAB. Canine ZONAB is the homologue of human DbpA, an E2F target gene that is overexpressed in different carcinomas. Since the ZONAB target genes that are involved in G1/S-phase transition are unknown, we employed the mammary epithelial cell line MCF-10A and cDNA arrays to screen for such genes. We identified genes encoding cell cycle and replication proteins whose expression was altered due to increased ZONAB expression. For proliferative cell nuclear antigen and cyclin D1 genes, we show that increased mRNA levels resulted in increased protein levels and we identified ZONAB-responsive elements in their promoters by using different approaches, including chromatin immunoprecipitation assays. RNA interference and overexpression of ZONAB affected the proliferation of both MCF-10A and MDCK cells as well as the differentiation of MDCK cells into polarized cysts in three-dimensional cultures. These results indicate that ZONAB regulates the transcription of genes that are important for G1/S-phase progression and links tight junctions to the transcriptional control of key cell cycle regulators and epithelial cell differentiation.


Applicability and Effectiveness of Closed Reduction of Nasal Fractures under Local Anesthesia.
Introduction A significant portion of patients treated in emergency departments have nasal fracture. It is important that the otolaryngologist know how to treat such damage. Objectives To evaluate the effectiveness of nasal fracture reduction under local anesthesia and tolerance to the procedure. Methods Twenty-four patients treated in the emergency department with closed reduction under local anesthesia were prospectively followed. Epidemiologic information and data regarding pain and complications during the management were noted. The degree of satisfaction was researched by visual analog scale. Results The majority of patients were male (75%), and the most common cause of injury was motor vehicle accident. We found a significant association between time to reduction and referred pain during the procedure. In patients in whom the procedure was delayed (over 3 days), there was less pain, and those who bled during the procedure had a shorter average time to reduction than the group of patients who did not bleed. Most patients were very satisfied, with more than 95% of these willing to undergo the same process again, if necessary. Conclusions The closed approach in the clinic under local anesthesia was effective and safe in restoration of the nose.


Axisymmetric lattice Boltzmann method revised.
A reformulated lattice Boltzmann model is described for incompressible axisymmetric flows with or without swirling. It is a further development and improvement on the author's axisymmetric lattice Boltzmann method. The main features of the revised scheme are (a) all the macroscopic variables such as velocities are determined in the same formulas as those in the conventional lattice Boltzmann approach to the Navier-Stokes equations and (b) the added sink or source and force terms are simple with no calculation for a derivative. Such features distinguish the present method from the other existing simplified schemes, leading to a simple and efficient model. The scheme is naturally suitable for generic incompressible axisymmetric rotational flows involving more physical phenomena. The numerical solutions to Womersley and cylindrical cavity flows are presented to demonstrate its accuracy and capability.


Toward synergy-based brain-machine interfaces.
This paper demonstrates a synergy-based brain-machine interface that uses low-dimensional command signals to control a high dimensional virtual hand. First, temporal postural synergies were extracted from the angular velocities of finger joints of five healthy subjects when they performed hand movements that were similar to activities of daily living. Two synergies inspired from the extracted synergies, namely, two-finger pinch and whole-hand grasp, were used in real-time brain control, where a virtual hand with 10 degrees of freedom was controlled to grasp or pinch virtual objects. These two synergies were controlled by electrocorticographic (ECoG) signals recorded from two electrodes of an electrode array that spanned motor and speech areas of an individual with intractable epilepsy, thus demonstrating closed loop control of a synergy-based brain-machine interface.


Cuproptosis regulator-mediated patterns associated with immune infiltration features and construction of cuproptosis-related signatures to guide immunotherapy.
Liver hepatocellular carcinoma (HCC) is a prevalent cancer that lacks a sufficiently efficient approach to guide immunotherapy. Additionally, cuproptosis is a recently identified regulated cell death program that is triggered by copper ionophores. However, its possible significance in tumor immune cell infiltration is still unclear. Cuproptosis subtypes in HCC were identified using unsupervised consensus cluster analysis based on 10 cuproptosis regulators expressions, and a cuproptosis-related risk signature was generated using univariate and LASSO Cox regression and validated using the ICGC data. Moreover, the relationship between signature and tumor immune microenvironment (TME) was studied through tumor immunotherapy responsiveness, immune cell infiltration, and tumor stem cell analysis. Finally, clinical specimens were analyzed using immunohistochemistry to verify the expression of the three genes in the signature. Two subtypes of cuproptosis regulation were observed in HCC, with different immune cell infiltration features. Genes expressed differentially between the two cuproptosis clusters in the TCGA were determined and used to construct a risk signature that was validated using the ICGC cohort. Greater immune and stromal cell infiltration were observed in the high-risk group and were associated with unfavorable prognosis. Elevated risk scores were linked with higher RNA stemness scores (RNAss) and tumor mutational burden (TMB), together with a greater likelihood of benefitting from immunotherapy. It was found that cuproptosis regulatory patterns may play important roles in the heterogeneity of immune cell infiltration. The risk signature associated with cuproptosis can assess each patient's risk score, leading to more individualized and effective immunotherapy.


Effect of cleistanthin A and B on adrenergic and cholinergic receptors.
The aim was to study the in vitro and in silico interactions of cleistanthin A and B on the adrenergic and cholinergic receptors using isolated animal tissues and bioinformatics tools. The alpha adrenergic receptor activities of cleistanthin A and B were studied in vitro using a guinea pig vas deferens preparation. The beta adrenergic receptor activities of cleistanthin A and B on an isolated rat heart were studied in vitro using a modified Langendorff apparatus. The effects of cleistanthin A and B on the nicotinic and muscarinic cholinergic receptors were studied in vitro using rabbit vas deferens and rabbit jejunum, respectively. All the drug responses were recorded using a data acquisition system through a variable force transducer. The receptor-ligand interactions of cleistanthin A and B with adrenergic and cholinergic receptor proteins were determined using the ArgusLab molecular modeling and drug docking program. Cleistanthin A and B significantly inhibited the actions of the alpha adrenergic receptor and the nicotinic cholinergic receptor. Cleistanthin A and B shifted the dose-response curve to the right with an increased EC(50) value of phenylephrine and acetylcholine. Both cleistanthin A and B did not have any significant effect on the beta adrenergic and muscarinic cholinergic receptors. Cleistanthin A and B block the alpha adrenergic and nicotinic cholinergic receptors, but these compounds do not interact at all with the beta adrenergic and muscarinic cholinergic receptors.


Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance.
Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy.


Cost-Utility analysis of tissue plasminogen activator therapy for acute ischaemic stroke: a Canadian healthcare perspective.
There are over 40000 ischaemic strokes annually in Canada, which result in significant morbidity, mortality and burden to the healthcare system. A recent, large clinical trial has evaluated tissue plasminogen activator (t-PA) intravenously for the treatment of acute ischaemic stroke with promising outcomes but with an increased risk of symptomatic intracranial haemorrhage. To compare clinical and economic outcomes of intravenous t-PA therapy (0.9 mg/kg, to a maximum of 90 mg, initiated within 3 hours of stroke onset) versus no t-PA for acute ischaemic stroke based on the outcomes achieved in the National Institute of Neurological Disorders and Stroke (NINDS) trial. A Markov model depicting the natural lifetime course after an initial acute ischaemic stroke. On the basis of this model, a simulated trial compared no t-PA with t-PA. A hypothetical cohort of 1000 patients with acute ischaemic stroke. Canadian healthcare system. Total acute stroke and post-stroke treatment costs and cumulative quality-adjusted life-years (QALYs). For a hypothetical cohort of 1000 patients, the estimated lifetime stroke costs were 103100000 Canadian dollars (SCan) [1999 values) in the t-PA arm ($Can103100 per patient) compared with SCan106900000 in the no t-PA arm ($Can106900 per patient), yielding a lifetime cost difference of $Can3800000 in favour of t-PA versus no t-PA (SCan3800 per patient). In the hypothetical cohort, t-PA treatment resulted in 13 130 QALYs versus 9670 QALYs with no t-PA treatment. This translated into a net benefit of 3460 additional QALYs per 1000 patients (3.46 QALYs per patient). No treatment, outcome or economic variables influenced the model outcome. From the standpoint of cost effectiveness, treatment of acute ischaemic stroke with intravenous t-PA is an economically attractive strategy.


Multiple benefits of personal FM system use by children with auditory processing disorder (APD).
Children with auditory processing disorders (APD) were fitted with Phonak EduLink FM devices for home and classroom use. Baseline measures of the children with APD, prior to FM use, documented significantly lower speech-perception scores, evidence of decreased academic performance, and psychosocial problems in comparison to an age- and gender-matched control group. Repeated measures during the school year demonstrated speech-perception improvement in noisy classroom environments as well as significant academic and psychosocial benefits. Compared with the control group, the children with APD showed greater speech-perception advantage with FM technology. Notably, after prolonged FM use, even unaided (no FM device) speech-perception performance was improved in the children with APD, suggesting the possibility of fundamentally enhanced auditory system function.


The effect of siRNA-VEGF on the growth of REC in retinal pigment epithelial cell and retinal endothelial cell co-culture system.
To investigate the effect of small interfering RNA (siRNA) targeting VEGF of retinal pigment epithelium (RPE) cells on the growth activity of human retinal vascular endothelial cells (RECs) under a co-culture system. By applying the vector (pGPU6)-based siRNA plasmid gene silence system, we specifically silenced VEGF expression of RPE cells (ARPE-19) through plasmid (pGPU6-VEGFA-siRNA) transfection. Reverse transcription polymerase chain reaction (RT-PCR) was applied for selecting the most efficient siRNA segment among three pGPU6-VEGF-siRNA groups (siRNA-1, siRNA-2 and siRNA-3). Treated RPE cells were co-cultured with RECs in a co-culture system made up of a 24-well culture plate and transwell inserts assembled inside During 7-day culture period, the growth capacity of RECs were observed and tested in the form of cell counting assay. Three groups were established in this study: RPE cells transfected with pGPU6-VEGF-siRNA and co-cultured with RECs (group A), RPE cells transfected with siRNA null vector and co-cultured with RECs (group B), and RECs cultured alone (group C). After transfection, VEGF expression of RPE cells in three pGPU6-VEGF-siRNA groups (siRNA-1, siRNA-2 and siRNA-3) evaluated by RT-PCR were 2.56 ± 0.45, 1.17 ± 0.38 and 4.39 ± 0.51, respectively (n=10). siRNA-2 was selected as the foremost segment for transfection (P<0.05, SNK-q test). During the 7-day co-culture period, an influence upon the growth of RECs was observed. Growth curve of RECs under co-culture showed a lower growth rate in group A than in group B (P<0.05, dunnett's test), but no significant difference between group A and group C was noted ( P>0.05, dunnett's test). RECs in group A proliferated much faster during the first four days post-transfection. Delivery of siRNA targeting VEGF plays an efficient role in down-regulating VEGF expression in RPE cells, therefore modulating the growth activity of RECs under a co-culture system in vitro. The application of this technique may provide novel evidence for the prevention and treatment of retinal neovascularisation diseases.


Silver Nanoparticle Exposure Induces Neurotoxicity in the Rat Hippocampus Without Increasing the Blood-Brain Barrier Permeability.
Silver nanoparticles (Ag-NPs) can enter the brain and subsequently induce neurotoxicity. However, the toxicity of Ag-NPs on the blood-brain barrier (BBB) and the underlying mechanism(s) of action on the hippocampus in vivo are not well understood. To investigate Ag-NP suspension (Ag-NPS)-induced toxicity on the BBB and neurons, Sprague-Dawley rats were randomly divided into 3 groups, and Ag-NPS, Ag-ion, and 5% sucrose solution (vehicle control) were administrated intravenously, respectively. After 24 h exposure to Ag-NPS, the BBB permeability was not significantly changed. However, the Ag concentrations in the brain tissues were only detected in the Ag-NPS group. Gene expression results indicated that the expression of Claudin 4 (tight junction protein) was significantly decreased. Furthermore, astrocyte foot swelling, neuron shrinkage and Ag-NP like particles were observed under transmission electron microscopy. Global gene expression analysis showed that 502 genes were up-regulated and 703 genes were down-regulated in the hippocampi treated with Ag-NPS. In the Ag-NPS-treated group, 78 biological functions were changed based on gene ontology (GO) and 34 signaling pathways were significantly changed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, which were associated with the neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, calcium signaling pathway and MAPK signaling pathway. In comparison, 27 GO and 9 KEGG pathways were changed in the released Ag-ion-treated group. Ag-NPS decreased C1qtnf3 expression and increased Adra1d expression to affect MAPK signaling pathway, which promoted inflammation and apoptosis in the hippocampus. Moreover, Ag-NPS significantly increased Spp1, Cacna1s and Tacr3 mRNAs expression, which may result in intracellular calcium increasing and initiate cell death. Furthermore, Ag-NPS affected calcium signaling pathway and neuroactive ligand-receptor (Grin2a, Drd2, and Adra1d), which are crucial in diverse cellular functions in the brain including cognition and neurodevelopment. These results draw our attention to the importance of Ag-NP-induced toxicity in the rat hippocampus and provide a better understanding of its toxicological mechanisms in vivo.


Trends in the surgical treatment of meniscal tears in patients with and without concurrent anterior cruciate ligament tears.
Objectives: Meniscal and anterior cruciate ligament (ACL) tears are common injuries. The purpose of this study was to determine trends in meniscal repair and meniscectomy both in the presence and absence of ACL reconstruction (ACLR).Methods: The PearlDiver database (www.pearldiverinc.com, Fort Wayne, IN) was queried for surgical management of patients who underwent arthroscopic meniscectomy (Current Procedural Terminology [CPT] codes 29880, 29881), meniscus repair (29882, 29883), and ACLR (29888) from 2010 to 2015. Patient groups included meniscectomy alone, meniscus repair alone, meniscus repair followed by meniscectomy, ACLR with meniscus repair, and ACLR with meniscus repair followed by meniscectomy. Linear regression was performed to determine the significance of yearly trend across each procedure. Statistical analysis was performed with RStudio, Version 1.1.442 (RStudio Inc. Boston, MA) for α value of .05.Results: The incidence of isolated meniscectomies decreased from 32.5/10,000 to 28.3/10,000 across the study period (p = 0.0230), whereas the incidence of isolated meniscus repairs and all meniscus repairs remained unchanged (p = 0.3000, p = 0.1260). For patients undergoing concomitant meniscal repair and ACLR, the highest proportion of patients was in the age range 15-24 years old with 45.7% of patients being 15-19. Of the ACLR, 18.6% involved a concomitant meniscus repair, and 54.0% involved a concomitant meniscectomy. The risk of subsequent meniscectomy was less in patients undergoing meniscal repair with ACLR than in patients undergoing isolated meniscal repair (10.8% versus 12.4%; aOR = 0.71, 95% CI 0.53-0.95, p = 0.0226).Conclusions: The highest rates of concurrent meniscal repair with ACLR are in the 15-24-year-old population. From 2010 to 2015, the rate of meniscectomy declined while that of isolated meniscal repairs, as well as meniscal repair with ACLR, remained stable. Patients undergoing meniscal repair with ACLR had lower rates of subsequent meniscectomy compared to patients undergoing isolated meniscal repair in the absence of ACL tear.Level of evidence: Level III.


Three controlled trials of weight loss with phenylpropanolamine.
A multisite double-blind study was designed to determine the effectiveness of a phenylpropanolamine-caffeine combination in achieving weight loss. Two-hundred and one obese adult patients were divided into three separate groups in which phenylpropanolamine/caffeine was compared with either placebo (6 weeks), mazindol (6 weeks), or diethylpropion (8 weeks). In these clinical trials, phenylpropanolamine/caffeine proved to be as effective as mazindol and diethylpropion and significantly more effective than placebo in achieving weight loss. Overall, phenylpropanolamine/caffeine had fewer side effects than mazindol and diethylpropion. Its use as an effective anorectic agent in the treatment of obesity is reviewed.


Nodal involvement by marginal zone B-cell lymphoma harboring t(14;22)(q32;q11) involving immunoglobulin heavy chain and light chain lambda as the sole karyotypically recognizable abnormality in a patient with systemic lupus erythematosus.
Recurrent non-random balanced chromosomal translocation, usually involving the immunoglobulin heavy chain (IgH) gene or an immunoglobulin light chain gene and a proto-oncogene, which results in the overexpression of the latter under the control of an enhancer or promoter of the former, is a hallmark of many types of non-Hodgkin lymphoma (NHL) of B-cell origin. However, translocations between IgH and the immunoglobulin (Ig) light chain lambda gene (IgL), namely, a t(14;22)(q32;q11), have rarely been described in B-cell NHL. Herein we report the first case of marginal zone B-cell lymphoma harboring a t(14;22)(q32;q11) as its sole genetic abnormality in a patient with a 12-year history of systemic lupus erythematosus (SLE). Other interesting findings of this case include: 1) the neoplastic B-cells lack expression of both surface and cytoplasmic Ig light chain as revealed by flow cytometry and 2) monoclonal rearrangement of Ig light chain kappa (IgK) only due to k-deleting element (kde) recombination event. This case illustrates the necessity of utilizing a multi-modality approach in the diagnosis of B-cell NHL.


CoMn2O4 embedded in MnOOH nanorods as a bifunctional catalyst for oxygen reduction and oxygen evolution reactions.
CoMn2O4 embedded in MnOOH nanorods (CoMn2O4-MnOOH NRs) was prepared using a two-step hydrothermal method involving the oxidation of Mn by Co species in preformed MnOOH NRs. The as-prepared CoMn2O4-MnOOH NRs exhibit an expectably remarkable performance for the ORR and the OER, indicating their great potential for widespread application in fuel cells and metal-air batteries.


Development and Validation of an Open-Source Grading Tool for Outcome Assessment in Limbal Stem Cell Treatment.
To design a grading system and validate an open-source tool to improve objective quantification and follow-up of limbal stem cell deficiency (LSCD) after treatment. A custom-made web-based grading system was developed for grading stem cell deficient eyes, termed the "Vascularisation, Haze, and Integrity" tool. For validation purposes, 60 corneal slit-lamp images of 30 limbal stem cell deficient eyes were graded by 3 groups of examiners: 3 corneal specialists (group A), 3 ophthalmologists with an expertise other than cornea (group B), and 3 nonclinicians (group C). The intragrader and intergrader agreement was evaluated using Fleiss weighted kappa coefficients and concurrent assessment of interrater and intrarater reliability (IRR) coefficients. The overall intergrader agreement was 0.78, 0.61, and 0.42 for superficial corneal vascularization, corneal haze, and epithelial integrity, respectively. All groups had good agreement for the vascularization parameter with the highest intergrader reliability in group A (IRR = 0.80) and the lowest in group C (IRR = 0.72). When assessing "haze," there was good agreement in groups A (IRR = 0.75) and B (IRR = 0.76) but low agreement in group C (IRR = 0.37). We report the development and evaluation of a novel method for grading results of limbal stem cell deficient eyes after treatment and provide this system as a free, open-source online tool. The grading tool offers an easy and standardized way of assessing the corneal surface in patients with LSCD, enables evaluation of progression over time, reduces assessment bias, and-if adopted universally-will harmonize outcome being reported between groups.


Intraoperative detection of patent foramen ovale by transesophageal echocardiography.
This study reports the intraoperative use of contrast and Doppler echocardiography techniques to diagnose patent foramen ovale (PFO). Fifty patients without known atrial septal defects undergoing elective cardiovascular surgery were studied. A 5-MHz esophageal echocardiographic probe was used to image the fossa ovalis (FO) and 10 ml agitated saline was injected into the right atrium during apnea. Echocardiographic contrast was then injected during end-inspiration at 20-cmH2O airway pressure. When opacification of the right atrium was complete, the airway pressure was released. During these maneuvers, color and pulsed-wave Doppler interrogation of the atrial septum were also performed. Right-to-left passage of saline contrast across the interatrial septum was seen in 11 of 50 patients (22%). Doppler echocardiography demonstrated a PFO in 2 patients without contrast evidence of shunting. Thus, the combination of contrast and Doppler echocardiography identified a 26% (13 of 50) prevalence of PFO, approximating the previously reported autopsy rate of 25%. These contrast and Doppler techniques may be useful in detecting patients at risk for paradoxical emboli and in identifying candidates for closure of the PFO.


One-pot synthesis of 3-functionalized (Z)-silyl enol ethers from 1-arylallylic alcohols by C,O-difunctionalization of dipotassio α,β-dianion intermediates.
Previously reported syntheses of 3-functionalized silyl enol ethers using allyloxysilanes are hindered by undesirable reactions owing to retro Brook rearrangements. In this study, various 3-functionalized (Z)-silyl enol ethers were synthesized from readily available 1-arylallylic alcohols using (trimethylsilyl)methylpotassium as a base. C,O-Difunctionalization of the in situ-generated dipotassio α,β-dianion with electrophiles and silyl chlorides is key to the success of this transformation. Control experiments confirmed that the dianion has higher nucleophilicity and thermal stability than related siloxyallylpotassiums.


A novel role of FoxO3a in the migration and invasion of trophoblast cells: from metabolic remodeling to transcriptional reprogramming.
The forkhead box O3a protein (FoxO3a) has been reported to be involved in the migration and invasion of trophoblast, but its underlying mechanisms unknown. In this study, we aim to explore the transcriptional and metabolic regulations of FoxO3a on the migration and invasion of early placental development. Lentiviral vectors were used to knock down the expression of FoxO3a of the HTR8/SVneo cells. Western blot, matrigel invasion assay, wound healing assay, seahorse, gas-chromatography-mass spectrometry (GC-MS) based metabolomics, fluxomics, and RNA-seq transcriptomics were performed. We found that FoxO3a depletion restrained the migration and invasion of HTR8/SVneo cells. Metabolomics, fluxomics, and seahorse demonstrated that FoxO3a knockdown resulted in a switch from aerobic to anaerobic respiration and increased utilization of aromatic amino acids and long-chain fatty acids from extracellular nutrients. Furthermore, our RNA-seq also demonstrated that the expression of COX-2 and MMP9 decreased after FoxO3a knockdown, and these two genes were closely associated with the migration/invasion progress of trophoblast cells. Our results suggested novel biological roles of FoxO3a in early placental development. FoxO3a exerts an essential effect on trophoblast migration and invasion owing to the regulations of COX2, MMP9, aromatic amino acids, energy metabolism, and oxidative stress.


[Post-traumatic stress disorder with psychotic features].
Post-traumatic stress disorder (PTSD) is often accompanied by psychiatric comorbidity, usually depressive and anxiety disorders. Comorbidity with psychosis has seldom been described. We present 6 case-studies of Israeli military veterans with PTSD and psychosis (all men aged 28-43). All developed PTSD shortly after a period of months or even years, sometimes following trauma-related triggering. Psychotic symptoms such as delusions or auditory hallucinations usually had paranoid or depressive features related in content to the traumatic experience. The combined course and interaction between PTSD and psychotic disorder is discussed, as well as the diagnosis of PTSD with psychotic features.


Synergistic antibacterial effect of apigenin with β-lactam antibiotics and modulation of bacterial resistance by a possible membrane effect against methicillin resistant Staphylococcus aureus.
Methicillin-resistant Staphylococcus aureus (MRSA) infections are easily spread among infected patients, where resistance has dramatically increased resulted in serious health issues. Therefore, there is a need to develop alternative natural or combination drug therapies. Apigenin (AP) is a natural poly phenolic flavonoid has been found to possess many beneficial biological actions. The aim of this study was to investigate the anti-MRSA efficacy and synergistic effect of apigenin (AP) and in combination with ampicillin (AM) and ceftriaxone (CEF). The antibacterial activity of apigenin was assessed by the broth macro dilution, checkerboard micro dilution method and time-kill assay. The mode of action was studied by outer and inner membrane permeabilisation assays, scanning electron microscopy and transmission electron microscopy. The minimum inhibitory concentration (MIC) of apigenin against gram positive and gram negative strain ranged from 32.5 to 62.5µg/ml. In checkerboard method apigenin markedly reduced the MIC of the antibiotics ampicillin 800 µg/ml shifted to 107 µg/ml (AM+AP) and ceftriaxone 58 µg/ml shifted to 2.6 µg/ml (CEF+AP) against MRSA. The synergistic activity of ampicillin and ceftriaxone plus apigenin combinations with FIC indices (CI) between 0.18-0.47. The modulation of methicillin-resistance by apigenin significantly enhanced the activities of ampicillin and ceftriaxone. The result of time-kill assays of the two drug combinations AM +AP and CEF+AP against MRSA showed significant inhibitory effect and reduced the colony count by approximately 99% after 8 h The results for outer membrane (OM) and inner membrane (IM) permeabilization showed that ampicillin and ceftriaxone in combination with apigenin damaged MRSA cytoplasmic membrane and caused subsequent leakage of intracellular constituents. Electron microscopy clearly showed that the above said combination also caused marked morphological damage of cell wall, cell shape and plasma membrane of this strain. From these results, it can be concluded that apigenin has the synergistic effect with ampicillin and ceftriaxone to reverse bacterial resistance against MRSA.


Feasibility of real-time echocardiographic evaluation during patient transport.
Echocardiography is a key diagnostic tool in evaluating patients with cardiac emergencies and chest trauma. The lack of qualified real-time interpretation limits its use by emergency first responders. Early diagnosis of cardiac emergencies has the potential to facilitate triage and medical intervention to improve outcomes. We investigated the feasibility of remote, real-time interpretation of echocardiograms during patient transport. Echocardiograms using a hand-carried ultrasound device were transmitted from an ambulance in transit to a tertiary care facility using a distributed mobile local area network. Transmitted studies were reviewed by a cardiologist for ability to interpret predefined features. Transmission quality and reliability were assessed. Echocardiographic images were successfully transmitted greater than 88% of transport time. The evaluation of left-ventricular size and function, and presence of pericardial effusion were greater than 90% concordant, but only 66% of all echocardiographic features were concordant. Most transmission losses were brief (<or=10 seconds) with little impact on interpretability. Wireless infrastructures in metropolitan areas provide the ability for real-time transmission of echocardiograms during patient transport of adequate quality for accurate interpretation.


Hidden Attractors in Discrete Dynamical Systems.
Research using chaos theory allows for a better understanding of many phenomena modeled by means of dynamical systems. The appearance of chaos in a given process can lead to very negative effects, e.g., in the construction of bridges or in systems based on chemical reactors. This problem is important, especially when in a given dynamic process there are so-called hidden attractors. In the scientific literature, we can find many works that deal with this issue from both the theoretical and practical points of view. The vast majority of these works concern multidimensional continuous systems. Our work shows these attractors in discrete systems. They can occur in Newton's recursion and in numerical integration.


The general surgical care practitioner improves surgical outpatient streamlining and the delivery of elective surgical care.
The feasibility of implementing a surgical care practitioner (SCP) role for the delivery of secondary care within the general surgery department of a district general hospital was evaluated. Streamlining patients into an SCP-led 'one-stop' gallbladder clinic for symptomatic uncomplicated cholelithiasis led to a reduction in follow-up clinic workload for major elective laparoscopic work and more appropriate triaging of primary care referrals. Each of these improvements contributed to an efficient service model.


RETROSPECTIVE ANALYSIS OF INTERVENTIONS PERFORMED BY EMERGENCY MEDICAL TEAMS IN POLAND BEFORE AND DURING THE SARS COV-2 PANDEMIC.
Introduction: The SARS-CoV-2 virus was recognized in December 2019 in China. From that moment it has quickly spread around the whole world. It causes COVID-19 disease manifested by breathlessness, coughing and high temperature. The COVID-19 pandemic has become a great challenge for humanity. The aim: To analyze interventions of emergency medical teams during the SAR-CoV-2 pandemic, and to compare obtained data with the same periods in 2018-2019. Material and methods: The study retrospectively analyzed interventions of emergency medical teams in the period from 15.03 to 15.05 in 2018 - 2020. 1,479,530 interventions of emergency medical teams were included in the study. The number of interventions, reasons for calls, and diagnoses made by heads of the emergency medical teams during the SARS-CoV-2 pandemic were compared to the same period in 2018-2019. Results: Authors observed the decline in the number of interventions performed by emergency medical teams during the pandemic in relation to earlier years by approximately 25%. The big decline concerned interventions that were the reason for calls to public places, such as "traffic accident" and "collapse". In the case of diagnoses made by the head of the emergency medical team, the diagnoses regarding stroke or sudden cardiac arrest remained at the similar level. Others showed a marked decline. Conclusions: Reduced social activity contributed to a reduced number of interventions by emergency medical teams in public places. The societal fear of the unknown also contributed to the decrease in the number of interventions performed by emergency medical teams. People began to avoid contact with other people.


Transplant of GABAergic precursors restores hippocampal inhibitory function in a mouse model of seizure susceptibility.
Defects in GABAergic function can cause epilepsy. In the last years, cell-based therapies have attempted to correct these defects with disparate success on animal models of epilepsy. Recently, we demonstrated that medial ganglionic eminence (MGE)-derived cells grafted into the neonatal normal brain migrate and differentiate into functional mature GABAergic interneurons. These cells are able to modulate the local level of GABA-mediated synaptic inhibition, which suggests their suitability for cell-based therapies. However, it is unclear whether they can integrate in the host circuitry and rescue the loss of inhibition in pathological conditions. Thus, as proof of principle, we grafted MGE-derived cells into a mouse model of seizure susceptibility caused by specific elimination of GABAergic interneuron subpopulations in the mouse hippocampus after injection of the neurotoxic saporin conjugated to substance P (SSP-Sap). This ablation was associated with significant decrease in inhibitory postsynaptic currents (IPSC) on CA1 pyramidal cells and increased seizure susceptibility induced by pentylenetetrazol (PTZ). Grafting of GFP(+) MGE-derived cells in SSP-Sap-treated mice repopulates the hippocampal ablated zone with cells expressing molecular markers of mature interneurons. Interestingly, IPSC kinetics on CA1 pyramidal cells of ablated hippocampus significantly increased after transplantation, reaching levels similar to the normal mice. More importantly, this was associated with reduction in seizure severity and decrease in postseizure mortality induced by PTZ. Our data show that MGE-derived cells fulfill most of the requirements for an appropriate cell-based therapy, and indicate their suitability for neurological conditions where a modulation of synaptic inhibition is needed, such as epilepsy.


Frequent ventricular ectopy after exercise as a predictor of death.
Exercise-induced ventricular ectopy predicts an increased risk of death in population-based cohorts. We sought to examine in a clinical cohort the prognostic importance of ventricular ectopy immediately after exercise, when reactivation of parasympathetic activity occurs. We hypothesized that ventricular ectopy after exercise (i.e., during the recovery phase) would predict an increased risk of death better than ventricular ectopy during exercise. We studied 29,244 patients (mean [+/-SD] age, 56+/-11 years; 70 percent men) who had been referred for symptom-limited exercise testing without a history of heart failure, valve disease, or arrhythmia. Frequent ventricular ectopy was defined by the presence of seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, ventricular couplets or triplets, ventricular tachycardia, ventricular flutter, torsade de pointes, or ventricular fibrillation. Frequent ventricular ectopy occurred only during exercise in 945 patients (3 percent), only during recovery in 589 (2 percent), and during both exercise and recovery in 491 (2 percent). There were 1862 deaths during a mean of 5.3 years of follow-up. Frequent ventricular ectopy during exercise predicted an increased risk of death (five-year death rate, 9 percent, vs. 5 percent among patients without frequent ventricular ectopy during exercise; hazard ratio, 1.8; 95 percent confidence interval, 1.5 to 2.1; P<0.001), but frequent ventricular ectopy during recovery was a stronger predictor (11 percent vs. 5 percent; hazard ratio, 2.4; 95 percent confidence interval, 2.0 to 2.9; P<0.001). After propensity matching for confounding variables, frequent ventricular ectopy during recovery predicted an increased risk of death (adjusted hazard ratio, 1.5; 95 percent confidence interval, 1.1 to 1.9; P=0.003), but frequent ventricular ectopy during exercise did not (adjusted hazard ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.53). Frequent ventricular ectopy during recovery after exercise is a better predictor of an increased risk of death than ventricular ectopy occurring only during exercise.


Percutaneous restoration of a kinked shunt. Case report.
A thin-walled atrial catheter used in shunting for hydrocephalus may become curled or kinked in the neck after it has been in normal position and functioning for years. The usual cause is a bout of severe coughing. Such a case is described together with a percutaneous method of restoration of the shunt by transfemoral catheterization utilizing a wire loop.


Hemodynamic stability during adrenalectomy for pheochromocytoma: A case control study of posterior retroperitoneal vs lateral transperitoneal approaches.
Hemodynamic stability is one of the most critical aspects of adrenal surgery for pheochromocytoma. Few articles have evaluated the hemodynamic status of patients undergoing posterior retroperitoneal adrenalectomy (PRA) for pheochromocytoma. The aim of this study is to compare the intraoperative hemodynamic parameters between lateral transperitoneal adrenalectomy (TPA) and PRA in this groups of patients.This report describes a retrospective study of 53 pheochromocytoma patients who underwent endoscopic adrenalectomy via transperitoneal (22 patients) or posterior retroperitoneal (31 patients) approaches from January 2008 to March 2015. Data from these patients were compared to investigate the differences in hemodynamic parameters between the 2 approaches.Clinical parameters at presentation were similar between the 2 groups, except for tumor size, which was larger in the TPA group. The PRA group is associated with reduced operative time, blood loss, and length of hospital stay compared to TPA even after adjusting for the tumor size. There was greater BP fluctuations and higher maximum systolic and diastolic blood pressure (BP) within the TPA group compared to PRA during univariate analysis. This was however not significant after adjusting for tumor size. There was no difference in the intraoperative inotropic support requirement between the 2 groups.PRA is associated with stable intraoperative hemodynamic status, as well as favorable perioperative outcomes compared to TPA in patients with small pheochromocytomas.