Novel inhibitors of surface layer processing in Clostridium difficile.
Clostridium difficile, a leading cause of hospital-acquired bacterial infection, is coated in a dense surface layer (S-layer) that is thought to provide both physicochemical protection and a scaffold for host-pathogen interactions. The key structural components of the S-layer are two proteins derived from a polypeptide precursor, SlpA, via proteolytic cleavage by the protease Cwp84. Here, we report the design, synthesis and in vivo characterization of a panel of protease inhibitors and activity-based probes (ABPs) designed to target S-layer processing in live C. difficile cells. Inhibitors based on substrate-mimetic peptides bearing a C-terminal Michael acceptor warhead were found to be promising candidates for further development.


A physiologically-based drug absorption modeling for orally disintegrating tablets.
The aim of this research was to simulate oral pharmacokinetic (PK) profiles of atorvastatin from orally disintegrating tablets (ODTs) dosed without water ingestion in fasted humans. The in vitro dissolution profiles of three different formulations of ODTs were evaluated with fasted state biorelevant media using a paddle dissolution apparatus, and the results were coupled with an in silico model to simulate the in vivo oral PK profiles of ODTs following administration to humans. Since the dissolution rates of the ODTs in the intestinal medium (FaSSIF-V2) were highly affected by pre-exposure of the tablets to the stomach medium (FaSSGF), the simulation model took account of the relationship between the gastric emptying time and the dissolution performance of the tablets in the small intestine. The ODTs were formulated with drug-containing pellets. After oral dosing of the ODTs without water ingestion, gastric emptying of the pellets was assumed to follow first order kinetics. Thus, rate constants ranging between 0.69 and 8.3 h-1 were applied in the PK simulations. The simulation model was built using Stella Professional® software. The results of the PK simulations suggest that the plasma concentration profiles of the ODTs can be described using the prediction model, but that different gastric emptying parameters for each ODT formulation are needed in humans.


Effectiveness of second-generation fibrin glue in endonasal operations.
We evaluated the efficacy and safety of the Quixil fibrin sealant after its application to endonasal operative sites. A total of 153 patients underwent nasal surgery. The rate of hemorrhagic complications was compared in the group with nasal packing and in the group in whom fibrin glue was used to stop postoperative bleeding. Our results indicate that the application of Quixil fibrin glue to the operative sites in various endonasal operations provides effective hemostasis and sealing. This fibrin glue is a more effective hemostatic agent than foam nasal packing and provides no complications, as can occur with packing. Patients with hypertension have no greater risk for postoperative bleeding if Quixil is used.


Agreement Between Actual Height and Estimated Height Using Segmental Limb Lengths for Individuals with Cerebral Palsy.
The purpose of this study was to determine the agreement between actual height or segmental length and estimated height from segmental measures among individuals with cerebral palsy. A convenience sample of 137 children and young adults with cerebral palsy (age 2-25 yrs) were recruited from a tertiary care center. Height, body mass, recumbent length, knee height, tibia length, and ulna length were measured. Estimated height was calculated using several common prediction equations. Agreement between measured and estimated height was determined using the Bland-Altman method. Limits of agreement were wide for all equations, usually in the range of ±10 cm. Repeatability of the individual measures was high, with a coefficient of variation of 1%-2% for all measures. The equation using knee height demonstrated a nonuniform difference in which height estimation worsened as overall height increased. Accurate measurement of height is important but very difficult in individuals with cerebral palsy. Segmental measures are highly repeatable and thus may be used on their own to monitor growth. However, when an accurate measure of height is needed to monitor nutritional status (i.e., for body mass index calculation), caution is warranted because there is only fair-to-poor agreement between actual height and estimated height.


Evaluation of patient-perceived satisfaction with photodynamic therapy for Bowen disease.
to formally evaluate patient concerns and patient-perceived satisfaction with photodynamic therapy (PDT) using topical application of 5-aminolevulinic acid for Bowen disease (BD). Initial focus groups and mailout questionnaire. tertiary care hospital. a novel 32-item self-reported patient satisfaction questionnaire was mailed out to all patients treated with PDT for BD from January 1, 2000, to March 31, 2008. a written questionnaire addressing side effects experienced, self-perceived effectiveness, and the personal and social consequences of PDT. one hundred thirty-two adults were treated with PDT for BD over this time period. Ninety-five patients (47% male, 53% female) completed the questionnaire. A majority (> 90%) indicated a very favourable impression of the effectiveness of PDT for BD and that side effects were mild. The most significant side effects were a burning sensation (21%) and crusting or scabbing (14%). Side effects were judged to be predictable. The process of treatment and overall time demands were judged by only 7% of respondents to be problematic. The most substantial limitations with PDT were social limitations secondary to treatment (26%), self-consciousness (28%), and skin appearance in the immediate posttreatment period (30%). Respondent reliability in response to questions was excellent. PDT is favourably received by those diagnosed with BD. PDT resulted in a high degree of perceived satisfaction for those patients with BD. Based on these data, PDT is supported as a viable method of treatment for BD.


Dysfunctional metacognition processes as risk factors for drunkorexia during adolescence.
Although metacognitive dysfunction has been associated with eating disorders, to our knowledge no study has yet explored the relation between metacognition and drunkorexia. The aim of the present study was to investigate the potential role of metacognitive processes in drunkorexia in a sample of adolescents. A total sample of 719 adolescents (353 females, 366 boys; age range 15-20) completed a self-report survey composed of Compensatory Eating and Behaviors in Response to Alcohol Consumption Scale, AUDIT-C, Metacognitions Questionnaire-30, and Positive Alcohol Metacognitions Scale. Our results showed that drunkorexia was associated with dysfunctional metacognitive processes; specifically, findings from logistic regression analysis revealed that the metacognitive beliefs in the need to control thoughts, the negative beliefs about the uncontrollability and danger of worrying and the positive metacognitions about alcohol use were significant predictors of drunkorexia. Our study suggests the relevance for prevention efforts to train adolescents to develop alternative self-regulation strategies and more adaptive ways of monitoring thoughts.


A new species of Ultratenuipalpus (Acari: Tenuipalpidae) from Cook Islands, with a key to the known species.
The genus Ultratenuipalpus (Acariformes: Tenuipalpidae) was represented by 24 species prior to this study. In this paper, we describe and illustrate Ultratenuipalpus avarua sp. nov, from Cocos sp. (Arecaceae) in Avarua, Rarotonga, the Cook Islands. A key to the world species of Ultratenuipalpus is provided.


Progestins' actions in the VTA to facilitate lordosis involve dopamine-like type 1 and 2 receptors.
In the ventral tegmental area (VTA), 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) facilitates lordosis. Whether this involves dopamine type 1 (D1) or dopamine type 2 (D2) receptors is of interest. Ovariectomized (ovx) rats with guide cannulae to the VTA were estradiol (E2) primed and pretested for lordosis. Rats were then infused with the D1 (Experiment 1) or D2 (Experiment 2) antagonists or agonists (0, 100, or 200 ng) to the VTA and were retested. After a second infusion of 3alpha,5alpha-THP (0, 100, or 200 ng) or vehicle, rats were tested 10, 60, and 120 min later. In Experiment 3, rats were administered a progestin receptor antagonist, RU38486, systemically or to the VTA 1 h prior to vehicle, SKF38393 and/or 3alpha,5alpha-THP infusions. 3alpha,5alpha-THP infusions increased lordosis over that seen with E2 priming. The D1 antagonist, SCH23390, attenuated 3alpha,5alpha-THP, but not E2-facilitated lordosis. The D1 agonist, SKF38393, augmented 3alpha,5alpha-THP, but not E2-facilitated lordosis. The D2 antagonist, sulpiride, had no significant effects on lordosis. The D2 agonist, quinpirole, prevented 3alpha,5alpha-THP-facilitated lordosis. RU38486 (subcutaneous) inhibited lordosis, whereas infusions to the VTA decreased lordosis produced by SKF38393 and 3alpha,5alpha-THP, but not 3alpha,5alpha-THP alone. Thus, 3alpha,5alpha-THP's actions in the VTA for lordosis may involve D1 and/or D2 receptors.


[A CASE OF RETROPERITONEAL HEMORRHAGE CAUSED BY THE INSERTION OF A URETERAL ACCESS SHEATH. A RARE COMPLICATION ASSOCIATED WITH FLEXIBLE TRANSURETHRAL LITHOTRIPSY (fTUL)].
A 77-year-old man with a right kidney stone was admitted to our hospital. A ureteroscope was introduced into the ureter without dilation under direct vision. We then performed flexible transurethral lithotripsy (f-TUL) using a ureteral access sheath and successfully fragmented the stone and extracted almost all the stone fragments without any complications. Just 3 hours after the operation, he suddenly developed right abdominal pain with a decrease in hemoglobin. A CT scan showed a retroperitoneal hemorrhage around the lower ureter. We herein describe a rare complication associated with flexible transurethral lithotripsy.


Differentially expressed miRNAs after GnRH treatment and their potential roles in FSH regulation in porcine anterior pituitary cell.
Hypothalamic gonadotropin-releasing hormone (GnRH) is a major regulator of follicle-stimulating hormone (FSH) secretion in gonadotrope cell in the anterior pituitary gland. microRNAs (miRNAs) are small RNA molecules that control gene expression by imperfect binding to the 3'-untranslated region (3'-UTR) of mRNA at the post-transcriptional level. It has been proven that miRNAs play an important role in hormone response and/or regulation. However, little is known about miRNAs in the regulation of FSH secretion. In this study, primary anterior pituitary cells were treated with 100 nM GnRH. The supernatant of pituitary cell was collected for FSH determination by enzyme-linked immunosorbent assay (ELISA) at 3 hours and 6 hours post GnRH treatment respectively. Results revealed that GnRH significantly promoted FSH secretion at 3 h and 6 h post-treatment by 1.40-fold and 1.80-fold, respectively. FSHβ mRNA at 6 h post GnRH treatment significantly increased by 1.60-fold. At 6 hours, cells were collected for miRNA expression profile analysis using MiRCURY LNA Array and quantitative PCR (qPCR). Consequently, 21 up-regulated and 10 down-regulated miRNAs were identified, and qPCR verification of 10 randomly selected miRNAs showed a strong correlation with microarray results. Chromosome location analysis indicated that 8 miRNAs were mapped to chromosome 12 and 4 miRNAs to chromosome X. Target and pathway analysis showed that some miRNAs may be associated with GnRH regulation pathways. In addition, In-depth analysis indicated that 10 up-regulated and 3 down-regulated miRNAs probably target FSHβ mRNA 3'-UTR directly, including miR-361-3p, a highly conserved X-linked miRNA. Most importantly, functional experimental results showed that miR-361-3p was involved in FSH secretion regulation, and up-regulated miR-361-3p expression inhibited FSH secretion, while down-regulated miR-361-3p expression promoted FSH secretion in pig pituitary cell model. These differentially expressed miRNAs resolved in this study provide the first guide for post-transcriptional regulation of pituitary gonadotrope FSH secretion in pig, as well as in other mammals.


Spectroscopic analysis of moss (Ceratodon purpureus and Physcomitrella patens) recombinant non-symbiotic hemoglobins.
Non-symbiotic hemoglobins (nsHbs) are O(2)-binding proteins widely distributed in land plants, including primitive bryophytes. Little is known about the properties of bryophyte nsHbs. Here, we report the spectroscopic characterization of two moss recombinant nsHbs, CerpurnsHb of Ceratodon purpureus and PhypatnsHb of Physcomitrella patens. Spectra showed that the absorption maxima of the ferrous and ferric forms of recombinant CerpurnsHb are located at 418, 531 and 557 nm and 407, 537, 569 (shoulder) and 632 (shoulder) nm, respectively, and of PhypatnsHb are located at 422, 529 and 557 nm and 407, 531, 571 (shoulder) and 647 (shoulder) nm, respectively. These absorption maxima are similar to those of rice Hb1. Also, the absorption maxima of the oxygenated ferrous form of recombinant CerpurnsHb and PhypatnsHb are located at 412, 541 and 575 nm and 414, 541 and 574 nm, respectively, similar to those of oxygenated rice Hb1 and cowpea leghemoglobin II. This evidence indicates that CerpurnsHb and PhypatnsHb are mostly hexacoordinate and that they bind O(2).


Young adults' familiarity with different cannabis product terms: the need for standardized cannabis surveys.
Cannabis legalization has resulted in the proliferation of cannabis products. Participants' familiarity with terms for these products may have implications for assessment, as unfamiliarity with particular terms may result in under-reports of use. A convenience sample of 861 college students from one U.S. university completed a survey in the spring of 2020 about their familiarity with a variety of cannabis product terms and use of a variety of cannabis products. Participants varied in their familiarity with cannabis product terms. For example, with regard to terms for cannabis concentrates with very high concentrations of THC, 85% of participants reported being familiar with the term "wax pen or THC oil," but only 27% reported being familiar with the term "butane hash oil (BHO)" (i.e., the oil that composes most concentrates). Moreover, of participants who reported use of concentrates based on selecting pictures of the products they had used (n = 324, 40%), 99% (n = 322) reported having seen a "wax pen or THC oil" based on a written list of product terms, whereas only 20% (n = 65) reported having seen "butane hash oil (BHO)." This suggests that asking about use of "butane hash oil" use may result in lower rates of cannabis concentrate use than asking about use of "wax pen/THC oil." With regard to terms for marijuana flower, 29% of participants (n = 248) reported being unfamiliar with the term marijuana "buds or flowers." Of participants who reported use of marijuana flower based on selecting pictures of the products they had used (38% of the sample, n = 329), only 86% (n = 282) reported having seen marijuana "buds or flowers" based on a written list of product terms. This suggests that asking about use of marijuana "buds or flowers" use could result in under-reporting due to lack of familiarity with that term. Finally, when asked to select pictures of the cannabis product(s) that participants thought constituted "marijuana," participants most commonly selected pictures of marijuana flower (93%), followed by wax pen/THC oil (57%) and edibles (49%). Young adults vary in their familiarity with cannabis product terms, and some may under-report cannabis use in surveys that rely on written cannabis product terms. Young adults also differ in terms of which cannabis products they think constitute "marijuana." Although participants' familiarity with specific cannabis product terms in this sample may not generalize to other populations, results highlight the need for standardized surveys of cannabis use that incorporate pictures of cannabis products to overcome issues related to variability in familiarity with cannabis product terms.


Adhesion of human breast carcinoma to extracellular matrix proteins is modulated by galectin-3.
In this report, we have analyzed the adhesive interactions of a breast carcinoma cell line, BT-549, and its galectin-3-transfected subclone 11-9-1-4 with laminin, collagen IV and fibronectin. We determined that 11-9-1-4 cells adhered much more rapidly (within 1 h of plating) to laminin- and collagen IV-coated wells than the galectin-3 null expressing BT-549 cells. However, after 24 h, both cell lines fully adhered to laminin and collagen IV. Both cell lines also achieved maximum adhesion to fibronectin within 30 min. Not only did 11-9-1-4 express galectin-3 in the usual punctate pattern on its cell surface, it demonstrated a higher surface expression of alpha 6 beta 1 integrin compared to BT-549. The 11-9-1-4 cells were able to invade through matrigel-coated polycarbonate filters at approximately 3 times the rate of BT-549 parental cells. Our data suggest that galectin-3 is essential for adhesion to laminin and collagen IV but not fibronectin by breast carcinoma cells. In addition, galectin-3 expression may modulate the surface expression of some of the integrins specific for laminin and collagen IV adhesion and invasion of basement membrane by breast carcinoma cells.


Serum levels of selected adipocytokines in benign and malignant parotid gland tumor patients.
The aim of this study was to evaluate serum levels of adiponectin, leptin, visfatin and IL-6 in patients with pleomorphic adenoma, Warthin's tumor and acinic cell carcinoma of the parotid gland. Venous blood samples were collected from 30 patients with pleomorphic adenoma, 21 patients with Warthin's tumor and 8 patients with acinic cell carcinoma. Serum adiponectin, leptin, visfatin, IL-6 and CRP concentrations were determined. Our results revealed significantly lower adiponectin serum levels in patients with malignant tumors compared to benign tumor individuals. Moreover, in benign cases the level was significantly higher compared to controls. Furthermore, serum leptin concentrations of benign tumor patients were higher compared to controls. Those differences, however, were observed only in males. The serum visfatin level was elevated in all tumor subjects compared to healthy individuals, whereas the serum IL-6 concentration was similar. We anticipate that adiponectin may play a potential protective role in salivary gland tumors. Also leptin and visfatin seem to play an important role in salivary gland tumor pathology, although in males and females leptin may act or be regulated in a different manner. The influence of visfatin on salivary gland tumors is probably independent of IL-6 production.


Genetic characterization and antimicrobial susceptibility of Mannheimia haemolytica isolated from the nasopharynx of feedlot cattle.
A surveillance study was undertaken to examine the population dynamics and antimicrobial resistance of Mannheimia haemolytica isolated from feedlot cattle. A total of 416 isolates were collected from the nasopharynx either upon entry or exit from two feedlots in southern Alberta, Canada. Isolates were serotyped, characterized by pulsed-field gel electrophoresis and tested for susceptibility to ten antimicrobial agents via disk diffusion. Resistant isolates were screened by PCR for select antimicrobial-resistance gene determinants. Isolates were highly diverse, with 335 unique pulsed-field profiles identified among 147 strongly related clusters (similarity ≥ 85%). Clonal spread of isolates throughout the feedlots was limited and no clear association was found between genetic relatedness of M. haemolytica and sampling event (entry or exit). Pulsed-field profiles sharing a common serotype and resistance phenotype tended to cluster together. The majority of isolates were identified as serotype 2 (74.5%) although both serotype 1 (11.9%) and 6 (12.7%) were detected. Only 9.54% of isolates exhibited antimicrobial resistance. Resistance to oxytetracycline was most prevalent (n=16), followed by ampicillin (n=10), and amoxicillin/clavulanic acid (n=7). Multi-drug resistance was observed in five isolates. The tetH gene was detected in all but two oxytetracycline resistant isolates. Other detectable resistance determinates included ermX and bla(ROB-1). In the two feedlots examined, M. haemolytica exhibited considerable genetic diversity and limited resistance to common veterinary antibiotics. Garnering further information on the linkage between genotype and phenotype should contribute toward a better understanding of the pathogenesis and dissemination of M. haemolytica in feedlots.


Coupled-cluster theory based upon the fragment molecular-orbital method.
The fragment molecular-orbital (FMO) method was combined with the single-reference coupled-cluster (CC) theory. The developed method (FMO-CC) was applied at the CCSD and CCSD(T) levels of theory, for the cc-pVnZ family of basis sets (n=D,T,Q) to water clusters and glycine oligomers (up to 32 molecules/residues using as large basis sets as possible for the given system). The two- and three-body FMO-CC results are discussed at length, with emphasis on the basis-set dependence and three-body effects. Two- and three-body approximations based on interfragment distances were developed and the values appropriate for their accurate application carefully determined. The error in recovering the correlation energy was several millihartree for the two-body FMO-CC method and in the submillihartree range for the three-body FMO-CC method. In the largest calculations, we were able to perform the CCSD(T) calculations of (H2O)32 with the cc-pVQZ basis set (3680 basis functions) and (GLY)32 with the cc-VDZ basis set (712 correlated electrons). FMO-CC was parallelized using the upper level of the two-layer parallelization scheme. The computational scaling of the two-body FMO-CC method was demonstrated to be nearly linear. As an example of timings, CCSD(T) calculations of (H2O)32 with cc-pVDZ took 13 min on an eight node 3.2-GHz Pentium4 cluster.


Mechanisms and implications in gene polymorphism mediated diverse reponses to sedatives, analgesics and muscle relaxants.
Responses to sedatives, analgesics and muscle relaxants vary among patients under general anesthesia, which could be ascribed to the disparities of clinical characteristics and genetic factors of individuals. Accumulating researches have indicated that gene polymorphisms of the receptors, transporters and metabolizing enzymes associated with anesthetics play a considerable role in their efficacy. However, a systematically summarized study on the mechanisms of gene polymorphisms on pharmacodynamics and pharmacokinetics of anesthetics is still lacking. In this paper, the recent researches on pharmacogenomics of sedatives, analgesics and muscle relaxants are comprehensively reviewed, and the contributions and mechanisms of polymorphisms to the differences of individual efficacy of these drugs are discussed, so as to provide guidance for the formulation of a rational anesthesia regimen for patients with various genotypes.


Decreased Spp1 Expression in Acute Myocardial Infarction after Ischemia and Reperfusion Injury.
With the progress of shock therapy and the establishment and promotion of methods such as thrombolytic therapy and percutaneous coronary intervention (PCI), many tissues and organs have been reperfused after ischemia which may cause even worse disorder called ischemia-reperfusion injury (IRI). mRNAs have been found to have significant impacts on ischemia-reperfusion through various mechanisms. In view of the accessibility of mRNAs from blood, we aimed to find the association between mRNA and ischemia-reperfusion. We used the GSE83472 dataset from the Gene Expression Omnibus (GEO) database to find differential RNA expression between ischemia-reperfusion tissue and control samples. In addition, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to find the biological property of 449 RNAs from GSE83472 via the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Besides, Gene Set Enrichment Analysis (GSEA), a tool to find the pathway orientation of a gene set, was used for further study in the four most significant KEGG pathways. Furthermore, we constructed a protein-protein interaction (PPI) network. In the end, we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting to measure and compare the expression of Spp1 in patients who accepted percutaneous coronary intervention. The bioinformatics analyses suggested that Spp1 was a hub gene in reperfusion after ischemia. The qRT-PCR result showed that the Spp1 expression was significantly downregulated in ischemia-reperfusion cells after PCI compared with normal samples and so as the western blotting. Spp1 might play an essential role in acute myocardial infarction after ischemia and reperfusion injury.


Sacroiliac Stretching Improves Glenohumeral Internal Rotation Deficit of the Opposite Shoulder in Baseball Players in a Randomized Control Trial.
Glenohumeral internal rotation deficit (GIRD) is a well-documented finding in throwing athletes. To investigate whether stretching the contralateral sacroiliac (SI) joint can improve GIRD in baseball players. After internal shoulder rotation was measured in 23 minor league baseball players, the players randomly were assigned to either a control (ie, sleeper stretch of the dominant shoulder) or experimental (ie, SI joint stretch contralateral to the dominant shoulder) group. Afterward, internal rotation (IR) of their dominant shoulders was remeasured. The mean initial end-range IR was 68.6° (SD = 7.9°) in the sleeper stretch group (n = 8) and 64.5° (SD = 5.1°) in the SI joint stretch group (n = 15). After stretching, the sleeper stretch group's mean end-range IR was 72.1° (SD = 7.2°), a 3.5° improvement (P = 0.1058), whereas the contralateral SI joint stretch group's mean end-range IR was 71.9° (SD = 6.6°), a 7.4° improvement (P = 0.0041). Stretching the contralateral SI joint improved GIRD more than the sleeper's stretch.


The role of c-kit and imatinib mesylate in uveal melanoma.
Uveal melanoma (UM) is the most common primary intraocular tumor in adults, leading to metastasis in 40% of the cases and ultimately to death in 10 years, despite local and/or systemic treatment. The c-kit protein (CD117) is a membrane-bound tyrosine kinase receptor and its overexpression has been observed in several neoplasms. Imatinib mesylate is a FDA approved compound that inhibits tyrosine quinase receptors, as well as c-kit. Imatinib mesylate controls tumor growth in up to 85% of advanced gastrointestinal stromal tumors, a neoplasia resistant to conventional therapy. Fifty-five specimens of primary UM selected from the archives of the Ocular Pathology Laboratory, McGill University, Montreal, Canada, were immunostained for c-kit. All cells displaying distinct immunoreactivity were considered positive. Four human UM cell lines and 1 human uveal transformed melanocyte cell line were tested for in vitro proliferation Assays (TOX-6) and invasion assay with imatinib mesylate (concentration of 10 microM). The c-kit expression was positive in 78.2% of the UM. There was a statistical significant decrease in the proliferation and invasion rates of all 5 cell lines. The majority of UM expressed c-kit, and imatinib mesylate does decrease the proliferation and invasion rates of human UM cell lines. These results justify the need for a clinical trial to investigate in vivo the response of UM to imatinib mesylate.


Rise in the number of notified human hantavirus infections since October 2011 in Baden-Wurttemberg, Germany.
From October 2011 to April 2012, 852 human hantavirus infections were notified in Germany, of which 580 (68%) were in Baden-Württemberg. Case numbers started to rise earlier than they did before the previous outbreaks in 2007 and 2010, and are the largest ever reported in this state during October to April of any year. The early rise could be due to a beech mast year in 2011, followed by an early and massive reproduction of the reservoir bank vole populations during winter 2011 and spring 2012.


[Acceptance of own disease by patients with diagnosed glaucoma].
The notion of glaucoma comprises a number of diseases which are all characterized by optic nerve damage. It was estimated that nearly 70 million people all over the world suffer from glaucoma and 10% of them have lost their sight because of glaucomatous optic nerve atrophy. The aim of this paper is to determine the acceptance level of the condition by patients with primary glaucoma as well as to study the relations between the acceptance level and the parameters influencing it directly or indirectly. The study included 50 patients (40 women and 10 men) aged between 20 and 90 with recognized primary open-angle glaucoma. A questionnaire and a standardized Acceptance of Illness Scale (AIS) were used to evaluate the study material. The observed differences and relation levels were subjected to statistical analysis with the use of the Student's t test as well as the chi2 test, and the statistical significance level was established at p < 0.05. Within the studied group, people between the ages of 61 and 70 (38%), with secondary education (48%), were the most numerous. The most frequent therapeutic method was local treatment (application of eye drops). Prescribed medication was taken on a regular basis by 86% of patients, lack of regularity was declared by 14% of them. The 26% of patients realize their duties less accurately than before and 12% of them declared the need of frequent breaks in their work. The analysis showed a statistically significant relation (p = 0.0005) between the acceptance level of the condition and refraining from various forms of activity. The low acceptance of patients' illness determined the increase of they resignation from all forms of physical activity. The consecutive degrees of disease acceptance (low, medium, high) are comprised in glaucoma patients in the same proportion, i.e. each degree comprises around 30% of patients the most serious problems accepting the illness. This means that the tolerance of the disease is observed in 1/3 of patients with glaucoma. The most serious problems in disease acceptance were determined in elderly people and those with elementary or vocational education.


Endovascular stentectomy using the snare over stent-retriever (SOS) technique: An experimental feasibility study.
Feasibility of endovascular stentectomy using a snare over stent-retriever (SOS) technique was evaluated in a silicon flow model and an in vivo swine model. In vitro, stentectomy of different intracranial stents using the SOS technique was feasible in 22 out of 24 (92%) retrieval maneuvers. In vivo, stentectomy was successful in 10 out of 10 procedures (100%). In one case self-limiting vasospasm was observed angiographically as a technique related complication in the animal model. Endovascular stentectomy using the SOS technique is feasible in an experimental setting and may be transferred to a clinical scenario.


Adrenergic β2-receptor mediates itch hypersensitivity following heterotypic chronic stress in rats.
Chronic stress is widely considered to trigger or enhance itch, especially for pruritic dermatitis. However, the molecular mechanisms linking chronic stress and itch are still unknown. The present study aimed to elucidate the role of adrenergic signaling in itch hypersensitivity following heterotypic chronic intermittent stress (HIS) in rats. HIS significantly increased hindlimb scratching, but not forepaw swiping, induced by intradermal injection of 5-hydroxytryptamine (5-HT) in the rat cheek. Coadministration of stress mediators such as norepinephrine or epinephrine dose-dependently increased both 5-HT-induced hindlimb scratching and 5-HT-induced forepaw swiping. HIS-induced itch hypersensitivity was attenuated by blockade of sympathetic signaling through guanethidine treatment, and systemic administration of the β-adrenoceptor antagonist propranolol and the β2-adrenoceptor antagonist butoxamine, but not on treatment with an α-adrenoceptor antagonist phentolamine and a β1-adrenoceptor antagonist atenolol. Moreover, HIS selectively increased the expression of β2-adrenoceptors and proinflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nerve growth factor (NGF)] in rat skin. The β-blockers propranolol and butoxamine abolished the upregulation of proinflammatory factors. The β2-adrenoceptor agonist terbutaline was sufficient to enhance the skin expression of TNF-α and IL-1β and to increase 5-HT-induced scratching in naive rats. Pretreatment with TNF-α could increase 5-HT-induced scratching. Together, these results demonstrate that β2-adrenoceptors mediate itch hypersensitivity following chronic stress by inducing proinflammatory factors, such as TNF-α, in the skin.


Current perspectives regarding the application and incorporation of silver nanoparticles into dental biomaterials.
The key idea of nanotechnology is to construct and preserve functional structures by means of exploiting atoms and molecules. Nanotechnology has proven to be crucial in pharmacological medicine, tissue engineering, clinical diagnosis, long term conservation of biological tissues in a cryogenic state, protein detection, tumor destruction and magnetic resonance imaging.The aim of this paper is to review the literature on the specific characteristics of nanostructured materials, their applications and advantages that they bring to dentistry. We conducted an electronic scientific database research that included PubMed, Cochrane and Medline. The following keywords were used: nanotechnology, nanodentistry and silver nanoparticles. Initially 1650 original articles were retrieved from the these mentioned international databases, which were screened in detail. We included literature reviews that dealt with the comprehensive applications of nanostructured particles and silver nanoparticles in particular, in all fields of contemporary dentistry. Case reports, clinical trials, editorials and opinion letters were excluded in the first phase of our research. Fifty two articles met all the selection criteria and were ultimately selected and reviewed. Nanotechnology deals with the production of various types of nanomaterials with potential applications in the field of biomedicine. Silver nanoparticles have the capacity to eliminate dental caries producing bacteria or repair teeth enamel with signs of dental decay. Nanodentistry will allow better oral health by use of nanostructured materials. Treatment opportunities that nanotechnology has to offer in contemporary dentistry include local anesthesia, permanent treatment of dental hypersensitivity, orthodontic and oral health care with nanorobotic dentifrice. The studies that we reviewed are largely in favor of nanotechnology and nanostructured materials, highlighting their qualities and enhancements they bring to the field of dentistry. Although many of these products that benefit from silver nanoparticles properties are still expensive and exclusive, we can foresee major improvements and demand regarding dental biomaterials with nanoparticles incorporated in the near future.


[Advances in perioperative antiviral therapy for HBV/HCV-associated hepatocellular carcinoma].
Chronic viral hepatitis has a high prevalence rate in China, and the presence or absence of hepatitis virus replication is closely associated with the surgical outcome of patients. Therefore, perioperative antiviral therapy becomes an important method for improving patients' outcome. On the basis of treatment modalities and features of different viral infections, this article elaborates on the strategies and effects of perioperative antiviral therapy, in order to guide clinical practice and improve patients' prognosis.


Infection prophylaxis for the patient with cancer.
Despite major advances in treatment, patients with cancer still are plagued by infections. Anti-infection prophylaxis begins with attempts to enhance host defenses, minimize natural barrier alterations, and reduce the number of pathogenic organisms in the patient's environment. Prevention of infection via immunomodulation also is effective to some extent. Immunoglobulin administration, leukocyte transfusion, vaccines, and lithium carbonate are integral parts of this approach to prophylaxis. Antimicrobial modulation also has been attempted. Oral nonabsorbable antibiotics have been used to reduce the number of potentially pathogenic gastrointestinal organisms. Systemic antibiotics have been evaluated for their prophylactic efficacy in patients with cancer. Obstacles to effective systemic prophylaxis include the risk of developing resistant populations of microorganisms and the inordinately large number of potentially pathogenic organisms. The oncology nurse must assume specific responsibilities when administrating prophylactic regimens. There are three crucial issues to be considered: risk factors, aspects of cost and reimbursement, and availability of the most recent treatment options.


[The influence of camera-to-object distance and focal length on the representation of faces].
When one thinks of the so-called barrel or wide-angle distortion, grotesquely warped faces may come to mind. For less extreme cases with primarily inconspicuous facial proportions, the question, however, still arises whether there may be a resulting impact on the identification of faces. In the first experiment, 3 test persons were photographed at a fixed camera-to-object distance of 2 m. In the second experiment, 18 test persons were each photographed at a distance of 0.5 m and 2.0 m. For both experiments photographs were taken from a fixed angle of view in alignment with the Frankfurt Plane. An isolated effect of the focal length on facial proportions could not be demonstrated. On the other hand, changes in the camera-to-object distance clearly influenced facial proportions and shape. A standardized camera-to-object distance for passport photos, as well as reconstruction of the camera-to-object distance from crime scene photos and the use of this same distance in taking photographs for comparison of suspects are called for. A proposal to refer to wide-angle distortion as the nearness effect is put forward.


Adhesion to patient safety protocols in emergency care units.
To investigate compliance of national patient safety protocols in Emergency Care Units (UPA) of the Paraná State. From April until September 2016, the exploratory stage of the action research was conducted on stratified sampling with 377 patients of eight units, with use of verification instrument of basic safety actions. The absence of systematic identification of patients, fall risk assessment and signaling and development of pressure injuries were evidenced. We observed that 52.8% of parenteral solutions in use were not identified and that, in only 29.4% of the cases, the allergic condition was investigated. In 80.6% of the emergency units there was availability of alcoholic solution to hand hygiene. We concluded that the non-compliance of basic actions concerning patient safety exposes users to preventable adverse events and demands systematized actions to comply with government guidelines and promote quality of health assistance.


Total and acylated ghrelin in liver cirrhosis: correlation with clinical and nutritional status.
The pathogenesis of anorexia in cirrhotic patients is complex and the appetite-modulating hormone ghrelin could be involved. Acylated ghrelin is the biologically active form that modifies insulin sensitivity and body composition. The aim of the present study was to compare acylated and total ghrelin concentration in patients with liver cirrhosis and to investigate the possible relationship between ghrelin and clinical and nutritional parameters. Sixty patients with viral liver cirrhosis who did not have hepatocellular carcinoma or acute infections were studied. Twenty healthy volunteers were recruited after matching for age, gender, and body mass index with the patients and served as controls. Fasting levels of total, acylated ghrelin, leptin, TNF-alpha and insulin were measured in all subjects, in addition, clinical and nutrition parameters were assessed. In cirrhotic patients, plasma levels of both acylated and total ghrelin were significantly higher than those in the controls. The mean plasma acylated ghrelin levels were significantly higher in Child C cirrhosis compared to Child A and B. Ghrelin (total and acylated) were negatively correlated with leptin in cirrhotic patients confirming the fact that leptin acts as a physiological counterpart of ghrelin. Nutritional and metabolic abnormalities in cirrhotic patients may be dependent on the changes in the ghrelin/leptin systems, mainly the acylated form of ghrelin.


Fluorescence images of DNA-bound YOYO between coupled silver particles.
Oligonucleotide-bound silver particles were coupled through hybridization with target complementary oligonucleotides. YOYO molecules were intercalated into DNA duplexes bound between the coupled metal particles. Fluorescence images of YOYO molecules were monitored by scanning confocal microscopy. Relative to the free single YOYO, the emission brightness of the image was enhanced 80-fold after intercalating the fluorophores into the DNA duplexes between the coupled silver particles. Some images of the labeled metal particle dimers were observed to be dumbbell-shaped, suggesting that the stretching of intercalated YOYO molecules was restricted because of the orientation effect of fluorophores. The shortened lifetime of YOYO molecules between the coupled metal particles indicated that the fluorescence was enhanced via a near-field interaction mechanism between the fluorophore and the metal nanoparticle.


Imaging features of cerebral and spinal cystic echinococcosis.
The main objective of this study was to describe the characteristic imaging features of cerebral and spinal hydatid disease (HD) in magnetic resonance imaging (MRI) and computed tomography (CT) in order to provide more effective differential diagnoses in endemic regions. We also aimed to use MRI and CT to evaluate whether the World Health Organization's (WHO) new classification of hepatic cystic echinococcosis (CE) could be used in the classification of cerebral HD. We retrospectively reviewed the CT and MR images of 30 patients who were diagnosed with cerebral and spinal HD between 1990 and 2014. The imaging findings were noted. All hydatid cysts were classified according to the WHO classification of hepatic CE, consisting of six types. The study group consisted of 49 CEs in 27 patients with cerebral HD and 12 CEs in three patients with spinal HD. Of the cysts, 14 were type CL (cystic lesion), 29 were type CE1, 11 were type CE2 and seven were type CE3. In other words, 54 cysts were in the active group and seven were in the transition group. Most of the cysts were type CL and CE1. Even though characteristic imaging features could be used in the differential diagnosis of HD, sometimes the differentiation of HD from other cystic lesions may be difficult. The use of WHO classification will provide standardisation of uniform treatment modality, as the treatment of HD, according to the stage of the disease, may be surgical or medical.


Electrostatic Charge on Flying Hummingbirds and Its Potential Role in Pollination.
Electrostatic phenomena are known to enhance both wind- and insect-mediated pollination, but have not yet been described for nectar-feeding vertebrates. Here we demonstrate that wild Anna's Hummingbirds (Calypte anna) can carry positive charges up to 800 pC while in flight (mean ± s.d.: 66 ± 129 pC). Triboelectric charging obtained by rubbing an isolated hummingbird wing against various plant structures generated charges up to 700 pC. A metal hummingbird model charged to 400 pC induced bending of floral stamens in four plants (Nicotiana, Hemerocallis, Penstemon, and Aloe spp.), and also attracted falling Lycopodium spores at distances of < 2 mm. Electrostatic forces may therefore influence pollen transfer onto nectar-feeding birds.


Associations of loneliness and social isolation with cardiovascular and metabolic health: a systematic review and meta-analysis protocol.
A growing number of studies suggest that social isolation and loneliness are associated with premature mortality and are more prevalent among people with mental illness than in the general population, outlining many potential paths to disease still to be elucidated. The purpose of this meta-analysis is to examine the relationship between loneliness, social isolation, and established cardiovascular/metabolic risk factors and disorders, especially in severe mental illness, and to account for potential heterogeneity in the literature. Studies that report measures of loneliness and/or social isolation along with cardiovascular/metabolic risk factors will be identified. PubMed, EMBASE (through Ovid SP), Scopus, and PsycINFO (through Ovid SP) will be searched, along with citation lists of retrieved articles and the Cochrane Database of Systematic Reviews. Grey literature will be searched using Google Scholar. Data will be extracted from eligible studies for a random effects meta-analysis. For each study, a summary effect size, heterogeneity, risk of bias, publication bias, and the effect of categorical and continuous moderator variables will be determined. This proposed systematic review and meta-analysis will identify and synthesise evidence to determine if there is an association between loneliness, social isolation, and cardiovascular/metabolic risk factors, with a special focus on severe mental illnesses. The results will help determine links and promising avenues of further research. PROSPERO CRD42018111911.


Impact of walking upon medical care expenditure in Japan: the Ohsaki Cohort Study.
Physical activity is expected to reduce medical costs by lowering the risk for a variety of chronic diseases. However, little is known about the actual magnitude of medical cost saved by physical activity. We attempted to quantify the association between time spent walking and medical care costs, based on a 4-year prospective observation of National Health Insurance (NHI) beneficiaries in rural Japan. In 27 431 Japanese men and women, aged 40-79 years, who had no functional limitation or conditions interfering with physical activity at the baseline survey in 1994, we ascertained all hospitalizations, outpatient visits, and the costs through computerized linkage with NHI claims history files between January 1995 and December 1998. Medical costs significantly reduced with longer time spent walking. Per capita medical cost was pound 111.80 per month (95% CI: 109.3, 114.2) in those who walked for < or =30 minutes/day, pound 108.10 (95% CI: 105.7, 110.5) in those who walked for 30 minutes-1 hour, and pound 97.30 (95% CI: 95.5, 99.0) in those who walked for > or =1 hour, after multivariate adjustment of potential confounders. This prospective study in Japan indicated that time spent walking was significantly associated with lower medical costs.


ATP-induced conformational changes of nucleotide-binding domains in an ABC transporter. Importance of the water-mediated entropic force.
ATP binding cassette (ABC) proteins belong to a superfamily of active transporters. Recent experimental and computational studies have shown that binding of ATP to the nucleotide binding domains (NBDs) of ABC proteins drives the dimerization of NBDs, which, in turn, causes large conformational changes within the transmembrane domains (TMDs). To elucidate the active substrate transport mechanism of ABC proteins, it is first necessary to understand how the NBD dimerization is driven by ATP binding. In this study, we selected MalKs (NBDs of a maltose transporter) as a representative NBD and calculated the free-energy change upon dimerization using molecular mechanics calculations combined with a statistical thermodynamic theory of liquids, as well as a method to calculate the translational, rotational, and vibrational entropy change. This combined method is applied to a large number of snapshot structures obtained from molecular dynamics simulations containing explicit water molecules. The results suggest that the NBD dimerization proceeds with a large gain of water entropy when ATP molecules bind to the NBDs. The energetic gain arising from direct NBD-NBD interactions is canceled by the dehydration penalty and the configurational-entropy loss. ATP hydrolysis induces a loss of the shape complementarity between the NBDs, which leads to the dissociation of the dimer, due to a decrease in the water-entropy gain and an increase in the configurational-entropy loss. This interpretation of the NBD dimerization mechanism in concert with ATP, especially focused on the water-mediated entropy force, is potentially applicable to a wide variety of the ABC transporters.


An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A.
Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3). 80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes. This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group. These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults. EudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13).


Direct flow cytometry of anaerobic bacteria in human feces.
We describe a flow cytometry method for analysis of noncultured anaerobic bacteria present in human fecal suspensions. Nonbacterial fecal compounds, bacterial fragments, and large aggregates could be discriminated from bacteria by staining with propidium iodide (PI) and setting a discriminator on PI fluorescence and by exclusion of events with large forward scatter. Since anaerobic bacteria, which account for over 99.9% of all fecal bacteria, die during sample preparation, a fixation step was not necessary. A second aim of this study was to investigate the technical possibility of measurement of in vivo IgA coating of fecal anaerobic bacteria as well as their bacterial size. Fecal samples of 22 healthy human volunteers were analyzed. The fluorescence distribution of IgA-coated bacteria labeled with fluorescein isothiocyanate (FITC)-anti-Hu-IgA had overlap with noncoated bacteria. However, with match region subtraction, detection of low levels of specific FITC fluorescence on IgA-coated bacteria was achieved. The median bacterial two-dimensional surface area was 1.0 microns2. To validate flow cytometry data, all samples were analyzed with an image analysis system as well. With this new method, a rapid evaluation of fecal flora with high sensitivity for specific FITC fluorescence is possible without culturing.


Nonimmunologic Donor-Recipient Pairing, HLA Matching, and Graft Loss in Deceased Donor Kidney Transplantation.
In kidney transplantation, nonimmunologic donor-recipient (D-R) pairing is generally not given the same consideration as immunologic matching. The aim of this study was to determine how nonimmunologic D-R pairing relates to independent donor and recipient factors, and to immunologic HLA match for predicting graft loss. Seven D-R pairings (race, sex, age, weight, height, cytomegalovirus serostatus, and HLA match) were assessed for their association with the composite outcome of death or kidney graft loss using a Cox regression-based forward stepwise selection model. The best model for predicting graft loss (including nonimmunologic D-R pairings, independent D-R factors, and/or HLA match status) was determined using the Akaike Information Criterion. Twenty three thousand two hundred sixty two (29.9%) people in the derivation data set and 9892 (29.7%) in the validation data set developed the composite outcome of death or graft loss. A model that included both independent and D-R pairing variables best predicted graft loss. The c-indices for the derivation and validation models were 0.626 and 0.629, respectively. Size mismatch (MM) between donor and recipient (>30 kg [D < R} and >15 cm [D < R]) was associated with poor patient and graft survival even with 0 HLA MM, and conversely, an optimal D-R size pairing mitigated the risk of graft loss seen with 6 HLA MM. D-R pairing is valuable in predicting patient and graft outcomes after kidney transplant. D-R size matching could offset the benefit and harm seen with 0 and 6 HLA MM, respectively. This is a novel finding.


Beneficial Effects on Pregnancy Outcomes of Thyroid Hormone Replacement for Subclinical Hypothyroidism.
Background. Hypothyroidism and raised thyroid antibody levels have been associated with adverse obstetrical outcomes. Several studies have investigated causal associations, but results have been inconsistent and few studies have reported the effects of thyroxine replacement therapy on pregnancy outcomes in hypothyroid patients. Objective. The primary study objective was to determine the outcome of pregnancies in women diagnosed with overt and subclinical hypothyroidism (SCH) (serum TSH > 2.5 mIU/L) and those with elevated circulating thyroid autoantibody levels in the first trimester of pregnancy and after the institution of appropriate thyroxine replacement therapy to maintain the serum TSH ≤ 2.5 mIU/L. Study Design. This prospective observational study was undertaken between 2013 and 2016. Blood samples were taken from 1025 women at presentation for thyroid stimulating hormone (TSH), anti-thyroglobulin antibodies (TGAb), and thyroid peroxidase antibodies (TPOAb). Those with a TSH > 2.5 mIU/L were treated with thyroxine and managed appropriately to ensure that the TSH was maintained ≤2.5 mIU/L. Outcomes in these patients were compared to those in euthyroid patients. Maternal antenatal complications and perinatal outcomes were recorded. Results. There were a total of 1025 patients of whom 382 (37.5%) were nulliparous. 10.1% had a TSH level > 2.5 mIU/L and 18.2% had at least one raised thyroid antibody level. No differences in adverse outcomes of pregnancy were evident in women treated for SCH or overt hypothyroidism compared to the euthyroid group. There was also no association between raised thyroid antibodies and adverse pregnancy outcomes in either group. Conclusion. There were no adverse outcomes of pregnancy found in pregnant women who had been diagnosed and treated with thyroxine for SCH at the time of presentation when compared to euthyroid patients. There was also no relationship with thyroid antibodies and adverse pregnancy outcomes in the two groups. It is not possible to unequivocally advocate for thyroxine replacement in pregnant women with subclinical and overt hypothyroidism until large scale randomized controlled trials are performed.


Tissue microarray analysis of cyclin D1 gene amplification and gain in colorectal carcinomas.
Colorectal cancer is one of the most common neoplastic diseases and one of the leading causes of cancer-related deaths. Elevated beta-catenin levels in colorectal cancer result in the binding of beta-catenin to LEF-1 and increased transcriptional activation of the CCND1 gene. Overexpression of cyclin D1 is observed in one third of colorectal tumors. CCND1 amplification is the main cause of protein overexpression in numerous human carcinomas. In colorectal cancer, however, no CCND1 amplification has been reported so far. The aim of this study was to determine the frequency of CCND1 amplifications and gains in a large number of colorectal carcinomas, arranged in a tissue microarray, in order to assess their role in colorectal cancer development. The copy number changes, detected by fluorescence in situ hybridization, were predominantly gains (7.6%) and only rarely amplifications (2.5%). In colorectal cancer, the CCND1 copy number increase was neither associated with the tumor phenotype (stage and grade) nor with the tumor localization (colon, rectum or sigmoid colon). In conclusion, even in a small number of colorectal tumors, CCND1 gene amplification is a possible mechanism for the increase in cyclin D1 oncoprotein.


Detection of Emodin Derived Glutathione Adduct in Normal Rats Administered with Large Dosage of Polygoni Multiflori Radix.
Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. PMR-associated hepatotoxicity has been drawing increasingly more attention in recent years in parallel with its wide utilization. Anthraquinones (AQs) are recognized as the main hepatotoxic components in PMR. However, the exact underlying mechanism of AQs poisoning is still not fully understood. Herein, we proposed a hypothesis that metabolic activation of AQs such as emodin was involved in PMR-induced liver injury, AQs followed to generate the electrophilic reactive metabolites and subsequently formed covalent adduct with cellular nucleophiles in the liver to exert hepatotoxicity. In the present study, the link of cytotoxicity of PMR in primary human hepatocytes and the depletion of glutathione (GSH) was investigated by MTT assay and UHPLC-QqQ-MS/MS analysis. The results showed that PMR depleted GSH and therefore induced cytotoxicity. Then, emodin-GSH adduct was identified in bile of liver injured rats after intragastric administration of PMR or emodin with the aid of UHPLC-QTOF-MS/MS method. Our findings not only provided confirmative evidence that the mechanism of hepatotoxicity induced by AQs in PMR involved key metabolic steps, but also revealed that emodin-GSH adduct had potential to be further developed as a sensitive and traceable biomarker for the assessment of PMR-induced liver injury.


Inner-Imaging Networks: Put Lenses Into Convolutional Structure.
Despite the tremendous success in computer vision, deep convolutional networks suffer from serious computation costs and redundancies. Although previous works address that by enhancing the diversities of filters, they have not considered the complementarity and the completeness of the internal convolutional structure. To respond to this problem, we propose a novel inner-imaging (InI) architecture, which allows relationships between channels to meet the above requirement. Specifically, we organize the channel signal points in groups using convolutional kernels to model both the intragroup and intergroup relationships simultaneously. A convolutional filter is a powerful tool for modeling spatial relations and organizing grouped signals, so the proposed methods map the channel signals onto a pseudoimage, like putting a lens into the internal convolution structure. Consequently, not only is the diversity of channels increased but also the complementarity and completeness can be explicitly enhanced. The proposed architecture is lightweight and easy to be implement. It provides an efficient self-organization strategy for convolutional networks to improve their performance. Extensive experiments are conducted on multiple benchmark datasets, including CIFAR, SVHN, and ImageNet. Experimental results verify the effectiveness of the InI mechanism with the most popular convolutional networks as the backbones.


The effect of aortic valve replacement on N-terminal natriuretic propeptides in patients with aortic stenosis.
Increased plasma concentrations of natriuretic peptides have been demonstrated to be associated with increased intracardiac pressure and left ventricular (LV) hypertrophy. After aortic valve replacement (AVR) in aortic stenosis patients, there is a relief of the left outflow obstruction with a substantial hemodynamic improvement. This is followed by a gradual regression of the LV hypertrophy. After AVR, reduction in LV filling pressure is expected to occur rapidly, while regression of LV hypertrophy will take place over a longer time period. On this basis we hypothesized that the plasma levels of N-terminal proatrial natriuretic peptide (NT-proANP) would be reduced early in the postoperative period, while N-terminal probrain natriuretic peptide (NT-proBNP), through its closer reflection of LV hypertrophy, would be sustained for a longer period. Two groups of patients with aortic stenosis undergoing AVR were followed for 4 and 12 months, respectively. Plasma concentrations of NT-proANP and NT-proBNP were measured before and after AVR and related to preoperative findings and changes in the aortic valve area index. Before AVR, the patients had significantly increased plasma levels of NT-proANP and NT-proBNP. After AVR, NT- proANP was decreased at 4 and 12 months but remained elevated compared with controls. N-terminal-proBNP tended to decrease, but did not change significantly. When the patients were followed for 12 months, only those with elevated preoperative pulmonary capillary wedge pressure had decreased peptide levels (NT-proANP: p = 0.017, NT-proBNP: p = 0.058). There was no regression of LV hypertrophy. The patients with the largest postoperative valve area index [1.27 (1.10-1.55) cm2/m2] had the largest reduction of NT-proBNP (47%). Those with the smallest valve area index [0.67 (0.54-0.73) cm2/m2] had no decrease in NT-proBNP. Our study suggests that a reduction in left atrial pressure is the main factor causing the change of NT-proANP level after AVR. A small prosthetic valve orifice area with a high aortic valve gradient might prevent regression of LV hypertrophy, thus representing a stimulus for increased cardiac secretion of NT-proBNP.


Primary cultures from fetal bovine brain.
This study describes a method of obtaining primary cultures from the cerebral cortex and the hypothalamus of bovine fetuses. We describe here the influence of tissue origin, developmental stage and culture medium conditions on cell differentiation and prevalence of neurons vs glial cells. To identify optimal conditions for obtaining and growing viable neurons and astrocytes in culture, we tested early, middle and late stages of development. Explants from cortex, early stages (week 10 of pregnancy out of 36) and low fetal calf serum concentration (1%) yielded maximum amounts of neurons. Fresh and thawed tissues gave comparable results.


Analysis of postoperative dysphagia after anterior cervical decompression and fusion.
Purpose: To investigate the incidence and risk factors of postoperative dysphagia after anterior cervical decompression and fusion (ACDF) in terms of demographic, procedural and anaesthetic perspectives.Materials and methods: Medical records and radiologic data of patients who underwent anterior cervical surgery performed by two surgeons in a single centre between January 2012 and December 2015 were retrospectively analysed. Patients with spinal tumours, infective spondylitis and traumatic cervical pathologies were excluded. Patients with preoperative dysphagia and previous history of anterior cervical surgery were also excluded. Finally, 127 patients were enrolled. Bazaz dysphagia score was used for the diagnosis of postoperative dysphagia.Results: The incidence of postoperative dysphagia was 10.2% at six weeks after ACDF. Nine patients showed mild dysphagia that fully recovered at three months after ACDF. Four patients showed moderate dysphagia that also recovered fully at six months after surgery. The incidence of postoperative dysphagia increased significantly in cases of C4 or C5 level involvements. Age, sex, hypertension, body mass index, postoperative soft tissue swelling, intubation difficulty and intubation tools were not significant risk factors of ACDF. Diabetes mellitus, two surgical levels, the use of plate, long anaesthetic and operative time and large intubation tube size were causative factors of postoperative dysphagia in multivariable analysis (p < 0.05).Conclusions: The incidence of postoperative dysphagia after ACDF was relatively low, and the prognosis was good.


Kinesin motion in the absence of external forces characterized by interference total internal reflection microscopy.
We study the motion of the kinesin molecular motor along microtubules using interference total internal reflection microscopy. This technique achieves nanometer scale resolution together with a fast time response. We describe the first in vitro observation of kinesin stepping at high ATP concentration in the absence of an external load, where the 8-nm step can be clearly distinguished. The short-time resolution allows us to measure the time constant related to the relative motion of the bead-motor connection; we deduce the associated bead-motor elastic modulus.


Intestinal GIST masquerading as an ovarian mass: Diagnosed on FNAC.
The preoperative diagnosis of metastatic intestinal gastrointestinal stromal tumors (GIST) on cytology can be quite difficult at times. The present case characterizes the cytomorphological and immunocytochemical features of GIST, emphasizing the utility of fine-needle aspiration cytology (FNAC) in the evaluation of spindle cell tumors of gastrointestinal tract. An accurate and early diagnosis of GIST affects the treatment, primarily allowing the use of tyrosine kinase inhibitors in unresectable or metastatic cases. Presence of highly cellular fragments of spindle-to-oval cells with variable degree of pleomorphism, atypia, and necrosis supplemented by immunocytochemistry can render a cytological diagnosis of GIST in dilemmatic clinical situations. Our case highlights the diagnostic role of FNAC in the evaluation of a pelvic mass, which was clinicoradiologically misdiagnosed as ovarian carcinoma.


Dynamic smile reanimation in facial nerve palsy.
Long-term facial paralysis results in degeneration of the distal nerve segment and atrophy of the supplied muscles. Options for these patients include free muscle transfer, temporalis myoplasty, and botulinum toxin injections for smile reanimation. In this study we aimed to evaluate the subjective and objective outcomes of these procedures. In our study, we retrospectively analyzed smile symmetry in patients with facial palsy (n=8) who underwent facial reanimation procedures. Subjective analysis showed high satisfaction in seven out of eight patients. Objective analysis showed statistically significant improvement postoperatively in both vertical and horizontal smile symmetry at rest and during maximum smile (P<0.001). Choosing the ideal procedure for the patients is the most critical aspect for facial reanimation. Though free muscle transfer is considered gold standard procedure, temporalis myoplasty also gives satisfactory results. Residual synkinesis which can lead to disturbing aesthetic deformity can be effectively treated with botulinum toxin.


Control of V(D)J recombinational accessibility of the D beta 1 gene segment at the TCR beta locus by a germline promoter.
The germline promoter region upstream of the D beta 1 gene segment in the murine TCR beta locus was deleted to assess its role in controlling V(D)J recombination. Associated with diminished D beta 1 region germline transcription, rearrangement of the D beta 1 but not the D beta 2 gene segment was reduced 10- to 20-fold. A corresponding reduction in RAG-mediated cleavage at the D beta 1 and J beta 1 signal sequences was apparent only when purified CD4- CD8- thymocytes were analyzed because, as we demonstrate, cleavage at these gene segments also occurred in CD4+ CD8+ thymocytes. These findings suggest that germline promoters regulate localized accessibility of gene segments for recombination and that in CD4+ CD8+ thymocytes TCR beta allelic exclusion does not result from inaccessibility of D beta gene segments.


Decreased intracellular histamine concentration and basophil activation in anaphylaxis.
Histamine is a crucial mediator in the development of anaphylaxis. Although histamine is promptly degraded because of its short half-life in plasma, basophils, which release histamine, remain in the blood for days. To explore basophils as a potential marker and their involvement in the pathogenesis of anaphylaxis, we evaluated the intracellular histamine concentration and the degree of basophil activation in anaphylaxis patients. We conducted a case-control study enrolling anaphylaxis patients and healthy controls. Basophil activation was evaluated by flow cytometry using up-regulation of CD203c expression. We enrolled 23 patients and measured their blood histamine concentration. Basophil activation was analyzed in seven of 23 patients. The median intracellular histamine concentrations at admission were significantly lower in patients compared with controls (16.4 ng/mL [interquartile range {IQR}, 2.70 to 34.0] vs. 62.3 ng/mL [IQR, 46.0 to 85.1]; p < 0.0001). The median basophil number at admission was also significantly lower in patients compared with controls (2.21 cell/μL [IQR, 0.75 to 12.3] vs. 21.0 cell/μL [IQR, 19.5 to 28.9]; p = 0.027). CD203c expression was not up-regulated in any of the seven patients in vitro, but it was up-regulated in response to anti-IgE stimulation in vitro in two patients at admission and four patients at follow-up. Anaphylaxis is associated with a decrease in intracellular histamine, and a reduced number and reactivity of peripheral basophils. Impaired basophil function and a decrease in their number and intracellular histamine levels in the circulation may reflect the underlying mechanism, suggesting that basophils may be a marker of anaphylaxis.


Dendrochilum hampelii (Coelogyninae, Epidendroideae, Orchidaceae) traded as 'Big Pink' is a new species, not a hybrid: evidence from nrITS, matK and ycf1 sequence data.
In 2013, an unidentified species of Dendrochilum appeared in cultivation under the commercial trade name 'Big Pink'. Using sequences of the nuclear ribosomal ITS1-5.8S-ITS2 region and of the plastid matK and ycf1 genes, we examined the phylogenetic relationships between 'Big Pink' and six other species of the phenetically defined Dendrochilum subgen. Platyclinis sect. Eurybrachium. Separate and combined analyses (using Bayesian, Maximum Likelihood and Parsimony inference) showed consistent placement of the unidentified species within a statistically well supported clade. Furthermore, the multi-copy nrITS marker showed clear distinct peaks. Thus, we found no evidence that 'Big Pink' could be a hybrid. Against this background, and further supported by species-specific mutations in (at least) nrITS and ycf1, we formally describe 'Big Pink' as a new species under the name Dendrochilum hampelii. Morphologically, it is most similar to Dendrochilum propinquum, but it differs in a number of characters. Of the two cultivated individuals available for our study, one was of unrecorded provenance. The other allegedly originated from the Philippines. Observations of the species occurring in the wild in the Philippines in the northern provinces of Bukidnon and Misamis Oriental on the island of Mindanao confirmed this.


[Regulation of food advertising on television for the prevention of childhood obesity].
Obesity is a serious global epidemic and the prevention strategies implemented have been insufficient. Numerous environmental factors have been associated with risk of obesity and their full consideration in prevention policies is important. The connection between food advertising on television and childhood obesity has been demonstrated. The large number of advertisements for unhealthy foods targeted at children through television and its possible impact on health has led some countries to legislate on this matter. However, a conceptual framework of reference enabling legislation must be internationally defined in order to achieve a real impact in preventing childhood obesity. This paper reviews scientific evidence on the relationship between food advertising and childhood obesity as a basis for developing public policies to regulate food marketing on television.


Decreased expression of epidermal cytoplasmic antigens in cultured human keratinocytes.
The expression of upper cytoplasmic (U-CYT) antigens which are expressed only in the superficial layers of the epidermis and are markers of epidermal cell differentiation in vivo and of basement zone (BMZ) antigens reacting with bullous pemphigoid serum was studied in keratinocytes in tissue culture. The cells were cultured at an acid pH (5.6-5.8) similar to that of skin and without feeder cells, dermal tissue, or collagen. It was found that the expression of U-CYT antigens decreased markedly in culture. These antigens were expressed in 45-65% of epidermal cells prepared from fresh skin, but in only 5-10% of cells which had been grown in primary culture over 1 mo, and in no cells in secondary or tertiary culture. By contrast, BMZ antigens continued to be expressed in culture. These antigens were expressed by 20-35% of epidermal cells prepared from fresh tissue and by 15-35% of keratinocytes in primary, secondary or tertiary culture. These findings indicate that U-CYT and BMZ antigens can be used to type subpopulations of human keratinocytes in suspension, and suggest that the differentiation of these cells in vitro differs from that which occurs in vivo.


[Study designs adopted in epidemiology of chronic diseases].
Clinical research is gaining interest among healthcare professionals. This review provides an in-depth analysis of key study designs used in epidemiology, which can help researchers use the right methodology to design and conduct a research project. Case-control studies evaluate the association between an exposure to a specific risk factor and a study endpoint. Cross-sectional studies are indicated to assess the prevalence of a given risk factor. Cohort studies consist of longitudinal studies, in which a population is followed over time. These studies allow to evaluate the association between a risk factor and one or more study endpoints which are absent at the time of the population enrollment. Experimental studies are designed to test the efficacy and safety of an intervention. Generally, they include two groups of individuals who are assigned to either an experimental treatment or a standard treatment, respectively. Meta-analyses are studies that summarize the evidence already published concerning a specific research question and constitute an important source for evidence-based medicine and for the production and updating of guidelines.


Intestinal Tuft Cells: Morphology, Function, and Implications for Human Health.
Tuft cells are a rare and morphologically distinct chemosensory cell type found throughout many organs, including the gastrointestinal tract. These cells were identified by their unique morphologies distinguished by large apical protrusions. Ultrastructural data have begun to describe the molecular underpinnings of their cytoskeletal features, and tuft cell-enriched cytoskeletal proteins have been identified, although the connection of tuft cell morphology to tuft cell functionality has not yet been established. Furthermore, tuft cells display variations in function and identity between and within tissues, leading to the delineation of distinct tuft cell populations. As a chemosensory cell type, they display receptors that are responsive to ligands specific for their environment. While many studies have demonstrated the tuft cell response to protists and helminths in the intestine, recent research has highlighted other roles of tuft cells as well as implicated tuft cells in other disease processes including inflammation, cancer, and viral infections. Here, we review the literature on the cytoskeletal structure of tuft cells. Additionally, we focus on new research discussing tuft cell lineage, ligand-receptor interactions, tuft cell tropism, and the role of tuft cells in intestinal disease. Finally, we discuss the implication of tuft cell-targeted therapies in human health and how the morphology of tuft cells may contribute to their functionality. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


In situ scanning probe microscopy studies of tetanus toxin-membrane interactions.
Despite the considerable information available with regards to the structure of the clostridial neurotoxins, and their inherent threat as biological warfare agents, the mechanisms underpinning their interactions with and translocation through the cell membrane remain poorly understood. We report herein the results of an in situ scanning probe microscopy study of the interaction of tetanus toxin C-fragment (Tet C) with supported planar lipid bilayers containing the ganglioside receptor G(T1b). Our results show that Tet C preferentially binds to the surface of fluid phase domains within biphasic membranes containing G(T1b) and that with an extended incubation period these interactions lead to dramatic changes in the morphology of the lipid bilayer, including the formation of 40-80 nm diameter circular cavities. Combined atomic force microscopy/total internal reflection fluorescence microscopy experiments confirmed the presence of Tet C in the membrane after extended incubation. These morphological changes were found to be dependent upon the presence of G(T1b) and the solution pH.


A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group.
The n-3 fatty acids in fish oil affect eicosanoid and cytokine production and therefore have the potential to alter renal hemodynamics and inflammation. The effects of fish oil could prevent immunologic renal injury in patients with IgA nephropathy. In a multicenter, placebo-controlled, randomized trial we tested the efficacy of fish oil in patients with IgA nephropathy who had persistent proteinuria. The daily dose of fish oil was 12 g; the placebo was a similar dose of olive oil. Serum creatinine concentrations, elevated in 68 percent of the patients at base line, and creatinine clearance were measured for two years. The primary end point was an increase of 50 percent or more in the serum creatinine concentration at the end of the study. Fifty-five patients were assigned to receive fish oil, and 51 to receive placebo. According to Kaplan-Meier estimation, 3 patients (6 percent) in the fish-oil group and 14 (33 percent) in the placebo group had increases of 50 percent or more in their serum creatinine concentrations during treatment (P = 0.002). The annual median changes in the serum creatinine concentrations were 0.03 mg per deciliter (2.7 mumol per liter) in the fish-oil group and 0.14 mg per deciliter (12.4 mumol per liter) in the placebo group. Proteinuria was slightly reduced and hypertension was controlled to a comparable degree in both groups. The cumulative percentage of patients who died or had end-stage renal disease was 40 percent in the placebo group after four years and 10 percent in the fish-oil group (P = 0.006). No patient discontinued fish-oil treatment because of adverse effects. In patients with IgA nephropathy, treatment with fish oil for two years retards the rate at which renal function is lost.


ROS produced by NOX promote the neurite growth in a PI3K/Akt independent manner.
Reactive oxygen species (ROS) function as signaling molecules in several physiologic and pathologic processes. In central nervous system, ROS are critical for differentiation, migration, polarization, and neurite growth. These actions are mediated by reversible oxidation of target proteins. On the other hand, PI3K/Akt signaling pathway is susceptible to be modulated by ROS and it has been implicated in neurite growth. In this study, we evaluated the participation of ROS in the neurite growth of cultured rat cerebellar granule neurons (CGN), as well as the possible regulation of the PI3K/Akt pathway by ROS during neurite outgrowth. For this purpose, CGN were treated with cellular or mitochondrial antioxidants, or an NOX inhibitor and neurite growth was evaluated. Moreover, to assess the participation Akt in this process, the p-Akt levels were measured in CGN treated with antioxidants or a NOX inhibitor. The effect of antioxidants on the neurite growth in the presence of a PI3K inhibitor was also measured. We found that cellular antioxidants and the NOX inhibitor decreased the neurite growth, but not the mitochondrial antioxidant. Interestingly, the antioxidants increased the p-Akt levels; however, the effect of antioxidants on neurite growth was no dependent on the Akt activity since the inhibitor of PI3K did not modify the antioxidant action on neurite growth. Our results show that the PI3K/Akt pathway participates in neurite growth and that ROS produced by NOX could function as signals in this process; however, this action is not mediated by a redox regulation of Akt activity.


PHENOTYPIC PLASTICITY AND HETEROCHRONY IN CICHLASOMA MANAGUENSE (PISCES, CICHLIDAE) AND THEIR IMPLICATIONS FOR SPECIATION IN CICHLID FISHES.
Cichlid fishes in African rift lakes have undergone rapid speciation, resulting in "species flocks" with more than 300 endemic species in some of the lakes. Most researchers assume that there is little phenotypic variation in cichlid fishes. I report here extensive phenotypic plasticity in a Neotropical cichlid species. I examined the influence of diet on trophic morphology during ontogeny in Cichlasoma managuense. Two groups of full siblings were fed two different diets for eight months after the onset of feeding; thereafter both groups were fed a common diet. Phenotypes that differed significantly at 8.5 months converged almost completely at 16.5 months. If feeding on two different diets is continued after 8.5 months, the phenotypes remain distinct. Differences in diet and possibly in feeding mode are believed to have caused these phenotypic changes. Phenotypic plasticity is described in terms of a qualitative model of heterochrony in which phenotypic change in morphology is explained as retardation of the normal developmental rate. If phenotypic expression of morphology is equally plastic in African cichlid species as it may be in the American cichlids, as exemplified by C. managuense, then taxonomic, ecological, and evolutionary analyses of "species flocks" may be in need of revision. However, Old World cichlids may be less phenotypically plastic than New World cichlids, and this may contribute to the observed differences in speciation rate and degree of endemism.


Combining the P300-complex trial-based concealed information test and the reaction time-based autobiographical implicit association test in concealed memory detection.
Despite the P300-concealed information test's validity in detecting concealed memory when it is conducted immediately after the mock crime, whether the P300-CIT's detection efficiency is moderated by time delay remains unknown. Here, we conducted a mock crime study in which guilty participants were tested immediately after the mock crime or 1 month later. An innocent group was also tested. Assuming that the autobiographical Implicit Association Test (aIAT) and the P300-CIT rely on nonoverlapping mechanisms for memory detection, participants were tested using both the P300-CIT and the reaction time (RT)-based aIAT. Results suggested that the sensitivity of both tests remains even after the 1-month delay. The indicators from the RT-aIAT and P300-CIT were uncorrelated, thus combining P300-CIT and aIAT data further increased the efficiency of memory detection.


A Novel Model System for Understanding Anticancer Activity of Hypoxia-Activated Prodrugs.
Reports on the comprehensive factors for design considerations of hypoxia-activated prodrugs (HAPs) are rare. We introduced a new model system composed of a series of highly water-soluble HAPs, providing a platform to comprehensively understand the interaction between HAPs and hypoxic biosystems. Specifically, four kinds of new HAPs were designed and synthesized, containing the same biologically active moiety but masked by different bioreductive groups. Our results demonstrated that the activity of the prodrugs was strongly dependent on not only the molecular structure but also the hypoxic tumor microenvironment. We found the presence of a direct linear relationship between cytotoxicity of the HAPs and the reduction potential of whole molecule/oxygen concentration/reductase expression. Moreover, limited blood vasculature in hypoxic regions was also a critical barrier for effective activation of the HAPs. This study offers a comprehensive insight into understanding the design factors required for HAPs.


A Molecular Method for the Identification of Honey Bee Subspecies Used by Beekeepers in Russia.
Apis mellifera L. includes several recognized subspecies that differ in their biological properties and agricultural characteristics. Distinguishing between honey bee subspecies is complicated. We analyzed the Folmer region of the COX1 gene in honey bee subspecies cultivated at bee farms in Russia and identified subspecies-specific SNPs. DNA analysis revealed two clearly distinct haplogroups in A. melliferamellifera. The first one was characterized by multiple cytosine-thymine (thymine-cytosine) transitions, one adenine-guanine substitution, and one thymine-adenine substitution. The nucleotide sequence of the second haplogroup coincided with sequences from other subspecies, except the unique C/A SNP at position 421 of the 658-bp Folmer region. A. melliferacarnica and A. melliferacarpatica could be distinguished from A. melliferamellifera and A. melliferacaucasica by the presence of the A/G SNP at position 99 of the 658-bp Folmer region. The G/A SNP at position 448 was typical for A. melliferacarnica. A. melliferacaucasicaCOX1 sequence lacked all the above-mentioned sites. We developed a procedure for rapid identification of honey bee subspecies by PCR with restriction fragment length polymorphism (RFLP) using mutagenic primers. The developed molecular method for honey bee subspecies identification is fast and inexpensive.


[Endoscopic treatment of upper gastrointestinal non-variceal bleeding].
Endoscopic hemostasis is the method of choice for the treatment of bleeding peptic ulcers. This retrospective study was carried out to evaluate its effectiveness in routine endoscopic practice. The records of all patients with gastrointestinal bleeding undergoing esophagogastroduodenoscopy (EGDS) at the Endoscopy Center of Ferrara in the last year were retrospectively evaluated. For each patient with peptic lesions, the following data were recorded: demographic characteristics, use of NSAIDs, co-morbidity, hemodynamic conditions, blood transfusions before EGDS, time between onset of symptoms and EGDS, endoscopic findings, method of endoscopic haemostasis carried out, Rockall score and outcome. If re-bleeding occurred, the data concerning the second therapeutic intervention were recorded as well. Seventy-six males and 45 females (age 34-92 years) entered the study. In 22% of cases no co-morbidity was present. Active bleeding was observed in 38% of cases, features consistent with recent bleeding in 54% of cases, and no sign of bleeding in 6.6% of cases. Peptic ulcer was observed in 89% of cases. Hemostasis was carried out in 81 patients (76 had adrenalin infiltration, 2 had argon plasma coagulator [APC], and 3 had both treatments); 26 patients had re-bleeding. The probability of re-bleeding was related to female gender (p<0.05; OR: 3.74), time between onset of symptoms and EGDS >24 hours (p<0.01; OR: 8.67), and presence of non-ulcer peptic pathology (p<0.05; OR: 0.15). Seven re-bleeding patients underwent surgery, 19 had endoscopic treatment. In 11 of these patients second hemostasis was resolutive, 8 bled again. Endoscopic hemostasis of bleeding peptic lesions is effective also in routine clinical practice. Adrenalin infiltration is safe, easy to perform, cheap and repeatable, and in our opinion it should be considered the technique of first choice in endoscopic hemostasis.


Achromobacter xylosoxidans Cellular Pathology Is Correlated with Activation of a Type III Secretion System.
Achromobacter xylosoxidans is increasingly recognized as a colonizer of cystic fibrosis (CF) patients, but the role that A. xylosoxidans plays in pathology remains unknown. This knowledge gap is largely due to the lack of model systems available to study the toxic potential of this bacterium. Recently, a phospholipase A2 (PLA2) encoded by a majority of A. xylosoxidans genomes, termed AxoU, was identified. Here, we show that AxoU is a type III secretion system (T3SS) substrate that induces cytotoxicity to mammalian cells. A tissue culture model was developed showing that a subset of A. xylosoxidans isolates from CF patients induce cytotoxicity in macrophages, suggestive of a pathogenic or inflammatory role in the CF lung. In a toxic strain, cytotoxicity is correlated with transcriptional activation of axoU and T3SS genes, demonstrating that this model can be used as a tool to identify and track expression of virulence determinants produced by this poorly understood bacterium.


Initial Experience of the Application of Third-generation Dual-source CT Scanner in High-pitch Angiography of Aorta.
Objective To evaluate the value of third-generation dual-source CT scanner in application of high-pitch aorta CT angiography(CTA). Methods Totally 59 patients clinically indicated for whole aorta angiography were divided into 2 groups using a simple random method:in group 1 there were 28 patients who underwent the examination on a third-generation dual-source CT device,with a collimation of 2×192×0.6 mm and a rotation time of 0.25 s;in group 2 there were 31 patients who underwent the examination on a second generation dual-source CT device,with a collimation of 2×128×0.6 mm and a rotation time of 0.28 s. Both groups were given the examination operated in dual-source high-pitch ECG-gating mode with a pitch of 3.0,a tube voltage of 100 kV,and automated tube current modulation using a reference tube current of 288 mA. A contrast material bolus of 45 ml with a flow of 4.5 ml/s followed by a 50 ml saline chaser in 5.0 ml/s was used. CTA scan was automatically started using a bolus tracking technique at the level of the original part of aorta after a trigger threshold of 100 HU was reached. The start delay was set to 6 s in both groups. Effective dose(ED),signal to noise ratio (SNR),contrast to noise ratio (CNR),and subjective diagnostic quality of both groups were evaluated. Results The mean ED were 19.44% lower (t=-3.989,P=0.000) in group 1 [(3.15±0.86)mSv] than in group 2 [(3.91±0.60)mSv]. These two groups showed no significant differences in SNR or CNR (all P >0.05). The subjective diagnostic quality values also showed no significant difference between two groups [(1.39±0.50)scores vs. (1.45±0.51)scores;W=814.5,P=0.651].Conclusion Compared with the second-generation dual-source CT scanner,the third-generation dual-source CT scanner in whole aorta CTA can remarkably reduce the radiation dose without affecting image quality.


Role of individual subunits of the Neurospora crassa CSN complex in regulation of deneddylation and stability of cullin proteins.
The Cop9 signalosome (CSN) is an evolutionarily conserved multifunctional complex that controls ubiquitin-dependent protein degradation in eukaryotes. We found seven CSN subunits in Neurospora crassa in a previous study, but only one subunit, CSN-2, was functionally characterized. In this study, we created knockout mutants for the remaining individual CSN subunits in N. crassa. By phenotypic observation, we found that loss of CSN-1, CSN-2, CSN-4, CSN-5, CSN-6, or CSN-7 resulted in severe defects in growth, conidiation, and circadian rhythm; the defect severity was gene-dependent. Unexpectedly, CSN-3 knockout mutants displayed the same phenotype as wild-type N. crassa. Consistent with these phenotypic observations, deneddylation of cullin proteins in csn-1, csn-2, csn-4, csn-5, csn-6, or csn-7 mutants was dramatically impaired, while deletion of csn-3 did not cause any alteration in the neddylation/deneddylation state of cullins. We further demonstrated that CSN-1, CSN-2, CSN-4, CSN-5, CSN-6, and CSN-7, but not CSN-3, were essential for maintaining the stability of Cul1 in SCF complexes and Cul3 and BTB proteins in Cul3-BTB E3s, while five of the CSN subunits, but not CSN-3 and CSN-5, were also required for maintaining the stability of SKP-1 in SCF complexes. All seven CSN subunits were necessary for maintaining the stability of Cul4-DDB1 complexes. In addition, CSN-3 was also required for maintaining the stability of the CSN-2 subunit and FWD-1 in the SCF(FWD-1) complex. Together, these results not only provide functional insights into the different roles of individual subunits in the CSN complex, but also establish a functional framework for understanding the multiple functions of the CSN complex in biological processes.


[The naso-labial fold: analysis and proposed techniques for correction].
The naso-labial fold is a permanent depression of the face which corresponds to the combined action of congenital and acquired factors such as cutaneous atrophy, bone resorption, muscular activity and skin ptosis. It is therefore not realistic to abandon any attempt to correct this complaint or to provide a universal solution to correct it; over the last four years, we have used EPTFE implants to fill the naso-labial fold: triangular, in one or two layers introduced via a gingival incision for the upper naso-labial part, with 2 mm large strips directly inserted through the skin for the lower labio-mental part. Tolerance and versatility were always remarkable; efficacy depends on the possible associated cutaneous ptosis: if major, a lifting procedure, more or less extensive, must be offered, which may also improve the projection of the malar area with an implant of the same material introduced via an oral or temporal approach. All other well known procedures (liposuction, fat grafts, collagen, etc.) may be employed but only as a complement to filling and traction procedures.


Suppression of interferon lambda signaling by SOCS-1 results in their excessive production during influenza virus infection.
Innate cytokine response provides the first line of defense against influenza virus infection. However, excessive production of cytokines appears to be critical in the pathogenesis of influenza virus. Interferon lambdas (IFN-λ) have been shown to be overproduced during influenza virus infection, but the precise pathogenic processes of IFN-λ production have yet to be characterized. In this report, we observed that influenza virus induced robust expression of IFN-λ in alveolar epithelial cells (A549) mainly through a RIG-I-dependent pathway, but IFN-λ-induced phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1) was dramatically inhibited in the infected cells. Remarkably, influenza virus infection induced robust expression of suppressor of cytokine signaling-1 (SOCS-1), leading to inhibition of STAT1 activation. Interestingly, the virus-induced SOCS-1 expression was cytokine-independent at early stage of infection both in vitro and in vivo. Using transgenic mouse model and distinct approaches altering the expression of SOCS-1 or activation of STAT signaling, we demonstrated that disruption of the SOCS-1 expression or expression of constitutively active STAT1 significantly reduced the production of IFN-λ during influenza virus infection. Furthermore, we revealed that disruption of IFN-λ signaling pathway by increased SOCS-1 protein resulted in the activation of NF-κB and thereby enhanced the IFN-λ expression. Together, these data imply that suppression of IFN-λ signaling by virus-induced SOCS-1 causes an adaptive increase in IFN-λ expression by host to protect cells against the viral infection, as a consequence, leading to excessive production of IFN-λ with impaired antiviral response.