Quality of life in women with breast cancer and the use of complementary and alternative medicine.
The aim of this study was to evaluate quality of life and complementary and alternative medicine use among patients with breast cancer in Turkey. The sample consists of women who had modified undergone radical mastectomy or breast conserving surgery. Data were collected using a questionnaire addressing personal/medical characteristics use of complementary and alternative medicine and the 36-Item Short Form Health Survey (SF-36) to measure quality of life. A majority of subjects underwent modified radical mastectomy procedures. The social and physical mean scores were the highest and role physical and role emotional mean score were the lowest. The most common complementary and alternative methods were praying, exercise, and herbs use. In conclusion, women with breast cancer have a moderate level of quality of life, and that they use complementary and alternative methods widely.


Dual effects of hexanol and halothane on the regulation of calcium sensitivity in airway smooth muscle.
Contraction of airway smooth muscle is regulated by receptor-coupled mechanisms that control the force developed for a given cytosolic calcium concentration (i.e., calcium sensitivity). Halothane antagonizes acetylcholine-induced increases in calcium sensitivity by inhibiting GTP-binding (G)-protein pathways. The authors tested the hypothesis that hexanol, like halothane, inhibits agonist-induced increases in calcium sensitivity in airway smooth muscle by inhibiting G-protein pathways. Calcium sensitivity was assessed using alpha-toxin-permeabilized canine tracheal smooth muscle. In selected experiments, regulatory myosin light chain phosphorylation was also determined by Western blotting in the presence and absence of 10 mm hexanol and/or 100 microm acetylcholine. Hexanol (10 mm) and halothane (0.76 mm) attenuated acetylcholine-induced calcium sensitization by decreasing regulatory myosin light chain phosphorylation during receptor stimulation. Hexanol also inhibited increases in calcium sensitivity due to direct stimulation of heterotrimeric G-proteins with tetrafluoroaluminate but not with 3 microm GTPgammaS, consistent with prior results obtained with halothane. In contrast, in the absence of receptor stimulation, both compounds produced a small increase in calcium sensitivity by a G-protein-mediated increase in regulatory myosin light chain phosphorylation that was not affected by pertussis toxin treatment. The authors noted dual effects of hexanol and halothane. In the presence of muscarinic receptor stimulation, hexanol, like halothane, decreases calcium sensitivity by interfering with heterotrimeric G-protein function. However, in the absence of muscarinic receptor stimulation, hexanol and halothane slightly increase calcium sensitivity by a G-protein-mediated process not sensitive to pertussis toxin. Hexanol may represent a useful experimental tool to study the effect of anesthetics on heterotrimeric G-protein function.


Tetramethylpyrazine protects retinal ganglion cells against H2O2‑induced damage via the microRNA‑182/mitochondrial pathway.
Glaucoma is the leading cause of irreversible blindness worldwide; the apoptosis of the retinal ganglion cells (RGCs) is a hallmark of glaucoma. Tetramethylpyrazine (TMP) is the main active component of Ligusticum wallichii Franchat, and has been demonstrated to improve a variety of injuries through its antioxidative and antiapoptotic properties. However, these effects of TMP on glaucoma have not been studied. The present study aimed to investigate the potential role of TMP in glaucoma and to elucidate its possible mechanisms responsible for these effects. An in vitro model was generated, in which primary RGCs (PRGCs) were treated with H2O2. Our study revealed that TMP protected against H2O2‑induced injury to PRGCs, as evidenced by enhanced cell viability, reduced caspase 3 activity and decreased cell apoptosis. We also reported that TMP treatment inhibited reactive oxygen species (ROS) production and malondialdehyde levels, but upregulated the antioxidative enzyme superoxide dismutase. In particular, TMP significantly increased the expression of microRNA‑182‑5p (miR‑182) in H2O2‑treated PRGCs, which was selected as the target miRNA for further research. In addition, our findings suggested that the protective effects of TMP on H2O2‑induced injury were attenuated by knockdown of miR‑182. The results of a luciferase reporter assay demonstrated that Bcl‑2 interacting protein 3 (BNIP3), an effector of mitochondria‑mediated apoptosis, was a direct target of miR‑182. In addition, TMP treatment significantly decreased the expression of BNIP3, Bax, cleaved‑caspase‑3 and cleaved‑poly(ADP‑ribose)polymerase, but increased that of Bcl‑2. Also, TMP treatment decreased the release of cytochrome c from mitochondria and improved mitochondrial membrane potential in H2O2‑treated RGCs. Of note, the inhibitory effects of TMP on the mitochondrial apoptotic pathway were suggested to be reversed by knockdown of miR‑182. Collectively, our findings provide novel evidence that TMP protects PRGCs against H2O2‑induced damage through suppressing apoptosis and oxidative stress via the miR‑182/mitochondrial apoptotic pathway.


BEAVR: a browser-based tool for the exploration and visualization of RNA-seq data.
The use of RNA-sequencing (RNA-seq) in molecular biology research and clinical settings has increased significantly over the past decade. Despite its widespread adoption, there is a lack of simple and interactive tools to analyze and explore RNA-seq data. Many established tools require programming or Unix/Bash knowledge to analyze and visualize results. This requirement presents a significant barrier for many researchers to efficiently analyze and present RNA-seq data. Here we present BEAVR, a Browser-based tool for the Exploration And Visualization of RNA-seq data. BEAVR is an easy-to-use tool that facilitates interactive analysis and exploration of RNA-seq data. BEAVR is developed in R and uses DESeq2 as its engine for differential gene expression (DGE) analysis, but assumes users have no prior knowledge of R or DESeq2. BEAVR allows researchers to easily obtain a table of differentially-expressed genes with statistical testing and then visualize the results in a series of graphs, plots and heatmaps. Users are able to customize many parameters for statistical testing, dealing with variance, clustering methods and pathway analysis to generate high quality figures. BEAVR simplifies analysis for novice users but also streamlines the RNA-seq analysis process for experts by automating several steps. BEAVR and its documentation can be found on GitHub at https://github.com/developerpiru/BEAVR. BEAVR is available as a Docker container at https://hub.docker.com/r/pirunthan/beavr.


Creating an oversight infrastructure for electronic health record-related patient safety hazards.
Electronic health records (EHRs) have potential quality and safety benefits. However, reports of EHR-related safety hazards are now emerging. The Office of the National Coordinator for Health Information Technology recently sponsored an Institute of Medicine committee to evaluate how health information technology use affects patient safety. In this article, we propose the creation of a national EHR oversight program to provide dedicated surveillance of EHR-related safety hazards and to promote learning from identified errors, close calls, and adverse events. The program calls for data gathering, investigation/analysis, and regulatory components. The first 2 functions will depend on institution-level EHR safety committees that will investigate all known EHR-related adverse events and near-misses and report them nationally using standardized methods. These committees should also perform routine safety self-assessments to proactively identify new risks. Nationally, we propose the long-term creation of a centralized, nonpartisan board with an appropriate legal and regulatory infrastructure to ensure the safety of EHRs. We discuss the rationale of the proposed oversight program and its potential organizational components and functions. These include mechanisms for robust data collection and analyses of all safety concerns using multiple methods that extend beyond reporting, multidisciplinary investigation of selected high-risk safety events, and enhanced coordination with other national agencies to facilitate broad dissemination of hazards information. Implementation of this proposed infrastructure can facilitate identification of EHR-related adverse events and errors and potentially create a safer and more effective EHR-based health care delivery system.


Molecular Pathology and Biomarkers.
The field of salivary gland tumor biology is quite broad, given the numerous subtypes of both benign and malignant tumors originating from the major and minor salivary glands. Knowledge about the molecular pathology of these lesions is still limited, and there are few clinically useful diagnostic and prognostic biomarkers. However, recent discoveries of certain key genomic alterations, such as chromosome translocations, copy number alterations, and mutations, provide new insights into the molecular pathogenesis of these lesions and may help to better define them. It is also hoped that this new knowledge can help to guide therapy, but this translation has been somewhat slow to develop, perhaps due to the rarity of these tumors and the lack of large, randomized studies. However, because of the limitations inherent in what surgery and radiation can provide, there is an urgent need for understanding of the mechanisms of carcinogenesis in these tumors individually, so that chemotherapy and/or targeted therapy can be rationally selected.


Mice lacking the USP2 deubiquitinating enzyme have severe male subfertility associated with defects in fertilization and sperm motility.
The ubiquitin-proteasome system plays an important role in spermatogenesis. However, the functions of deubiquitinating enzymes in this process remain poorly characterized. We previously showed that the deubiquitinating enzyme USP2 is induced in late elongating spermatids. To identify its function, we generated mice lacking USP2. Usp2 -/- mice appeared normal, and the weights of major organs, including the testis, did not differ from wild type (Usp2 +/+). However, although the numbers of testicular spermatids and epididymal spermatozoa were normal in Usp2 -/- males, these animals had a severe defect in fertility, yielding only 12% as many offspring as Usp2 +/+ littermates. Spermatogenesis in Usp2 -/- mice was morphologically normal except for the presence of abnormal aggregations of elongating spermatids and formation of multinucleated cells in some tubules. The epididymal epithelium was morphologically normal in Usp2 -/- mice, but some abnormal cells other than sperm were present in the lumen. Usp2 -/- epididymal spermatozoa manifested normal motility when incubated in culture media, but rapidly became immotile when incubated in PBS in contrast to Usp2 +/+ spermatozoa, which largely maintained motility under this condition. Usp2 -/- and +/+ spermatozoa underwent acrosome reactions in vitro with similar frequency. In vitro fertilization assays demonstrated a severe defect in the ability of Usp2 -/- spermatozoa to fertilize eggs. This could be bypassed by intracytoplasmic sperm injection or removal of the zona pellucida, which resulted in fertilization rates similar to that of Usp2 +/+ mice. We demonstrate for the first time, using mouse transgenic approaches, a role for the ubiquitin system in fertilization.


Partial agonist and antagonist activities of a mutant scorpion beta-toxin on sodium channels.
Scorpion β-toxin 4 from Centruroides suffusus suffusus (Css4) enhances the activation of voltage-gated sodium channels through a voltage sensor trapping mechanism by binding the activated state of the voltage sensor in domain II and stabilizing it in its activated conformation. Here we describe the antagonist and partial agonist properties of a mutant derivative of this toxin. Substitution of seven different amino acid residues for Glu(15) in Css4 yielded toxin derivatives with both increased and decreased affinities for binding to neurotoxin receptor site 4 on sodium channels. Css4(E15R) is unique among this set of mutants in that it retained nearly normal binding affinity but lost its functional activity for modification of sodium channel gating in our standard electrophysiological assay for voltage sensor trapping. More detailed analysis of the functional effects of Css4(E15R) revealed weak voltage sensor trapping activity, which was very rapidly reversed upon repolarization and therefore was not observed in our standard assay of toxin effects. This partial agonist activity of Css4(E15R) is observed clearly in voltage sensor trapping assays with brief (5 ms) repolarization between the conditioning prepulse and the test pulse. The effects of Css4(E15R) are fit well by a three-step model of toxin action involving concentration-dependent toxin binding to its receptor site followed by depolarization-dependent activation of the voltage sensor and subsequent voltage sensor trapping. Because it is a partial agonist with much reduced efficacy for voltage sensor trapping, Css4(E15R) can antagonize the effects of wild-type Css4 on sodium channel activation and can prevent paralysis by Css4 when injected into mice. Our results define the first partial agonist and antagonist activities for scorpion toxins and open new avenues of research toward better understanding of the structure-function relationships for toxin action on sodium channel voltage sensors and toward potential toxin-based therapeutics to prevent lethality from scorpion envenomation.


Implementation of standardized nutrition guidelines by renal dietitians is associated with improved nutrition status.
Standardized nutrition guidelines that focus on a nutrition care process have been used by dietitians treating renal patients in Australia for over 3 years. We show the impact of this implementation on the nutritional status of a cohort of hemodialysis patients. We conducted a retrospective observational study, investigating a cohort of maintenance hemodialysis patients after the implementation of a systematic approach to the patient's nutritional care. This study took place in public and private in-center hemodialysis units. Patients included a cohort of 65 maintenance hemodialysis patients (mean age +/- SD, 64 +/- 15 years; 58% male; dialysis vintage median [interquartile range], 22 [10 to 46] months). All participants were provided with a dietary interview at least every 6 months, with intensive follow-up where required, and were monitored monthly regarding weight and biochemistry. Outcomes were assessed annually between May 2004 and December 2006, after the implementation of this model of care. Energy and protein intake according to dietary interview, nutritional status according to subjective global assessment, and data regarding dry weight and biochemistry (including albumin, potassium, and phosphate) were collected by the dietitian at each facility. Change in each outcome measure over time was assessed using repeated-measures analysis. The proportion of patients with malnutrition (subjective global assessment B or C) decreased from 14% at baseline to 3% after 2 years. Serum albumin, potassium, and dry weight remained stable throughout the study period, and there was a significant decrease in serum phosphate over time (mean +/- SD,1.8 +/- 0.5 to 1.5 +/- 0.5 mmol/L, P = .004). Dietary energy and protein intake changed significantly over the study period (P = .001 and P = .022, respectively), with the highest mean intake recorded during the final follow-up assessment. The implementation of a systematic approach to patient care, in line with nutrition management guideline recommendations, was associated with an improvement in nutritional status and dietary intake in this cohort of maintenance hemodialysis patients, without the need for increased resources or dietitian time.


Global survey of antibody to Hantaan-related viruses among peridomestic rodents.
A global serological survey of rodents was conducted to determine the distribution and prevalence of antibody to Hantaan-related viruses, which are the causative agents of haemorrhagic fever with renal syndrome (HFRS) in man. Over 1700 rodent sera from more than 20 sites worldwide were examined by immunofluorescent antibody assay. High-titred positive sera were further tested by plaque reduction neutralization tests with prototype Hantaan virus and urban rat-associated Hantaan-like virus. Antibody-positive rodents were found in most, but not all, sites sampled. The highest antibody prevalence rates were found in Baltimore, MD, USA and Bélem, Brazil, and Rattus norvegicus was the species most often found positive. Bandicota indica and B. bengalensis, species previously not recognized as hosts of hantaviruses, were also positive. Neutralization tests detected antibody in Rattus sera specific for urban rat-associated Hantaan-like virus, but failed to establish the specificity of antibody in Bandicota sera. These results indicate that Hantaan-related viruses exist beyond the currently recognized boundaries of HFRS in man and suggest that human HFRS-like disease might be occurring in other areas of the world where rodent-human contact is common.


Chemically homogeneous and thermally reversible oxidation of epitaxial graphene.
With its exceptional charge mobility, graphene holds great promise for applications in next-generation electronics. In an effort to tailor its properties and interfacial characteristics, the chemical functionalization of graphene is being actively pursued. The oxidation of graphene via the Hummers method is most widely used in current studies, although the chemical inhomogeneity and irreversibility of the resulting graphene oxide compromises its use in high-performance devices. Here, we present an alternative approach for oxidizing epitaxial graphene using atomic oxygen in ultrahigh vacuum. Atomic-resolution characterization with scanning tunnelling microscopy is quantitatively compared to density functional theory, showing that ultrahigh-vacuum oxidization results in uniform epoxy functionalization. Furthermore, this oxidation is shown to be fully reversible at temperatures as low as 260 °C using scanning tunnelling microscopy and spectroscopic techniques. In this manner, ultrahigh-vacuum oxidation overcomes the limitations of Hummers-method graphene oxide, thus creating new opportunities for the study and application of chemically functionalized graphene.


Regulation of intracellular trafficking of human CD1d by association with MHC class II molecules.
CD1 family members are antigen-presenting molecules capable of presenting bacterial or synthetic glycolipids to T cells. Here we show that a subset of human CD1d molecules are associated with major histocompatibility complex (MHC) class II molecules, both on the cell surface and in the late endosomal/lysosomal compartments where class II molecules transiently accumulate during transport. The interaction is initiated in the endoplasmic reticulum with class II-invariant chain complexes and appears to be maintained throughout the class II trafficking pathway. A truncated form of CD1d which lacks its cytoplasmic YXXZ internalization motif is transported to late endosomal/lysosomal compartments in the presence of class II molecules. Furthermore, the same CD1d deletion mutant is targeted to lysosomal compartments in HeLa cells expressing class II molecules and invariant chain by transfection. The deletion mutant was also found in lysosomal compartments in HeLa cells expressing only the p33 form of the invariant chain. These data suggest that the intracellular trafficking pathway of CD1d may be altered by class II molecules and invariant chain induced during inflammation.


Network Pharmacology Prediction: The Possible Mechanisms of Cinobufotalin against Osteosarcoma.
To explore the active compounds and targets of cinobufotalin (huachansu) compared with the osteosarcoma genes to obtain the potential therapeutic targets and pharmacological mechanisms of action of cinobufotalin on osteosarcoma through network pharmacology. The composition of cinobufotalin was searched by literature retrieval, and the target was selected from the CTD and TCMSP databases. The osteosarcoma genes, found from the GeneCards, OMIM, and other databases, were compared with the cinobufotalin targets to obtain potential therapeutic targets. The protein-protein interaction (PPI) network of potential therapeutic targets, constructed through the STRING database, was inputted into Cytoscape software to calculate the hub genes, using the NetworkAnalyzer. The hub genes were inputted into the Kaplan-Meier Plotter online database for exploring the survival curve. Functional enrichment analysis was identified using the DAVID database. 28 main active compounds of cinobufotalin were explored, including bufalin, adenosine, oleic acid, and cinobufagin. 128 potential therapeutic targets on osteosarcoma are confirmed among 184 therapeutic targets form cinobufotalin. The hub genes included TP53, ACTB, AKT1, MYC, CASP3, JUN, TNF, VEGFA, HSP90AA1, and STAT3. Among the hub genes, TP53, ACTB, MYC, TNF, VEGFA, and STAT3 affect the patient survival prognosis of sarcoma. Through function enrichment analysis, it is found that the main mechanisms of cinobufotalin on osteosarcoma include promoting sarcoma apoptosis, regulating the cell cycle, and inhibiting proliferation and differentiation. The possible mechanisms of cinobufotalin against osteosarcoma are preliminarily predicted through network pharmacology, and further experiments are needed to prove these predictions.


Beyond polycystic kidney disease.
Tuberous sclerosis(TS) is an autosomal dominant disease caused by mutations in TSC1 and TSC2 genes. TSC2 gene is located in chromosome 16p13.3, adjacent to PKD1 gene, responsible for the autosomal dominant polycystic kidney disease. In a rare subgroup of patients, the presence of a deletion which simultaneously affects the TSC2 and PKD1 genes has been confirmed. TSC2/PKD1-Contiguous Gene Syndrome is characterised by the early appearance of autosomal dominant polycystic kidney disease in combination with several phenotypic manifestations of TS. We present a 13-year-old girl with bilateral renal cysts detected at the age of 9 months. At the age of 13, she was referred to the Dermatology Outpatients Clinic due to a facial cutaneous eruption. She presented with facial erythema, fibroadenomas with malar distribution and disseminated hypomelanotic macules, meeting the criteria for TS. TSC2/PKD1 Contiguous Gene Syndrome deletion was suspected, being later confirmed by genetic testing.


Autoerotic asphyxia by hanging.
A case of sexual asphyxial death by hanging is presented. A 41-year-old man was found dead hanging by a towrope. A mirror was placed in front of a table, reflecting him in full height. A photograph of a celebrity mannequin was found against him. The towrope was arranged for the compression of the neck, and controlled voluntarily by a shower apparatus. Autopsy findings revealed an ascending ligature mark, 2 cm in width on the neck. Although this is a very ancient behaviour, we are presenting a very rare case from Turkey. We aim to discuss sexual asphyxiation phenomenon together with the features of the previous Turkish cases on the aspect of the forensic viewpoint, as well as the similarities and differences between different nations and religious.


Trends in Cardiovascular Implantable Electronic Device Insertion Between 1988 and 2018 in Olmsted County.
This study sought to describe trends in cardiovascular implantable electronic device (CIED) insertion over the past 3 decades in Olmsted County. Trends in CIED insertion in the United States have not been extensively studied. The Rochester Epidemiology Project is a medical records linkage system comprising the records of all residents of Olmsted County from 1966 to the present. CIED insertion between 1988 and 2018 was determined using International Classification of Diseases-Ninth Revision, International Classification of Diseases-10th Revision, and Current Procedural Terminology codes. Age- and sex-adjusted incidence rates, adjusted to the 2010 US White population, were calculated. Trends in incidence over time, across age groups, and between sex are estimated using Poisson regression models. The age- and sex-adjusted incidence of device implants for the study period were as follows: overall CIED: 82.4 (95% CI: 79.2-85.6); permanent pacemaker (PPM): 62.9 (95% CI: 60.0-65.7); implantable cardioverter-defibrillator (ICD): 14.0 (95% CI: 12.6-15.3); and cardiac resynchronization therapy (CRT): 5.6 (95% CI: 4.7-6.4) per 100,000 per year. The overall incidence of CIED insertion increased between 1988 to 1993 and 2000 to 2005 and then decreased between 2000 to 2005 and 2012 to 218 (P < 0.0001). PPM and ICD insertion incidence followed these trends, whereas the incidence of CRT insertion increased between 2000 to 2005 and 2012 to 2018. CIED insertion incidence increased with age (P < 0.0001). CIED insertion incidence was greater in men (116.3 vs 57.3 per 100,000 per year in men vs women; P < 0.0001). The overall survival of CRT recipients improved (P = 0.0044). The incidence values for PPM and ICD implants are decreasing, while the incidence of CRT implants is increasing. CIEDs are increasingly inserted in the elderly, men, and patients with higher comorbidities.


Horizontal gene transfer and mutation: ngrol genes in the genome of Nicotiana glauca.
Ngrol genes (NgrolB, NgrolC, NgORF13, and NgORF14) that are similar in sequence to genes in the left transferred DNA (TL-DNA) of Agrobacterium rhizogenes have been found in the genome of untransformed plants of Nicotiana glauca. It has been suggested that a bacterial infection resulted in transformation of Ngrol genes early in the evolution of the genus Nicotiana. Although the corresponding four rol genes in TL-DNA provoked hairy-root syndrome in plants, present-day N. glauca and plants transformed with Ngrol genes did not exhibit this phenotype. Sequenced complementation analysis revealed that the NgrolB gene did not induce adventitious roots because it contained two point mutations. Single-base site-directed mutagenesis at these two positions restored the capacity for root induction to the NgrolB gene. When the NgrolB, with these two base substitutions, was positioned under the control of the cauliflower mosaic virus 35S promoter (P35S), transgenic tobacco plants exhibited morphological abnormalities that were not observed in P35S-RirolB plants. In contrast, the activity of the NgrolC gene may have been conserved after an ancient infection by bacteria. Discussed is the effect of the horizontal gene transfer of the Ngrol genes and mutations in the NgrolB gene on the phenotype of ancient plants during the evolution of N. glauca.


The mitochondrial and peroxisomal pathways of fatty acid oxidation in rat liver.
In this brief review a survey is presented of our present knowledge of mitochondrial and peroxisomal fatty acid oxidation. For mitochondrial fatty acid oxidation, emphasis is placed on the key regulatory role of the carnitine acyltransferase system and its modulation by malonyl-Co-A. Also, the concept of opposite regulation of fatty acid synthesis and oxidation in response to nutritional or hormonal stimuli is presented. For peroxisomal fatty acid oxidation, the key features of the system are summarized together with various approaches used to measure the contribution of the peroxisomal pathway to overall fatty acid oxidation. The conclusion is reached that this contribution is minor, at least for the most abundant fatty acids palmitate and oleate.


Generalizability: the trees, the forest, and the low-hanging fruit.
Clinical and epidemiologic investigations are paying increasing attention to the critical constructs of "representativeness" of study samples and "generalizability" of study results. This is a laudable trend and yet, these key concepts are often misconstrued and conflated, masking the central issues of internal and external validity. The authors define these issues and demonstrate how they are related to one another and to generalizability. Providing examples, they identify threats to validity from different forms of bias and confounding. They also lay out relevant practical issues in study design, from sample selection to assessment of exposures, in both clinic-based and population-based settings.


Enhanced tumour uptake of radiolabelled antibodies by hyperthermia: Part I: Timing of injection relative to hyperthermia.
Improving drug and macromolecular delivery of anti-cancer agents to tumours results in greater efficacy without increased toxicity. The current study was undertaken to assess the effects of the timing of injection of tumour specific and non-specific monoclonal antibodies (mAbs) relative to a hyperthermia treatment on tumour and normal tissue uptake. Using a local hyperthermia protocol of 45 min at 43 degrees C, uptake in tumour and normal tissues was measured at 1, 4, 12, 24, 48 and 72 h after injection. An anti-tenascin chimeric mAb, ch81C6, served as the specific mAb in a D-54 MG glioma xenograft mouse model. The chimeric mAb chTPS3.2 served as the control. A five-to-eight-fold increase in uptake of the tumour-targeted mAb was achieved in the heated tumours when compared with the non-heated tumours at 1 h. Differences in absolute tumour uptake of the specific mAb between the mice injected prior to hyperthermia and mice injected post-hyperthermia were seen only at 1 and 12 h. The median uptakes in the tumours of mice injected pre-heat were 25%ID/g at 1 h and 43.5%ID/g at 12 h, while in the animals injected post-hyperthermia the median uptakes were 45.5%ID/g and 80.2%ID/g, respectively. Blood levels of both the specific and non-specific mAbs were consistently higher over the initial 12 h period in the mice injected post-hyperthermia. Normal tissue uptake was also increased at most time points in the mice injected post-hyperthermia. The clinical importance of the differences in specific mAb uptake in tumour detected statistically at 1 and 12 h is questionable, given the highly variable nature of mAb uptake in vivo. Tumour targeting mAbs administered in combination with heat may be injected either prior to or immediately following hyperthermia treatment, with the expectation that levels of uptake in tumour will be relatively equivalent. Absolute normal tissue levels will be higher in patients receiving the mAb post-hyperthermia.


In vitro mutagenesis of trypsinogen: role of the amino terminus in intracellular protein targeting to secretory granules.
The mouse anterior pituitary tumor cell line, AtT-20, targets secretory proteins into two distinct intracellular pathways. When the DNA that encodes trypsinogen is introduced into AtT-20 cells, the protein is sorted into the regulated secretory pathway as efficiently as the endogenous peptide hormone ACTH. In this study we have used double-label immunoelectron microscopy to demonstrate that trypsinogen colocalizes in the same secretory granules as ACTH. In vitro mutagenesis was used to test whether the information for targeting trypsinogen to the secretory granules resides at the amino (NH2) terminus of the protein. Mutations were made in the DNA that encodes trypsinogen, and the mutant proteins were expressed in AtT-20 cells to determine whether intracellular targeting could be altered. Replacing the trypsinogen signal peptide with that of the kappa-immunoglobulin light chain, a constitutively secreted protein, does not alter targeting to the regulated secretory pathway. In addition, deletion of the NH2-terminal "pro" sequence of trypsinogen has virtually no effect on protein targeting. However, this deletion does affect the signal peptidase cleavage site, and as a result the enzymatic activity of the truncated trypsin protein is abolished. We conclude that neither the signal peptide nor the 12 NH2-terminal amino acids of trypsinogen are essential for sorting to the regulated secretory pathway of AtT-20 cells.


Traditional Versus Optimum Power Load Training in Professional Cyclists: A Randomized Controlled Trial.
To compare the effectiveness of optimum power load training (OPT, training with an individualized load and repetitions that maximize power output) and traditional resistance training (TRT, same number of repetitions and relative load for all individuals) in professional cyclists. Participants (19 [1] y, peak oxygen uptake 75.5 [6] mL/kg/min) were randomly assigned to 8 weeks (2 sessions per week) of TRT (n = 11) or OPT (n = 9), during which they maintained their usual cycle training schedule. Training loads were continuously registered, and measures of muscle strength/power (1-repetition maximum and maximum mean propulsive power on the squat, hip thrust, and lunge exercises), body composition (assessed by dual-energy X-ray absorptiometry), and endurance performance (assessed on both an incremental test and an 8-min time trial) were collected before and at the end of the intervention. OPT resulted in a lower average intensity (percentage of 1-repetition maximum) during resistance training sessions for all exercises (P < .01), but no differences were found for overall training loads during resistance or cycling sessions (P > .05). Both programs led to significant improvements in all strength/power-related parameters, muscle mass (with no changes in total body mass but a decreased fat mass), and time-trial performance (all Ps < .05). A trend toward increased power output at the respiratory compensation point was also found (P = .056 and .066 for TRT and OPT, respectively). No between-groups differences were noted for any outcome (P > .05). The addition of either TRT or OPT to an endurance training regimen of elite cyclists results in similar improvements of body composition, muscle strength/power, and endurance performance.


The effects of a calcium antagonist, nimodipine, upon physiological responses of the cerebral vasculature and its possible influence upon focal cerebral ischaemia.
The effects of a calcium antagonist, nimodipine, were tested on the response of the cerebral circulation to arterial pCO2 and blood pressure changes. The effects of reduced blood flow upon oedema formation and extracellular ion homeostasis under nimodipine preloading were studied. Both open and closed skull primate models were used, with alpha-chloralose anaesthesia. Nimodipine infusion increased basal blood flow in the open skull, but not the closed skull animals. Autoregulation to increased blood pressure was little affected. Responses to arterial pCO2 changes and autorerulation to reduced blood pressure were severely imparied. Residual blood flow after middle cerebral artery occlusion was significantly higher with nimodipine than in controls. The threshold levels of blood flow for the development of cortical oedema and for disturbance of ion homeostasis were, however, increased, suggesting that nimodipine interferes with cellular energy metabolism and increases the susceptibility of tissue to ischaemic damage.


Pharmacokinetics of phenylbutazone in camels.
To document disposition variables of phenylbutazone and its metabolite, oxyphenbutazone, in camels (Camelus dromedarius) after single i.v. bolus administration of phenylbutazone, with a view to making recommendation on avoiding violative residues in racing camels. 6 healthy camels (4 males, 2 females), 5 to 7 years old, and weighing from 350 to 450 kg. Blood samples were collected to 0, 5, 10, 15, 45, and 60 minutes and at 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 26, 28, 30, 40, 48, 50, 53, and 60 hours after i.v. administration of 4.5 mg of phenylbutazone per kg of body weight. Urine was obtained in fractions during the entire blood sample collection period. Serum and urine phenylbutazone concentrations were measured by high-performance liquid chromatography; assay sensitivity was 100 ng/ml. Serum oxyphenbutazone concentration was measured by gas chromatography/mass spectrometry; assay sensitivity was 10 ng/ml. Disposition of phenylbutazone was best described by a two-compartment open model. Mean +/- SEM elimination half-life was 13.44 +/- 0.44 hours. Total body clearance was 12.63 +/- 1.64 mg/kg/h. Renal clearance was between 0.3 and 0.4% of total body clearance. The elimination half-life of oxyphenbutazone was 23.9 +/- 2.09 hours. The elimination half-life and total body clearance of phenylbutazone in camels are intermediate between reported values in horses and cattle. Extrapolation of a dosage regimen from either species to camels is, therefore, not appropriate. Elimination of phenylbutazone in camels is mainly via metabolism. Owing to the long half-life of phenylbutazone and of oxyphenbutazone, and to the zero drug concentration regulation adopted by the racing commissioner in the United Arab Emirates, practicing veterinarians would be advised not to use phenylbutazone in camels for at least 7 days prior to racing.


[Surgical tactics in patients with postburn cicatricial esophageal stenosis].
Surgical policy during the first years after burn was aimed at the recovery of natural nutrition. To achieve that, esophageal bougienage (503 cases) or total retrosternal esophagoplasty from the large intestine (192 cases) were performed. The authors hold that in order to attain complete medical rehabilitation for the patients, it is necessary to remove all the cicatricially changed tissues. Esophageal resection was performed in 78 patients, including 27 with preservation of the n. vagus. In the long-term postburn period, a problem arises as to the surgical correction of functional and morphological alterations associated with the establishment of artificial esophagus (80 cases including 35 patients who were operated on by S. S. Yudin). While choosing surgical policy it is necessary to take into account both the technical skills of a surgeon and the whole complex of changes in the patient's body, which have already developed and are going to develop in the future.


Color-selective photocurrent enhancement in coupled J-aggregate/nanowires formed in solution.
J-aggregates are ordered clusters of coherently coupled molecular dyes, (1) and they have been used as light sensitizers in film photography due to their intense absorptions. Hybrid structures containing J-aggregates may also have applications in devices that require spectral specificity, such as color imaging or optical signaling. (2) However the use of J-aggregates in optoelectronic devices has posed a long-standing challenge (3, 4) due to the difficulty of controlling aggregate formation and the low charge carrier mobility of many J-aggregates in solid state. In this paper, we demonstrate a modular method to assemble three different cyanine J-aggregates onto CdSe nanowires, resulting in a photodetector that is color-sensitized in three specific, narrow absorption bands. Both the J-aggregate and nanowire device components are fabricated from solution and the sensitizing wavelength is switched from blue to red to green, using only solution-phase exchange of the J-aggregates on the same underlying device.


Caffeine Intake, Coffee Consumption, and Risk of Cutaneous Malignant Melanoma.
Caffeine has been shown to prevent ultraviolet radiation-induced carcinogenesis and to inhibit growth of melanoma cells in experimental studies. We evaluated the association among caffeine intake, coffee consumption, and melanoma risk among three large cohort studies. The analysis used data from 89,220 women in the Nurses' Health Study II (1991-2009), 74,666 women in the Nurses' Health Study (1980-2008), and 39,424 men in the Health Professionals Follow-up Study (1986-2008). We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CIs) of melanoma associated with dietary intakes. We documented 2,254 melanoma cases over 4 million person-years of follow-up. After adjustment for other risk factors, higher total caffeine intake was associated with a lower risk of melanoma (≥393 mg/day vs. <60 mg/day: HR = 0.78, 95% CI = 0.64, 0.96; Ptrend = 0.048). The association was more apparent in women (≥393 mg/day vs. <60 mg/day: HR = 0.70, 95% CI = 0.58, 0.85; Ptrend = 0.001) than in men (HR = 0.94, 95% CI = 0.75, 1.2; Ptrend = 0.81), and more apparent for melanomas occurring on body sites with higher continuous sun exposure (head, neck, and extremities; ≥393 mg/day vs. <60 mg/day: HR = 0.71, 95% CI = 0.59, 0.86; Ptrend = 0.001) than for melanomas occurring on body sites with lower continuous sun exposure (trunk including shoulder, back, hip, abdomen, and chest; HR = 0.90, 95% CI = 0.70, 1.2; Ptrend = 0.60). This pattern of association was similar to that for caffeinated coffee consumption, whereas no association was found for decaffeinated coffee consumption and melanoma risk. Increasing caffeine intake and caffeinated coffee consumption is associated with decreased risk of cutaneous malignant melanomas.


Effect of microwell chip structure on cell microsphere production of various animal cells.
The formation of three-dimensional cell microspheres such as spheroids, embryoid bodies, and neurospheres has attracted attention as a useful culture technique. In this study, we investigated a technique for effective cell microsphere production by using specially prepared microchip. The basic chip design was a multimicrowell structure in triangular arrangement within a 100-mm(2) region in the center of a polymethylmethacrylate (PMMA) plate (24x24 mm(2)), the surface of which was modified with polyethylene glycol (PEG) to render it nonadhesive to cells. We also designed six similar chips with microwell diameters of 200, 300, 400, 600, 800, and 1000 microm to investigate the effect of the microwell diameter on the cell microsphere diameter. Rat hepatocytes, HepG2 cells, mouse embryonic stem (ES) cells, and mouse neural progenitor/stem (NPS) cells formed hepatocyte spheroids, HepG2 spheroids, embryoid bodies, and neurospheres, respectively, in the microwells within 5 days of culture. For all the cells, a single microsphere was formed in each microwell under all the chip conditions, and such microsphere configurations remained throughout the culture period. Furthermore, the microsphere diameters of each type of cell were strongly positively correlated with the microwell diameters of the chips, suggesting that microsphere diameter can be factitiously controlled by using different chip conditions. Thus, this chip technique is a promising cellular platform for tissue engineering or regenerative medicine research, pharmacological and toxicological studies, and fundamental studies in cell biology.


Alobar holoprosencephaly and Trisomy 13 (Patau syndrome).
Holoprosencephaly (HPE) is a congenital defect of the brain, median structures, and face resulting from an incomplete cleavage of the primitive brain during early embryogenesis. The authors report a case of trisomy 13 syndrome diagnosed at prenatal follow up. The preterm newborn lived only 5 hours, and died because of severe respiratory failure. The autopsy findings disclosed facial, skull, limbs, cardiac, and cerebral malformations. Among the latter, the presence of alobar HPE, the central theme of this report, was evident. The most common nonrandom chromosomal abnormality in patients with HPE is trisomy 13. The most severe variant, namely alobar HPE, is shown in this case report. Discussion on this severe anomaly, along with the case report with details of Patau's syndrome, is the goal of this report.


A preliminary electron backscattered diffraction study of sintered NdFeB-type magnets.
This paper reports, for the first time, the use of electron backscattered diffraction (EBSD) to study orientation in sintered NdFeB type magnets. The magnetic properties of NdFeB magnets are greatly improved if a strong crystallographic texture is firstly achieved, namely, the direction of the c-axis is along the direction of magnetization. A systematic survey of sample preparation techniques showed that samples that were mechanically polished and then etched gave the most reliable EBSD data. Analyses were made using both fully automated EBSD scans and by EBSD measurements taken after manual movement of the beam. The EBSD results are presented as secondary electron SEM micrographs, orientation images and 001 pole figures. For the selection of grains investigated, the deviation of the c-axis was shown to be between 10 degrees and 30 degrees from the ideal [001]//magnetization direction. It is demonstrated that EBSD is a valuable tool for characterizing the microstructure and texture relationships and for assessing the performance of the processing routes of NdFeB magnets.


The turnover rate of rabbit urinary Tamm-Horsfall glycoprotein.
1. The turnover rate of urinary Tamm-Horsfall glycoprotein in rabbits was determined by two different methods. The first involved measurement of the pool size of the glycoprotein in rabbit kidney and the daily urinary excretion rate by a radioimmunoassay from which the turnover rate was calculated. 2. The second method made use of the incorporation in vivo of Na(2) (14)CO(3) and sodium [(14)C]acetate. After a single intramuscular injection of one of these compounds, urine collections were made every 24h and the glycoprotein was isolated and its specific radioactivity was determined. 3. Incorporation of the label into urinary HCO(3) (-), urea and plasma fibrinogen was also examined. The specific radio-activities of the O-acetyl, sialic acid, aspartic acid and glutamic acid residues isolated from the Tamm-Horsfall glycoprotein were compared and their half-lives were compared with that of the intact glycoprotein. The two methods gave results in quite close agreement and indicated a half-life for the glycoprotein of approx. 9h. 4. An attempt was made to localize the glycoprotein within the kidney and within the cell. It is present throughout the kidney, but was not detected in the brush-border fraction isolated from the proximal tubules. From differential cell-centrifugation studies, the glycoprotein seemed to be predominantly present in the soluble fraction (100000g supernatant). This suggests that it is either largely a soluble cytoplasmic component or is very loosely bound to a membrane, being readily released under the gentlest homogenization procedure. 5. The half-life of Tamm-Horsfall glycoprotein in human kidney was found by the radioimmunoassay method to be approx. 16h. The similarity between the composition of Tamm-Horsfall glycoprotein and human erythropoietin is discussed.


Cost-efficiency aspects for fish passage restoration in the Ruhr River Basin.
The protection and sustainable management of the aquatic ecosystems is the central aim of the European Water Framework Directive. Due to the aspiration for good ecological status of the water bodies free fish passage will play an important part in river basin management. The Ruhr River has seen severe anthropogenic modifications due to urbanisation and industrialisation in the 19th and 20th centuries leading in the existence of approx. 1300 weirs within the Ruhr River Basin. The majority of the barriers are assessed as not passable or restricted passable. Against this background the Ruhrverband made a holistic approach towards restoring fish passage within the Ruhr catchment. Besides the scientific and technical aspects, such as the determination of potential (spawning) habitats and the development of measures in order to reach them, they also considered cost-benefit-ratio considerations for the Ruhr catchment as a whole as well as for site-specific designs of fish passage structures. Various benefits were evaluated taking into account different fields of economic interest. The model of financing all necessary measures should involve all responsible parties benefiting from the water utilizations. Such a mutual procedure delivers a fair cost distribution as well as an efficient implementation of measures.


Cost-Effectiveness of Once-Daily Single-Inhaler COPD Triple Therapy in Spain: IMPACT Trial.
Given between-country differences in healthcare systems, treatment costs, and disease management guidelines, country-specific cost-effectiveness analyses are important. This study evaluated the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI among patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations from a Spanish healthcare system perspective. Baseline data and treatment effects from the IMPACT trial were populated into the validated GALAXY COPD progression model. Utilities were estimated using Spanish observational data. Direct healthcare costs (2019 €) were informed by Spanish public sources. A 3% discount rate for costs and benefits was applied. The time horizon and treatment duration were 3 years (base case). One-way sensitivity, scenario, and probabilistic sensitivity analyses were performed. FF/UMEC/VI treatment resulted in fewer exacerbations over 3 years (4.130 vs 3.648) versus FF/VI, with a mean (95% confidence interval [CI]) incremental cost of €444 (€149, €713) per patient and benefit of 0.064 (0.053, 0.076) quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of €6887 per QALY gained. FF/UMEC/VI was a dominant treatment strategy versus UMEC/VI, resulting in fewer exacerbations (4.130 vs 3.360), with a mean (95% CI) incremental cost of -€450 (-€844, -€149) and benefit of 0.054 (0.043, 0.064) QALYs. FF/UMEC/VI was cost-effective versus FF/VI and UMEC/VI across all analyses. FF/UMEC/VI was predicted to be a cost-effective treatment option versus FF/VI or UMEC/VI in symptomatic COPD patients at risk of exacerbations in Spain, across all scenarios and sensitivity analyses.


Does daughter deficit promote paternal substance use? Evidence from China.
China and various other countries have experienced unbalanced sex ratios in the marriage market, which triggers intense competition and pressure to get married. Meanwhile, China has more smokers and drinkers than any other countries in the world. This paper provides evidence on smoking and alcohol use as a stress coping strategy for the competitive marriage market. This paper utilizes two household longitudinal datasets from rural China-a national survey and a regional survey-to examine paternal substance use in response to skewed sex ratios of their children's generation. The longitudinal feature of the two datasets enables us to explore within household variation in smoking and alcohol use. Sex ratios are matched using a 1% sample of the 2000 China Population Census. Strikingly, paternal smoking and alcohol use are more intense for families with a son living in communities with higher sex ratios. In contrast, those with a daughter do not demonstrate this pattern. Coping with the marriage market pressure is a plausible pathway linking the observed skewed sex ratios and intense substance use. High male-to-female sex ratios promote smoking and alcohol drinking among fathers with sons. Considering the highly competitive marriage market in the coming decade and the prevalent substance use that generates lasting health impacts and large negative externalities to society, policies that address the skewed sex ratios could lead to substantial welfare gains.


Homoeostasis between the GTPase Spg1p and its GAP in the regulation of cytokinesis in S. pombe.
Cytokinesis in Schizosaccharomyces pombe begins at mitotic entry, when the site of division is defined by formation of the contractile acto-myosin ring (CAR) at the cell cortex. Contraction of the CAR and formation of the division septum are triggered at the end of mitosis by septation initiation network (SIN) proteins associated with the spindle pole body (SPB). SIN signalling requires activation of the GTPase Spg1p, which is regulated by the bipartite GTPase-activating protein (GAP) Byr4p-Cdc16p. We show that, for Spg1p to associate with the SPB, it must be bound to its GAP or to its mitotic effector, the protein kinase Cdc7p. Analysis of the GAP proteins reveals that the steady-state level of Byr4p reflects that of Spg1p. Furthermore, if the interaction of Byr4p with Spg1p is compromised, the level of Byr4p decreases dramatically. The adaptation of the level of Byr4p to that of Spg1p requires the presence of Cdc16p and is mediated by proteasome-dependent destruction. It requires neither association with the SPB nor an active SIN. We propose a mechanism that limits the amount of the Byr4p-Cdc16p GAP to the amount required to inhibit Spg1p signalling.


Study of changes in lipid profile and insulin resistance in Egyptian patients with chronic hepatitis C genotype 4 in the era of DAAs.
Chronic hepatitis C virus (HCV) infection is associated with altered metabolism, including dyslipidemia and insulin resistance. These contribute to disease progression and influences the response to therapy. To investigate the relationships of new direct-acting antiviral drugs, simeprevir/sofosbuvir, with lipid profile and insulin resistance (IR). Eighty chronic hepatitis C genotype 4 patients were included; they were divided into four groups according to the severity of fibrosis as detected by fibroscan. Forty healthy persons volunteered as a control group. Lipid profile changes and IR were analyzed at baseline and after the end of treatment, and any effect of these changes on the response to treatment was studied. Before treatment, the levels of serum triglycerides were significantly higher in patients than in the control, and the levels of fasting insulin showed a progressive increase with advancing stage of fibrosis. At the end of treatment, there were a significant reduction in serum triglycerides, FBS, fasting insulin, and homeostasis model for the assessment of IR (P < 0.001), and a significant elevation of serum cholesterol and low-density lipoprotein (LDL)-c, high-density lipoprotein (HDL)-c, and LDL/HDL ratio (P = 0.001). An end-of-treatment response (week 12) was achieved in (99%) of the treated cases with 99% sustained viral response for 12 weeks post-treatment (week 24). Significant lipid profile changes were detected at the end of treatment. Serum lipid levels and IR are no longer predictors of response to DAAs. Follow-up of the lipid profile is warranted to avoid any possible remote effect of atherosclerotic heart disease.


Neurosystems: brain rhythms and cognitive processing.
Neuronal rhythms are ubiquitous features of brain dynamics, and are highly correlated with cognitive processing. However, the relationship between the physiological mechanisms producing these rhythms and the functions associated with the rhythms remains mysterious. This article investigates the contributions of rhythms to basic cognitive computations (such as filtering signals by coherence and/or frequency) and to major cognitive functions (such as attention and multi-modal coordination). We offer support to the premise that the physiology underlying brain rhythms plays an essential role in how these rhythms facilitate some cognitive operations.


Bayesian networks for clinical decision support in lung cancer care.
Survival prediction and treatment selection in lung cancer care are characterised by high levels of uncertainty. Bayesian Networks (BNs), which naturally reason with uncertain domain knowledge, can be applied to aid lung cancer experts by providing personalised survival estimates and treatment selection recommendations. Based on the English Lung Cancer Database (LUCADA), we evaluate the feasibility of BNs for these two tasks, while comparing the performances of various causal discovery approaches to uncover the most feasible network structure from expert knowledge and data. We show first that the BN structure elicited from clinicians achieves a disappointing area under the ROC curve of 0.75 (± 0.03), whereas a structure learned by the CAMML hybrid causal discovery algorithm, which adheres with the temporal restrictions, achieves 0.81 (± 0.03). Second, our causal intervention results reveal that BN treatment recommendations, based on prescribing the treatment plan that maximises survival, can only predict the recorded treatment plan 29% of the time. However, this percentage rises to 76% when partial matches are included.


The Formation of Symmetrical Gestalts Is Task-Independent, but Can Be Enhanced by Active Regularity Discrimination.
The brain can organize elements into perceptually meaningful gestalts. Visual symmetry is a useful tool to study gestalt formation, and we know that there are symmetry-sensitive regions in the extrastriate cortex. However, it is unclear whether symmetrical gestalt formation happens automatically, whatever the participant's current task is. Does the visual brain always organize and interpret the retinal image when possible, or only when necessary? To test this, we recorded an ERP called the sustained posterior negativity (SPN). SPN amplitude increases with the proportion of symmetry in symmetry + noise displays. We compared the SPN across five tasks with different cognitive and perceptual demands. Contrary to our predictions, the SPN was the same across four of the five tasks but selectively enhanced during active regularity discrimination. Furthermore, during regularity discrimination, the SPN was present on hit trials and false alarm trials but absent on miss and correct rejection trials. We conclude that gestalt formation is automatic and task-independent, although it occasionally fails on miss trials. However, it can be enhanced by attention to visual regularity.


Mining Data From Plasma Cell Differentiation Identified Novel Genes for Engineering of a Yeast Antibody Factory.
Saccharomyces cerevisiae is a common platform for production of therapeutic proteins, but it is not intrinsically suited for the manufacturing of antibodies. Antibodies are naturally produced by plasma cells (PCs) and studies conducted on PC differentiation provide a comprehensive blueprint for the cellular transformations needed to create an antibody factory. In this study we mined transcriptomics data from PC differentiation to improve antibody secretion by S. cerevisiae. Through data exploration, we identified several new target genes. We tested the effects of 14 genetic modifications belonging to different cellular processes on protein production. Four of the tested genes resulted in improved antibody expression. The ER stress sensor IRE1 increased the final titer by 1.8-fold and smaller effects were observed with PSA1, GOT1, and HUT1 increasing antibody titers by 1. 6-, 1. 4-, and 1.4-fold. When testing combinations of these genes, the highest increases were observed when co-expressing IRE1 with PSA1, or IRE1 with PSA1 and HUT1, resulting in 3.8- and 3.1-fold higher antibody titers. In contrast, strains expressing IRE1 alone or in combination with the other genes produced similar or lower levels of recombinantly expressed endogenous yeast acid phosphatase compared to the controls. Using a genetic UPR responsive GFP reporter construct, we show that IRE1 acts through constitutive activation of the unfolded protein response. Moreover, the positive effect of IRE1 expression was transferable to other antibody molecules. We demonstrate how data exploration from an evolutionary distant, but highly specialized cell type can pinpoint new genetic targets and provide a novel concept for rationalized cell engineering.


Establishing Standards on Colors from Natural Sources.
Color additives are applied to many food, drug, and cosmetic products. With up to 85% of consumer buying decisions potentially influenced by color, appropriate application of color additives and their safety is critical. Color additives are defined by the U.S. Federal Food, Drug, and Cosmetic Act (FD&C Act) as any dye, pigment, or substance that can impart color to a food, drug, or cosmetic or to the human body. Under current U.S. Food and Drug Administration (FDA) regulations, colors fall into 2 categories as those subject to an FDA certification process and those that are exempt from certification often referred to as "natural" colors by consumers because they are sourced from plants, minerals, and animals. Certified colors have been used for decades in food and beverage products, but consumer interest in natural colors is leading market applications. However, the popularity of natural colors has also opened a door for both unintentional and intentional economic adulteration. Whereas FDA certifications for synthetic dyes and lakes involve strict quality control, natural colors are not evaluated by the FDA and often lack clear definitions and industry accepted quality and safety specifications. A significant risk of adulteration of natural colors exists, ranging from simple misbranding or misuse of the term "natural" on a product label to potentially serious cases of physical, chemical, and/or microbial contamination from raw material sources, improper processing methods, or intentional postproduction adulteration. Consistent industry-wide safety standards are needed to address the manufacturing, processing, application, and international trade of colors from natural sources to ensure quality and safety throughout the supply chain.


Ultrastructure of eosinophils and basophils stimulated to develop in human cord blood mononuclear cell cultures containing recombinant human interleukin-5 or interleukin-3.
We used recombinant human interleukins (IL) and cultured human cord mononuclear cells to determine the cell lineages supported by the inclusion of the individual interleukins-5, -3, or -4 in the cultured media. Cultures were examined by electron microscopy at 2-, 3-, and 5-week culture intervals. We found that IL-5 primarily supported the eosinophilic lineage with lesser numbers of basophils, that IL-3 initially supported all granulocyte lineages but eventually supported the eosinophilic lineage with lesser numbers of basophils, and that IL-4 did not support the development of granulocyte lineages in these cultures. At early culture intervals in either IL-5 or IL-3, eosinophilic and basophilic myelocytes were seen in variable proportions. Mature cells of these lineages developed later. Both mature eosinophils and basophils showed morphologic evidence of activation similar to those described for tissue eosinophils and basophils in various disorders. Mast cells were absent in all cultures. Recognition of the variable morphologies associated with maturation and activation of human eosinophils and basophils is important for the correct identification of cell lineages that develop in cultures containing human recombinant interleukins.


[From diagnosis to symptoms].
The diagnosis of anorexia nervosa is one of the easiest to make in that it is a positive diagnosis, not a differential diagnosis. It is defined by a few criteria which together become almost pathognomonic: excessive restriction of energy intake combined with an irrational fear of weight and an altered body image. Even if weight is at the heart of the medical team's concerns, it is important to question the pathology in its history, in order to put it in to context, and sometimes to understand the para-logic and its function in the patient's life history. It is necessary to work on emotions and cognitions in addition to behaviour.


A dual-responsive colorimetric probe for the detection of Cu2+ and Ni2+ species in real water samples and human serum.
The monitoring of heavy transition metals has increasingly attracted great attention because they pollute the environment and have unique physiological functions. Chemosensors are useful tools for monitoring heavy transition metals due to their simple visualization, excellent sensitivity and high selectivity. Herein, we have developed a novel chemosensor for the detection of water-soluble Cu2+ and Ni2+ species with different mechanisms, and low detection limits of 2.1 nM for Cu2+ and 1.2 nM for Ni2+ were obtained. The colorimetric probe CPH has been applied to qualitative and quantitative detection of Cu2+ and Ni2+ species in real samples.


Characterization and propagation of tumor initiating cells derived from colorectal liver metastases: trials, tribulations and a cautionary note.
Tumor initiating cells (TIC) are increasingly being put forward as a potential target for intervention within colorectal cancer. Whilst characterisation and outgrowth of these cells has been extensively undertaken in primary colorectal cancers, few data are available describing characteristics within the metastatic setting. Tissue was obtained from patients undergoing surgical resection for colorectal liver metastases, and processed into single cell suspension for assessment. Tumor initiating cells from liver metastases were characterised using combinations of EPCAM, Aldehyde dehydrogenase activity, CD133 and CD26. CD133 expression was significantly lower in patients who had received chemotherapy, but this was accounted for by a decrease observed in the male patient cohort only. ALDHhigh populations were rare (0.4 and 0.3% for EPCAM+/ALDHhigh/CD133- and EPCAM+/ALDHhigh/CD133+ populations respectively) and below the limits of detection in 28% of samples. Spheroid outgrowth of metastatic tumor cells across all samples could not be readily achieved using standard spheroid-formation techniques, thus requiring further method validation to reliably propagate cells from the majority of tissues. Spheroid formation was not enhanced using additional growth factors or fibroblast co-culture, but once cells were passaged through NOD-SCID mice, spheroid formation was observed in 82% samples, accompanied by a significant increase in CD26. Order of spheroid forming ability was ALDHhigh>CD133>CD26. Samples sorted by these markers each had the ability to reform ALDHhigh, CD133 and CD26 positive populations to a similar extent, suggestive of a high degree of plasticity for each population. Ex vivo TIC models are increasingly being utilised to assess efficacy of therapeutic interventions. It is therefore essential that such investigations use well-characterised models that are able to sustain TIC populations across a large patient cohort in order that the inherent heterogeneity observed in cancer populations is maintained.


[Incremental cost effectiveness of multifocal cataract surgery].
Supplementation of cataract patients with multifocal intraocular lenses involves an additional financial investment when compared to the corresponding monofocal supplementation, which usually is not funded by German health care insurers. In the context of recent resource allocation discussions, however, the cost effectiveness of multifocal cataract surgery could become an important rationale. Therefore an evidence-based estimation of its cost effectiveness was carried out. Three independent meta-analyses were implemented to estimate the gain in uncorrected near visual acuity and best corrected visual acuity (vision lines) as well as the predictability (fraction of patients without need for reading aids) of multifocal supplementation. Study reports published between 1995 and 2004 (English or German language) were screened for appropriate key words. Meta effects in visual gain and predictability were estimated by means and standard deviations of the reported effect measures. Cost data were estimated by German DRG rates and individual lens costs; the cost effectiveness of multifocal cataract surgery was then computed in terms of its marginal cost effectiveness ratio (MCER) for each clinical benefit endpoint; the incremental costs of multifocal versus monofocal cataract surgery were further estimated by means of their respective incremental cost effectiveness ratio (ICER). An independent meta-analysis estimated the complication profiles to be expected after monofocal and multifocal cataract surgery in order to evaluate expectable complication-associated additional costs of both procedures; the marginal and incremental cost effectiveness estimates were adjusted accordingly. A sensitivity analysis comprised cost variations of +/- 10 % and utility variations alongside the meta effect estimate's 95 % confidence intervals. Total direct costs from the health care insurer's perspective were estimated 3363 euro, associated with a visual meta benefit in best corrected visual acuity and near visual acuity of 5.1 lines (95 % confidence interval 3.8 - 6.4 lines) and 6.1 lines (4.7 - 7.5 lines), respectively, and a meta predictability estimate of 81 % (72 - 89 %). The mean MCER for best corrected visual acuity results became 659 euro per gained visual acuity line (sensitivity range 473 - 973 euro). For near visual acuity, a mean MCER of 555 euro (sensitivity range 404 - 787 euro) per gained visual line was found. In terms of incremental costs, multifocal cataract surgery implied an additional mean investment of 63 euro (sensitivity range 0 - 234 euro) per additionally gained near visual acuity line, and 5 euro (0 - 18 euro) per additionally gained percentage point in predictability, when compared to monofocal cataract surgery as the standard treatment. The meta-analysis on complication profiles revealed posterior capsule opacification (meta incidence 20 %) and vitreous loss (meta incidence 2 %) as the complications to be expected most frequently. The cost adjustment for expectable complication patterns after multifocal cataract surgery implied total direct costs of 3491 euro, resulting in marginal costs of 576 euro per line (sensitivity range 419 - 817 euro per line) gained in near visual acuity and 684 euro per line (491 - 1011 euro per line) gained in best corrected visual acuity. Bearing incremental costs of 63 euro per additionally gained vision line (near visual acuity) in mind, multifocal cataract surgery comprises a cost effective alternative to the monofocal standard treatment.


Role of ATP-hydrolysis in the dynamics of a single actin filament.
We study the stochastic dynamics of growth and shrinkage of single actin filaments taking into account insertion, removal, and ATP hydrolysis of subunits either according to the vectorial mechanism or to the random mechanism. In a previous work, we developed a model for a single actin or microtubule filament where hydrolysis occurred according to the vectorial mechanism: the filament could grow only from one end, and was in contact with a reservoir of monomers. Here we extend this approach in two ways--by including the dynamics of both ends and by comparing two possible mechanisms of ATP hydrolysis. Our emphasis is mainly on two possible limiting models for the mechanism of hydrolysis within a single filament, namely the vectorial or the random model. We propose a set of experiments to test the nature of the precise mechanism of hydrolysis within actin filaments.


[Studies on estramustine-binding protein in the human prostate].
In the present study, size exclusion HPLC was used to analyse the properties of Estramustine-binding protein (EMBP) in the cytosol of human benign prostatic hypertrophy (BPH). The typical size exclusion HPLC separation profile of 3H-Estramustine-labelled cytosol of BPH showed four radioactive peaks that corresponded to the V0, 250K, 68K and 45K protein regions. The specific binding protein for Estramustine is contained mainly in the 250K protein region and in part in the V0 region. In the presence of sodium molybdate, the specific Estramustine binding to a 250K protein was increased to a level which was about 2.5 times as much as the value in the absence of sodium molybdate. The specific Estramustine binding to a 250K protein under the condition of no DCC treatment and the addition of sodium molybdate was 600% of the value obtained under the condition of DCC treatment and no addition of sodium molybdate. These results suggested that sodium molybdate stabilized the specific Estramustine-binding activity to a 250K protein and that specific Estramustine binding to a 250K protein seemed to be weaker than the binding of androgen to androgen receptor.


Gongs galore: phaleristic study of the relative risk of a healing art related New Year Honour.
To compare proportional representation of healthcare specialty workers, in receipt of New Year Honours (NYHs) and examine system bias. Observational study of UK honours system including comparative analysis of proportional representation of the UK medical workforce. Recipients of NYHs from 2010 to 2019. Absolute risk of receiving an NYH, related to medical specialty, gender and geographical region. Relative risk (RR) of receiving an NYH for services to healthcare related to specialty. 11 207 NYHs were bestowed, with 368 (3.3%) awarded to healthcare professionals: 212 (57.6%) women, 156 (42.4%) men. The RR of a healthcare professional receiving an NYH was 0.76 (95% CI 0.68 to 0.84, p<0.001) when compared with the remaining UK workforce. Doctors received most NYHs (n=181), with public health, clinical oncology and general medicine specialties most likely to be rewarded (RR 20.35 (95% CI 9.61 to 43.08, p<0.001), 8.43 (95% CI 2.70 to 26.30, p<0.001) and 8.22 (95% CI 6.22 to 10.86, p<0.001)), respectively; anaesthetists received fewest NYHs (RR 0.52 (95% CI 0.13 to 2.10), p=0.305). Men were more likely to receive NYHs than women (OR 0.44, 95% CI 0.36 to 0.54; p<0.001). Two hundred and fifty-four NYHs (69.0%) were bestowed on residents of England (60, 16.3% London), 49 (13.3%) Scotland (p=0.003), 39 (10.6%) Wales (p<0.001) and 26 (7.1%) Northern-Ireland (p<0.001). Relative risk of receiving an NYH varied over 150-fold by specialty, twofold by gender and threefold by geographical location. Public health physicians are perceived to be the pick of the parade.


Three-Dimensional Printed Models for Lateral Skull Base Surgical Training: Anatomy and Simulation of the Transtemporal Approaches.
Three-dimensional (3D) printing holds great potential for lateral skull base surgical training; however, studies evaluating the use of 3D-printed models for simulating transtemporal approaches are lacking. To develop and evaluate a 3D-printed model that accurately represents the anatomic relationships, surgical corridor, and surgical working angles achieved with increasingly aggressive temporal bone resection in lateral skull base approaches. Cadaveric temporal bones underwent thin-slice computerized tomography, and key anatomic landmarks were segmented using 3D imaging software. Corresponding 3D-printed temporal bone models were created, and 4 stages of increasingly aggressive transtemporal approaches were performed (40 total approaches). The surgical exposure and working corridor were analyzed quantitatively, and measures of face validity, content validity, and construct validity in a cohort of 14 participants were assessed. Stereotactic measurements of the surgical angle of approach to the mid-clivus, residual bone angle, and 3D-scanned infill volume demonstrated comparable changes in both the 3D temporal bone models and cadaveric specimens based on the increasing stages of transtemporal approaches (PANOVA <.003, <.007, and <.007, respectively), indicating accurate representation of the surgical corridor and working angles in the 3D-printed models. Participant assessment revealed high face validity, content validity, and construct validity. The 3D-printed temporal bone models highlighting key anatomic structures accurately simulated 4 sequential stages of transtemporal approaches with high face validity, content validity, and construct validity. This strategy may provide a useful educational resource for temporal bone anatomy and training in lateral skull base approaches.


Migraine associated with menstruation.
Many women report increased frequency of migraine in association with menstruation. The term 'menstrual' migraine is often used despite lack of an agreed definition. The International Headache Society has classified most headaches but not 'menstrual' migraine. A proposed definition is based on the finding that the prevalence of migraine increases on day 1 +/- 2 of the menstrual cycle. Attacks occurring at this time of the cycle are typically without aura. Effective acute therapy is the mainstay of management for menstrual and non-menstrual attacks although there is some evidence that attacks linked to menstruation are less responsive to treatment compared with migraine at other times of the cycle. If several attacks occur throughout the cycle, standard prophylactic agents should be used. Women with exclusive 'menstrual' migraine may benefit from perimenstrual prophylaxis but this should only be instigated once the association between migraine and menstruation has been confirmed with prospective records kept for a minimum of three cycles. NSAIDs are the treatment of choice in reducing migraine associated with menorrhagia and/or dysmenorrhoea, otherwise perimenstrual oestrogen supplements using percutaneous or transdermal oestrogens are recommended. Combined oral contraceptives are useful for women requiring contraception although there is a tendency for attacks to occur during the pill-free interval. If these are contraindicated, depot progestogen is an alternative as it also inhibits ovulation and can improve migraine, provided amenorrhoea is achieved. Oral progestogen-only contraception has little place in the management of 'menstrual' migraine as it does not inhibit ovulation and is often associated with a disrupted menstrual cycle. Some women consulting with menstrual migraine are menopausal and may be considering hormone replacement therapy. Studies suggest that non-oral routes of delivery of oestrogen, which provide stable levels, are more likely to improve migraine than oral oestrogens, which produce variable day-to-day levels. Too low a dose of oestrogen is ineffective at controlling symptoms but too high a dose, particularly if coupled with surges of endogenous oestrogen, can trigger migraine aura. Once the route and dose has been optimised, continuous oestrogens can control migraine as well as menopausal symptoms. Additional progestogen, necessary for unhysterectomised women, can exacerbate migraine. To minimise this, progesterone derivatives or non-oral routes of delivery are recommended, with continuous regimens used where possible.


Predictors of physical activity 6 months postintervention in the active for life initiative.
Understanding who is most and least likely to remain active after the completion of physical activity (PA) interventions can assist in developing more targeted and effective programs to enhance prolonged behavior change. The purpose of this study was to examine predictors of meeting PA recommendations 6 months postintervention in participants enrolled in Active for Life. Participants from 2 behavioral PA programs [158 Active Choices (AC); 1025 Active Living Every Day (ALED)] completed surveys 6 months after completion of the active intervention. Analyses examined predictors of meeting PA recommendations at follow-up. The following were significant predictors: In ALED: self-report health status, satisfaction with body function, and self-efficacy at baseline; PA status at posttest; changes in self-efficacy, perceived stress, and satisfaction with body function and appearance from baseline to posttest. In AC: PA status at post-test. The ultimate goal of health promotion programs is to teach the behavioral skills necessary to sustain behavior change once an active intervention is complete. The findings from this study suggest that predicting PA behavior after cessation of PA interventions may not be straightforward, and predictor variables may operate differently in different intervention approaches.


Prostate-specific antigen (PSA) screening and follow-up investigations in Māori and non-Māori men in New Zealand.
Māori men in New Zealand have higher mortality from prostate cancer, despite having lower incidence rates. The objective of this study was to examine patterns of screening for prostate cancer in primary care and follow-up investigations after an elevated prostate-specific antigen (PSA) result in Māori and non-Māori men in order to help explain the observed differences in incidence and mortality. Men aged 40+ years were identified from 31 general practices across the Midland Cancer Network region. Computerised practice records were cross-referenced with laboratory data to determine the number and value of PSA tests undertaken between January 2007 and December 2010. Screening rates were calculated for the year 2010 by age, ethnicity, and practice. For men with an elevated PSA result information on specialist referrals and biopsy was extracted from practice records. Practice characteristics were assessed with respect to screening rates for Māori and non-Māori men. The final study population included 34,960 men aged 40+ years; 14% were Māori. Māori men were less likely to be screened in 2010 compared with non-Māori men (Mantel Haenszel (M-H) age-adjusted risk ratio (RR), 0.52 [95% CI, 0.48, 0.56]). When screened, Māori men were more than twice as likely to have an elevated PSA result compared with non-Māori men (M-H age-adjusted RR, 2.16 [95% CI, 1.42, 3.31]). There were no significant differences between Māori and non-Māori men in the rate of follow-up investigations and cancer detection. Māori provider practices showed equal screening rates for Māori and non-Māori men, but they were also the practices with the lowest overall screening rates. Māori men were half as likely to be screened compared to non-Māori men. This probably explains the lower reported incidence of prostate cancer for Māori men. Practice characteristics had a major influence on screening rates. Large variation in screening behaviour among practices and differences in follow-up investigations for men with an elevated PSA result seems to reflect the uncertainty among GPs regarding PSA screening and management.


Antioxidant requirements of endurance athletes: implications for health.
This review discusses studies investigating the effects of antioxidant supplementation on exercise-induced oxidative stress with a focus on the health implications. The aim is to determine antioxidant requirements for endurance athletes. Overall, differences in methodology make it difficult to compare the relatively small number of published studies on this topic. The types of studies needed to more adequately assess the health effects of antioxidant supplements in athletes (long-term interventions with hard end points) have not been done. Therefore, there is currently insufficient evidence to recommend antioxidant supplements for endurance athletes.


Nonparaxial propagation properties of a vector partially coherent dark hollow beam.
Based on the generalized Raleigh-Sommerfeld diffraction integrals, analytical nonparaxial propagation formulas for the elements of the cross-spectral density matrix of a vector partially coherent dark hollow beam (DHB) in free space are derived. The effect of spatial coherence and beam waist sizes on the statistical properties of a nonparaxial vector DHB is studied numerically. It is found that one can modulate the statistical properties of a nonparaxial vector DHB by varying its initial spatial coherence, which will be useful in some applications where nonparaxial beams are commonly encountered.


The growth of turkeys 1. Growth of the body and feathers and the chemical composition of growth.
1. The potential growth of modern turkey genotypes was measured using male and female BUT 6 (BUT) and Hybrid Converter (HYB) strains. At one-day-old, 720 male and 960 female poults were randomly allocated to 48 littered pens in two houses with 30 males or 40 females of each strain per pen. Five feeds of decreasing protein content were fed to both sexes during the growing period. 2. Birds were weighed at 1, 7, 14, 21, 35, 56, 77, 119 d (males only), 126 d (females only) and 140 d (males only) and, on each occasion, six birds were selected and removed for carcass analysis. 3. Growth was similar in both strains, but the growth rate of females appeared to decline relative to the earlier trajectory after 70 d, and this tendency being greater in HYB females. 4. HYB birds of both sexes had more feathers than BUT to 77 d, but thereafter these differences were non-significant. A single allometry between feather and body protein weight was observed over all genotypes with no differences apparent between sexes within strains. The Gompertz curve adequately described the growth of body protein, water and ash. 5. Body lipid (g/100g bodyweight) declined in the early stages of growth. This might reflect an energy deficiency in the diet or might indicate that the present description of lipid growth does not apply in turkeys as it does in other species. 6. Whereas the description of body growth, feather growth and the chemical components of growth given in this paper may not fully reflect the true potential of the genotypes used, nevertheless they provide useful information regarding the latest genotypes available in the turkey industry. Some of the observations suggested that current performance might be improved if further research is conducted regarding dietary energy transactions.


Peritoneal inflammation in pigs is associated with early mitochondrial dysfunction in liver and kidney.
The objective of this study was to investigate early effects of peritoneal inflammation on the mitochondrial function in the vital organs, liver and kidney, and their relation to inflammatory and oxidative stress mediators. The study was performed on 14 domestic pigs. Peritoneal inflammation was induced in anesthetized pigs after a midline laparotomy by autologous feces. Fluid resuscitation maintained a MAP above 60 mmHg. Animals were sacrificed 12 h later, and tissue samples were obtained to determine mitochondrial function, mRNA levels of relevant genes [inducible NO synthase (iNOS), inducible HO (HO-1), tumor necrosis factor-alpha (TNF-alpha)], generation of reactive oxygen species (ROS), and HO-1 activity. We found impaired mitochondrial function in both liver and kidney, based on decreased state 3 respiration in the liver and increased states 2 and 4 respiration in the kidney at 12 h. This was accompanied by increased TNF-alpha protein in the blood and up-regulation of TNF-alpha mRNA in the liver. Free iron was elevated in the liver but not in the kidney. In the kidney, mitochondrial ROS production was increased. Nitric oxide levels in blood remained unchanged, corresponding to unchanged levels of iNOS mRNA expression in liver and kidney. Similarly, HO-1 mRNA and heme oxygenase (HO)-activity were unchanged. The inflammatory response in the absence of characteristic septic symptoms was not associated with morphological organ damage at this early time point. Peritoneal inflammation in pigs caused mitochondrial dysfunction in liver and kidney, preceding signs of organ damage. We did not find proof that mitochondrial dysfunction was due to increased levels of either nitric oxide (NO) or products of HO, but it was accompanied by increased levels of oxidative stress markers.


Growth of tetrahedral silver nanocrystals in aqueous solution and their SERS enhancement.
Silver nanocrystals with tetrahedral shapes and {111} faces have been synthesized by the light-driven growth method in an aqueous solution. The nanocrystals of T(d) symmetry were formed under the effect of tartrate and citrate as the structural-directing reagents at the appropriate stages of reaction. Further, the nanocrystals may be assembled through electrostatic interaction to develop large-scale particle surfaces with sharp vertexes, which can generate strong localized electromagnetic field for surface-enhanced Raman scattering (SERS) studies. Benzenethiol was used as the probe to evaluate their SERS enhancement, and enhancement factors of up to 10(6) are reached. As a kind of promising material, these novel nanocrystals will be applied in surface enhanced spectroscopy and plasmonics field.


High- and Low-Performing Adult Cochlear Implant Users on High-Variability Sentence Recognition: Differences in Auditory Spectral Resolution and Neurocognitive Functioning.
Postlingually deafened adult cochlear implant (CI) users routinely display large individual differences in the ability to recognize and understand speech, especially in adverse listening conditions. Although individual differences have been linked to several sensory (''bottom-up'') and cognitive (''top-down'') factors, little is currently known about the relative contributions of these factors in high- and low-performing CI users. The aim of the study was to investigate differences in sensory functioning and neurocognitive functioning between high- and low-performing CI users on the Perceptually Robust English Sentence Test Open-set (PRESTO), a high-variability sentence recognition test containing sentence materials produced by multiple male and female talkers with diverse regional accents. CI users with accuracy scores in the upper (HiPRESTO) or lower quartiles (LoPRESTO) on PRESTO in quiet completed a battery of behavioral tasks designed to assess spectral resolution and neurocognitive functioning. Twenty-one postlingually deafened adult CI users, with 11 HiPRESTO and 10 LoPRESTO participants. A discriminant analysis was carried out to determine the extent to which measures of spectral resolution and neurocognitive functioning discriminate HiPRESTO and LoPRESTO CI users. Auditory spectral resolution was measured using the Spectral-Temporally Modulated Ripple Test (SMRT). Neurocognitive functioning was assessed with visual measures of working memory (digit span), inhibitory control (Stroop), speed of lexical/phonological access (Test of Word Reading Efficiency), and nonverbal reasoning (Raven's Progressive Matrices). HiPRESTO and LoPRESTO CI users were discriminated primarily by performance on the SMRT and secondarily by the Raven's test. No other neurocognitive measures contributed substantially to the discriminant function. High- and low-performing CI users differed by spectral resolution and, to a lesser extent, nonverbal reasoning. These findings suggest that the extreme groups are determined by global factors of richness of sensory information and domain-general, nonverbal intelligence, rather than specific neurocognitive processing operations related to speech perception and spoken word recognition. Thus, although both bottom-up and top-down information contribute to speech recognition performance, low-performing CI users may not be sufficiently able to rely on neurocognitive skills specific to speech recognition to enhance processing of spectrally degraded input in adverse conditions involving high talker variability.


Autophagy and Human Neurodegenerative Diseases-A Fly's Perspective.
Neurodegenerative diseases in humans are frequently associated with prominent accumulation of toxic protein inclusions and defective organelles. Autophagy is a process of bulk lysosomal degradation that eliminates these harmful substances and maintains the subcellular environmental quality. In support of autophagy's importance in neuronal homeostasis, several genetic mutations that interfere with autophagic processes were found to be associated with familial neurodegenerative disorders. In addition, genetic mutations in autophagy-regulating genes provoked neurodegenerative phenotypes in animal models. The Drosophila model significantly contributed to these recent developments, which led to the theory that autophagy dysregulation is one of the major underlying causes of human neurodegenerative disorders. In the current review, we discuss how studies using Drosophila enhanced our understanding of the relationship between autophagy and neurodegenerative processes.


Telomeres and telomerase in lung cancer.
Protected telomeres ensure normal chromosomal segregation during mitosis but at the same time can endow genetically abnormal cancer cells with immortality. Telomerase has a pivotal role in telomere protection, both in normal and cancer cells. Understanding the functional interplay between telomere shortening and telomerase expression in cancer cells is of critical importance to elucidating the precise mechanisms by which these cells are able to bypass telomere crisis and become immortal.


DNA repair protein O6-alkylguanine-DNA alkyltransferase is phosphorylated by two distinct and novel protein kinases in human brain tumour cells.
We showed recently that human O(6)-alkylguanine-DNA alkyltransferase (AGT), an important target for improving cancer chemotherapy, is a phosphoprotein and that phosphorylation inhibits its activity [Srivenugopal, Mullapudi, Shou, Hazra and Ali-Osman (2000) Cancer Res. 60, 282-287]. In the present study we characterized the cellular kinases that phosphorylate AGT in the human medulloblastoma cell line HBT228. Crude cell extracts used Mg(2+) more efficiently than Mn(2+) for phosphorylating human recombinant AGT (rAGT) protein. Both [gamma-(32)P]ATP and [gamma-(32)P]GTP served as phosphate donors, with the former being twice as efficient. Specific components known to activate protein kinase A, protein kinase C and calmodulin-dependent kinases did not stimulate the phosphorylation of rAGT. Phosphoaminoacid analysis after reaction in vitro with ATP or GTP showed that AGT was modified at the same amino acids (serine, threonine and tyrosine) as in intact HBT228 cells. Although some of these properties pointed to casein kinase II as a candidate enzyme, known inhibitors and activators of casein kinase II did not affect rAGT phosphorylation. Fractionation of the cell extracts on poly(Glu/Tyr)-Sepharose resulted in the adsorption of an AGT kinase that modified the tyrosine residues and the exclusion of a fraction that phosphorylated AGT on serine and threonine residues. In-gel kinase assays after SDS/PAGE and non-denaturing PAGE revealed the presence of two AGT kinases of 75 and 130 kDa in HBT228 cells. The partly purified tyrosine kinase, identified as the 130 kDa enzyme by the same assays, was strongly inhibited by tyrphostin 25 but not by genestein. The tyrosine kinase used ATP or GTP to phosphorylate the AGT protein; this reaction inhibited the DNA repair activity of AGT. Evidence that the kinases might physically associate with AGT in cells was also provided. These results demonstrate that two novel cellular protein kinases, a tyrosine kinase and a serine/threonine kinase, both capable of using GTP as a donor, phosphorylate the AGT protein and affect its function. The new kinases might serve as potential targets for strengthening the biochemical modulation of AGT in human tumours.


Krill oil extract suppresses the proliferation of colorectal cancer cells through activation of caspase 3/9.
Currently available treatments for colorectal cancer (CRC) associate with numerous side-effects that reduce patients' quality of life. The effective nutraceuticals with high anti-proliferative efficacy and low side-effects are desirable. Our previous study has reported that free fatty acids extract (FFAE) of krill oil induced apoptosis of CRC cells, possibly associated with changes in mitochondrial membrane potential (MMP). The aims of this study were to compare the anti-proliferative efficacy of FFAE from krill oil on CRC cells with commonly used chemotherapeutic drug, Oxaliplatin, and to investigate the molecular mechanisms underlying the anti-proliferative effects of krill oil with a focus on intrinsic mitochondrial death pathway. Three human CRC cell lines, including DLD-1, HT-29 and LIM-2405, and one mouse CRC cell line, CT-26, were treated with FFAE of KO and the bioactive components of krill oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 24 h and 48 h. Similarly, these cell lines were treated with Oxaliplatin, a commonly used drug for CRC treatment, for 24 h. The effects of FFAE of KO, EPA, DHA and Oxaliplatin on cell proliferation, mitochondrial membrane potential and reactive oxygen species (ROS) were determined via WST-1, JC-10, and ROS assays respectively. The expression of caspase-3, caspase-9 and DNA damage following treatments of FFAE of KO was investigated via western blotting and immunohistochemistry. The FFAE of KO, EPA and DHA significantly inhibited cell proliferation and increased formation of ROS in all four cell lines (P < 0.01). A small dose of FFAE from KO ranged from 0.06 μL/100 μL to 0.12 μL/100 μL containing low concentrations of EPA (0.13-0.52 μM) and DHA (0.06-0.26 μM) achieved similar anti-proliferative effect as Oxaliplatin (P > 0.05). Treatments with the FFAE of KO, EPA and DHA (2:1 ratio) resulted in a significant increase in the mitochondrial membrane potential (P < 0.001). Furthermore, the expression of active forms of caspase-3 and caspase-9 was significantly increased following the treatment of FFAE of KO. The present study has demonstrated that the anti-proliferative effects of krill oil on CRC cells are comparable with that of Oxaliplatin, and its anti-proliferative property is associated with the activation of caspase 3/9 in the CRC cells.


[Investigation of biotechnological strains of microorganisms for their hygienic standardization].
By analyzing the findings and databases on the hygienic standardization of industrial microorganisms, the authors have improved a research program for industrial strains on substantiating their safe exposure levels in workplace and ambient airs. A shortened program is proposed to investigate gram-positive bacteria and nocardioformic actinomycetes (Lactobacillus, Micrococcus, Propionibacterim, Brevibacterim, Rhodococcus), which have no negative effect. It is necessary to study gram-negative bacteria and micromycetes (Pseudomonas, Alcaligenes, Acinetobacter, Arthrobacter, Aspergillus, Penicillum, Candida), which have pronounced immunotropic and dysbiotic properties by the full program, by including the evaluation of all observed negative effects. On the basis of this group, the priority microorganisms that confer a real danger to workers' health in developing allergic diseases have been listed.