Abdominal pregnancy after in vitro fertilization and embryo transfer.
Ectopic pregnancy continues to be a major complication of in vitro fertilization (IVF) and embryo transfer. We report the first abdominal pregnancy occurring after this therapeutic approach. The patient, a 35-year-old female, presented a frozen pelvis with a history of severe endometriosis and a left salpingectomy. After the transfer of four concepti in her second IVF/embryo transfer attempt, she became pregnant. Unfortunately, ultrasound evaluation five weeks later showed an ectopic pregnancy in the cul-de-sac. During laparotomy, it was noticed that implantation had taken place near the mesentery of the sigmoid and rectosigmoid. A right cornual tubal ligation was performed. Although the benefit of IVF/embryo transfer far outweighs the risk of an ectopic pregnancy, it is imperative that physicians who care for patients after IVF/embryo transfer be fully aware of the possibility of this complication in this high-risk population.


Paratesticular liposarcoma--a case report.
A case of paratesticular liposarcoma in a 60 year male is presented for its rarity. The tumour was a dedifferentiated liposarcoma (DDL) seen in the original excision.


Rare-variant genome-wide association studies: a new frontier in genetic analysis of complex traits.
Genome-wide association studies have, in the last few years, identified thousands of common genetic variants associated with common complex traits and diseases, implicating many genes not previously known to be involved in the biology of those traits. However, these variants have so far explained little of the population variance in trait values or disease susceptibility. As large-scale genome sequencing efforts have revealed the extent of genetic variation at the low end of the frequency range in human populations, the effects of rare variants have been proposed as an explanation of the 'missing genetic variance.' Improved technologies for genotyping rare variants, including inexpensive whole-genome and whole-exome sequencing and rare-variant genotyping chips, coupled with novel analytical methods, are making genome-wide scans for the effects of rare variants possible, and seem likely to usher in a new era in the genetic analysis of complex traits.


Effects of prefrontal bipolar and high-definition transcranial direct current stimulation on cortical reactivity and working memory in healthy adults.
Transcranial direct current stimulation (tDCS) is a well-recognised neuromodulatory technology which has been shown to induce short-lasting changes in motor-cortical excitability. The recent and rapid expansion of tDCS into the cognitive domain, however, necessitates deeper mechanistic understanding of its neurophysiological effects over non-motor brain regions. The present study utilised transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to probe the immediate and longer-term effects of both a bipolar (BP-tDCS) and more focal 4×1 High-Definition tDCS (HD-tDCS) montage applied over the left DLPFC on TMS-evoked potentials (TEPs) and oscillations in 19 healthy adult participants. 2-back working memory (WM) performance was also assessed as a marker of cognitive function. Region of interest (ROI) analyses taken from the F1 electrode directly adjacent to the stimulation site revealed increased P60 TEP amplitudes at this location 5min following BP-tDCS and 30min following HD-tDCS. Further global cluster based analyses of all scalp electrodes revealed widespread neuromodulatory changes following HD-tDCS, but not BP-tDCS, both five and 30min after stimulation, with reductions also detected in both beta and gamma oscillatory power over parieto-occipital channels 30min after stimulation. No significant changes in WM performance were observed following either HD-tDCS or BP-tDCS. This study highlights the capacity for single-session prefrontal anodal tDCS montages to modulate neurophysiological processes, as assessed with TMS-EEG.


Strategies to overcome DC dysregulation in the tumor microenvironment.
Dendritic cells (DCs) play a key role to modulate anti-cancer immunity in the tumor microenvironment (TME). They link innate to adaptive immunity by processing and presenting tumor antigens to T cells thereby initiating an anti-tumor response. However, subsets of DCs also induce immune-tolerance, leading to tumor immune escape. In this regard, the TME plays a major role in adversely affecting DC function. Better understanding of DC impairment mechanisms in the TME will lead to more efficient DC-targeting immunotherapy. Here, we review the different subtypes and functions of DCs in the TME, including conventional DCs, plasmacytoid DC and the newly proposed subset, mregDC. We further focus on how cancer cells modulate DCs to escape from the host's immune-surveillance. Immune checkpoint expression, small molecule mediators, metabolites, deprivation of pro-immunogenic and release of pro-tumorigenic cytokine secretion by tumors and tumor-attracted immuno-suppressive cells inhibit DC differentiation and function. Finally, we discuss the impact of established therapies on DCs, such as immune checkpoint blockade. Creative DC-targeted therapeutic strategies will be highlighted, including cancer vaccines and cell-based therapies.


Hyperthermia-induced inhibition of respiration and mitochondrial protein denaturation in CHL cells.
Respiration of Chinese hamster lung V79 cells, as assayed by O2 consumption, increases linearly from 8 to 40 degrees C when plotted in the Arrhenius fashion but is strongly inhibited above 40 degrees C. The protein of mitochondria isolated from V79 cells undergoes structural transitions at 28 and 40 degrees C. This is supported by changes in the fluorescence excitation spectrum of conjugated pyrene maleimide and, to a lesser extent, intrinsic protein fluorophores. Electron spin resonance labelling studies with a derivative of tempo maleimide imply that extensive protein unfolding coincides with the 40 degrees C transition. The structural transition at 40 degrees C correlates well with inhibition of O2 consumption, is irreversible and is probably due to protein denaturation, while the change at 28 degrees C is reversible and has no effect on O2 consumption. Previous studies indicate the presence of a broad lipid transition extending from approximately 8 to 30 degrees C in mitochondrial membranes with all lipids being in the liquid-crystalline state above 30 degrees C. Thus, the onset of the lipid transition may induce the observed protein conformational change at 28 degrees C, but inhibition of respiration above 40 degrees C can be explained by protein denaturation alone. The region from 28 to 40 degrees C of stable protein conformation corresponds to the temperature range of V79 cell growth.


The incidence rate of bacterial food poisonings in the Lublin province in the years 1976-1998.
The aim of the paper was to analyse the bacterial poisonings in the Lublin province in the years 1976-1998. The analysis was based on the archive materials of the Regional Unit for Control of Epidemics and Hygiene Promotion in Lublin. To illustrate the discussed issues the exemplifying bacterial food poisonings in closed mass nutrition institutions in 1990 were examined. The studies revealed that the bacterial food poisonings were most frequently caused by Salmonella enteritidis and one of the basic carriers was the food prepared from animal-derived materials. The incidence of Salmonella infections is constantly growing while that of Staphylococcus aureus and Clostridium botulinum infections is decreasing. In 1990 closed mass nutrition institutions in which the poisonings occurred had positive pre-infection sanitary scores, according to the hygiene classification sheet, which suggests that their staff followed the sanitary and hygienic regulations on an irregular basis.


["Episkepsis". Thoughts on Anna Freud's visit to Athens].
Describes Anna Freud's visit to Athens, comparing it with Freud's own visit. Refers to the creation of the first psychoanalytic group in Greece. Tells the circumstances and motivations which attended its formation and the role played by Princess M. Bonaparte. Conclusions concern all projects involving efforts to spread psycho-analysis and ensure its survival in today's world.


Aquaporins: New Targets for Cancer Therapy.
Aquaporins are a family of integral membrane proteins that are expressed in all living organisms and play vital roles in transcellular and transepithelial water movement. Cell viability and motility are critical for progression of cancer. Cell survival requires the suitable concentration of water and solutes. The balance is largely maintained by aquaporins whose major function is the transport of water and small solutes across the plasma membrane. The important role of aquaporins has received more and more attention in the recent years. A number of recent studies have revealed that aquaporins may be involved in cell migration and angiogenesis. This review will highlight the expression of aquaporins in different malignant neoplasms. Remarkably, we will summarize the influence of drugs on aquaporins, not only the traditional Chinese medicine but also the Western medicine. Therapeutic targeting of aquaporins may thus be advantageous for blocking the mechanism common for a number of key cancer phenotypes.


Stereocontrolled Synthesis of 19'-Deoxyperidinin.
The stereocontrolled convergent synthesis of 19'-deoxyperidinin, 2, which might be a useful peridinin analog to understand the ICT characteristics, was efficiently achieved by sequential Pd-catalyzed cross-coupling reactions using bidirectionally extensible conjugated C5 olefin segments. The crucial 5(2H)-ylidenedihydrofuran function of 2 was successfully constructed by the Au-catalyzed regio- and stereoselective 5-exo-dig etherification.


Rare Epithelioid Leiomyoma of the Vagina Exhibiting a Pelvic Mass.
Epithelioid leiomyoma of the vagina is extremely rare. Smooth muscle tumors of the vagina usually present with a submucosal growth pattern or a pedunculated growth pattern from the anterior vaginal wall into the vaginal cavity. Here we report a case of a 43-year-old woman with a solid epithelioid leiomyoma and a palpable mass in the pouch of Douglas. Transvaginal biopsy and angiography showed the epithelioid leiomyoma feeding from the vaginal artery behind the posterior vagina. An abdominal wide excision of the tumor with a partial vaginectomy was performed. Our use of ultrasound-guided needle biopsy and angiography was useful for preoperative diagnosis of a vaginal epithelioid leiomyoma exhibiting a pelvic mass.


Cold hardiness and postfreeze metabolism in caterpillars of Hypercompe scribonia (Arctiidae: Lepidoptera).
Insects evolve levels of cold hardiness that are sufficient to meet the severity of thermal conditions in their hibernacula. This study examined freeze tolerance and related features in caterpillars of Hypercompe scribonia, which is the overwintering stage for this species, to compare with existing data for more northerly distributed species in Arctiidae that also overwinter as caterpillars. All specimens were collected from western Pennsylvania during mid-October 2004 and 2006 and eventually acclimated to 3 degrees C for > or = 4 wk. All caterpillars initially survived freezing at -3 degrees C, which converted approximately 45% of their body water into ice, and one third of them developed into moths. In contrast, freezing at -10 degrees C was invariably lethal to caterpillars, even in the short term. Body composition (hemolymph osmolality, hemolymph glycerol, body mass, and water content) of caterpillars was stable between the 2 yr, with glycerol accounting for 3-5% of their solute. Thawed caterpillars showed an initial decline in routine aerobic metabolism that persisted through the first 6 h of the recovery period. H. scribonia caterpillars have a level of freeze tolerance that is adequate for hibernaculum conditions in western Pennsylvania; however, it is limited with respect to the tolerance levels of other arctiid caterpillars whose ranges extend northward well into colder regions of North America.


Outcomes of Sacral Nerve Stimulation For Faecal Incontinence in Northern Ireland.
Sacral nerve root stimulation (SNS) is an effective and developing therapy for faecal incontinence, a debilitating condition that can result in social and personal incapacitation. The objectives of this study are to assess the morbidity of the procedure, improvement in the incontinence scores and Quality of Life (QoL) following SNS. Patients were identified from the Northern Ireland regional SNS service from 2006 to 2012. Numbers of patients who had temporary placement and permanent placement were collated. Pre and postoperative assessment of severity of incontinence and QoL was performed using Cleveland Clinic Incontinence Score (CCIS) and Short Form-36 (SF-36) respectively. Statistical analysis was undertaken using Wilcoxon signed rank test. Morbidity was assessed by retrospective review of patient records. Seventy-five patients were considered for trial of a temporary SNS. Sixty-one proceeded to insertion of a temporary SNS and, of these, 40 elected to have a permanent SNS. There was a significant reduction in the pre-SNS and post-SNS Cleveland Clinic Incontinence Scores from median of 14 to 9 respectively (p=0.008). There was a significant improvement in Role Physical (p=0.017), General Health (p=0.02), Vitality (p=0.043), Social Functioning (p=0.004), Role Emotional (p=0.007), Mental Health (p=0.013) and Mental Health Summary (p=0.003). However, this is not reflected in the bodily pain and physical functional domains. Permanent sacral nerve stimulation is effective and results in significant improvement of faecal incontinence scores and quality of life.


Site-specific, thiol-mediated conjugation of fluorescent probes to cysteine-modified diabodies targeting CD20 or HER2.
Small, engineered antibody fragments such as diabodies (50 kDa noncovalent dimers of single-chain Fv fragments) are useful alternatives to their larger antibody counterparts. However, due to their size, they are more susceptible to disruption of their antigen binding sites when modified using random conjugation techniques. Previous work has demonstrated the utility of a C-terminal cysteine modification for site-specific radiolabeling of an anti-CEA diabody, resulting in the creation of a cys-diabody (CysDb). In the present work, the adaptability of the CysDb system was explored by creating two additional CysDbs: one specific for CD20 and one for HER2. Purified CysDbs of both specificities demonstrated behavior consistent with stable, covalent dimers harboring a readily reducible disulfide bond. Each CysDb was site-specifically conjugated to three different fluorophores for optical detection: the large fluorescent proteins phycoerythrin (PE) and allophycocyanin (APC), and the small fluorescent molecule Alexa Fluor488. Fluorophore-conjugated CysDbs bound specifically to their targets in both antigen systems and with each different fluorescent tag as determined by flow cytometry. In vitro specific antigen binding was observed in the presence of a mixture of specific and nonspecifically conjugated CysDbs. Conjugates retained both specificity and fluorescence, demonstrating the successful expansion of the CysDb repertoire to new targets and to new site-specific conjugation possibilities.


Direct cyanation of heteroaromatic compounds mediated by hypervalent iodine(III) reagents: In situ generation of PhI(III)-CN species and their cyano transfer.
Hypervalent iodine(III) reagents mediate the direct cyanating reaction of a wide range of electron-rich heteroaromatic compounds such as pyrroles 1, thiophenes 3, and indoles 5 under mild conditions (ambient temperature), without the need for any prefunctionalization. Commercially available trimethylsilylcyanide is usable as a stable and effective cyanide source, and the reaction proceeds in a homogeneous system. The N-substituent of pyrroles is crucial to avoid the undesired oxidative bipyrrole coupling process, and thus a cyano group was introduced selectively at the 2-position of N-tosylpyrroles 1 in good yields using the combination of phenyliodine bis(trifluoroacetate) (PIFA), TMSCN, and BF3.Et2O at room temperature. In the reaction mechanism, cation radical intermediates of heteroaromatic compounds are involved as a result of single electron oxidation, and the key to successful transformations seems to depend on the oxidation potential of the substrates used. Thus, the reaction was also successfully extended to other heteroaromatic compounds having oxidation potentials similar to that of N-tosylpyrroles such as thiophenes 3 and indoles 5. However, regioisomeric mixtures of the products derived from the reaction at the 2- and 3-positions were obtained in the case of N-tosylindole 5a. Further investigation performed in our laboratory provided insights into the real active iodine(III) species during the reaction; the reaction is induced by an active hypervalent iodine(III) species having a cyano ligand in situ generated by ligand exchange reaction at the iodine(III) center between trifluoroacetoxy group in PIFA and TMSCN, and effective cyanide introduction into heteroaromatic compounds is achieved by means of the high cyano transfer ability of the hypervalent iodine(III)-cyano intermediates. In fact, the reaction of N-tosylpyrrole 1a with a hypervalent iodine(III)-cyano compound (e.g., (dicyano)iodobenzene 8), in the absence of TMSCN, took place to afford the 2-cyanated product 2a in good yield, and an effective preparation of the intermediates is of importance for successful transformation. 1,3,5,7-Tetrakis[4-{bis(trifluoroacetoxy)-iodo}phenyl]adamantane 12, a recyclable hypervalent iodine(III) reagent, was also comparable in the cyanating reactions as a valuable alternative to PIFA, affording a high yield of the heteroaromatic cyanide by facilitating isolation of the cyanated products with a simple workup. Accordingly, after preparing the active hypervalent iodine(III)-CN species by premixing of a recyclable reagent 12, TMSCN, and BF3.Et2O for 30 min in dichloromethane, reaction of a variety of pyrroles 1 and thiophenes 3 provided the desired cyanated products 2 and 4 in high yields. The iodine compound 13, recovered by filtration after replacement of the reaction solvent to MeOH, could be reused without any loss of activity (the oxidant 12 can be obtained nearly quantitatively by reoxidation of 13 using m-CPBA).


[Quality control of radical lymphadenectomy for gastric cancer].
D2 lymphadenectomy is currently the worldwide standard operation for locally advanced gastric cancer. There were no major modifications for extent of standard lymphadenectomy in Japanese gastric cancer treatment guidelines 2014(ver.4). Prophylactic para-arotic lymphadenectomy is not recommended. Although there is no high level evidence, D2+No14v may be beneficial to patients who are suspected to harbor metastasis to No6 node, and D2+No13 lymphadenectomy may be an option in a potentially curative gastrectomy for tumors invading the duodenum. According to the finial results of JCOG1001, bursectomy is not recommended as a standard procedure for cT3/4 gastric cancer. Incidence of gastric cancer is quite high in China while overall operation level of gastric cancer is unequal. How to ensure the quality of radical gastrectomy is a recently important topic meanwhile the lymphadenectomy extent should be standard. Operational quantity per year in hospital and surgeons is considered as the final factors for the quality of radical gastrectomy. Centralization of gastric cancer surgery may be needed for the improvement of gastric cancer care in China. Education and training for the specialist are imperative for good outcomes of gastric cancer surgery. Ex vivo dissection for lymph nodes is effective method of precise staging and individual adjuvant treatment for gastric cancer patients.


Glucose transport inhibitors protect against 1,2-cyclohexanedione-produced potassium loss from human red blood cells.
It has been suggested that the glucose transport system of human erythrocytes contains an arginine shield to prevent the leak of potassium through the transporter. To investigate this suggestion we treated human erythrocytes with the specific arginine reagent 1,2-cyclohexanedione. Under conditions which produce a covalent reaction between arginine and the reagent, a steady leak of potassium occurs. If glucose, maltose or the inhibitor phloretin are present during the reaction the extent of the leak is reduced. These findings support the view that arginines have a role in preventing potassium loss through the glucose transporter.


Presence of the rare D-variant heat-stable, placental-type alkaline phosphatase in normal human testis.
In 11 adult testes studied, about 0.3 to 4.6% of the total alkaline phosphatase activity was heat stable and L-phenylalanine sensitive but L-homoarginine insensitive. The testicular heat-stable enzyme was more susceptible to inhibition by L-leucine and ethylenediaminetetraacetate than were the normal placental and intestinal enzymes. By antibody-directed enzyme inhibition test, the testicular heat-stable enzyme cross-reacted completely with normal placental enzyme but clearly distinguished itself from a heat-stable component of normal intestinal enzyme. Thus, placental alkaline phosphatase D-variant is synthesized in testis, indicating that the gene for elaborating this placental protein is probably already active in the testicular cells. The high incidence of this protein in cancers of testis and ovary is probably due to its increased production by gonadal genes present in the genome of these particular tumors.


Xiaotan Sanjie decoction attenuates tumor angiogenesis by manipulating Notch-1-regulated proliferation of gastric cancer stem-like cells.
To determine the underlying mechanisms of action and influence of Xiaotan Sanjie (XTSJ) decoction on gastric cancer stem-like cells (GCSCs). The gastric cancer cell line MKN-45 line was selected and sorted by FACS using the cancer stem cell marker CD44; the stemness of these cells was checked in our previous study. In an in vitro study, the expression of Notch-1, Hes1, Vascular endothelial growth factor (VEGF), and Ki-67 in both CD44-positive gastric cancer stem-like cells (GCSCs) and CD44-negative cells was measured by Western blot. The effect of XTSJ serum on cell viability and on the above markers was measured by MTT assay and Western blot, respectively. In an in vivo study, the ability to induce angiogenesis and maintenance of GCSCs in CD44-positive-MKN-45- and CD44-negative-engrafted mice were detected by immunohistochemical staining using markers for CD34 and CD44, respectively. The role of XTSJ decoction in regulating the expression of Notch-1, Hes1, VEGF and Ki-67 was measured by Western blot and real-time polymerase chain reaction. CD44(+) GCSCs showed more cell proliferation and VEGF secretion than CD44-negative cells in vitro, which were accompanied by the high expression of Notch-1 and Hes1 and positively associated with tumor growth (GCSCs vs CD44-negative cells, 2.72 ± 0.25 vs 1.46 ± 0.16, P < 0.05) and microvessel density (MVD) (GCSCs vs CD44-negative cells, 8.15 ± 0.42 vs 3.83 ± 0.49, P < 0.001) in vivo. XTSJ decoction inhibited the viability of both cell types in a dose-dependent manner in vitro. Specifically, a significant difference in the medium- (82.87% ± 6.53%) and high-dose XTSJ groups (77.43% ± 7.34%) was detected at 24 h in the CD44(+) GCSCs group compared with the saline group (95.42% ± 5.76%) and the low-dose XTSJ group (90.74% ± 6.57%) (P < 0.05). However, the efficacy of XTSJ decoction was reduced in the CD44(-) groups; significant differences were only detected in the high-dose XTSJ group at 48 h (78.57% ± 6.94%) and 72 h (72.12% ± 7.68%) when compared with the other CD44- groups (P < 0.05). Notably, these differences were highly consistent with the Notch-1, Hes1, VEGF and Ki-67 expression in these cells. Similarly, in vivo, XTSJ decoction inhibited tumor growth in a dose-dependent manner. A significant difference was observed in the medium- (1.76 ± 0.15) and high-dose XTSJ (1.33 ± 0.081) groups compared with the GCSCs control group (2.72 ± 0.25) and the low-dose XTSJ group (2.51 ± 0.25) (P < 0.05). We also detected a remarkable decrease of MVD in the medium- (7.10 ± 0.60) and high-dose XTSJ (5.99 ± 0.47) groups compared with the GCSC control group (8.15 ± 0.42) and the low-dose XTSJ group (8.14 ± 0.46) (P < 0.05). Additionally, CD44 expression was decreased in these groups [medium- (4.43 ± 0.45) and high-dose XTSJ groups (3.56 ± 0.31) vs the GCSC control (5.96 ± 0.46) and low dose XTSJ groups (5.91 ± 0.38)] (P < 0.05). The significant differences in Notch-1, Hes1, VEGF and Ki-67 expression highly mirrored the results of XTSJ decoction in inhibiting tumor growth, MVD and CD44 expression. Notch-1 may play an important role in regulating the proliferation of GCSCs; XTSJ decoction could attenuate tumor angiogenesis, at least partially, by inhibiting Notch-1.


Hybridization characteristics of biomolecular adaptors, covalent DNA--streptavidin conjugates.
Semisynthetic, covalent streptavidin-DNA adducts are versatile molecular connectors for the fabrication of both nano- and microstructured protein arrays by use of DNA hybridization. In this study, the hybridization characteristics of six adduct species, each containing a different DNA sequence of 21 or 24 bases, have been compared. First, the adducts were conjugated to biotinylated alkaline phosphatase, and their binding to immobilized oligomer complements of similar lengths was quantified in a microplate assay. The binding efficiency observed varied to a great extent with the specific sequence of the oligonucleotide attached, and could not be predicted from affiliated thermodynamic data of duplex stability. To further elucidate the hybridization properties, the hybridization rate constants of association and dissociation (kassn and kdissn) have been determined for both unconjugated oligonucleotides and protein adducts, using a surface plasmon resonance biosensor. The kassn values observed for the oligonucleotides are in the range of 9 x 10(3) to 2 x 10(5) M[-1] s(-1) and correlate with structural properties of the probe strands. Up to 3-fold decreased kassn values were obtained for the corresponding protein adducts. Likewise, values were observed for kdissn ranging from 1.4 x 10(-4) to 1.9 x 10(-5) s[-1] for the oligonucleotides. The dissociation of the analogous protein conjugates was reduced by up to 5-fold. The extent of this decrease correlates with the formation of homodimeric or intramolecular aggregation of probe strands. A mechanistic model for explaining these data is based on attractive intramolecular interaction between the nucleic acid and protein moiety.


Low-dose 4D cone-beam CT via joint spatiotemporal regularization of tensor framelet and nonlocal total variation.
Excessive radiation exposure is still a major concern in 4D cone-beam computed tomography (4D-CBCT) due to its prolonged scanning duration. Radiation dose can be effectively reduced by either under-sampling the x-ray projections or reducing the x-ray flux. However, 4D-CBCT reconstruction under such low-dose protocols is prone to image artifacts and noise. In this work, we propose a novel joint regularization-based iterative reconstruction method for low-dose 4D-CBCT. To tackle the under-sampling problem, we employ spatiotemporal tensor framelet (STF) regularization to take advantage of the spatiotemporal coherence of the patient anatomy in 4D images. To simultaneously suppress the image noise caused by photon starvation, we also incorporate spatiotemporal nonlocal total variation (SNTV) regularization to make use of the nonlocal self-recursiveness of anatomical structures in the spatial and temporal domains. Under the joint STF-SNTV regularization, the proposed iterative reconstruction approach is evaluated first using two digital phantoms and then using physical experiment data in the low-dose context of both under-sampled and noisy projections. Compared with existing approaches via either STF or SNTV regularization alone, the presented hybrid approach achieves improved image quality, and is particularly effective for the reconstruction of low-dose 4D-CBCT data that are not only sparse but noisy.


Expression of activated RAF accelerates cell differentiation and RB protein down-regulation but not hypophosphorylation.
Expression of an activated raf transgene accelerated the terminal myeloid differentiation of HL-60 human promyelocytic leukemia cells induced by retinoic acid. A similar result was obtained when 1,25-dihydroxyvitamin D3 was used to induce monocytic differentiation. The stable transfectants were derived by transfecting HL-60 cells with DNA encoding an N-terminal truncated raf-1 protein. In normal HL-60 cells retinoic acid is known to induce a colony-stimulating factor-1 (CSF-1)-dependent metabolic cascade culminating in G0 arrest and phenotypic conversion. Early in this cascade, expression of the RB tumor suppressor gene product is down-regulated. A progressive redistribution of the form of the protein from largely hyperphosphorylated protein to the hypophosphorylated form begins later with G0 arrest and differentiation. In the activated raf-transfected cells, RB down regulation occurred more rapidly, consistent with accelerated differentiation. But the conversion to the hypophosphorylated form was not accelerated and occurred after G0 arrest and phenotypic conversion to myeloid differentiated cells. Thus raf activation appears to be a component of the induced metabolic cascade culminating in terminal differentiation. In this cascade raf activation promotes RB down-regulation. The data are consistent with a model in which raf is an effector of the CSF-1-dependent metabolic cascade which culminates in terminal cell differentiation, and RB downregulation is one of the downstream consequences of RAF action. Furthermore, they indicate that RB down-regulation may be an essential component of the cellular processes causing G0 arrest and differentiation, but RB hypophosphorylation is more likely a consequence thereof and not a cause.


Copper-Catalyzed Modular Assembly of Polyheterocycles.
Easy operation, readily accessible starting materials, and short syntheses of the privileged scaffold indeno[1,2-c]isoquinolinone were achieved by an multicomponent reaction (MCR)-based protocol via an ammonia-Ugi-four component reaction (4CR)/copper-catalyzed annulation sequence. The optimization and scope and limitations of this short and general sequence are described. The methodology allows an efficient construction of a wide variety of indenoisoquinolinones in just two steps.


Enhancing cavitation dynamics and its mechanical effects with dual-frequency ultrasound.
Objective.Acoustic cavitation and its mechanical effects (e.g. stress and strain) play a primary role in ultrasound applications. Introducing encapsulated microbubbles as cavitation nuclei and utilizing dual-frequency ultrasound excitation are highly effective approaches to reduce cavitation thresholds and enhance cavitation effects. However, the cavitation dynamics of encapsulated microbubbles and the resultant stress/strain in viscoelastic tissues under dual-frequency excitation are poorly understood, especially for the enhancement effects caused by a dual-frequency approach. The goal of this study was to numerically investigate the dynamics of a lipid-coated microbubble and the spatiotemporal distributions of the stress and strain under dual-frequency excitation.Approach.The Gilmore-Zener bubble model was coupled with a shell model for the nonlinear changes of both shell elasticity and viscosity to accurately simulate the cavitation dynamics of lipid-coated microbubbles in viscoelastic tissues. Then, the spatiotemporal evolutions of the cavitation-induced stress and strain in the surrounding tissues were characterized quantitatively. Finally, the influences of some paramount parameters were examined to optimize the outcomes.Main results.We demonstrated that the cavitation dynamics and associated stress/strain were prominently enhanced by a dual-frequency excitation, highlighting positive correlations between the maximum bubble expansion and the maximum stress/strain. Moreover, the results showed that the dual-frequency ultrasound with smaller differences in its frequencies and pressure amplitudes could enhance the bubble oscillations and stress/strain more efficiently, whereas the phase difference manifested small influences under these conditions. Additionally, the dual-frequency approach seemed to show a stronger enhancement effect with the shell/tissue viscoelasticity increasing to a certain extent.Significance.This study might contribute to optimizing the dual-frequency operation in terms of cavitation dynamics and its mechanical effects for high-efficient ultrasound applications.


Calibrated microphone array recordings reveal that a gleaning bat emits low-intensity echolocation calls even in open-space habitat.
Echolocating bats use ultrasound for orientation and prey capture in darkness. Ultrasound is strongly attenuated in air. Consequently, aerial-hawking bats generally emit very intense echolocation calls to maximize detection range. However, call levels vary more than tenfold (>20 dB) between species and are tightly linked to the foraging strategy. The brown long-eared bat (Plecotus auritus) is a primarily gleaning, low-amplitude species that may occasionally hawk airborne prey. We used state-of-the-art calibrated acoustic 3D-localization and automated call analysis to measure P. auritus' source levels. Plecotus auritus emits echolocation calls of low amplitude (92 dB rmsSPL re. 20 µPa at 10 cm) even while flying in open-space. While P. auritus thus probably benefits from delayed evasive manoeuvres of eared insects, we propose that low-amplitude echolocation did not evolve as an adaptive countermeasure, but is limited by morphological constraints.


In Silico Design of Halogen-Bonding-Based Organocatalyst for Diels-Alder Reaction, Claisen Rearrangement, and Cope-Type Hydroamination.
Using DFT calculations, we investigated the use of halogen bonding (XB) interactions to accelerate and control organic reactions, namely Diels-Alder reaction, Claisen rearrangement, and Cope-type hydroamination. Our designed triarylbenzene tripodal organocatalyst is characterized by three halogen bond donors, perfluoro-iodophenyl groups. The calculated transition states unravel multiple halogen bonds between the iodine atoms and various types of halogen bond acceptors (lone pair, π and σ bonds). These cooperative noncovalent interactions provide efficient binding between the catalyst and substrate (∼15 kcal/mol binding energy) and are the key factors for transition-state stabilization and molecular recognition. On the basis of our DFT calculations and calculated turnover frequencies, the XB-catalyzed reactions are found to be competitive with the corresponding hydrogen bonding catalysis reported in literature.


Brain electrical activity in depression described by equivalent dipoles.
The majority of neurophysiological investigations of waking EEG in depression have been relatively disappointing. Since the topographic distribution of brain electrical activity over the scalp in the frequency domain (FFT-power) varies considerably when choosing another site for the reference, it is not surprising that various investigators reported contradictory results. The aim of the present study was to investigate differences in brain electrical activity in a sample of depressed patients as compared to healthy subjects using a newly developed method called FFT approximation. As the major finding healthy subjects and depressed patients demonstrated significantly divergent patterns of localization between frequency bands in the anterior-posterior direction. The investigation suggests that a non-invasive neurophysiological methods gives results which are comparable to those obtained by other functional and structural imaging methods in depressive illness.


Pediatric nevoid basal cell carcinoma syndrome.
Nevoid basal cell carcinoma syndrome (NBCCS) is a rare, autosomal-dominant, cancer-predisposing, multisystem disorder. The clinical manifestations of NBCCS include multiple basal cell carcinomas (BCCs), odontogenic keratocysts, palmar or plantar pits, and calcification of the falx cerebri. We present a case of an 11-year-old boy with Fitzpatrick skin type V who presented with multiple facial lesions and a history of maxillary keratocysts. Skin biopsy was consistent with pigmented BCC of the right nasolabial fold. Further clinical workup revealed multiple pigmented BCCs, palmoplantar pits, and calcification of the tentorium. Genetic testing revealed a heterozygous mutation in the patched 1 gene, PTCH1, consistent with NBCCS. This case highlights the treatment considerations in pediatric cases of NBCCS in Fitzpatrick skin type V patients.


Detection and imaging of thermochromic ink compounds in erasable pens using desorption electrospray ionization mass spectrometry.
Thermochromic ink pens are widely accessible worldwide and have gained popularity among the general public. These pens are very useful to undo mistakes while writing important documents or exams. They are also, however, misused in committing crimes such as counterfeiting checks or wills. Thus, the forensics community is in need of techniques that will allow these forgeries to be detected rapidly, reliably and conveniently. Thermochromic ink compounds were investigated using Desorption Electrospray Ionization (DESI) coupled with an LTQ mass spectrometer and Thin-Layer Chromatography (TLC). Tandem mass spectrometric analysis was conducted using Electrospray Ionization (ESI) coupled with an Orbitrap LTQ mass spectrometer performing Collision-Induced Dissociation (CID) for identification of ink traces. Chemical marker ions characteristic of the state of ink (visible or invisible) were identified and mapped in ink traces by the use of DESI-MS imaging. These ions can be employed by forensic experts as fingerprint markers in forged documents. The marker ions were also characterised by conducting tandem mass spectrometry using paper spray in an Orbitrap LTQ mass spectrometer. Specific chemical components yielding ions of m/z 400, 405, 615 and 786 were distinguished as only being apparent in the invisible and reappeared state of the ink. The absence of these compounds in the original state of the ink enabled their recognition as useful chemical determinants in detecting forgery. DESI-MSI was thus shown to be a very useful, convenient and reliable technique for detecting forgery in paper documents due to its fast and reproducible mode of analysis, with no sample preparation and minimal damage to the document under investigation. Copyright © 2017 John Wiley & Sons, Ltd.


[Plasma cell leukaemia].
We report a case of primary plasma cell leukaemia, with an absolute count of plasma cells of 53 Giga/L, diagnosed in a 83-year-old woman. The patient's condition improved, with no circulating plasma cells after 3 weeks of treatment, in response to the combination of thalidomide and dexamethasone administered for 5 days followed by thalidomide alone. The clinical presentation, the morphological, flow cytometric and pathophysiological characteristics of the plasma cell leukaemia and the treatment are summarised in this paper.


Responses of red nucleus neurons to antidromic and synaptic activation.
An account is given of the responses of 432 red nucleus (RN) neurons with axons projecting down the spinal cord. Almost half were in an initial series of 18 experiments on anesthetized cats, and the remainder were in a second series of 12 experiments on decerebrate unanesthetized cats. The differences between the two series were of little significance. All recording was from single neurons using extracellular glass microelectrodes that were inserted throught the right superior colliculus and directed to the right red nucleus at a standard orientation. Identification of RN neurons was both by location, checked by subsequent histology, and by antidromic invasion from the spinal cord. The spinal stimulating electrodes were placed in proximity to the left rubrospinal tract at C2 and L2 segmental levels. Axonal conduction velocities were calculated from the latency differential between the L2 and C2 antidromic responses and were usually in the range 60-130 m/s, 97% of all neurons located in the red nucleus had axons projecting to the C2 level, and 37% projected to the L2 level. The responses of 229 RN neurons were observed with stimulation applied to the contralateral (left) interpositus nucleus. In 10 (5%) there were antidromic responses to both interpositus and C2 stimulation, a finding in good agreement with the anatomical description of rare axon collaterals from rubrospinal fibers to the interpositus nucleus. In 209 (91%), there was a clear monosynaptic excitation. The impulse generation was at a latency usually of 1.0-1.8 ms, which a modal value of 1.4 ms. The afferent inputs to RN neurons were provided by stimulation either of predominantly cutaneous nerves in all four limbs or of cutaneous mechanoreceptors of the contralateral forelimb and hindlimb...


The etiology of erectile dysfunction and contributing factors in different age groups in Turkey.
The aim of the present study was to determine the pathophysiological factors which cause erectile dysfunction (ED), as well as the risk factors in different age groups in Turkey. A total of 948 patients with ED who were admitted to three andrology clinics were evaluated in terms of etiological factors. They underwent a multidisciplinary diagnostic evaluation. Erectile dysfunction was classified as primarily organic, primarily psychogenic, mixed or unknown in etiology. Psychogenic ED was diagnosed in 65.4% of the patients and organic ED was diagnosed in 34.6% of patients overall. In patients under 40 years, the rate of psychogenic ED was 83% and the rate of organic ED was 17%, but in the patients over 40 years, the rate of psychogenic ED was 40.7% and the rate of organic ED was 59.3%. The causes of organic ED were identified as arteriogenic ED, 40.5%; cavernosal factor (venogenic) ED, 10%; neurogenic ED, 12.5%; endocrinologic ED, 1.8%; mixed type ED, 11.8%; and drug induced ED, 4.5%. Our data represent a higher ratio of ED in patients under 40, which are mostly psychogenic, This finding potentially results from local social and cultural differences.


Clinical application of the World Health Organization analgesic ladder.
One resource that has spurred the development of new standards for the assessment and treatment of pain is the World Health Organization (WHO) analgesic ladder, a three-step guide to the administration of analgesia and adjuvant medication for the treatment of pain. Correct application of the ladder is dependent upon knowledge of the interactions and side effects of the nonsteroidal anti-inflammatory drugs, opioids, and adjuvants recommended at each step of the ladder. Equianalgesic conversion can help provide correct dosing when changing opioids. Because of their altered metabolism and increased risk for epigastric complications, the elderly should receive special consideration when such medications are administered.


The spectroscopic signature of the "all-surface" to "internally solvated" structural transition in water clusters in the n = 17-21 size regime.
The existence of a transitional size regime where preferential stabilization alternates between "all-surface" (all atoms on the surface of a cluster) and "internally solvated" (one water molecule at the center of the cluster, fully solvated) configurations with the addition or the removal of a single water molecule, predicted earlier with the flexible, polarizable (many-body) Thole-type model interaction potential (TTM2-F), has been confirmed from electronic structure calculations for (H2O)n, n = 17-21. The onset of the appearance of the first "interior" configuration in water clusters occurs for n = 17. The observed structural alternation between interior (n = 17, 19, 21) and all-surface (n = 18, 20) global minima in the n = 17-21 cluster regime is accompanied by a corresponding spectroscopic signature, namely, the undulation in the position of the most redshifted OH stretching vibrations according to the trend: interior configurations exhibit more redshifted OH stretching vibrations than all-surface ones. These most redshifted OH stretching vibrations form distinct groups in the intramolecular region of the spectra and correspond to localized vibrations of donor OH stretches that are connected to neighbors via "strong" (water dimer-like) hydrogen bonds and belong to a water molecule with a "free" OH stretch.


Ventricular Diastolic Pressure Ratio as a Marker of Treatment Response in Pulmonary Hypertension.
Pulmonary hypertension (PH) is diagnosed and classified through right-sided heart catheterization, with a number of hemodynamic markers used to help guide treatment decisions. These markers may not reflect the complex remodeling of the right ventricle or the interplay between ventricles and struggle to predict treatment response. This study investigates the use of a novel marker: the ratio of left ventricular end-diastolic pressure to right ventricular end-diastolic pressure (LVEDP/RVEDP) in predicting treatment outcomes in a cohort of patients with PH. We performed a retrospective analysis of patients with PH at INOVA Fairfax Hospital's advanced lung disease program with simultaneous left-sided and right-sided heart catheterization. The primary end point was the time to clinical improvement, defined by an improvement in distance walked on the 6-min walk test (6MWT) of > 35 m in a year without interceding hospitalization for worsening PH or the need for additional PH therapy. A total of 51 patients were included in the final analysis, 21 of whom (41.2%) had a salutary treatment effect with a mean improvement in the 6MWT of 75 m. Treatment responders were more likely to have a lower LVEDP/RVEDP ratio (1.08 vs 1.62; P = .051). This association persisted in the final multivariate regression model after adjustment for age and sex and controlling for severity of PH (OR, 0.17; 95% CI, 0.03-0.65; P = .024). The LVEDP/RVEDP ratio is a novel marker for therapeutic response in patients with PH treated with pulmonary vasodilator medications and may offer robust predictive value independent of existing markers of disease severity.


Johnson tucker: instrumentation for better internal wire fixation.
This article introduces a new surgical instrument that will aid in the use of wire fixation. Its advantages and disadvantages are discussed. The method in which it is used is demonstrated.


Controllable Orientation of Ester-Group-Induced Intermolecular Halogen Bonding in a 2D Self-Assembly.
Halogen bonding with high specificity and directionality in the geometry has proven to be an important type of noncovalent interaction to fabricate and control 2D molecular architectures on surfaces. Herein, we first report how the orientation of the ester substituent for thienophenanthrene derivatives (5,10-DBTD and 5,10-DITD) affects positive charge distribution of halogens by density functional theory, thus determining the formation of an intermolecular halogen bond and different self-assembled patterns by scanning tunneling microscopy. The system presented here mainly includes heterohalogen X···O═C and X···S halogen bonds, H···Br and H···O hydrogen bonds, and I···I interaction, where the directionality and strength of such weak bonds determine the molecular arrangement by varying the halogen substituent. This study provides a detailed understanding of the role of ester orientation, concentration, and solvent effects on the formation of halogen bonds and proves relevant for identification of multiple halogen bonding in supramolecular chemistry.


Electromagnetic fields and infant incubators.
Two models of infant incubators were studied to determine the strength of the magnetic field generated by the heater and fan motors. Measurements were taken at intervals along the center line of the incubator. The results show that fields greater than 100 milligauss and 25 milligauss were measured in the C-86 and C-100 model Isolettes, respectively.


Increased conversion ratio of tryptophan to niacin in severe food restriction.
The effect of food restriction on the conversion ratio of tryptophan to niacin was investigated, because it is known that the conversion ratio is influenced by nutritional factors. A 20% casein diet was fed to rats ad libitum (control), 1/2 the food of the control. 1/4 the food of the control, or starved for 9 days, and urine samples were collected to measure the urinary excretion of such tryptophan metabolites as kynurenic acid, xanthurenic acid, and nicotinamide. The conversion ratio in the 1/2, 1/4, or starving group increased at day 1 of the experiment, but returned to the original value from day 2. Only in the starving group did the conversion ratio extremely increase from day 6 to day 9, being about 5-times higher than that of the original value on day 9. The possible mechanism by which the conversion ratio increased during food restriction is discussed.


Ultrasonographic evaluation of juxtadiaphragmatic masses in children.
The authors suggest that ultrasound be used in the evaluation of juxtadiaphragmatic lesions before resorting to other radiographic methods. This technique gives accurate diagnoses, serves as a guide for further studies, and might obviate more extensive procedures.


Quality of hypertension pharmacotherapy in Quebec: a population-based study.
Choosing the initial pharmacotherapy for new antihypertensive users and ensuring adherence to therapy can be problematic. We sought to assess the quality of pharmacotherapy among new users of antihypertensives in Quebec, and to measure persistence with treatment in the short and longer term. Using provincial administrative databases, a historical population-based study was conducted with a cohort of Quebec adults who filled their first antihypertensive prescription between January 1, 2007, and December 31, 2009. We described antihypertensive treatment for those with a diagnosis of hypertension (HTN) in the 5 years preceding initiation of drug therapy. Conformity with criteria for optimal use based on the 2006 Canadian Hypertension Education Program (CHEP) was evaluated. Persistence with treatment was estimated at 3 months, 1 year and 2 years after pharmacotherapy initiation. Among the 79,181 new antihypertensive users with HTN who started treatment between 2007 and 2009, 82.5% were first prescribed only one drug, usually an angiotensin II receptor blocker or an angiotensin-converting enzyme inhibitor and rarely a diuretic. 24.2% of newly treated hypertensive persons aged 60 or older in our sample received a beta-blocker, which is not recommended practice. The initial treatment conformed to CHEP recommendations for 72.8% of those with uncomplicated HTN. After 3 months, 69.8% of new users still persisted with their treatment. This proportion remained stable after 1 year (69.1%) and 2 years (69.2%). Conformity of antihypertensive treatment with CHEP criteria, and patient persistence with therapy, was fairly high for new users in the province of Quebec. Research is needed, however, on how to further improve pÉÉharmacotherapy quality and persistence in new users.


Dopaminergic Plasticity in the Bilateral Hippocampus Following Threat Reversal in Humans.
When a cue no longer predicts a threat, a diminished ability to extinguish or reverse this association is thought to increase risk for stress-related disorders. Despite the clear clinical relevance, the mediating neurochemical mechanisms of threat reversal have received relatively little study. One neurotransmitter implicated in rodent research of changing associations with threat is dopamine. To study whether dopamine is involved in threat reversal in humans, we used high-resolution positron emission tomography (PET) coupled with 18F-fallypride. Twelve healthy volunteers (6 F/6 M) underwent three PET scans: (i) at baseline, (ii) following threat conditioning (the response to a cue associated with electric wrist shock), and (iii) following threat reversal (the response to the same cue now associated with safety). We observed moderate evidence of reduced dopamine D2/3 receptor availability, consistent with greater dopamine release, in the bilateral anterior hippocampus following threat reversal, in response to a safety cue that was previously associated with threat, as compared to both baseline and during exposure to the same cue prior to threat reversal. These findings offer the first preliminary evidence that the response to a previously threatening cue that has since become associated with safety involves dopaminergic neurotransmission within the hippocampus in healthy humans.


Heart rate variability during hemodialysis is an indicator for long-term vascular access survival in uremic patients.
Vascular access (VA) is the lifeline of hemodialysis patients. Although the autonomic nervous system might be associated with VA failure (VAF), it has never been addressed in previous studies. This study aimed to evaluate the predictive values of the heart rate variability (HRV) indices for long-term VA outcomes. This retrospective study was conducted using a prospectively established cohort enrolling 175 adult chronic hemodialysis patients (100 women, mean age 65.1 ± 12.9 years) from June 2010 to August 2010. Each participant received a series of HRV measurements at enrollment. After a 60-month follow-up period, we retrospectively reviewed all events and therapeutic procedures of the VAs which existed at the enrollment and during the follow-up period. During the 60-month follow-up period, 37 (26.8%) had VAF but 138 (73.2%) didn't. The values of most HRV indices were statistically increased during hemodialysis since initiation in the non-VAF group, but not in the VAF group. Among all participants, the independent indicators for VAF included higher normalized high-frequency (nHF) activity [hazard ratio (HR) 1.04, p = 0.005], lower low-frequency/high-frequency (LF/HF) ratio (HR 0.80, p = 0.015), experience of urokinase therapy (HR 11.18, p = 0.002), percutaneous transluminal angioplasty (HR 2.88, p = 0.003) and surgical thrombectomy (HR 2.36, p = 0.035), as well as higher baseline serum creatinine (HR 1.07, p = 0.027) and potassium level (HR 1.58, p = 0.037). In subgroup analysis, a lower sympathetic activity indicated by lower LF/HF ratio was an independent indicator for VAF (HR 0.61, p = 0.03) for tunneled cuffed catheter, but conversely played a protective role against VAF (HR 1.27, p = 0.002) for arteriovenous fistula. HRV is a useful tool for predicting long-term VAF among hemodialysis patients.


Post-stroke bilateral heterotopic ossification: An acute problem with long-lasting consequences.
Heterotopic ossification (HO) is a complication of injury to the central nervous system in which production of lamellar bone within the soft tissues occurs resulting in pain, reduced range of motion (ROM) and loss of functional capacity. Heterotopic ossification is rarely seen in stroke patients and mostly affects the paretic side. In this article, we present a case of established bilateral HO of the hips soon after stroke onset. A 77-year-old female patient with a five-month history of stroke presented to our rehabilitation clinic. Physical examination revealed sensorimotor aphasia, right-sided hemiplegia, bilateral painful limited ROM of the hips and left knee contracture. An anteroposterior X-ray of the pelvis revealed previously undiagnosed bilateral HO of the hips. The patient and her relatives declined operative interventions. The patient was discussed in the departmental meeting and it was agreed that she would not be able to partake in an active inpatient rehabilitation program. She was discharged with a home exercise plan. This case highlights the importance of HO, of both the paretic and non-paretic side, being included in the differential diagnosis of post-stroke patients presenting with joint pain and reduced ROM, both acutely and in the long-term. This may aid the timely diagnosis and management of HO, a pathology which has detrimental effects on functionality.


Selective reduction of multiple pregnancies in the first trimester or early second trimester.
Nine cases of multiple pregnancies, including 7 sets of triplets and 2 sets of quadruplets, were enrolled for selective fetal reduction between March 1989 and July 1990 at the National Taiwan University Hospital. Under transabdominal or transvaginal ultrasound guidance, potassium chloride was injected into the fetal cardiac chamber to kill the selected fetus during the 10-14th gestational week. The number of fetuses was reduced to two in all cases. No maternal complications occurred during the procedure. Six gravidas have given birth to 6 sets of healthy twins; two pregnancies are progressing smoothly at 26 and 23 weeks of gestation, respectively, and one case underwent spontaneous abortion 4 weeks after the procedure. Selective fetal reduction under ultrasound guidance is an acceptable method of preventing high perinatal mortality and morbidity of immature fetuses in grand multiple pregnancies.


The role of the C8 proton of ATP in the regulation of phosphoryl transfer within kinases and synthetases.
The kinome comprises functionally diverse enzymes, with the current classification indicating very little about the extent of conserved regulatory mechanisms associated with phosphoryl transfer. The apparent Km of the kinases ranges from less than 0.4 μM to in excess of 1000 μM for ATP. It is not known how this diverse range of enzymes mechanistically achieves the regulation of catalysis via an affinity range for ATP varying by three-orders of magnitude. We have demonstrated a previously undiscovered mechanism in kinase and synthetase enzymes where the overall rate of reaction is regulated via the C8-H of ATP. Using ATP deuterated at the C8 position (C8D-ATP) as a molecular probe it was shown that the C8-H plays a direct role in the regulation of the overall rate of reaction in a range of kinase and synthetase enzymes. Using comparative studies on the effect of the concentration of ATP and C8D-ATP on the activity of the enzymes we demonstrated that not only did C8D-ATP give a kinetic isotope effect (KIE) but the KIE's obtained are clearly not secondary KIE effects as the magnitude of the KIE in all cases was at least 2 fold and in most cases in excess of 7 fold. Kinase and synthetase enzymes utilise C8D-ATP in preference to non-deuterated ATP. The KIE obtained at low ATP concentrations is clearly a primary KIE demonstrating strong evidence that the bond to the isotopically substituted hydrogen is being broken. The effect of the ATP concentration profile on the KIE was used to develop a model whereby the C8H of ATP plays a role in the overall regulation of phosphoryl transfer. This role of the C8H of ATP in the regulation of substrate binding appears to have been conserved in all kinase and synthetase enzymes as one of the mechanisms associated with binding of ATP. The induction of the C8H to be labile by active site residues coordinated to the ATP purine ring may play a significant role in explaining the broad range of Km associated with kinase enzymes.


Estimating alcohol-attributable liver disease mortality: A comparison of methods.
Alcohol is a leading contributor to liver disease, however, estimating the proportion of liver disease deaths attributable to alcohol use can be methodologically challenging. We compared three approaches for estimating alcohol-attributable liver disease deaths (AALDD), using the USA as an example. One involved summing deaths from alcoholic liver disease and a proportion from unspecified cirrhosis (direct method); two used population attributable fraction (PAF) methodology, including one that adjusted for per capita alcohol sales. For PAFs, the 2011-2015 Behavioral Risk Factor Surveillance System and per capita sales from the Alcohol Epidemiologic Data System were used to derive alcohol consumption prevalence estimates at various levels (excessive alcohol use was defined by medium and high consumption levels). Prevalence estimates were used with relative risks from two meta-analyses, and PAFs were applied to the 2011-2015 average annual number of deaths from alcoholic cirrhosis and unspecified cirrhosis (using National Vital Statistics System data) to estimate AALDD. The number of AALDD was higher using the direct method (28 345 annually) than the PAF methods, but similar when alcohol prevalence was adjusted using per capita sales and all alcohol consumption levels were considered (e.g. 25 145 AALDD). Using the PAF method, disaggregating non-drinkers into lifetime abstainers and former drinkers to incorporate relative risks for former drinkers yielded higher AALDD estimates (e.g. 27 686) than methods with all non-drinkers combined. Using PAF methods that adjust for per capita sales and model risks for former drinkers yield more complete and possibly more valid AALDD estimates.


[Evaluation of methods to calculate dialysis dose in daily hemodialysis].
Daily dialysis has shown excellent clinical results because a higher frequency of dialysis is more physiological. Different methods have been described to calculate dialysis dose which take into consideration change in frequency. The aim of this study was to calculate all dialysis dose possibilities and evaluate the better and practical options. Eight patients, 6 males and 2 females, on standard 4 to 5 hours thrice weekly on-line hemodiafiltration (S-OL-HDF) were switched to daily on-line hemodiafiltration (D-OL-HDF) 2 to 2.5 hours six times per week. Dialysis parameters were identical during both periods and only frequency and dialysis time of each session were changed. Time average concentration (TAC), time average deviation (TAD), normalized protein catabolic rate (nPCR), Kt/V, equilibrated Kt/V (eKt/V), equivalent renal urea clearance (EKR), standard Kt/V (stdKt/V), urea reduction ratio (URR), hemodialysis product and time off dialysis were measured. Daily on-line hemodiafiltration was well accepted and tolerated. Patients maintained the same TAC although TAD decreased from 9.7 +/- 2 in baseline to a 6.2 +/- 2 mg/dl after six months, p < 0.01. No significant changes were observed in weekly Kt/V and eKt/V throughout the study. However EKR, stdKt/V and weekly URR were increased during D-OL-HDF in 24-34%, 46% and 50%, respectively. Hemodialysis product was raised in a 95% and time off dialysis was reduced to half. Dialysis frequency is an important urea kinetic parameter which there are to take in consideration. It's necessary to use EKR, stdKt/V or weekly URR to calculate dialysis dose for an adequate comparison between different frequency dialysis schedules.


Leading Change from Within: Student-Led Reforms to Advance Anti-Racism within Medical Education.
Racism, physician biases against Indigenous, Black, and racialized people, and the resultant poor health outcomes have been the subject of many institutional position statements and calls to action. Across Canada, undergraduate medical education programs have recognized the importance of addressing racism, but material changes to curriculum and learning environments to incorporate anti-racist lenses have yet to be actualized. To bridge a gap seen within the curriculum, the authors of this manuscript led the co-development, organization, and implementation of a student-led anti-racism initiative at the University of Calgary's Cumming School of Medicine. The initiative consisted of a class-wide anti-racism training session and a strategic review of student governance policies, including elections and decision-making processes through an anti-racist lens to advance equity within student learning environments. Anti-racism praxis was embedded within the co-creation of the anti-racism training by incorporating cultural safety and ethical engagement principles along with paid consultations with racialized students and faculty to identify pertinent topics and inform training priorities. Through this initiative, the authors offer an approach for the larger medical community to consider in their own local efforts to advance anti-racism advocacy and curricular change. This initiative highlighted the unique role of students in disrupting the status quo and modeling an anti-racist lens in their actions and self-governance.


[Level of interferon-gamma, tumor necrosis factor alpha, and antibodies to them in blood serum from Parkinson disease patients].
Serum levels of interferon-gamma (IF gamma), tumor necrosis factor alpha (TNF alpha) and autoantibodies (a-AT) to these cytokines were investigated in patients with Parkinson's disease (PD). The increased levels of TNF alpha (50%) and IF gamma (35%) were found in PD patients. There was close correlation between the serum level of TNF alpha and the manifestation of neurological symptoms (r = 0.434; p < 0.05), and between levels of IF gamma and the duration of this disease (r = 0.4511, p < 0.05) and patients age as well (r = 0.4358; p < 0.05). There was increased level of a-AT to TNF alpha in PD patients versus healthy controls (130.3 +/- 11.92 and 105.3 +/- 4.62, respectively, p < 0.05). The combined increase of levels of a-AT to TNF alpha and IF gamma (r = 0.91, p < 0.01) close reverse correlation between duration of PD and levels of a-AT to TNF alpha and IF gamma (r = 0.4644 and r = 0.606, respectively, p < 0.01) were also recognised. The data obtained suggest the involvement of TNF alpha and IF gamma into the pathological process during PD, which requires further investigation in this direction.


Practical considerations for chimeric antigen receptor design and delivery.
The development of chimeric antigen receptor (CAR)-modified immune cells has become a highly active field of research since the introduction of this approach in 1989. New ideas are constantly being proposed and tested, resulting in CARs that are more effective and specialized. Areas covered: Many aspects of CAR design and administration can be varied in order to achieve the best possible outcomes; optimization of this therapeutic schema is an active area of research. Here, the authors summarize the work that has been carried out thus far to assess different adaptations for each portion of the CAR itself. They also discuss the various methods used for CAR transgene transfer into effector cells. Expert opinion: While the field has made significant advancements in terms of expansion and testing of the variations available for CAR therapy, it remains difficult to ascertain which options are truly superior and under what conditions. Continued research in this area, as well as in aspects such as improving the safety profile and the anti-tumor potency of CARs, will be required to bring this therapy from early-phase clinical trials to standard of care as an effective treatment for a broad range of tumor types.


A Danish randomized trial comparing breast-preserving therapy with mastectomy in mammary carcinoma. Preliminary results.
The present study comprises 847 women operated upon for invasive breast carcinoma at 19 surgical departments and enrolled in protocol DBCG-82TM from January 1983 to November 1987. Among them 662 (78%) were allocated for breast-preserving therapy or mastectomy by randomization, while 185 patients (22%) did not accept randomization. Within the randomized group 6% could not be entered into adjuvant protocols, i.e. subsequent programmes of postoperative therapy and follow-up. This left 619 evaluable patients. In the non-randomized series 26% did not fulfil the demands for entrance into the adjuvant protocols, leaving 136 evaluable patients, 60 of whom had chosen a breast-preserving operation and 76 mastectomy. In the randomized series the patients in the two treatment arms were comparable in age, menopausal status, site of tumour, pathoanatomical diameter of the tumour, number of removed axillary lymph nodes, number of metastatic axillary lymph nodes, and distribution on adjuvant regimens. Ninety per cent of the patients in the randomized group accepted the method offered, whereas 10% declined and wanted the alternate form of operation. The median follow-up period was approximately 1.75 years. The cumulative recurrence rate in the randomized group was 13% and in the non-randomized group 7%. These results are preliminary. Life-table analyses have not so far demonstrated differences in recurrence-free survival either in the randomized or the non-randomized series.


Tailored Approach to Evaluation and Management of Early Onset Neonatal Sepsis in a Safety-Net Teaching Hospital in Northeast Florida.
Objective Early onset neonatal sepsis (EONS) remains a significant cause of morbidity and mortality in newborns in the immediate postnatal period. High empiric antibiotic use in well-appearing infants with known risk factors for sepsis led the American Academy of Pediatrics (AAP) to revise its 2010 guidelines for the evaluation and management of EONS to avoid overuse of antibiotics. In this recent clinical report, the AAP provided a framework that outlined several evidence-based approaches for sepsis risk assessment in newborns that can be adopted by institutions based on local resources and structure. One of these approaches, the sepsis risk calculator (SRC) developed by Kaiser Permanente, has been widely validated for reducing unnecessary antibiotic exposure and blood work in infants suspected of having EONS. In order to determine the utility and safety of modifying our institution's protocol to the SRC, we implemented a two-phased approach to evaluate the use of SRC in our newborn nursery. Phase 1 utilized a retrospective review of cases with SRC superimposition. If results from Phase 1 were found to be favorable, Phase 2 initiated a trial of the SRC for a six-month period prior to complete implementation. Methods Phase 1 consisted of retrospectively applying the SRC to electronic medical records (EMR) of infants ≥ 35 weeks' gestational age admitted to the newborn nursery with risk factors for EONS between June 2016 and May 2017. We compared actual antibiotic use as determined by the unit's EONS protocol for evaluation and management based on 2010 Centers for Disease Control and Prevention (CDC) and AAP guidelines to SRC-recommended antibiotic use. We used EMR to determine maternal and infant data, blood work results, and antibiotic usage as well as used daily progress notes by the clinical team to determine the clinical status of the infants retrospectively. Based on the projected reduction in blood work and antibiotics use with the retrospective superimposition of SRC on this cohort of infants and identification of our high-risk patient subset, we developed a novel, hybrid EONS protocol that we implemented and assessed throughout Phase 2, a six-month period from August 2018 to January 2019, as a prospective observational study. Results Phase 1 (SRC superimposition) demonstrated that the use of the SRC would have reduced empiric antibiotic use from 56% to 13% in the study cohort when compared with 2010 CDC/AAP guidelines. However, these same findings revealed use of the SRC would have resulted in delayed evaluation and initiation of antibiotics in 2 of 4 chorioamnionitis-exposed infants with positive blood cultures. During Phase 2 (n=302), with the implementation of our tailored approach (SRC implementation with additional blood culture in chorioamnionitis-exposed infants), 12 (4%) neonates received empiric antibiotic treatment compared to nine (3%) neonates who would have been treated per strict adherence to SRC recommendations. No neonate had culture-positive EONS. Continued use of 2010 CDC/AAP guidelines would have led to empiric antibiotic use in 38 (12.6%) infants in this cohort. Conclusion We developed a novel hybrid approach to the evaluation and management of neonates at increased risk of EONS by tailoring SRC recommendations to our safety-net population. Our stewardship effort achieved a safe and significant reduction in antibiotic usage compared to prior usage determined using CDC/AAP guidelines.


Robust adaptive microphone array processing for hearing aids: realistic speech enhancement.
The problem of combining the outputs of an array of microphones as a single input for a hearing aid is investigated. Emphasis is placed on the conservative prediction of realistically achievable performance gains provided by the array over a single microphone. Performance improvement is measured as a change in the speech reception threshold (SRT) between single microphone and multimicrophone conditions. Consistent with previous work, predictions of this change in SRT using intelligibility averaged gain, [symbol: see text] are shown to be good. Consequently, this measure is used, along with changes in signal-to-noise ratios (SNRs), to evaluate array performance. The results presented include the effects of acoustic headshadow, small room reverberation, microphone placement uncertainty, and desired speaker location uncertainty. It is in this context that realistic predictions of speech enhancement provided by robust adaptive microphone array processors are discussed. Performance improvements are demonstrated relative to the "best" single microphone in the array for three types of spatial filters: Fixed, robust block processed, and robust adaptive. The performance of the robust block processed arrays is shown to be attainable with adaptive implementations. One fundamental criterion employed in robust beamformer design directly limits the amount of cancellation of the desired signal that can occur.


Coping with shifting nest predation refuges by European reed Warblers Acrocephalus scirpaceus.
Predation, the most important source of nest mortality in altricial birds, has been a subject of numerous studies during past decades. However, the temporal dynamics between changing predation pressures and parental responses remain poorly understood. We analysed characteristics of 524 nests of European reed warblers monitored during six consecutive breeding seasons in the same area, and found some support for the shifting nest predation refuge hypothesis. Nest site characteristics were correlated with nest fate, but a nest with the same nest-site attributes could be relatively safe in one season and vulnerable to predation in another. Thus nest predation refuges were ephemeral and there was no between-season consistency in nest predation patterns. Reed warblers that lost their first nests in a given season did not disperse farther for the subsequent reproductive attempt, compared to successful individuals, but they introduced more changes to their second nest sites. In subsequent nests, predation risk remained constant for birds that changed nest-site characteristics, but increased for those that did not. At the between-season temporal scale, individual birds did not perform better with age in terms of reducing nest predation risk. We conclude that the experience acquired in previous years may not be useful, given that nest predation refuges are not stable.


Competitive advantage and tolerance of selected shochu yeast in barley shochu mash.
A shochu yeast strain, Saccharomyces cerevisiae BAW-6, was previously isolated from Kagoshima yeast strain Ko, and has since been utilized in shochu production. The BAW-6 strain carries pho3/pho3 homozygous genes in contrast to the heterozygous PHO3/pho3 genes in the parental Ko strain. However, absence of the PHO3 gene per se cannot explain the fermentation superiority of BAW-6. Here, we demonstrate the growth advantage of the BAW-6 strain over the Ko strain by competitive cultivation in barley shochu preparation, where alcohol yield and nihonshudo of the former strain were higher than those of the latter strain. In addition, the maximum growth rate of BAW-6 was less affected than that of Ko by high Brix values of barley koji medium, suggesting that BAW-6 is less sensitive to growth inhibitory compounds derived from barley or barley koji. The tolerance of BAW-6 to growth inhibitory compounds, cerulenin and diethylstilbestrol (an H⁺-ATPase inhibitor), was also higher than that of other yeast strains. Consistent with BAW-6's tolerance to diethylstilbestrol in the presence of 8% ethanol (pH 4.5), H⁺-ATPase activity, but not transcription of its gene, was higher in BAW-6 than in Ko. We conclude that the BAW-6 strain is associated with certain gene alterations other than PHO3, such that it can maintain cellular ion homeostasis under conditions of ethanol stress during the latter phase of fermentation.


[Quantitative determination of nine furanocoumarins for quality evaluation of Angelica dahurica from different habitats].
A UPLC method has been developed for simultaneous determination of nine furanocoumarins of Angelica dahurics,and was used for quality evaluation of A. dahurica from different habitats. ACQUITY UPLC BEH C18 chromatographic column was employed,the separation was performed with the mobile phase consisting of acetonitrile and water,and the detection wavelength was set at254 nm. This method was used to simultaneously determine the content of xanthotoxol,oxypeucedaninhydrate,byak-angelicin,psoralen,xanthotoxin,bergapten,oxypeucedanin,imperatorin and isoimperatorin in A. dahurica from different habitats. Then,the further quality assessment of the drug was carried out by similarity evaluation,cluster analysis( CA),principal component analysis( PCA),and orthogonal partial least squares discriminant analysis( OPLS-DA). The content order of measured furanocoumarins from high to low was: oxypeucedanin>imperatorin>isoimperatorin>oxypeucedaninhydrate>bergapten>byak-angelicin>xanthotoxin>xanthotoxol>psoralen,with the mean content 2. 844,1. 277,0. 649 2,0. 216 2,0. 129 8,0. 062 68,0. 052 68,0. 019 30,0. 018 19 mg·g-1,respectively. There were difference between the batches of the drug,and the quality was influenced by smouldering sulphur based on the results of chemical pattern recognition and content determination. Finally,six active ingredients were recognized as the quality makers using OPLS-DA method. The validated UPLC fingerprint combined with chemical pattern recognition method can be used in the quality control and evaluation of A. dahurica.


A review of nasal, paranasal, and skull base tumors invading the orbit.
Tumors that invade the orbit are uncommon. The majority are meningiomas arising from the sphenoid ridge (66%). Others are bone and cartilage tumors arising from the surrounding bones of the orbit, pituitary adenomas, and epithelial tumors arising from the paranasal sinuses and nasal cavity. Meningiomas occur more often in women, whereas epithelial tumors have a predilection for men. Meningiomas and epithelial tumors typically present in the sixth decade of life, whereas bone tumors tend to affect individuals in their third decade of life. Patients often present with a combination of ophthalmological and otorhinolaryngological symptoms, including proptosis, pain, decreased visual acuity, restrictions in motility of the eye, epistaxis, and nasal obstruction. Sarcomas and benign bone and cartilage tumors arise from surrounding structures, whereas carcinomas usually arise from the paranasal sinuses. Surgery is the mainstay of treatment. Depending on the aggressiveness and histology of the tumor, surgery may be combined with radiation and chemotherapy. The prognosis is generally poor, but varies depending on histology and cell origin, size of the tumor, and degree of invasion. Meningiomas and benign bone tumors have the best prognoses. Sinonasal undifferentiated carcinomas, small-cell neuroendocrine carcinomas, osteosarcomas, and rhabdomyosarcomas have poorer prognoses.


Self-assembly, optical behavior, and permeability of a novel capsule based on an azo dye and polyelectrolytes.
A novel capsule composed of an azo dye, Congo red (CR), and different polymers, including poly(styrenesulfonate, sodium salt) (PSS), poly(allylamine hydrochloride) (PAH), and poly(diallyldimethylammonium chloride) (PDDA), have been successfully fabricated by the layer-by-layer self-assembly technique. The stepwise linear deposition process was monitored by means of UV-visible absorption measurements. The formation of hollow capsules was verified by confocal laser scanning microscopy (CLSM) and scanning force microscopy (SFM). The resulting hollow PSS/PAH/CR/PDDA capsules displayed a sensitive response to visible light. Optical changes of the hollow capsules prior to and after the photoreaction were investigated in detail by means of UV-visible spectroscopy, CLSM, and SFM. It was found that the photochemical reaction of the assembled hollow capsules depends strongly on the matrix. Qualitative results on the permeability of the hollow capsule walls with CR as one component indicate that the permeability of the walls can be easily photo-controlled at varying irradiation time intervals without addition of external chemicals.


Atmospheric and oceanic impacts of Antarctic glaciation across the Eocene-Oligocene transition.
The glaciation of Antarctica at the Eocene-Oligocene transition (approx. 34 million years ago) was a major shift in the Earth's climate system, but the mechanisms that caused the glaciation, and its effects, remain highly debated. A number of recent studies have used coupled atmosphere-ocean climate models to assess the climatic effects of Antarctic glacial inception, with often contrasting results. Here, using the HadCM3L model, we show that the global atmosphere and ocean response to growth of the Antarctic ice sheet is sensitive to subtle variations in palaeogeography, using two reconstructions representing Eocene and Oligocene geological stages. The earlier stage (Eocene; Priabonian), which has a relatively constricted Tasman Seaway, shows a major increase in sea surface temperature over the Pacific sector of the Southern Ocean in response to the ice sheet. This response does not occur for the later stage (Oligocene; Rupelian), which has a more open Tasman Seaway. This difference in temperature response is attributed to reorganization of ocean currents between the stages. Following ice sheet expansion in the earlier stage, the large Ross Sea gyre circulation decreases in size. Stronger zonal flow through the Tasman Seaway allows salinities to increase in the Ross Sea, deep-water formation initiates and multiple feedbacks then occur amplifying the temperature response. This is potentially a model-dependent result, but it highlights the sensitive nature of model simulations to subtle variations in palaeogeography, and highlights the need for coupled ice sheet-climate simulations to properly represent and investigate feedback processes acting on these time scales.


Using the plurality of codon positions to identify deleterious variants in human exomes.
A codon position could perform different or multiple roles in alternative transcripts of a gene. For instance, a non-synonymous position in one transcript could be a synonymous site in another. Alternatively, a position could remain as non-synonymous in multiple transcripts. Here we examined the impact of codon position plurality on the frequency of deleterious single-nucleotide variations (SNVs) using data from 6500 human exomes. Our results showed that the proportion of deleterious SNVs was more than 2-fold higher in positions that remain non-synonymous in multiple transcripts compared with that observed in positions that are non-synonymous in one or some transcript(s) and synonymous or intronic in other(s). Furthermore, we observed a positive relationship between the fraction of deleterious non-synonymous SNVs and the number of proteins (alternative splice variants) affected. These results demonstrate that the plurality of codon positions is an important attribute, which could be useful in identifying mutations associated with diseases. email@example.com Supplementary data are available at Bioinformatics online.


A wellness program for first year medical students.
Entering medical students experience distress symptoms due to the demands of the intensive curriculum, adjustment to new environments and increased responsibilities. The purpose of this controlled, randomized study was to determine the effects of a structured wellness program on measures of anxiety, depression and frequency of acute illness in 449 first year medical students. The effects of eight sessions of stress management were compared to a wait list control group. High risk students were identified based on scores on psychological inventories and number of recent life events (WLE). Results showed that depression, anxiety scores and frequency of acute illness were higher in women than in men, and were higher in students with multiple life events. Significant decreases were observed in depression in the intervention group students when WLE was the covariate (p = .045). Further, the high risk group showed consistently lower depression scores after the intervention compared to high risk wait list controls (p = .003), and these changes were maintained at the end of school year. There were no significant changes in anxiety or frequency of acute illness. Wellness programs can be implemented in medical school and may be particularly useful for entering students with elevated psychological distress.


The population genetics of the haemoglobinopathies.
The haemoglobinopathies are the commonest single gene disorders known, and are so common in some regions of the world that the majority of the population carries at least one genetic abnormality affecting the structure or synthesis of the haemoglobin molecule. The prevalence of the common haemoglobinopathies (the alpha- and beta-thalassaemias, HbS, HbC and HbE) is almost certainly a result of the protection they provide against malaria, as the epidemiological evidence reviewed in this chapter shows. World-wide, the distributions of malaria and the common haemoglobinopathies largely overlap, and micro-epidemiological surveys have confirmed the close relationship between the disorders. However, there are complications to this picture which appear to undermine the malaria hypothesis. First, in some areas, malaria and haemoglobinopathies are not coincident. Second, the malaria hypothesis does not easily explain why no two regions of the world have the same haemoglobinopathy or combination of haemoglobinopathies. The majority of mutations have arisen only once and are regionally specific. By using molecular characterization of mutations and the analysis of haplotypes on haemoglobinopathy-bearing chromosomes it is possible to show how a combination of selection by malaria, genetic drift and population movements can explain the first complication. In order to explain the second, we have argued that malaria selection has operated relatively recently on human populations (within the last 5000 years). The present distribution is then seen as the result of selection elevating sporadic mutations in local populations. In the absence of sufficient gene flow to spread all mutations to all populations, the consequence is a patchwork distribution of haemoglobinopathies. Given time, we would expect the mutations that protect and do not compromise the health of their carriers to become widely disseminated, but it is likely that human intervention will alter this process of natural selection.


Age of first drunkenness and risks for all-cause mortality: A 27-year follow-up from the epidemiologic catchment area study.
Early-onset drunkenness is associated with an increased risk of developing an alcohol use disorder (AUD), which predicts excess mortality risk. Here, we estimated mortality risk for drinkers with and without early drunkenness. For 14,848 adult participants interviewed about drinking, drunken episodes, and AUD in 1981-83 for the Epidemiologic Catchment Area in New Haven (Connecticut), Baltimore (Maryland), St. Louis (Missouri), and Durham (North Carolina), we linked National Death Index records through 2007. Cox regression modeling estimates showed excess mortality for drinkers with age of first drunkenness earlier than 15 years old (hazard ratio, HR: 1.47, 95% CI: 1.25, 1.72) and when first drunkenness occurred at or after age 15 (HR: 1.20, 95% CI: 1.11, 1.29), as compared with adults who had never been drunk. Consistent results were observed, irrespective of AUD history. That is, early drunkenness signaled excess mortality risk even in absence of AUD. In a large community sample from four cities in the US, early age of onset of drunkenness predicts mortality risk. We discuss experiments to investigate the possible causal significance of this predictive association.


Fabrication of SiC nanoparticles by physical milling for ink-jet printing.
Here we tried to show the possibility of mechanical milling method for fabrication of SiC nanoparticles and ink-jet printing method to make SiC patterns for use as several applications, e.g., micro hotplates. Planetary milling was employed to fabricate the nano-scale SiC particles from coarse powders. After 100 hours of milling, the size of the SiC particles decreased to about 100 nm, which was sufficient for the formulation of ink for ink-jet printing. The SiC particles were dispersed in an ink system consisted of ethylene glycol and ethanol with a small amount of additives. The ink with SiC nanoparticles could be successfully printed on an alumina substrate by the ink-jet printing method.


First report of Colletotrichum fructicola causing anthracnose on water hyacinth in China.
Water hyacinth (Eichhornia crassipes), a worst invasive aquatic weed has been caused the widespread problems for the water bodies and water resources, particularly the case in China. Plant pathogens are a promising alternative as biocontrol agents (Dagno et al. 2011), but success in this strategy will require the selection of some highly virulent pathogen strains. In September 2020, irregular necrotic lesions on leaves, stems, as well as crown and petiole rots symptoms, occurred on water hyacinth, in Minjiang and Xiyuanjiang watershed, in Fuzhou, China. Fragments from symptomatic leaf tissue (5x5mm) were superficially disinfected in 0.1% MgCl2 solution for 30 s, followed by rinsing three times in sterile water, placed on potato dextrose agar (PDA), and then incubated in darkness at 28°C for 5 days. Two fungal isolates (F3 and F11) were recovered and obtained pure cultures from the affected leaves and deposited in the Institute of Oceanography, Minjiang University. The colonies were stale, with felted, dense, pale grey aerial mycelium, scattered dark based acervuli with orange conidial masses near centre; in reverse side pinkish orange with patches of grey pigment near centre. The hyphae were septate, branched, and 2 to 6 µm in width. Appressoria were not observed. Conidiogenous cells were 20-24 × 3.5-4.5 µm, cylindric to flask-shaped, towards margin the conidiophores with a much looser structure, conidiogenous loci at apex and often also at septa. Asci were 60-80 × 15-20 µm, cylindric to subfusoid, 8-spored. Ascospores were 17-23 × 4-6 µm, gently curved, tapering to quite narrow, rounded ends. Perithecia mature after about 15 days, and were dark brown, subglobose, and 50-150 μm in diameter, and with scattered, dark brown setae about 50-80 µm long. Conidia were 15-25 × 4.5-6 μm, unicellular, colorless, and cylindrical to fusiform. Genomic DNA from two isolates was extracted with a modified DNA Midi Kit (TIANGEN, Inc., Beijing, China), and amplified using ITS4/ITS1F, CL1/CL2A, CHS-79F/CHS-345R, T1/T2 and GDF/GDR primers by PCR (Weir et al. 2012; White et al. 1990). Sequences of F3 and F11 were submitted to GenBank (accession no. ITS, MW307302, MW307303; CAL, MW303427, MW303429; CHS-1, MW303428, MW303430; TUB, MW531006, MW531007; GADPH, MW531008, MW531009). A phylogenetic tree using the maximum likelihood methods and including ITS-CHS-CAL-TUB-GADPH concatenated sequences from Colletotrichum gloeosporioides complex was obtained (Cai et al. 2009; Damm et al. 2018; Weir et al. 2012). Phylogenetic analyses revealed that isolate F3 and F11 were grouped into the clade C. fructicola. To test Koch's postulates, conidial suspensions (107 CFU/ml) of the isolate F3 and F11 were micro-injected into 20 water hyacinth seedlings per isolate. Another 20 seedlings were injected with water without conidia as control. Inoculated plants were kept in 50-liter plastic tanks, and maintained in a greenhouse at room temperature (19-24ºC) for two weeks. The Koch's test was conducted twice. After 10 days, typical anthracnose symptoms similar to the field appeared on the inoculated leaves, while the control leaves remained asymptomatic. The C. fructicola was re-isolated and identified by microscopy, PCR and sequencing, but not on non-inoculated controls. Anthracnose disease caused by C. fructicola has been reported affecting numerous plants worldwide, including cotton, coffea, grape, citrus, ect (Guarnaccia et al. 2017). However, to our knowledge, this is the first report of C. fructicola causing anthracnose on water hyacinth in China. Further studies for the efficacy of C. fructicola and/or of the genus Colletotrichum as biocontrol agent for water hyacinth or another aquatic plant are required (Ding et al. 2007; Dagno et al. 2012).


Ethical issues in the study of bereavement: the opinions of bereaved adults.
Few studies examine ethical issues in bereavement research and none survey the opinions of bereaved individuals who have not previously participated in bereavement research. This study examined the theoretical opinions of bereaved adults about ethical issues such as attitudes toward bereavement research, timing and methods of recruitment, and competency to consent. Participants felt positively about bereavement research, although opinions about timing and method of recruitment were varied. The results also suggest that bereaved individuals should be considered competent to consent to bereavement research participation. Conclusions may guide bereavement researchers and research ethics boards in the design and review of bereavement studies.


Catalytical mechanism of the phenylalanyl-tRNA synthetase from yeast. Reactivity of ATP in the absence of phenylalanine.
Phenylalanyl-tRNA synthetase catalyses an AMP-ATP exchange under conditions where no aminoacylation of tRNA occurs. A plausible explanation for this reaction had not been given so far. The results of the present investigation provide evidence for the following interpretation. tRNAPhe induces a polarisation of the ATP in complex with the enzyme; this stimulates (a) the formation of phenylalanyl-adenylate in the presence of phenylalanine, (b) the hydrolysis of ATP in the absence of phenylalanine and AMP and (c) the transfer of diphosphoryl onto AMP in the presence of AMP, especially when phenylalanine is absent.


Analysing the implementation and effects of safe staffing policies in acute hospitals.
Several high-profile inquiries and reports, including the Report of the Mid Staffordshire NHS Foundation Trust Public Inquiry, by Sir Robert Francis QC, have identified that nurse staffing is an essential factor in patient safety and patient mortality rates. Since the Francis report, several policies and initiatives aimed at ensuring safe staffing in the NHS have been developed alongside guidance and evidence-based safe staffing tools, while the Care Quality Commission has been tasked with ensuring compliance with these policies. In 2015, the National Institute for Health Research (NIHR) Policy Research Programme commissioned research to examine the extent to which safe staffing policies have translated into practice locally in the NHS. This article summarises and examines the main findings of this research and suggests that, although policies have raised the profile of nurse staffing, nursing shortages have impeded their implementation.


Hormone replacement therapy aggravates postmenopausal urinary incontinence.
(1) In the WHI trials, which involved more than 20 000 women, the frequency of urinary incontinence increased among postmenopausal women taking hormone replacement therapy compared with placebo. Among women who were continent at enrollment, the frequency of stress incontinence at 1 year was 16% with an oestrogen-progestin combination, compared with 9% with placebo (relative risk 1.87, 95% confidence interval: 1.61-2.18). Among women who were already incontinent, the relative risk of aggravation with hormone replacement therapy compared with placebo was about 1.40. (2) The results of another trial involving nearly 3000 women were similar. (3) Other, smaller trials failed to show any positive impact of oestrogen-progestin therapy on urinary incontinence in postmenopausal women. (4) In practice, postmenopausal hormone replacement therapy does not protect against urinary incontinence; on the contrary, it may trigger or worsen urinary incontinence.


Healthcare-seeking behaviour, barriers and mental health of non-domestic migrant workers in Singapore.
Low-wage migrant workers are vulnerable to healthcare inequities. We sought to identify potential barriers to healthcare and risk factors for mental health issues in non-domestic migrant workers in Singapore, and identify high-risk subgroups. A cross-sectional, interviewer-administered survey of 433 non-domestic migrant workers was conducted at subsidised clinics and a foreign worker dormitory from July to August 2016. Questions assessed healthcare usage patterns, affordability issues, barriers to care and psychological distress using a validated screening scale (Kessler-6). Bangladeshi workers surveyed were more likely to be single, have more financial dependents, a lower level of education and salary and pay higher agent fees (p<0.01). 61.4% of workers reported that they had insurance, but had poor understanding of whether it covered inpatient/outpatient expenses. The majority of workers had not, or were not sure if they had, received information about company-bought insurance (72.4%). Among those who had, most reported that information was not in their native language (67.7%). Non-specific psychological distress was found in 21.9%, as estimated by the Kessler-6 scale. Multivariate analysis found that psychological distress was independently associated with Bangladeshi nationals (OR 2.98, 95% CI 1.58 to 5.62; p=0.001) and previous experience of financial barriers to healthcare (OR 3.86, 95% CI 2.25 to 6.62; p<0.0001). We identified gaps in non-domestic migrant workers' knowledge of healthcare coverage, and substantial financial barriers to healthcare. The Bangladeshi population in our study was at higher risk of such barriers and psychological distress. These represent areas for further research and intervention.