Properties and photochemistry of a halorhodopsin from the haloalkalophile, Natronobacterium pharaonis.
Pharaonis halorhodopsin is a light-driven transport system for chloride, similarly to the previously described halorhodopsin, but we find that it transports nitrate as effectively as chloride. We studied the photoreactions of the purified, detergent-solubilized pharaonis pigment with a gated multichannel analyzer. At a physiological salt concentration (4 M NaCl), the absorption spectra and rate constants of rise and decay for intermediates of the photocycle were similar to those for halorhodopsin. In buffer containing nitrate, halorhodopsin exhibits a second, truncated photocycle; this difference in the photoreaction of the pigment occurs when an anion is bound in such a way as to preclude transport. As expected from the lack of anion specificity in the transport, the photocycle of pharaonis halorhodopsin was nearly unaffected by replacement of chloride with nitrate. All presumed buried positively charged residues, which might play a role in anion binding, are conserved in the two pigments. At the extracellular end of the presumed helix C, however, an arginine residue is found in halorhodopsin, but not in pharaonis halorhodopsin, and an arginine-rich segment between the presumed helices A and B in halorhodopsin is replaced by a less positively charged sequence in pharaonis halorhodopsin (Lanyi, J. K., Duschl, A., Hatfield, G. W., May, K., and Oesterhelt, D. (1990) J. Biol. Chem. 265, 1253-1260). One or both of these alterations may explain the difference in the anion selectivity of the two proteins.


The association of urethrorrhagia and urethral stricture disease.
Urethrorrhagia characterized by terminal hematuria and/or bloody spotting of the underwear between episodes of voiding is a common problem of childhood. We describe a series of boys with urethrorrhagia and associated clinical and endoscopic findings. The records of boys presenting between 1990 and 2005 with urethrorrhagia were retrospectively reviewed for age, symptoms, symptom duration, physical examination, radiographic evaluation, laboratory data and endoscopic findings. Of 66 boys, 50 presented with classic symptoms of terminal hematuria and/or blood spotting, and 16 with atypical symptoms who underwent cystoscopy with similar findings. Endoscopic evaluation was performed in 55 (82%) patients for prolonged symptomatology or recurrent symptoms and revealed four distinct patterns: Group 1, three (5%) patients with a normal appearing urethra; Group 2, 27 (49%) patients who were found to have inflammation or hyperemia of the bulbar urethra; Group 3, 17 (31%) cases in which there was a white membranous exudate or mucosal irregularity; and Group 4, eight (14%) patients who were found to have stricture disease on cystoscopy. Stricture developed after initial cystoscopy in six cases. Consistent with previous studies, a subset of patients developed urethral stricture disease after presenting with urethrorrhagia. As eight patients had a urethral stricture on initial cystoscopy, and those with strictures are clinically indistinguishable symptomatically from those without, we feel that uroflow and selective cystoscopy are important tools for the work-up of severe and persistent cases of urethrorrhagia. Group 3 may represent a population at significant risk for the development of stricture disease warranting closer follow up and evaluation. The white membranous exudate found on cystoscopy may represent a pre-stricture lesion as evidenced by four cases that subsequently developed strictures.


Sonic Hedgehog Signature in Pediatric Primary Bone Tumors: Effects of the GLI Antagonist GANT61 on Ewing's Sarcoma Tumor Growth.
Osteosarcoma (OS) and Ewing's sarcoma (ES) are the most common malignant bone tumors in children and adolescents. In many cases, the prognosis remains very poor. The Sonic hedgehog (SHH) signaling pathway, strongly involved in the development of many cancers, regulate transcription via the transcriptional factors Gli1-3. In this context, RNAseq analysis of OS and ES cell lines reveals an increase of some major compounds of the SHH signaling cascade in ES cells, such as the transcriptional factor Gli1. This increase leads to an augmentation of the transcriptional response of Gli1 in ES cell lines, demonstrating a dysregulation of Gli1 signaling in ES cells and thus the rationale for targeting Gli1 in ES. The use of a preclinical model of ES demonstrates that GANT61, an inhibitor of the transcriptional factor Gli1, reduces ES primary tumor growth. In vitro experiments show that GANT61 decreases the viability of ES cell, mainly through its ability to induce caspase-3/7-dependent cell apoptosis. Taken together, these results demonstrates that GANT61 may be a promising therapeutic strategy for inhibiting the progression of primary ES tumors.


68Ga-FAPI-04 Positron Emission Tomography Distinguishes Malignancy From 18F-FDG-Avid Colorectal Lesions.
Lesions with a high uptake of 18F-fluorodeoxyglucose (18F-FDG) on positron emission tomography-computed tomography (PET-CT) can be benign and malignant. New radiotracers, such as the gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor 4 (FAPI-04), could be used to diagnose colorectal carcinoma. This study aimed to evaluate the efficacy of 68Ga-FAPI-04 PET in differentiating benign from malignant 18F-FDG-avid colorectal lesions. An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced rat colorectal tumor model was developed. Double-tracer 68Ga-FAPI-04 and 18F-FDG PET-CT were applied in the rat model and 22 patients. The PET-CT data were analyzed with enteroscopy, histopathologic observations, immunohistochemistry (IHC) staining, and radioautography results. One hundred seventy-two patients with pathologically confirmed colorectal lesions were enrolled in FAP IHC staining. We found that 68Ga-FAPI-04 PET-CT imaging accurately distinguished the malignant from benign inflammatory lesions in an AOM/DSS-induced rat colorectal tumor model. Of 22 patients with gastric cancer but without colorectal carcinoma, 8 had 18F-FDG uptake in the colorectum, but 68Ga-FAPI-04 PET was negative in these sites. An inflammatory lesion or adenoma did not interfere with 68Ga-FAPI-04 PET imaging. Among the 18F-FDG-avid colorectal lesions, 80 of 94 pathologically malignant lesions (85.1%) were FAP-positive, and only 16 of the 78 premalignant or benign lesions (20.5%) had a weak 68Ga-FAPI-04 uptake. 68Ga-FAPI-04 PET-CT could be used to distinguish between benign and malignant 18F-FDG-avid colorectal lesions.


Cholangiocarcinoma and Crohn's disease.
Cholangiocarcinoma is an infrequent complication of inflammatory bowel disease. Although increasing numbers of cholangiocarcinomas are being reported in association with ulcerative colitis, the occurrence of this disease in patients with Crohn's disease is rare. To understand this complication better, we have reported the case of a patient with Crohn's disease in whom cholangiocarcinoma subsequently developed and reviewed the literature.


[Role of general practitioners in cancer screening: A survey in the French armed forces].
The French Military Health Service organizes medical survey of 340,000 military men. The aim of the present study was to evaluate the practices of solid cancer screening of general practitioners in military medical units and to compare the results with the recommendations of the French National Institute of Cancer. We conducted a prospective, observational study among general practitioners in Army Medical Unit by sending them a self-assessment questionnaire. Physicians should report on their practices for screening cancers with official screening recommendations. Compliance rates with the recommendations were reviewed. Screening practices for other cancers (prostate cancer, melanoma, thyroid cancer, lung cancer, testicular cancer) were assessed. A total of 133 questionnaires were analyzed. Despite a strong involvement of army general health practitioners, guidelines adherence rates (examination frequency, ages of screening beginning and ending) were of 4% for cervical cancer, 7% for breast cancer, and 37% for colorectal cancer. Those rates are comparable to those reported with civilian general practitioners. For cancers without screening recommendation, practitioners felt highly concerned, especially for the most common cancers among the military population. One third of physicians stated that they had diagnosed a testicular cancer through routine screening. Military general health practitioners feel themselves concerned by solid cancer screening, and more particularly for cancers that are the most prevalent in young adults. However, current guidelines are neither known nor applied in routine.


Coprophagy: an unusual source of essential carotenoids.
The rare Egyptian vulture (Neophron percnopterus) stands out among the Old World vultures (Family Accipitridae) because of its brightly ornamented head, which is coloured yellow by carotenoid pigments, and its practice of feeding on faeces. Here we show that Egyptian vultures obtain these pigments from the excrement of ungulates. To our knowledge, this is the first demonstration that faeces can be used as a source of carotenoids by a vertebrate.


[Does indirect binocular ophthalmoscopy influence the results of retinal deteachement surgery (author's transl)].
The statistical comparison of two collectivs of patients showed, that with routine use of indrect binocular ophthalmoscopy and renunciation of drainage of the subretinal fluid (49% of the cases) the curing rate of the cases which were operated with a combination of cryopexie and plombage raised from 75% to 96%. Even the results of visual acuity improved.


Motility of the pathogen and intestinal immunity of the host in experimental cholera.
1) Motility seems to be required for an intimate association with the intestinal mucosa which is necessary for efficient toxin delivery in the pathogenicity of V. cholerae. 2) A vaccine of semipurified flagella (CF) afforded a high degree of active and passive immunity in the rabbit ileum to both homologous and heterologous challenge strains. 3) The nature of the immunoglobulin type involved in the active immunity elicited by CF was not clear but preliminary indications implicate both s-IgA and IgG.


Interaction of the 47-kDa talin fragment and the 32-kDa vinculin fragment with acidic phospholipids: a computer analysis.
In recent in vitro experiments, it has been demonstrated that the 47-kDa fragment of the talin molecule and the 32-kDa fragment of the vinculin molecule interact with acidic phospholipids. By using a computer analysis method, we determined the hydrophobic and amphipathic stretches of these fragments and, by applying a purpose-written matrix method, we ascertained the molecular amphipathic structure of alpha-helices. Calculations for the 47-kDa mouse talin fragment (residues 1-433; NH2-terminal region) suggest specific interactions of residues 21-39, 287-342, and 385-406 with acidic phospholipids and a general lipid-binding domain for mouse talin (primary amino acid sequence 385-401) and for Dictyostelium talin (primary amino acid sequence 348-364). Calculations for the 32-kDa chicken embryo vinculin fragment (residues 858-1066; COOH-terminal region) and from nematode vinculin alignment indicate for chicken embryo vinculin residues 935-978 and 1020-1040 interactions with acidic phospholipids. Experimental confirmation has been given for vinculin (residues 916-970), and future detailed experimental analyses are now needed to support the remaining computational data.


Cautionary tales from the neonatal intensive care unit: diapers may mislead urinary output estimation in extremely low birthweight infants.
To examine the validity of the weighing of modern polyacrylate diapers to determine urine output in the extremely low birth weight infant nursed in a humidified incubator. Observational study with repeated measures using high-absorbency cellulose/polyacrylate diapers and a humidified incubator in a modeled clinical scenario. A tertiary referral neonatal intensive care unit. Six dry diapers were placed into eight levels of humidity, between 55% and 90% inclusive, in an incubator set at 37 degrees C. Hourly weight increments were recorded. The study was repeated with 5 mL of normal saline added to the diaper to mimic prior urine output. Results were compared by Kruskal-Wallis nonparametric analysis of variance. Dry diapers increased in weight for each humidity level after 1 hr (p < .05). This was significantly greater at higher humidity. The maximum increase was a median of 3.06 g (range, 2.47-3.31 g) at 85% humidity after 6 hrs. When 5 mL of 0.9% saline had been added, the diaper weight changes depended on environmental relative humidity. At > or = 80% humidity, the diapers continued to gain weight; at 70% or 75% humidity, they did not change weight; and at < or = 65% humidity, the diapers lost weight. Maximal evaporative loss was median 1.11 g (range, 0.8-1.24 g) at 6 hrs in 55% relative humidity. The use of diaper weighing in high-humidity infant environments may not be an accurate measure of actual urine output in the extremely low birth weight infant. This study demonstrates the need for caution when interpreting this measure, and we discuss some possible clinical approaches to ameliorate this difficulty.


Experiences with atrial pacing.
The records of 187 patients with permanent atrial pacemakers implanted between 1970 and 1980 were studied retrospectively to define the indications, outcome and short- and long-term complications of single-chamber atrial pacing. Pacemakers were implanted in 145 (77%) patients with tachybrady syndrome, 35 (19%) with sinus bradycardia and 7 (4%) with ventricular arrhythmia. Intact atrioventricular (AV) conduction was defined as absence of second- or third-degree heart block with incremental atrial pacing to a heart rate of 120 beats/min before implantation. The average follow-up was 30 months, including 87 patients (46%) who were followed an average of 48 months. Four patients developed significant conduction disease requiring placement of a ventricular lead. Complications included 4 lead fractures (all coronary sinus leads), 10 dislodgments (9 coronary sinus, 1 tined atrial "J") and 6 threshold rises requiring repositioning of the lead. Eight dislodgments occurred within an average of 5.6 days. The average increase in threshold that required repositioning occurred at 14 days. The average lead fracture occurred at 25 months. Atrial pacing is safe and effective for patients with sinoatrial node disorder (sick sinus syndrome) and intact AV conduction. Progression to clinically significant AV block is uncommon. Complications occur early with coronary sinus leads and are less common with newer leads.


[Prone position favors motor development of infants].
To determine the motor development in infants sleeping in the supine position compared to infants sleeping in the prone position, and to compare the levels of motor development of infants playing only in the supine position and of infants playing in the prone position as well. Prospective blinded comparing study. Department of Physical Therapy, Maasziekenhuis, Boxmeer, the Netherlands. Various measuring instruments were used in the home environment to determine the levels of motor development at the age of 5 months of 21 healthy infants born at term selected from a group of 160 infants attending the infant welfare clinic. Infants sleeping in the prone position (n = 8) showed a higher motor development than infants sleeping in the supine position (n = 13). Infants playing in the prone and supine position (n = 5) had a higher motor development than infants who played exclusively in the supine position (n = 15). Sleeping and playing in the prone position was accompanied by a higher motor development in healthy mature-born infants at the age of 5 months.


Identification of the domains required for the localization of Prp19p to lipid droplets or the nucleus.
Prp19p is a protein found in the nucleus, cytosol or lipid droplets depending on the cell type. Prp19p participates in pre-mRNA splicing, in neuronal/astroglial cell fate decisions or in adipocyte lipid droplet biogenesis. In this study, the motifs of Prp19p that are necessary for its localization to lipid droplets or the nucleus in 3T3-L1 adipocytes are investigated using a series of truncated mutants of Prp19p that were fused to EGFP and transiently introduced into differentiated 3T3-L1 adipocytes. Immunofluorescence microscopy revealed that a domain of amino acids 167-250 is necessary for the recruitment of Prp19p to lipid droplets and that a domain of amino acids 1-166 is necessary for the recruitment of Prp19p to a nucleus.


Polysaccharide-based nanoparticles fabricated from oppositely charged curdlan derivatives for curcumin encapsulation.
In this study, carboxylic curdlan (Cur-48) and negatively charged ferulic acid (FA)-grafted carboxylic curdlan (Cur-48-g-FA) were separately used to fabricate polyelectrolyte nanoparticles (PNPs: PNPs-CQ and PNPs-CFQ) with positively charged quaternized curdlan (Qcurd) for curcumin delivery. Results showed that curcumin-loaded PNPs-CQ and PNPs-CFQ had particle sizes of 338.1 and 301.3 nm, zeta potentials of -19.07 and -24.10 mV, and encapsulation efficiencies of 76.32% and 83.54%, respectively. Curcumin was properly encapsulated inside the two PNPs through electrostatic interactions and hydrogen bonds. Compared with free curcumin, entrapped curcumin in the two PNPs exhibited better redispersion performance, thermo- and photostability, and sustained release property. Furthermore, FA molecules surrounding the surface of PNPs-CFQ were conductive to the entrapped curcumin's particulate characteristics, stability, release behavior, and antioxidant potentials. Therefore, our findings indicated that PNPs formulated via Cur-48-g-FA and Qcurd can provide a novel delivery platform for encapsulation of hydrophobic nutrients, including curcumin, in functional foods.


Tomorrow I could be in trouble…but the sun will come out next year: the effect of temporal distance on adolescents' judgments of life satisfaction.
In a series of three studies, we examined adolescents' judgments of temporal life satisfaction (LS). We based our predictions in the notion of temporal distance influence in the level of construal of near- and distant-future events. In Study 1 we found that adolescents enhance future and present LS while devaluating past LS. Manipulating temporal distance in Study 2 and 3 and examining differences between- and within-subjects, respectively, we found that adolescents expected to be more satisfied with their life in the distant- than in the near-future. Moreover, framing LS in the near-future led adolescents to expect lower LS than they reported one week earlier. In contrast, expectations for own LS in the distant-future were not higher than self-reported LS measured one week before the experiment. The authors discuss implications for theory development and implications in the study of adolescents' LS.


Comparative study of the "point-by-point technique" and the "scanning technique" for laser treatment of port-wine stain.
Photocoagulation using the argon laser has been proven to be an effective method for the treatment of port-wine stains (PWS). However, it is very difficult to reproduce the parameters of laser treatment. This leads to inaccurate energy dosages secondary to the difference in treatment patterns. The aim of this study was to compare the conventional point-by-point technique (PT) for PWS treatment against a new scanning technique (ST) using a device called "Hexascan" (PREIN & Partners, Ferney-Voltaire, France). A total of 249 patients (171 females and 78 males) using the argon laser have been studied in a retrospective study. Clinical results are presented. For each technique, blanching and hypertrophic scarring were examined. The results are classified into two groups: satisfactory and unsatisfactory. The clinical results show that the ST with the Hexascan is superior to the conventional PT. Scarring is drastically reduced because overdosage and overheating are avoided. Because of precisely controlled spot patterns, quality and homogeneity of blanching is improved. Treatment time can be reduced to 20% of that of the PT.


Rational peptide-based tumour vaccine development and T cell monitoring.
Antigen-specific vaccination is a promising emerging treatment option for cancer patients. Results from early clinical vaccination trials with tumour peptides in patients with metastatic disease have shown tumour regressions in few patients usually with limited disease. Current clinical studies focus on the development of more potent vaccination strategies and on the vaccination of patients with occult or small volume metastatic disease. The novel generation of sensitive T-cell assays allowing direct quantitation and characterisation of specific T cells provide an essential tool for further systematic clinical development of vaccine protocols. There is accumulating evidence from clinical cancer vaccination trials of a relation between the induction of specific T cells and clinical efficacy.


Effect of corticosubcortical iron deposition on dysfunction in CADASIL is mediated by white matter microstructural damage.
Iron dysregulation may attenuate cognitive performance in patients with CADASIL. However, the underlying pathophysiological mechanisms remain incompletely understood. Whether white matter microstructural changes mediate these processes is largely unclear. In the present study, 30 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients were confirmed via genetic analysis and 30 sex- and age-matched healthy controls underwent multimodal MRI examinations and neuropsychological assessments. Quantitative susceptibility mapping and peak width of skeletonized mean diffusivity (PSMD) were analyzed. Mediation effect analysis was performed to explore the interrelationship between iron deposition, white matter microstructural changes and cognitive deficits in CADASIL. Cognitive deterioration was most affected in memory and executive function, followed by attention and working memory in CADASIL. Excessive iron in the temporal-precuneus pathway and deep gray matter specific to CADASIL were identified. Mediation analysis further revealed that PSMD mediated the relationship between iron concentration and cognitive profile in CADASIL. The present findings provide a new perspective on iron deposition in the corticosubcortical circuit and its contribution to disease-related selective cognitive decline, in which iron concentration may affect cognition by white matter microstructural changes in CADASIL.


Effect of two Chinese medicinal compounds, blood-activating and water-draining medicine, on tumor necrosis factor α and nuclear factor κ B expressions in rats with intracerebral hemorrhage.
To investigate the effect of blood-activating Chinese medicinal compounds and water-draining Chinese medicinal compounds on tumor necrosis factor alpha (TNF-α) and nuclear factor kappaB (NF-κ B) expressions in rats with intracerebral hemorrhage (ICH) at the acute stage, and to monitor their therapeutic effect and mechanism of action on inflammation and cerebral edema. A rat model of cerebral hemorrhage was achieved by injecting autologous arterial blood into the caudate nucleus. A total of 168 rats were randomly divided into 4 groups: blood-activating medicine group (n=42), water-draining medicine group (n=42), sham operated group (n=42), and the model group (n=42). A series of brain samples were obtained at days 1, 3 and 5 after ICH from rats in all groups. Protein expression levels of TNF-α and NF-κ B were measured by immunohistochemical staining and gene expression levels of TNF-α and NF-κ B were measured by real-time fluorescent PCR. Compared to the sham operated group, protein expression levels of TNF-α and NF-κ B in the model group significantly increased (P<0.01). Protein and gene expressions of TNF-α from the blood-activating medicine group and water-draining medicine group significantly decreased when compared to those in the model group P<0.05). Meanwhile, compared to the model group, the expression of NF-κ B in the blood-activating medicine group significantly decreased (P<0.05), while expression of NF-κ B in the water-draining medicine group did not differ (P>0.05). Blood-activating Chinese medicinal compounds and water-draining Chinese medicinal compounds can alleviate inflammation of peripheral tissue and cerebral edema. However, the blood-activating Chinese medicinal compounds were more effective than the water-draining Chinese medicinal compounds. The possible effective mechanism may be by means of inhibiting the activation of NF-κ B so as to suppress the transcription of target genes including gene expression of TNF-α.


Concept analysis of dignity-centered care for people with chronic progressive disease.
This concept analysis describes attributes, antecedents, and consequences of dignity-centered care for people with chronic progressive disease. Rodgers' method of concept analysis was used to clarify the concept's defining attributes. Databases searched were PubMed, MEDLINE, EMBASE, CINAHL, and Ichushi-Web by NPO Japan Medical Abstracts Society, in English and Japanese, from 1976 to 2017. The combination of MESH and keywords used were (dignity), and (care), and (chronic disease) or (chronic illness). Three antecedents were identified: loss of physical function and reduced psychological capacity, independence and role; living with uncertainty of illness; and multi-faceted distress. There were four attributes identified: bolstering self-esteem, reducing multi-faceted distress, continued relationship, and protecting individual's rights. Four consequences were identified: improved self-esteem, relief from multi-faceted distress, deepening the purpose and meaning of life, and maintaining and/or improving the quality of life. Dignity-centered care is defined as: care that results in improvement of self-esteem, deepens purpose and meaning of life, maintains and improves quality of life and provides relief from multi-faceted distress. This happens through protecting the individual's rights, bolstering self-esteem and reducing multi-faceted distress through continued relationships with family, friends, and providers. There is a need for continued involvement with those individuals who have lost physical function, psychological capacity, autonomy, and role. They live with uncertainty of illness and exhibit multi-faceted distress. This concept is a fulcrum for patient and nurse reciprocity enabling both to realize greater integrity and respect, and is useful for nursing practice and research.


Active living research: partnerships that count.
There is growing recognition that partnerships with policy-makers and practitioners are critical, if active living research has any chance of being translated into policy and practice. These partnerships provide researchers insight into policy-relevant research questions; create an appetite for the research findings amongst policy-makers; and help create 'champions' for the research who can assist in advocating for the findings to be translated. Drawing on experience, this commentary describes partnerships that have worked in Australia, and reflects on lessons that have contributed to success.


High-performance liquid chromatographic assay for the simultaneous monitoring of mefloquine and its acid metabolite in biological samples using protein precipitation and ion-pair extraction.
A high-performance liquid chromatographic (HPLC) method is presented for the simultaneous determination of mefloquine and its acid metabolite in plasma and whole blood. Plasma and whole blood are deproteinized with a combination of zinc and acetonitrile before extraction. Mefloquine and its acid metabolite are extracted simultaneously at pH 4 by methyl tert.-butyl ether, where mefloquine is extracted as an ion pair with heptanesulphonate. After evaporation of the organic phase, the residue is dissolved in mobile phase and injected on to the chromatographic column. A reversed-phase column (Spherisorb ODS-1) is used with acetonitrile-phosphate buffer (0.1 mol/l, pH 2.5) (42:58) containing 40 mmol/l perchlorate as the mobile phase. N,N-Dioctylamine was added to the mobile phase to give a concentration of 0.1% and the pH was adjusted to 2.3-2.7 with concentrated phosphoric acid. The method permits the determination of 0.10 mumol/l (30 ng/ml) mefloquine and its acid metabolite in plasma. The coefficient of variation was 5-6% at the therapeutic level (mefloquine 1-4 mumol/l, its carboxylic metabolite 2-6 mumol/l) in 0.5-ml samples. An alternative method is also described with a similar clean-up procedure that uses protein precipitation with zinc-acetonitrile as a sample pretreatment for therapeutic monitoring of mefloquine and metabolite in plasma and whole blood. Using this method, 0.25 mumol/l mefloquine and its metabolite can be determined. The results from the two methods correlate well.


Bis{2-[(pyridin-4-yl-κN)sulfan-yl]pyrazine}-silver(I) tetra-fluoridoborate.
In the title mononuclear complex, [Ag(C(9)H(7)N(3)S)(2)]BF(4), the Ag(I) ion adopts a virtually linear coordination geometry [N-Ag-N = 178.06 (11)°] with the two ligands bound to the metal atom via the pyridine N atoms. The metal-coordinated pyridine rings are almost coplanar, making a dihedral angle of 1.5 (2)°, while the two pendent pyrazine rings are arranged on the same side of the N-Ag-N line. Along the a axis, the mononuclear coordination units are stacked with π-π inter-actions between the pyridine rings [centroid-centroid distance = 3.569 (4) Å], leading to infinite chains. The chains are inter-connected through inter-molecular N(pyrazine)⋯π(pyrazine) inter-actions forming layers parallel to the ab plane [N⋯centroid = 3.268 (5) Å]. These layers are further stacked along the c-axis direction, furnishing a three-dimensional supra-molecular framework with the tetra-fluoridoborate anions embedded within the inter-stices.


Calpain as a Therapeutic Target for Hypoxic-Ischemic Encephalopathy.
Hypoxic-ischemic encephalopathy (HIE) is a complex pathophysiological process with multiple links and factors. It involves the interaction of inflammation, oxidative stress, and glucose metabolism, and results in acute and even long-term brain damage and impairment of brain function. Calpain is a family of Ca2+-dependent cysteine proteases that regulate cellular function. Calpain activation is involved in cerebral ischemic injury, and this involvement is achieved by the interaction among Ca2+, substrates, organelles, and multiple proteases in the neuronal necrosis and apoptosis pathways after cerebral ischemia. Many calpain inhibitors have been developed and tested in the biochemical and biomedical fields. This study reviewed the potential role of calpain in the treatment of HIE and related mechanism, providing new insights for future research on HIE.


Application of atmospheric pressure field desorption for the analysis of anionic surfactants in commercial detergents.
Recent work has shown that field desorption (FD) and field ionization (FI) using activated field emitters may be performed at atmospheric pressure, too. While some limitations apply to atmospheric pressure field desorption (APFD) mass spectrometry (MS), the method can deliver both positive and negative even electron ions of highly polar or ionic compounds. Furthermore, APFD even permits the generation of positive molecular ions of polycyclic aromatic compounds. Here, an application of negative-ion APFD for the analysis of anionic surfactants contained in commercial detergent products for body care, household, and technical uses is presented. The samples include liquid soaps and shower gels, dishwashing liquids, and cooling lubricants. Surfactant solutions in methanol/water or pure methanol at 2-10 µl ml-1 were deposited on commercial 13-µm activated tungsten emitters. The emitters were positioned in front of the atmospheric pressure interface of a Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometer by means of a slightly modified nano-electrospray ionization (nanoESI) source. The entrance electrode of the interface was set to positive high voltage with respect to the emitter at ground potential. Under these conditions, negative-ion desorption was achieved. The surfactant anions, organic sulfates and organic sulfonates, were characterized by accurate mass-based formula assignments, and in part, by tandem mass spectrometry. The negative-ion APFD spectra were compared to results by negative-ion electrospray ionization (ESI) either obtained using the FT-ICR mass spectrometer or by using a trapped ion mobility-quadrupole-time-of-flight (TIMS-Q-TOF) instrument when product ions of low m/z needed to be detected in tandem MS.


What functions of the sperm cell are measured by in vitro fertilization of zona-free hamster eggs?
Human spermatozoa were capacitated in media containing either high concentrations (3.5%) of human serum albumin (HSA) or low concentrations (0.3%) of bovine serum albumin (BSA). The effects of both capacitation media were assessed immediately and after overnight preincubation (18 to 24 hours) by adding a mixture of nonliving human oocytes and living zona-free hamster eggs to the sperm suspension. Overnight preincubation of sperm in media containing 3.5% HSA enhanced sperm fusion with hamster vitelli, but the capacity for zona penetration was lost. These effects could be attributed to the concentration of HSA rather than a general effect of albumin concentration, because overnight preincubation in 3.5% BSA did not interfere with zona penetration. During overnight incubation in 3.5% HSA, the percentage of acrosome reactions increased, as did alterations in the equatorial segment of the acrosome-reacted sperm. The percentage of motile sperm remained high after overnight incubation in 3.5% HSA, but both the mean swimming speed and flagellar activity on the zona surface declined. The sperm also lost their ability for strong zona binding after overnight incubation in 3.5% HSA.


The In Vitro Efficacy of Essential Oils and Antifungal Drugs Against Prototheca zopfii.
The algae of the genus Prototheca are environmental pathogens whose main reservoir is the habitat of cows. They can cause protothecosis in domestic and wild animals, as well as human beings, with the main etiological agents being Prototheca zopfii in animals and Prototheca wickerhamii in humans. The aim of the study was to evaluate the in vitro activity of selected essential oils and antifungal antibiotics against P. zopfii isolates. The material consisted of nine P. zopfii strains isolated from the milk of cows suffering from mastitis. Eight essential oils produced by POLLENA-AROMA, Poland, and nine antifungal agents were tested. The effects of essential oils on P. zopfii were evaluated by microdilution with liquid Sabouraud dextrose broth, and susceptibility to antifungal agents was tested using the disk-diffusion method. All used essential oils inhibited the activity of P. zopfii isolates, with MIC values ranging from 0.2 to 10.5 μl/ml. Cinnamon, clove, and thyme demonstrated the highest activity against the tested P. zopfii strains at concentrations ranging from 0.6 to 1.0 μl/ml. Of the antifungal agents, the tested strains were the most sensitive to nystatin (100 %). The tested essential oils can be used to complement protothecosis therapy in animals and human beings.


Negation and its impact on the accessibility of text information.
Prior experiments have shown that sentences such as (1) Mary bakes bread but no cookies lead to a reduced accessibility of the concept mentioned in the negated phrase, whereas sentences such as (2) Elizabeth burns the letters but not the photographs do not. In the present article, two explanations for this result are investigated. According to situation model theory (Johnson-Laird, 1983; van Dijk & Kintsch, 1983), the reason is that the entity mentioned within the negated phrase in (2) is not absent from the described situation. According to discourse representation theory (Kamp, 1981), in contrast, the negation operator in (2) does not reduce the accessibility of the negated concept, because the corresponding discourse referent is not introduced but merely referred to within the operator's scope. In two experiments, participants were presented with narrative texts including negation sentences that either introduced or referred to entities, and that either described a situation in which only the nonnegated or only the negated entity was present. The accessibility of the relevant concepts was measured by means of a probe recognition task. The results support the situation models explanation.


Evaluating internal and ocular residual astigmatism in Chinese myopic children.
To investigate the nature of internal astigmatism (IA) and ocular residual astigmatism (ORA) in Chinese myopic children and to identify factors that may influence IA and ORA. A total of 206 eyes of 206 myopic children (97 boys and 109 girls; 10.95 ± 2.2 years) were enrolled in this cross sectional study. Total ocular astigmatism (TOA), anterior corneal astigmatism (ACA), posterior corneal astigmatism (PCA) and total corneal astigmatism (TCA) were measured directly using either a Hartmann-Shack wavefront sensor or a Pentacam. IA and ORA were calculated by Fourier vector analyses (the definitions of IA and ORA are: IA = TOA - ACA - PCA, ORA = TOA - ACA). Spearman or Pearson correlation was adopted to detect multiple factors that may influence IA and ORA, which were then predicted by linear regressions. Modified compensation factors were applied to evaluate the inter-relationship between corneal astigmatism and ORA. While the mean values of IA and ORA were -0.52 DC × 94.8° and -0.63 DC × 93.0°, respectively, the percentage of ORA power over 1.00 D was as high as 28.64%. Full or under-compensation of ACA by ORA predominated in the enrolled subjects. The mean ORA J0 and J45 were -0.311 ± 0.236 and -0.032 ± 0.156 D, respectively, negatively correlated with the corresponding ACA components (J0: r = -0.276, J45: r = -0.616, p < 0.001). While age was not correlated with either IA or ORA (p > 0.1), the power of IA or ORA was correlated inversely with the axial length (IA: r = -0.193, p = 0.005; ORA: r = -0.169, p = 0.015) and positively with the spherical equivalent refraction (IA r = 0.195, p = 0.005; ORA r = 0.213, p = 0.002) and power of corneal astigmatism (IA-ACA: r = 0.302, IA-TCA: r = 0.368, ORA-ACA: r = 0.334, ORA-TCA: r = 0.293). Girls had larger IA powers than boys (0.741 ± 0.345 D vs 0.651 ± 0.340, p = 0.036). Full or under-compensation of ACA by ORA is common in Chinese myopic children, and the compensation efficiency may decrease with age. Among Chinese children with myopia, a larger ORA is more prevalent with less myopia and greater corneal astigmatism.


TEL Methods Used for the Learning of Clinical Neuroanatomy.
Ubiquity of information technology is undoubtedly the most substantial change to society in the twentieth and twenty-first centuries and has resulted in a paradigm shift in how business and social interactions are conducted universally. Information dissemination and acquisition is now effortless, and the way we visualise information is constantly evolving. The face of anatomy education has been altered by the advent of such innovation with Technology-Enhanced Learning (TEL) now commonplace in modern curricula.With the constant development of new computing systems, the temptation is to push the boundaries of what can be achieved rather than addressing what should be achieved. As with clinical practice, education in healthcare should be evidence driven. Learning theory has supplied educators with a wealth of information on how to design teaching tools, and this should form the bedrock of technology-enhanced educational platforms. When analysing resources and assessing if they are fit for purpose, the application of pedagogical theory should be explored and the degree to which it has been applied should be considered.


Distribution and functional characterization of human Nav1.3 splice variants.
The focus of the present study is the molecular and functional characterization of four splice variants of the human Nav1.3 alpha subunit. These subtypes arise due to the use of alternative splice donor sites of exon 12, which encodes a region of the alpha subunit that resides in the intracellular loop between domains I and II. This region contains several important phosphorylation sites that modulate Na+ channel kinetics in related sodium channels, i.e. Nav1.2. While three of the four Nav1.3 isoforms, 12v1, 12v3 and 12v4 have been previously identified in human, 12v2 has only been reported in rat. Herein, we evaluate the distribution of these splice variants in human tissues and the functional characterization of each of these subtypes. We demonstrate by reverse transcriptase-polymerase chain reaction (RT-PCR) that each subtype is expressed in the spinal cord, thalamus, amygdala, cerebellum, adult and fetal whole brain and heart. To investigate the functional properties of these different splice variants, each alpha subunit isoform was cloned by RT-PCR from human fetal brain and expressed in Xenopus oocytes. Each isoform exhibited functional voltage-dependent Na+ channels with similar sensitivities to tetrodotoxin (TTX) and comparable current amplitudes. Subtle shifts in the V 1/2 of activation and inactivation (2-3 mV) were observed among the four isoforms, although the functional significance of these differences remains unclear. This study has demonstrated that all four human splice variants of the Nav1.3 channel alpha subunit are widely expressed and generate functional TTX-sensitive Na+ channels that likely modulate cellular excitability.


Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma.
Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALK(del2-3)) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK(del2-3) was autophosphorylated in NB-1 cells as well as in ALK(del2-3)-transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK(del2-3)-transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALK(del2-3)-expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.


Plasma antidiuretic hormone in cases with the early onset of profound unilateral deafness.
The p-ADH level in cases of juvenile unilateral profound deafness (JUPD) and the timecourse of the level were examined to investigate whether or not an increase of p-ADH is involved in the development of delayed endolymphatic hydrops (DEH) in JUPD. In 90 consecutive patients with unilateral profound or total sensorineural deafness with the onset in early childhood, pure-tone audiometric examination and the measurement of p-ADH and plasma osmolality (p-OSM) were followed up once or twice a year as far as possible. At every testing, we performed careful history-taking about episodic vertigo/dizziness, fluctuant hearing loss, and tinnitus in order to find out whether patients had experienced these clinical signs of the development of DEH. Means and standard deviation (S.D.) of p-ADH level and osmolality in all samples tested (n=368) were 7.3+/-7.0 pg/mL (0.7-52.0 pg/mL), and 288.6+/-4.4 mOsm/L (273-306 mOsm/L), respectively. The mean of p-ADH level was much higher than those previously reported in children and adolescents. High levels of p-ADH (over 5.0 pg/mL) were often observed in subjects between 6 and 19 years of age, but not so frequently in subjects of 20 years of age or older. Long-term follow-up of p-ADH levels revealed that DEH frequently developed in cases with persistent elevation of p-ADH. The elevation of p-ADH is likely to promote the development of DEH in cases of JUPD, although the underlying mechanism remains to be elucidated.


The occurrence of myocardial bridges on coronary arteries in the common seal (Phoca vitulina vitulina).
Myocardial bridging in the common seal (Phoca vitulina vitulina) has been described in 4 hearts. In a collection of 40 hearts 10 cases(20%) were present. In most of the hearts the vessels in the sulcus interventricularis subsinuosus are overbridged.


Endothelial nitric oxide synthase and fractalkine chemokine receptor polymorphisms on angiographically assessed coronary atherosclerosis.
The CX3CR1 is a fractalkine chemokine receptor expressed by leukocytes attracting them to the arterial wall inflammation. The endothelial nitric oxide synthase (eNOS) produces nitric oxide that acts on the vascular wall and circulating blood cells, lessening the inflammatory atherogenic damage. We determined if -786T > C and E298D eNOS and 745G>A CX3CR1 variants were associated with CAD risk and/or severity in Southern Brazilians of European descent. We investigated these polymorphisms in 358 patients who had undergone coronary angiography and 129 non-symptomatic controls by PCR followed by restriction analyses. The 745 G > A CX3CR1 variant was not associated with CAD in this sample. Patients with significant CAD (coronary stenosis >or = 75%) presented higher frequencies of the eNOS -786C, but not of 298D allele than those observed among patients in whom significant CAD was ruled out by angiography (control group 1, p = 0.022) and non-symptomatic controls (control group 2, p < 0.001). The eNOS haplotypes derived from these 2 sites revealed that the frequency of haplotypes carrying the -786C allele (-786C/298D and -786C/298E) was increased and of the wild haplotype (-786T/298E) was decreased in patients with significant CAD (p = 0.003). After controlling for other classical risk factors carriers of haplotypes containing the -786C allele were at increased CAD risk (-786C/298D, OR = 2.95, p = 0.007; and -786C/298E, OR = 2.41, p = 0.030). The -786T > C was the polymorphism associated with severe CAD in this study. Haplotype analyses can be extremely helpful in unraveling the influence of different markers within a gene.


Effect of glutaraldehyde on the humoral immunogenicity and structure of porcine dermal collagen membranes.
Our previous studies showed that the biodegradation rate of cross-linked porcine dermal collagen membrane (PDCM) could be retarded without changing its biocompatible character. The purpose of this study was to assay the humoral immune response of PDCM reconstitute with glutaraldehyde (GA) and observe their surface architectures. PDCM reconstituted with GA (0, 0.01, 0.05, and 3%) was implanted in 30 Sprague-Dawley rats. Sample sera were collected 3, 6, and 9 weeks after surgery and assayed with ELISA. The architectures of PDCMs were observed under SEM (100x). The study showed that non cross-linked PDCM induced the highest immune response than any other cross-linked PDCMs (by optical density (OD) values, P<0.05). It also possessed the most active cross-reactivity to the serum of rats from any other PDCMs groups (by Sheffe test, P<0.05). The surface architectures observed under SEM presented four structures: fibrillar, porous, channeled, and sheet-like structures as PDCM was conditioned with 0, 0.01, 0.05, and 3% GA, respectively. Resulting from the study are that changing the concentration of GA can modulate the surface characters of PDCMs and change their immunogenicity. Reconstitution of PDCM may not change the conformation of antigenic determinants of PDCM but rather hinder the epitopes by changing the surface stereo structure of this collagen.


Experimental investigation of the effect of middle ear in bone conduction.
Experimental investigation of the contribution of the middle ear to bone conduction (BC) hearing sensation. Experiments were conducted on 6 fresh cadaver whole head specimens. The electromagnetic actuators from a commercial bone conduction hearing aid (BCHA), Baha® 5 SuperPower and BoneBridge (BB), were used to provide stepped sine stimulus in the range of 0.1-10 kHz. The middle ear transfer function (METF) of each cadaver head was checked against the ASTM F2504-05 standard. In a first step, the stapes stimulus into the cochlea, under BC, was estimated based on the differential velocity between the stapes footplate and the promontory. This was based on sequential measurements of the 3D velocity of the stapes footplate and the promontory. In parallel, the differential tympanic membrane (TM) pressure was recorded by measuring sound pressure in the middle ear and in the external auditory canal each measured 1-2 mm from the TM. The measurement procedure was then sequentially repeated, after: a) opening the middle ear cavity; b) ISJ interruption; c) closing the middle ear cavity. At the end, the velocity at each actuator is measured for comparison purposes. Stapes footplate and promontory motion was quantified as the 3D motion at a single measurement point via a three-dimensional laser Doppler vibrometer (3D LDV) system. The combined motion was used for all motion parameters. The METF, based on the combined motion, matches better to the ASTM standard, making the measurements resilient to oblique measurement directions. The Baha actuator produced ∼10 dB SPL more output than the BB above 2 kHz. This resulted in 2-5 dB increase in the differential pressure across the TM, after middle ear cavity opening, for Baha stimulation, and up to 9 dB drop (around 2 kHz) for BB stimulation. The differential stapes motion follows linearly the level of motion of the stimulation area, however, it is affected by actuator resonances in a more complex way. Interruption of the ISJ, reduces the differential motion of the stapes with 1-5 dB, only at 1-3 kHz. Combined velocity more objectively describes the stapes and skull motion, than any individual motion component. The state of the ME cavity and the ISJ affect the cochlear input of the stapes, however, the effect is limited in frequency and magnitude.


Colorimetric sensor arrays for the differentiation of baijiu based on amino-acid-modified gold nanoparticles.
It is of great significance for quality control to realize the discrimination for baijiu from different brands and origins. Strong-aroma-type baijiu (SAB), one of the most important Chinese aroma-type baijiu, exhibits the largest variety and market share. In this study, we proposed colorimetric sensor arrays based on gold nanoparticles (AuNPs) modified with different amino acids (AAs) to recognize the organic acids, and further distinguish different SABs. Three representative AAs, namely methionine (Met), tryptophan (Trp), and histidine (His), were selected to modify the AuNPs surface. The investigation of the effect of the main ingredients of SAB on AA@AuNPs aggregation confirmed that this aggregation mainly resulted from organic acids. Moreover, this aggregation was successfully used for differentiating 11 organic acids. Different pH conditions can not only cause changes of the content of organic acids in baijiu, but also disrupt the balance among flavor substances of baijiu to some extent. Consequently, the AA@AuNPs arrays under two pH conditions have been successfully applied to distinguish 14 kinds of SABs from different brands and origins. The proposed colorimetric sensor method is simple, rapid, and visualized and provides a potential application prospect for the quality control of baijiu and other alcoholic beverages.


Intrinsic Descriptor Guided Noble Metal Cathode Design for Li-CO2 Battery.
To date, the effect of noble metal (NM) electronic structures on CO2 reaction activity remains unknown, and explicit screening criteria are still lacking for designing highly efficient catalysts in CO2 -breathing batteries. Herein, by preferentially considering the decomposition of key intermediate Li2 CO3 , an intrinsic descriptor constituted of the d x 2 - y 2 ${{\rm{d}}}_{{x}^2 - {y}^2}$ orbital states and the electronegativity for predicting high-performance cathode material are discovered. As a demonstration, a series of graphene-supported noble metals (NM@G) as cathodes are fabricated via a fast laser scribing technique. Consistent with the preliminary prediction, Pd@G exhibits an ultralow overpotential (0.41 V), along with superior cycling performance up to 1400 h. Moreover, the overall thermodynamic reaction pathways on NM@G confirm the reliability of the established intrinsic descriptor. This basic finding of the relationship between the electronic properties of noble metal cathodes and the performance of Li-CO2 batteries provides a novel avenue for designing remarkably efficient cathode materials for metal-CO2 batteries.


Optimization of Ohmic Contacts to p-GaAs Nanowires.
The performance of Ohmic contacts applied to semiconductor nanowires (NWs) is an important aspect for enabling their use in electronic or optoelectronic devices. Due to the small dimensions and specific surface orientation of NWs, the standard processing technology widely developed for planar heterostructures cannot be directly applied. Here, we report on the fabrication and optimization of Pt/Ti/Pt/Au Ohmic contacts for p-type GaAs nanowires grown by molecular beam epitaxy. The devices were characterized by current-voltage (IV) measurements. The linearity of the IV characteristics curves of individual nanowires was optimized by adjusting the layout of the contact metal layers, the surface treatment prior to metal evaporation, and post-processing thermal annealing. Our results reveal that the contact resistance is remarkably decreased when a Pt layer is deposited on the GaAs nanowire prior to the traditional Ti/Pt/Au multilayer layout used for p-type planar GaAs. These findings are explained by an improved quality of the metal-GaAs interface, which was evidenced by grazing incidence X-ray diffraction measurements in similar metallic thin films deposited on GaAs (110) substrates. In particular, we show that Ti exhibits low degree of crystallinity when deposited on GaAs (110) surface which directly affects the contact resistance of the NW devices. The deposition of a thin Pt layer on the NWs prior to Ti/Pt/Au results in a 95% decrease in the total electrical resistance of Be-doped GaAs NWs which is associated to the higher degree of crystallinity of Pt than Ti when deposited directly on GaAs (110).


Comparison of in vitro methods for the production of Paenibacillus larvae endospores.
Paenibacillus larvae endospores are the infectious particles of the honey bee brood disease, American Foulbrood. We demonstrate that our previously published protocol (Alvarado et al., 2013) consistently yields higher numbers and purer preparations of P. larvae endospores, than previously described protocols, regardless of the strain tested (B-3650, B-3554 or B-3685).


Barium ions reduce contraction kinetics in rat tracheal smooth muscle.
In isolated rat tracheal smooth muscle, contraction was induced by electrical field stimulation (= EL; frequency = 30 Hz; pulse duration = 0.17 ms), 10 mumol/l acetylcholine (= ACh), potassium depolarization (137 mmol/l K), or by 10 mmol/l barium (= BA). Contraction kinetics were studied by analyzing tension recovery after cessation of a 1.8 s length vibration (100 Hz sinusoidal; amplitude = 6% of the muscle length). The contraction speed was high during EL as can be seen from the short time constant of post-vibration tension recovery (tau = 5.90 +/- 0.14 s) found 30 s after onset of stimulation. The time constants of tension recovery during long-term (50 min) activation averaged 12.88 +/- 0.32 s (K) and 13.24 +/- 0.17 s (ACh) when the vibration was stopped 8-45 min after onset of activation. As both of these stimuli act mainly via cholinergic receptors, similar down-regulated contraction kinetics occur under steady-state conditions of tonic contraction. However, during barium activation steady-state conditions need a 45 min agonist incubation, and the time constant of post-vibration tension recovery was extended to 34.05 +/- 2.21 s. Thus, calcium may be replaced by barium in the force generation process but it produces slower cycling of cross-bridges.


Stock return anomalies identification during the Covid-19 with the application of a grouped multiple comparison procedure.
This study investigates the impact of COVID-19 pandemic on the Chinese stock market in 2020. Using daily data of three industries, this study addresses the identification of abnormal stock returns as a multiple hypothesis testing problem and proposes to apply a grouped comparison procedure for better detection. By comparing the numbers of daily signals and numbers of stocks with abnormal positive and negative returns, the empirical result shows that the three industries perform differently under the pandemic. Compared to the non-grouped testing procedure, the signals found by the grouped procedure are more prominent, which is advantageous for some situations when there tends to be abnormal performance clustering at the occurrence of major event. This paper on stock return anomalies gives a new perspective on the impact of major events to the stock market, like the global outbreak disease.


Gallium-mediated allyl transfer from bulky homoallylic alcohol to aldehydes via retro-allylation: stereoselective synthesis of both erythro- and threo-homoallylic alcohols.
Retro-allylation of bulky gallium homoallylic alkoxides occurs to generate (Z)- and (E)-crotylgallium reagents stereospecifically, starting from erythro- and threo-homoallylic alcohols, respectively. The (Z)- and (E)-crotylgallium reagents immediately reacted with aromatic aldehydes to afford the corresponding erythro- and threo-homoallylic alcohols, respectively. [reaction: see text]


Defining A Framework and Evaluation Metrics for Sustainable Global Surgical Partnerships: A Modified Delphi Study.
To use expert consensus to build a concrete and realistic framework and checklist to evaluate sustainability in Global Surgery Partnerships (GSPs). Partnerships between high- and low-resourced settings are often created to address the burden of unmet surgical need. Reflecting on the negative, unintended consequences of asymmetrical partnerships, global surgery community members have proposed frameworks and best practices to promote sustainable engagement between partners, though these frameworks lack consensus. This project proposes a cohesive, consensus-driven framework with accompanying evaluation metrics to guide sustainability in GSPs. A modified Delphi technique with purposive sampling was used to build consensus on the definitions and associated evaluation metrics of previously proposed pillars (Stakeholder Engagement, Multidisciplinary Collaboration, Context-Relevant Education and Training, Bilateral Authorship, Multisource Funding, Outcome Measurement) of sustainable GSPs. Fifty global surgery experts from 34 countries with a median of 9.5 years of experience in the field of global surgery participated in three Delphi rounds. Consensus was achieved on the identity, definitions, and a 47-item checklist for the evaluation of the six pillars of sustainability in GSPs. 29% of items achieved consensus in the first round, whereas 100% achieved consensus in the second and third rounds. We present the first framework for building sustainable GSPs using the input of experts from all World Health Organization regions. We hope this tool will help the global surgery community to find non-colonial solutions to addressing the gap in access to quality surgical care in low-resource settings.


Curative Analysis of Patients with Hepatocellular Carcinoma Using Transcatheter Arterial Chemoembolization Combined with Radiofrequency Ablation.
BACKGROUND Transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) can improve the survival of patients with hepatocellular carcinoma (HCC). The purpose was to explore the characteristics of high-risk and low-risk groups of HCC patients receiving combination therapy using a decision tree model. MATERIAL AND METHODS This retrospective cohort study investigated HCC patients treated with a combination of TACE and RFA at our hospital from 2012 to 2018. Decision tree analysis was used to study the 1-year prognosis of patients, and patients were divided into high-risk and low-risk groups. RESULTS We included a total of 142 patients with HCC, 21.83% female and 78.17% male, with the median age of 60 years old. The median follow-up was 13.5 months; 39.44% of patients had progressive disease or death (high-risk group) and 60.56% of patients did not have progressive disease or survival (low-risk group). The area under the curve (AUC) of the decision tree model was 0.846. There were significant differences in sex (P=0.003), age (P=0.038), tumor number (P=0.043), number of RFAs in the first treatment cycle (P.


Cross-species vaccination in wild and exotic animals.
These are two examples of organisms which may cause morbidity and/or mortality among numerous unrelated species. Since it is cost prohibitive in most instances to have a biological licensed for wild or exotic species, it remains a challenge to the zoo or wildlife veterinarian to determine if a licensed vaccine for other species is safe and efficacious for a particular exotic species.


Isolation of novel single-chain Cro proteins targeted for binding to the bcl-2 transcription initiation site by repertoire selection and subunit combinatorics.
New designed DNA-binding proteins may be recruited to act as transcriptional regulators and could provide new therapeutic agents in the treatment of genetic disorders such as cancer. We have isolated tailored DNA-binding proteins selected for affinity to a region spanning the transcription initiation site of the human bcl-2 gene. The proteins were derived from a single-chain derivative of the lambda Cro protein (scCro), randomly mutated in its recognition helices to construct libraries of protein variants of distinct DNA-binding properties. By phage display-afforded affinity selections combined with recombination of shuffled subunits, protein variants were isolated, which displayed high affinity for the target bcl-2 sequence, as determined by electrophoretic mobility shift and biosensor assays. The proteins analyzed were moderately sequence-specific but provide a starting point for further maturation of desired function.


The orthodontic management of patients with cleft lip and palate: from birth to the late mixed dentition.
This is the first of two papers outlining the orthodontic management of patients with cleft lip and palate. This paper will review orthodontic input into children with cleft lip and palate from birth to the late mixed dentition before definitive orthodontics. It will emphasise the importance of timing in alveolar bone grafting, the role of the general dental practitioner and the impact of timing on definitive orthodontic outcome.


Structural and functional characterization of the Sin Nombre virus L protein.
The Bunyavirales order is a large and diverse group of segmented negative-strand RNA viruses. Several virus families within this order contain important human pathogens, including Sin Nombre virus (SNV) of the Hantaviridae. Despite the high epidemic potential of bunyaviruses, specific medical countermeasures such as vaccines or antivirals are missing. The multifunctional ~250 kDa L protein of hantaviruses, amongst other functional domains, harbors the RNA-dependent RNA polymerase (RdRp) and an endonuclease and catalyzes transcription as well as replication of the viral RNA genome, making it a promising therapeutic target. The development of inhibitors targeting these key processes requires a profound understanding of the catalytic mechanisms. Here, we established expression and purification protocols of the full-length SNV L protein bearing the endonuclease mutation K124A. We applied different biochemical in vitro assays to provide an extensive characterization of the different enzymatic functions as well as the capacity of the hantavirus L protein to interact with the viral RNA. By using single-particle cryo-EM, we obtained a 3D model including the L protein core region containing the RdRp, in complex with the 5' promoter RNA. This first high-resolution model of a New World hantavirus L protein shows striking similarity to related bunyavirus L proteins. The interaction of the L protein with the 5' RNA observed in the structural model confirms our hypothesis of protein-RNA binding based on our biochemical data. Taken together, this study provides an excellent basis for future structural and functional studies on the hantavirus L protein and for the development of antiviral compounds.


Characterization and expression analysis of Nod-like receptor 3 (NLRC3) against infection with Piscirickettsia salmonis in Atlantic salmon.
The nucleotide binding oligomerization domain like receptors, or NOD like receptors (NLRs), are intracellular receptors responsible for recognizing pathogens in vertebrates. Several NLR mammalian models have been characterized and analyzed but few studies have been performed with teleost species. In this study, we analyzed the nucleotide sequence of six mRNA variants of NLRC3 in Atlantic salmon (SsNLRC3), and we deduced the amino acid sequence coding for two different isoforms with a total length of 1135 amino acids and 1093 amino acids. We analyzed the phylogeny of all variants, including a Piscirickettsia salmonis infection in Atlantic salmon. All variants and their expression pattern during infection were analyzed using real-time qPCR. One of the analyzed variants was over-expressed during the early stages of Piscirickettsia salmonis infection, and we were able to identify two different SsNLRC3 isoforms. Lastly, we observed that an alteration in the amino acid sequence of one of the isoforms can directly affect the pathogen recognition function.


Pharmacologic treatment for urgency-predominant urinary incontinence in women diagnosed using a simplified algorithm: a randomized trial.
The purpose of this study was to evaluate clinical outcomes associated with the initiation of treatment for urgency-predominant incontinence in women diagnosed by a simple 3-item questionnaire. We conducted a multicenter, double-blinded, 12-week randomized trial of pharmacologic therapy for urgency-predominant incontinence in ambulatory women diagnosed by the simple 3-item questionnaire. Participants (N = 645) were assigned randomly to fesoterodine therapy (4-8 mg daily) or placebo. Urinary incontinence was assessed with the use of voiding diaries; postvoid residual volume was measured after treatment. After 12 weeks, women who had been assigned randomly to fesoterodine therapy reported 0.9 fewer urgency and 1.0 fewer total incontinence episodes/day, compared with placebo (P ≤ .001). Four serious adverse events occurred in each group, none of which was related to treatment. No participant had postvoid residual volume of ≥ 250 mL after treatment. Among ambulatory women with urgency-predominant incontinence diagnosed with a simple 3-item questionnaire, pharmacologic therapy resulted in a moderate decrease in incontinence frequency without increasing significant urinary retention or serious adverse events, which provides support for a streamlined algorithm for diagnosis and treatment of female urgency-predominant incontinence.


Genomic insights in ascending aortic size and distensibility.
Alterations in the anatomic and biomechanical properties of the ascending aorta (AAo) can give rise to various vascular pathologies. The aim of the current study is to gain additional insights in the biology of the AAo size and function. We developed an AI based analysis pipeline for the segmentation of the AAo, and the extraction of AAO parameters. We then performed genome-wide association studies of AAo maximum area, AAo minimum area and AAo distensibility in up to 37,910 individuals from the UK Biobank. Variants that were significantly associated with AAo phenotypes were used as instrumental variables in Mendelian randomization analyses to investigate potential causal relationships with coronary artery disease, myocardial infarction, stroke and aneurysms. Genome-wide association studies revealed a total of 107 SNPs in 78 loci. We annotated 101 candidate genes involved in various biological processes, including connective tissue development (THSD4 and COL6A3). Mendelian randomization analyses showed a causal association with aneurysm development, but not with other vascular diseases. We identified 78 loci that provide insights into mechanisms underlying AAo size and function in the general population and provide genetic evidence for their role in aortic aneurysm development.


Defining and assessing wisdom: a review of the literature.
With increasing longevity and a growing focus on successful aging, there has been a recent growth of research designed to operationalize and assess wisdom. We aimed to (1) investigate the degree of overlap among empirical definitions of wisdom, (2) identify the most commonly cited wisdom subcomponents, (3) examine the psychometric properties of existing assessment instruments, and (4) investigate whether certain assessment procedures work particularly well in tapping the essence of subcomponents of the various empirical definitions. We searched PsychINFO-indexed articles published through May 2012 and their bibliographies. Studies were included if they were published in a peer-reviewed journal and (1) proposed a definition of wisdom or (2) discussed the development or validation of an instrument designed to assess wisdom. Thirty-one articles met inclusion criteria. Despite variability among the 24 reviewed definitions, there was significant overlap. Commonly cited subcomponents of wisdom included knowledge of life, prosocial values, self-understanding, acknowledgment of uncertainty, emotional homeostasis, tolerance, openness, spirituality, and sense of humor. Published reports describing the psychometric properties of nine instruments varied in comprehensiveness but most measures were examined for selected types of reliability and validity, which were generally acceptable. Given limitations of self-report procedures, an approach integrating multiple indices (e.g., self-report and performance-based measures) may better capture wisdom. Significant progress in the empirical study of wisdom has occurred over the past four decades; however, much needs to be done. Future studies with larger, more diverse samples are needed to determine the generalizability, usefulness, and clinical applicability of these definitions and assessment instruments. Such work will have relevance for the fields of geriatrics, psychiatry, psychology, sociology, education, and public health, among others.


Impact of fibrosis on liver-related event incidence in nonalcoholic fatty liver disease: A multicenter observational study.
There are few reports on the prognosis of liver-related events in Japanese patients with nonalcoholic fatty liver disease (NAFLD). We undertook an observational study to compare the prognosis between fibrotic and nonfibrotic groups in Japanese NAFLD patients. Prognosis in 393 NAFLD patients who underwent liver biopsy between April 2013 and April 2015 at multiple centers were investigated. The time to onset of liver-related events, cardiovascular events, development of extrahepatic cancers, and death were compared between the pathologically fibrotic nonalcoholic steatohepatitis (NASH) group and nonalcoholic fatty liver (NAFL) + nonfibrotic NASH group. A similar analysis was carried out based on the fibrotic classification diagnosed using four noninvasive fibrosis prediction models. The mean age and body mass index at the time of liver biopsy was 55.7 years old and 28.04 kg/m2 , respectively The cumulative incidence of liver-related events at 1080 days after liver biopsy was 5.79% in the pathologically fibrotic NASH group and 0% in the NAFL + nonfibrotic NASH group, with a significant difference (p = 0.0334). The cumulative incidence of liver-related events was significantly higher in the positive group for the prediction model than in the negative group in all four models (all p values were <0.0001). There was no significant difference between the pathologically fibrotic NASH group and NAFL + nonfibrotic NASH group in terms of cumulative incidence of cardiovascular events, development of extrahepatic cancers, and death. The incidence of liver-related events was significantly higher in the fibrotic NASH group than that of the NAFL + nonfibrotic NASH group in Japanese NAFLD patients.


Further evidence for low-dose combinations in patients with left ventricular hypertrophy.
Left ventricular hypertrophy (LVH) is a powerful independent risk predictor for cardiovascular disease and reversal of LVH has become a primary goal of antihypertensive management. Recent evidence has confirmed that most hypertensive patients will benefit from a low-dose combination strategy to manage their hypertension, and two trials have recently examined the effect of this strategy on left ventricular mass. The REASON study (pREterax in regression of Arterial Stiffness in a contrOlled double-bliNd study) compared the low-dose combination of an angiotensin-converting enzyme (ACE) inhibitor and a diuretic with beta-blocker monotherapy in hypertensive patients with LVH, and the PICXEL study (Preterax In a double-blind Controlled study versus Enalapril in LVH) compared the same low-dose combination with ACE inhibitor monotherapy in hypertensive patients with echocardiographic LVH. The REASON study demonstrated that the low-dose combination produced a significantly greater change in left ventricular mass after 1 year than the beta-blocker, despite inducing a similar change in mean blood pressure. Additionally, perindopril/indapamide reduced central (carotid) and peripheral (brachial) systolic blood pressure (SBP) and pulse pressure (PP) to a significantly greater extent than beta-blocker, and these benefits were more pronounced for the central values; LVH is affected more by central rather than peripheral haemodynamic changes. Results of the analysis of the PICXEL study showed a significantly greater decrease in LVH parameters and blood pressure over 1 year in favour of the low-dose combination. This reduction cannot be entirely explained by the better efficacy of the low-dose combination on blood pressure reduction.


An experimental study of floral display and fruit set in Chilopsis linearis (Bignoniaceae).
To examine the effects of pollen and resource availability on floral display and fruit set in Chilopsis linearis three different types of experimental manipulations were performed. Pollen availability to individual inflorescences was altered by combinations of hand-pollinations and/or pollinator exclusions. Number of flowers produced per inflorescence was determinate; it was not affected by pollination, although flowers of the unpollinated treatment lasted longer. Fruit set was increased over natural levels by an average of 540% by hand-pollinating individual inflorescences. There was also a negative correlation between inflorescence size and percent fruit set in all treatments tested. Attempts to vary resources available to individual inflorescences and entire trees showed no significant effect on fruit set. These results show that, at the level of individual inflorescences, fruit and seed production in Chilopsis linearis are pollen limited and not resource limited. The problem of testing for resource limitation of female reproductive success in iteroparous plants and the effect of inflorescence size on female components of fitness are also discussed.


Tyrosine-rich crystals in pleomorphic adenomas of parotid glands.
Histochemical methods for proteins were applied to crystals found in pleomorphic adenomas of the parotid. Positive reactions were obtained with methods for tyrosine, tryptophan, arginine and sulphydryl groups, and indicate a greater complexity of composition than has previously been acknowledged.


Grip Strength in Women Being Treated for Breast Cancer and Receiving Adjuvant Endocrine Therapy: Systematic Review.
Adjuvant endocrine therapy in breast cancer has increased survival rates; however, it is not without musculoskeletal side effects. The purpose of this review was to systematically and critically appraise the available scientific evidence concerning the effect of adjuvant endocrine treatment on grip strength in women being treated for breast cancer. The National Library of Medicine (MEDLINE-PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Excerpta Medical Database by Elsevier (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Physiotherapy Evidence Database (PEDro) were searched from inception to February 2017 for appropriate papers that could answer the focused question. The searches were independently screened by 2 reviewers. The data from 7 papers that met the eligibility criteria were processed for further analysis. The collective data and the statistical analysis of all included studies were summarized and presented in a descriptive manner. If not provided, based on data from the individual included studies, a mean percent change in grip strength was calculated. The included studies evaluating aromatase inhibitors had inconclusive outcomes, and studies with a follow-up of 6 or 12 months showed a percent reduction in grip strength varying from 0.1% to 9.7%. None of the included studies showed a significant decrease in grip strength in tamoxifen users, with a percent reduction in grip strength varying from 1.4% to 2.2%. The 7 studies included cohort studies lacking a control group. There is inconclusive evidence for a small decrease in grip strength in women treated for breast cancer who are also receiving aromatase inhibitors. In those that use tamoxifen, grip strength did not change significantly.


Opiate-mediated inhibition of the release of cholecystokinin and substance P, but not neurotensin from cat hypothalamic slices.
The neuroactive peptides neurotensin (NT), substance P (SP) and cholecystokinin (CCK) have been shown to be distributed in the hypothalamus. These peptides may be part of hypothalamic mechanisms which regulate the release of pituitary hormones and feeding behavior. Numerous experiments have demonstrated opiate modulation of anterior pituitary hormone release. These effects have been reported to be mediated via a hypothalamic mechanism, which modulates the secretion of releasing, release inhibiting factors or other neuroactive peptides such as SP, CCK and NT. We have examined the effects of morphine on the potassium-stimulated, calcium-dependent release of SP, CCK and NT from cat hypothalamic slices. The potassium-stimulated release of SP and CCK was profoundly depressed by the addition of morphine (10(-5) M) in a naloxone-reversible manner. This morphine inhibition was shown to be stereospecific, levorphanol (10(-7) M) depressed the release, while dextrophan (10(-7) M) was inactive. Gel filtration chromatography of the potassium-stimulated release was determined to be isographic with authentic NT, SP and CCK-8, respectively. There was no indication of any gastrin-like activity. These data may suggest a regulatory mechanism through which opiates exert some of their neuroendocrine or feeding regulatory effects.


Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent.
A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10 μM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11β-HSD1. In this model, compound 1 binds into the catalytic site of 11β-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+).


Temporal regularity of cerebral activity at rest correlates with slowness of reaction times in intellectual disability.
Intellectual disability (ID) is described as a general slowness in behavior and an inadequacy in adaptive skills. The present study examines whether behavioral slowness in ID could originate from abnormal complexity in brain signals. Participants (N = 29) performed a reaction times (RTs) task assessing their individual information processing speeds. Half of the participants had moderate intellectual disability (intelligence quotient (IQ) < 70). Continuous electroencephalogram recording during the resting period was used to quantify brain signal complexity by approximate entropy estimation (ApEn). For all participants, a negative correlation between RTs and IQ was found, with longer RTs coinciding with lower IQ. This behavioral slowness in ID was associated with increased temporal regularity in electrocortical brain signals. Behavioral slowness in ID subjects is closely related to lower brain signal complexity. Brain signal ApEn is shown to correspond with processing speed for the first time: in ID participants, the higher the regularity in brain signals at rest, the slower RTs will be in the active state. ID should be understood as a lack of lability in the cortical transition to the active state, weakening the efficiency of adaptive behavior.


Amiodarone and desethylamiodarone increase intrasynaptosomal free calcium through receptor mediated channel.
Long term amiodarone (AM) therapy has been associated with several side effects including neurotoxicity. Since AM alters Ca2+ regulated events, we have studied its effects on the compartmentation of free Ca2+ in the synaptosomes as an attempt to understand the mechanism of AM and its metabolite, desethylamiodarone (DEA)-induced neurotoxicity. Intact brain synaptosomes were prepared from male Sprague-Dawley rats. Both AM and DEA produced a concentration dependent increase in intrasynaptosomal free Ca2+ concentration ([Ca2]i) to micromolar levels. The increase in [Ca2]i was not transient and a steady rise was observed with time. Omission of Ca2+ from the external medium prevented the AM- and DEA-induced rise in [Ca2+]i suggesting that AM and DEA increased the intracellular [Ca2+]i due to increased influx of Ca2+ from external medium. AM- and DEA-induced increase in intrasynaptosomal [Ca2+]i was neither inhibited by a calcium channel blocker, verapamil, nor with a Na+ channel blocker, tetrodotoxin. However, the blockade of [Ca2+]i rise by AM and DEA was observed with MK-801, a receptor antagonist indicating that AM and DEA induced rise in [Ca2+]i is through receptor mediated channel. Both AM and DEA also inhibited N-methyl-D-aspartic acid (NMDA)-receptor binding in synaptic membranes in a concentration dependent manner, DEA being more effective, indicating that AM and DEA compete for the same site as that of NMDA and confirm the observation that these drugs increase intrasynaptosomal [Ca2+]i through receptor mediated channel. 45Ca accumulation into brain microsomes and mitochondria was significantly inhibited by AM and DEA, but without any effect on the Ca2+ release from these intracellular organelles.(ABSTRACT TRUNCATED AT 250 WORDS)


Single-stage breast reconstruction with the anterior approach latissimus dorsi flap and permanent implants.
Traditional latissimus dorsi myocutaneous flap breast reconstruction results in a large wound on the back, difficult inset of flap, and skin color disparity. An anterior approach to harvesting the latissimus dorsi muscle flap reduces morbidity, and with skin-sparing mastectomy, immediate single-stage reconstruction with a permanent implant is provided. A retrospective review was performed of patients who underwent skin-sparing mastectomies and immediate reconstruction with the anterior approach latissimus dorsi muscle flap and permanent implant with 6- to 12-month follow-up. All procedures were performed by a single surgeon at three facilities from January of 2008 through December of 2008. Data included the patient's age; body mass index; history of axillary dissection, chemotherapy, or irradiation; occurrence of seroma, flap necrosis, infection, or cellulitis; and the need for further surgery. Fifty-eight reconstructions were performed in 36 patients (bilateral, 22 patients). Major complications included pulmonary embolism in one patient, removal of both implants in one patient because of infection, and removal of one implant because of hematoma. Minor complications included seroma in 40 of 58 procedures (68.9 percent), flap necrosis in seven (12 percent), cellulitis in four (6.8 percent), and a secondary procedure for cosmesis in four (6.8 percent). Seroma formation was more frequent in patients with a body mass index greater than 25 kg/m², patients aged older than 50 years, and after axillary dissection (p > 0.05). The anterior approach latissimus dorsi muscle flap with permanent implants provides a single-stage reconstructive option after skin-sparing mastectomy. Postoperative morbidity is comparable to that of the traditional latissimus dorsi muscle flap. Therapeutic, IV.


Construction and validation of a prognostic model for lung adenocarcinoma based on endoplasmic reticulum stress-related genes.
Lung adenocarcinoma (LUAD) is one of the most universal types of cancer all over the world and its morbidity continues to rise year by year. Growing evidence has demonstrated that endoplasmic reticulum stress is highly activated in cancer cells and plays a key role in regulating the fate of cancer cells. However, the role and mechanism of endoplasmic reticulum stress in lung adenocarcinoma genesis and development remains unclear. In this research, we developed a prognostic model to predict the overall survival of patients with LUAD utilizing endoplasmic reticulum stress-related genes and screened out potential small molecular compounds, which could assist the clinician in making accurate decisions and better treat LUAD patients. Firstly, we downloaded 419 endoplasmic reticulum stress-related genes (ERSRGs) from Molecular Signatures Database (MSigDB). Secondly, we obtained information about the transcriptome profiling and corresponding clinical data of 59 normal samples and 535 lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) database. Next, we used the DESeq2 package to identify differentially expressed genes related to endoplasmic reticulum stress. We performed univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis to establish a prognostic model for LUAD patients based on ERSRGs. Then, we carried out univariate and multivariate independent prognostic analysis of endoplasmic reticulum stress-related gene (ERSRG) score and some clinical traits of lung adenocarcinoma. Additionally, we developed a clinically applicable nomogram for predicting survival for LUAD patients over one, three, and five years. Moreover, we carried out a drug sensitivity analysis to identify novel small molecule compounds for LUAD treatment. Finally, we examined the tumor microenvironment (TME) and immune cell infiltrating analysis to explore the interactions between immune and cancer cells. 142 differentially expressed ERSRGs were identified by using the DESeq2 package. A prognostic model was built based on 7 differentially expressed ERSRGs after performing univariate Cox regression, LASSO regression, and multivariate Cox regression analysis. According to the results of univariate and multivariate independent prognostic analysis, we found ERSRG score can be used as an independent prognostic maker. Using the Kaplan-Meier curves, we found low-risk patients had higher survival probability than high-risk patients in both training set and test set. A nomogram was drawn to predict 1-, 3-, and 5-year survival probability. The calibration curves explained good performance of the model for the prediction of survival. Phenformin, OSU-03012, GSK-650394 and KIN001-135 were identified as the drugs most likely to provide important information to clinicians about the treatment of LUAD patients. A prognostic prediction model was established based on 7 differentially expressed ERSRGs (PDX1, IGFBP1, DDIT4, PPP1R3G, CFTR, DERL3 and NUPR1), which could effectively predict the prognosis of LUAD patients and give a reference for clinical doctors to help LUAD patients to make better treatment tactics. Based on the 4 small molecule compounds (Phenformin, OSU-03012, GSK-650394 and KIN001-135) we discovered, targeting endoplasmic reticulum stress-related genes may also be a therapeutic approach for LUAD patients.


Alcohol, smoking and illicit drug use in pediatric systemic lupus erythematosus patients.
To evaluate alcohol, smoking and/or illicit drug use, and history of bullying in adolescent childhood-onset systemic lupus erythematosus and healthy controls. 174 adolescents with pediatric rheumatic diseases were selected. All of the 34 childhood-onset systemic lupus erythematosus patients and 35 healthy controls participated in this study. A cross-sectional study included demographic/anthropometric data and puberty markers assessments; structured questionnaire and CRAFFT screening interview. McNemar tests indicated an excellent test-retest reliability of the structured questionnaire (p=1.0). The median current age was similar between childhood-onset systemic lupus erythematosus patients and controls [15 (12-18) vs. 15 (12-18) years, p=0.563]. The median of menarche age was significantly higher in childhood-onset systemic lupus erythematosus patients compared to controls [12 (10-15) vs. 11.5 (9-15) years, p=0.041], particularly in those that lupus had occurred before first menstruation [13 (12-15) vs. 11.5(9-15) years, p=0.007]. The other puberty marker and sexual function parameters were similar in both groups (p>0.05). Alcohol use was similar in both childhood-onset systemic lupus erythematosus patients and controls (38% vs. 46%, p=0.628). A trend of lower frequency of CRAFFT score ≥2 (high risk for substance abuse/dependence) was evidenced in childhood-onset systemic lupus erythematosus patients compared to controls (0% vs. 15%, p=0.053). Bullying was reported similarly for the two groups (43% vs. 44%, p=0.950). Further analysis in lupus patients regarding alcohol/smoking/illicit drug use showed no differences in demographic data, puberty markers, history of bullying, sexual function, contraceptive use, disease activity/damage scores, clinical/laboratorial features and treatments (p>0.05). This study showed high frequencies of early alcohol use in lupus adolescents and healthy controls, despite of a possible low risk for substance abuse/dependence in childhood-onset systemic lupus erythematosus patients.


Video laryngoscopy versus direct laryngoscopy for double-lumen endotracheal tube intubation: a retrospective analysis.
The authors hypothesized that video laryngoscopy (VL) facilitated double-lumen tube (DLT) insertion compared with direct laryngoscopy (DL). A retrospective analysis. An academic hospital. Patients older than 18 years of age undergoing thoracic surgery requiring DLT placement between 2005 and 2011. Patients without airway predictors of difficult intubation who were intubated under DL with Macintosh (DL-MAC, n = 40) or Miller (DL-MIL, n = 44) blades and VL with McGrath MAC (Aircraft Medical, Edinburgh, UK) and C-MAC (Karl Storz, Tuttlingen, Germany) laryngoscopes (n = 46) were included in the study. Patients who were intubated with both VL devices were grouped into a VL group. Patients in all 3 groups had comparable preoperative demographics. Mallampati scores and ease of manual ventilation after the induction of anesthesia were also similar in all groups. The Cormack Lehane (C-L) grade views were significantly higher in patients in the DL-MAC than in the DL-MIL and VL groups (p < 0.006). The number of intubation attempts was similar in all 3 groups; however, the percentage of intubation reported to be difficult was higher in the DL-MAC than in the other 2 groups (p = 0.014). No damage to the airway was found in any of the groups. DLT placement using VL appeared to overcome some of the limitations of DL-MAC but was similar to DL-MIL. The authors speculated that the ease of placement was related to the improved visualization of the vocal cords because there was a significantly greater number of C-L views 3 and 4 in the DL-MAC group as compared with the VL and DL-MIL groups. Hence, the authors advocate using VL, particularly when the laryngoscopist is inexperienced using DL-MIL for DLT placement.


Antileukemic activity of glycated fibrinogen-methotrexate conjugates.
The aim of the study was to compare the antileukemic activity of methotrexate (MTX) conjugates with native and glycated fibrinogen. We expected that conjugates based on glycated fibrinogen would reveal higher antileukemic activity because of decreased plasmin digestibility and a higher retention rate of glycated fibrinogen in the body. Fibrinogen was glycated using a high-temperature procedure at 65-85 degrees C. Glycated fibrinogens were examined with respect to their ability to clot and susceptibility to plasmin digestion. Native fibrinogen (F) and fibrinogens glycated at 65 and 73 degrees C (F65 and F73) were conjugated with MTX and tested in mice bearing P388 leukemia, at a dose of 40 mg of MTX per kg of body weight. Glycated fibrinogens retained their ability to clot. Compared to native fibrinogen, they were more resistant to digestion by plasmin. All tested conjugates revealed higher antitumor activity than the free drug. Increases in average lifespan over the control group were 34% for free MTX, 137% for F-MTX, 151% for F65-MTX and 91% for F73-MTX. The differences between the antitumor activities of all conjugates were not statistically significant. It seems necessary to compare the antitumor activities of MTX conjugates based on native and glycated fibrinogen in different tumor models, to demonstrate the expected differences.


Dosimetric impact of statistical uncertainty on Monte Carlo dose calculation algorithm in volumetric modulated arc therapy using Monaco TPS for three different clinical cases.
To study the dosimetric impact of statistical uncertainty (SU) per plan on Monte Carlo (MC) calculation in Monaco™ treatment planning system (TPS) during volumetric modulated arc therapy (VMAT) for three different clinical cases. During MC calculation SU is an important factor to decide dose calculation accuracy and calculation time. It is necessary to evaluate optimal acceptance of SU for quality plan with reduced calculation time. Three different clinical cases as the lung, larynx, and prostate treated using VMAT technique were chosen. Plans were generated with Monaco™ V5.11 TPS with 2% statistical uncertainty. By keeping all other parameters constant, plans were recalculated by varying SU, 0.5%, 1%, 2%, 3%, 4%, and 5%. For plan evaluation, conformity index (CI), homogeneity index (HI), dose coverage to PTV, organ at risk (OAR) dose, normal tissue receiving dose ≥5 Gy and ≥10 Gy, integral dose (NTID), calculation time, gamma pass rate, calculation reproducibility and energy dependency were analyzed. CI and HI improve as SU increases from 0.5% to 5%. No significant dose difference was observed in dose coverage to PTV, OAR doses, normal tissue receiving dose ≥5 Gy and ≥10 Gy and NTID. Increase of SU showed decrease in calculation time, gamma pass rate and increase in PTV max dose. No dose difference was seen in calculation reproducibility and dependent on energy. For VMAT plans, SU can be accepted from 1% to 3% per plan with reduced calculation time without compromising plan quality and deliverability by accepting variations in point dose within the target.


Use of the Hollow-Fiber Infection Model to Measure the Effect of Combination Therapy of Septic Shock Exposures of Meropenem and Ciprofloxacin against Intermediate and Resistant Pseudomonas aeruginosa Clinical Isolates.
Meropenem-ciprofloxacin combination therapy was compared to the respective monotherapy in a Hollow-Fiber Infection Model against two Pseudomonas aeruginosa isolates. Following initial kill of ∼ 5-logs by each monotherapy, rapid regrowth occurred within 24 h, reaching 108 - 1010 CFU/mL at 120 h. In contrast, combination therapy achieved > 5-log kill within 6 h and suppressed bacterial regrowth throughout. The results suggest that meropenem-ciprofloxacin combination may provide significantly enhanced bacterial killing and resistance suppression against P. aeruginosa.