TATA box-binding protein-associated factor 12 is important for RAS-induced transformation properties of colorectal cancer cells.
Activating mutations in the RAS proto-oncogene result in constant stimulation of its downstream pathways, further leading to tumorigenesis. Transcription factor IID (TFIID) can be regulated by cellular signals to specifically alter transcription of particular subsets of genes. To investigate potential links between the regulation of TFIID function and the RAS-induced carcinogenesis, we monitored the expression of the TATA box-binding protein and its associated factors (TAF) in human colon carcinoma cells. We primarily identified TAF12 levels as being up-regulated in cell lines bearing natural RAS mutations or stably overexpressing a mutated RAS isoform via a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-dependent pathway. We further showed by electrophoretic mobility shift assays and chromatin immunoprecipitation that the ETS1 protein was interacting with an ETS-binding site on the TAF12 promoter and was regulating TAF12 expression. The binding was enhanced in extracts from oncogenic RAS-transformed cells, pointing to a role in the RAS-mediated regulation of TAF12 expression. Reduction of TAF12 levels by small interfering RNA treatment induced a destabilization of the TFIID complex, enhanced E-cadherin mRNA and protein levels, and reduced migration and adhesion properties of RAS-transformed cells with epithelial to mesenchymal transition. Overall, our study indicates the importance of TAF12 in the process of RAS-induced transformation properties of human colon cells and epithelial to mesenchymal transition, most notably those related to increased motility, by regulating specifically expression of genes such as E-cadherin.


Breastfeeding protects against infectious diseases during infancy in industrialized countries. A systematic review.
Firstly, this review was performed to assess the effect of breastfeeding on infections during infancy in industrialized countries. Secondly, the effect of duration and exclusiveness of breastfeeding were explored. Studies were identified using Medline, Cochrane Library, Science Citation Index and by a manual search from bibliographies of articles from August 1986 to January 2008. Follow-up, case-control and randomized controlled trial (RCT) studies performed in an industrialized country, published in English, with breastfeeding as a determinant, with overall infections, gastrointestinal or respiratory tract infections as a major outcome, and at least 40 participants in the study were included. Using Bauchner's criteria published in a review in 1986, two reviewers and a peer reviewer assessed the internal validity of those studies. Twenty-one studies that met the inclusion and internal validity criteria were included. These included 16 follow-up and four case-control studies and one RCT. Four out of five studies observed decreased effects on overall infections in breastfed infants. With regard to gastrointestinal infections, six out of eight studies suggested that breastfeeding had a protective effect. Thirteen out of 16 studies concluded that breastfeeding protects infants against respiratory tract infections. Five studies combined duration and exclusiveness of breastfeeding. All studies observed a protective dose/duration-response effect on gastrointestinal or respiratory tract infections. These studies strongly suggest that breastfeeding protects infants against overall infections, gastrointestinal and respiratory tract infections in industrialized countries. The optimal duration of exclusive breastfeeding for protection against infectious diseases needs to be studied in more detail.


A survey of surgically resected pituitary incidentalomas and a comparison of the clinical features and surgical outcomes of non-functioning pituitary adenomas discovered incidentally versus symptomatically.
Pituitary tumors are discovered either incidentally by imaging studies (incidentalomas) or via evaluation of certain clinical symptoms (symptomatic tumors). In this study, we first surveyed patients with incidentalomas who underwent surgery. Cases included 62.3% non-functioning adenomas (NFPAs), 14.5% functioning adenomas, and 13.8% Rathke's cleft cysts. Next, we compared the clinical features and surgical outcomes of 145 patients whose preoperative diagnosis was NFPA (incidentalomas [n = 79] vs. symptomatic tumors [n = 66]). The patients with incidentalomas were older (59.9 vs. 55.3 years, p < 0.05) and had smaller tumors compared with the patients with symptomatic tumors (mean maximum diameter: 23.1 vs. 27.5 mm, p < 0.01). The main reason for undergoing imaging studies was headache (n = 25) in the incidentaloma group and visual disturbance (n = 46) in the symptomatic tumor group. The incidence of preoperative pituitary hormone deficiencies was lower in the incidentaloma than symptomatic tumor group (growth hormone deficiency: 37.7% vs. 66.7%, p < 0.01; gonadotropin deficiency: 19.0% vs. 39.4%, p < 0.01; adrenocorticotropic hormone deficiency: 3.8% vs. 18.2%, p < 0.01; thyroid stimulating hormone deficiency: 6.3% vs. 12.1%, p = 0.25). Postoperative pituitary function was better preserved in the incidentaloma than symptomatic tumor group (no deficiency: 58.2% vs. 28.8%, p < 0.01). The difference in postoperative complications between groups was not statistically significant (incidentalomas vs. symptomatic tumors: 21.5% vs. 19.7%, p = 0.84). In conclusion, incidentalomas were detected while smaller size and lower incidence of hormone deficiency than symptomatic tumors, and the pituitary hormones were also preserved after surgery. It is important to observe incidentalomas carefully and to judge whether to operate appropriately before they become symptomatic tumors.


The role of melanocortins in body weight regulation: opportunities for the treatment of obesity.
Five G-protein-coupled melanocortin receptors (MC(1)-MC(5)) are expressed in mammalian tissues. The melanocortin receptors support diverse physiological functions, including the regulation of hair color, adrenal function, energy homeostasis, feed efficiency, sebaceous gland lipid production and immune and sexual function. The melanocortins (adrenocorticotropic hormone (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), beta-MSH and gamma-MSH) are agonist peptide ligands for the melanocortin receptors and these peptides are processed from the pre-prohormone proopiomelanocortin (POMC). Peptide antagonists for the melanocortin MC(1), MC(3) and MC(4) receptors include agouti-related protein (AgRP) and agouti. Diverse lines of evidence, including genetic and pharmacological data obtained in rodents and humans, support a role for the melanocortin MC(3) and MC(4) receptors in the regulation of energy homeostasis. Recent advances in the development of potent and selective peptide and non-peptide melanocortin receptor ligands are anticipated to help unravel the roles for the melanocortin receptors in humans and to accelerate the clinical use of small molecule melanocortin mimetics.


Human responses to repeated high G stimulated aerial combat maneuvers.
Five subjects wearing standard USAF anti-G suits and seated at a 65 degrees back angle were exposed to a simulated aerial combat maneuver (SACM) which was repeated 5 times with 4-min 1-G rests between each SACM exposure. The SACM was 122 s in duration with 10 s acceleration peaks of 10, 8, and 6 G; between these peaks, the subject was at 4 G for 15 s. This series of repeated SACM exposure fatigued four of the five subjects. Heart rate and rhythm, arterial oxygen saturation, expired gases, lactate, pyruvate, glucose, CPK enzymes and isoenzymes, blood volume, subjective fatigue measurements, and subject performance were examined relative to the development of fatigue, the energy cost of the M-1, and tolerance to the SACM. All physiologic-metabolic parameters were significantly affected by the repeated SACMs. However, only heart rate changes appeared to be correlated with developing fatigue. A significant amount of energy is required to perform the M-1. Subjects whose energy-metabolic and cardiovascular states are least disturbed by high G exposure are those persons who will perform best and become least fatigued during repeated aerial combat maneuvers.


Hydrogen Gas in Cancer Treatment.
Gas signaling molecules (GSMs), composed of oxygen, carbon monoxide, nitric oxide, hydrogen sulfide, etc., play critical roles in regulating signal transduction and cellular homeostasis. Interestingly, through various administrations, these molecules also exhibit potential in cancer treatment. Recently, hydrogen gas (formula: H2) emerges as another GSM which possesses multiple bioactivities, including anti-inflammation, anti-reactive oxygen species, and anti-cancer. Growing evidence has shown that hydrogen gas can either alleviate the side effects caused by conventional chemotherapeutics, or suppress the growth of cancer cells and xenograft tumor, suggesting its broad potent application in clinical therapy. In the current review, we summarize these studies and discuss the underlying mechanisms. The application of hydrogen gas in cancer treatment is still in its nascent stage, further mechanistic study and the development of portable instruments are warranted.


Mycobacterium avium subspecies paratuberculosis triggers intestinal pathophysiologic changes in beige/scid mice.
We investigated whether infection of beige/scid mice with Mycobacterium avium subspecies paratuberculosis can induce intestinal pathophysiologic changes. Six-week-old beige/scid mice were inoculated intraperitoneally with M. paratuberculosis, then were killed 32 weeks after inoculation when the small intestine was evaluated for physiologic and morphologic abnormalities. All infected mice developed clinical disease. The lamina propria of the intestine from infected mice was mildly infiltrated with mononuclear cells containing acid-fast bacteria, and had significantly increased villus width. In vitro physiologic studies in Ussing chambers indicated that M. paratuberculosis infection caused significant abnormalities in intestinal transport parameters. Baseline short circuit current and potential difference were abnormally high in tissues from infected, compared with control mice, indicative of increased ion secretion. Baseline conductance was significantly decreased in infected mice, suggesting that intestinal tissue from infected mice was less permeable to ions. The change in short circuit current following transmural electrical and glucose stimulation was significantly reduced in intestines from infected mice, suggesting that inflamed intestine had neural and/or epithelial cell damage. We conclude that infection of beige/scid mice with M. paratuberculosis triggers significant intestinal pathophysiologic changes consistent with chronic inflammation. These functional abnormalities may contribute to the pathogenesis of the wasting syndrome seen in bovids with paratuberculosis. This animal model provides evidence that T cell-independent mechanisms are sufficient to cause mucosal pathophysiologic changes and inflammation in response to a specific pathogen, and may be of relevance to inflammatory bowel disease in humans.


Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome.
Arrhythmic events in long-QT syndrome type 1 (LQT1) may be associated with exercise, acute arousal, or rest/sleep. We aimed to identify trigger-specific risk factors for cardiac events in patients with LQT1. The study population comprised 721 genetically confirmed patients with LQT1 from the US portion of the International LQTS Registry. Multivariate analysis was used to assess the independent contribution of prespecified clinical and mutation-specific factors to the development of a first reported triggered event, associated with exercise, arousal, or sleep/rest. Cardiac events occurred in 221 study patients, of whom 121 (55%) were associated with exercise, 30 (14%) with arousal, 47 (21%) with sleep/rest, and 23 (10%) with other triggers. Multivariate analysis showed that males <13 years had a 2.8-fold (P < .001) increase in the risk for exercise-triggered events whereas females ≥13 years showed a 3.5-fold (P = .002) increase in the risk for sleep/rest nonarousal events. Cytoplasmic-loop mutations within the transmembrane region, involved in adrenergic channel regulation, were associated with the increased risk for both exercise- and arousal-triggered events (hazard ratio = 6.19 [P < .001] and 4.99 [P < .001], respectively) but were not associated with events during sleep/rest (hazard ratio = 0.72; P = .46). Beta-blocker therapy was associated with a pronounced 78% (P < .001) reduction in the risk for exercise-triggered events but did not have a significant effect on events associated with arousal or sleep/rest. In patients with LQT1, cardiac events triggered by exercise, arousal, or rest/sleep are associated with distinctive risk factors and response to medical therapy. These findings can be used for improved recommendations for lifestyle modifications and therapeutic management in this population.


Friend murine leukemia virus-induced leukemia is associated with the formation of mink cell focus-inducing viruses and is blocked in mice expressing endogenous mink cell focus-inducing xenotropic viral envelope genes.
In these studies, we have shown data that are consistent with the hypothesis that mink cell focus-inducing viruses (MCF) play an important role in the generation of an erythroproliferative disease developing after injection of certain strains of newborn mice with ecotropic Friend murine leukemia virus (F-MuLV). Resistance to this disease is correlated with the endogenous expression of an MCF/xenotropic virus-gp70-related protein that may interfere with the replication or spread of MCF viruses. These ideas are supported by the following observations: (a) after infection with F-MuLV, only 6/13 strains of mice-developed disease, and studies with crosses between susceptible and resistant strains indicated that resistance was dominant. Although F-MuLV was shown to replicate equally well in all strains tested, viruses coding for MCF-specific viral envelope proteins could be detected only in the spleens of mice from strains that were resistant to F-MuLV-induced disease and not in the spleens of mice from strains that were resistant to F-MuLV-induced disease; (b) a Friend MCF (Fr-MCF) virus isolated from the spleen of an F-MuLV-infected mouse from a susceptible strain induced the same erythroproliferative disease when injected as an appropriate pseudotype into mice from susceptible but not resistant strains of mice; and (c) resistant but not susceptible strains of mice endogenously express MCF/xenotropic virus-related envelope glycoproteins that may be responsible for resistance by blocking receptors for MCF viruses. These results not only indicate that Fr-MCF virus is a crucial intermediate in the induction of disease by F-MuLV, but also suggest that a novel gene, either an MCF/xenotropic virus-related envelope gene or a gene controlling its expression, is responsible for resistance to erythroleukemia induced by F-MuLV.


Impact of catheter and surgical ablation on arrhythmia treatment in a tertiary referral centre.
Invasive cardiac electrophysiology studies began as diagnostic studies. The past decade has seen the introduction of several new treatments which have broadened the scope of invasive electrophysiology studies. In particular, the development of catheter ablation techniques increasingly allows curative treatment to be delivered in the catheter laboratory. The workload of electrophysiological procedures has steadily increased in our tertiary referral centre. Over 1000 patients have been treated in the past 20 years and it is projected that 219 new patients will be treated in 1991 and 342 procedures will be carried out. Over 25% of patients now receive either catheter or surgical ablation and almost 80% of these are cured permanently without the need for further drug treatment. The development of safer techniques for catheter ablation has led to its increased use and a decline in surgical ablations. Because catheter ablation is a much simpler and less traumatic procedure than surgical ablation there are great advantages both for the patient and in terms of cost-effectiveness. Antitachycardia pacing, relatively common in 1985, has now largely been supplanted by ablation and implantation of defibrillators. As the tendency to non-pharmacological treatment increases and evidence mounts that cost-effectiveness is greater for electrophysiological treatments, the implications for the funding of electrophysiology services grow. The initially high cost of curative treatment needs to be balanced against the longer term and potentially higher costs of palliative drug treatment. The potential to cure patients with catheter procedures may lead to a greater demand for this expertise and a need for an increase in training and facilities.


Serum IgE levels in patients with inflammatory bowel disease.
The role of allergy in the pathogenesis of inflammatory bowel disease (IBD) is unclear. The present study was performed to evaluate serum levels of IgE and other immunoglobulin classes in patients with IBD. Patients with IBD had significantly elevated serum levels of both IgG and IgM in the presence of normal levels of IgA. Serum concentration of IgE, as well as the prevalence of patients with "high IgE" were significantly increased in IBD. Among patients with IBD, those with Crohn's disease or those in relapse had the highest levels of IgE. The possibility that allergy plays a pathogenic role in a subset of IBD is discussed.


Theoretical modeling of fiber laser at 810 nm based on thulium-doped silica fibers with enhanced 3H4 level lifetime.
A compact upconversion fiber laser operating around 810 nm is proposed using thulium-doped silica-based fiber with locally modified thulium environment by high alumina codoping. Using a comprehensive numerical model of thulium doped fiber we investigate performance of the proposed laser. Comparison with two other thulium hosts, fluoride glass and standard silica, is presented. Efficient lasing can be expected even for silica based fiber for specific ranges of the fiber and laser cavity parameters, especially when 3H4 lifetime is enhanced. With moderate pump power of 5 W at wavelength of 1064 nm, the predicted output power of the upconversion laser is about 2 W at 810 nm.


Light forces the pace: optical manipulation for biophotonics.
The biomedical sciences have benefited immensely from photonics technologies in the last 50 years. This includes the application of minute forces that enable the trapping and manipulation of cells and single molecules. In terms of the area of biophotonics, optical manipulation has made a seminal contribution to our understanding of the dynamics of single molecules and the microrheology of cells. Here we present a review of optical manipulation, emphasizing its impact on the areas of single-molecule studies and single-cell biology, and indicating some of the key experiments in the fields.


Pharmacogenomics in oncology care.
Cancer pharmacogenomics have contributed a number of important discoveries to current cancer treatment, changing the paradigm of treatment decisions. Both somatic and germline mutations are utilized to better understand the underlying biology of cancer growth and treatment response. The level of evidence required to fully translate pharmacogenomic discoveries into the clinic has relied heavily on randomized control trials. In this review, the use of observational studies, as well as, the use of adaptive trials and next generation sequencing to develop the required level of evidence for clinical implementation are discussed.


Behavior maintained under a second-order schedule by intramuscular injection of morphine or cocaine in rhesus monkeys.
Three rhesus monkeys lived in primate cages provided with response keys and enclosed in isolation chambers. During experimental sessions on Monday, Wednesday and Friday, the chamber door was closed and every 10th key-pressing response during a 60-minute interval produced a 2-second red light, but had no other programmed consequences (the 10-response fixed-ratio component of the second-order schedule; FR 10). The first FR 10 component completed after the 60-minute interval had elapsed produced a red light which remained on for 2 minutes while the chamber door was opened; the monkey then extended his arm and was given an intramuscular injection of drug (the 60-minute fixed-interval component of the second-order schedule; FI 60 min). Under this second-order schedule of intramuscular drug injection, repeated sequences of rapid responding were maintained during each session by 0.75 to 3.0 mg/kg injections of either morphine or cocaine. Patterns of responding characteristic of FR schedules were controlled by the 2-second red lights; a pause in responding after each 2-second red light was followed by a sustained high rate of responding until the light was produced again. Pauses in responding became progressively shorter as time elapsed in the 60-minute interval. When saline injections were substituted for drug injections, responding markedly decreased. When responding was maintained by 3.0 mg/kg morphine injections, pretreatment with 0.03 mg/kg of nalorphine increased responding, while pretreatment with 0.1 or 0.3 mg/kg of nalorphine decreased responding.


Bright or dark immune complexes of anti-TAMRA antibodies for adapted fluorescence-based bioanalysis.
Fluorescence labels, for example fluorescein or rhodamin derivatives, are widely used in bioanalysis applications including lateral-flow assays, PCR, and fluorescence microscopy. Depending on the layout of the particular application, fluorescence quenching or enhancement may be desired as the detection principle. Especially for multiplexed applications or high-brightness requirements, a tunable fluorescence probe can be beneficial. The alterations in the photophysics of rhodamine derivatives upon binding to two different anti-TAMRA antibodies were investigated by absorption and fluorescence-spectroscopy techniques, especially determining the fluorescence decay time and steady-state and time-resolved fluorescence anisotropy. Two monoclonal anti-TAMRA antibodies were generated by the hybridoma technique. Although surface-plasmon-resonance measurements clearly proved the high affinity of both antibodies towards 5-TAMRA, the observed effects on the fluorescence of rhodamine derivatives were very different. Depending on the anti-TAMRA antibody either a strong fluorescence quenching (G71-DC7) or a distinct fluorescence enhancement (G71-BE11) upon formation of the immune complex was observed. Additional rhodamine derivatives were used to gain further information on the binding interaction. The data reveal that such haptens as 5-TAMRA could generate different paratopes with equal binding affinities but different binding interactions, which provide the opportunity to adapt bioanalysis methods including immunoassays for optimized detection principles for the same hapten depending on the specific requirements.


Inositol 1,2-cyclic 4,5-trisphosphate is not a product of muscarinic receptor-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis in rat parotid glands.
We have employed a neutral-pH extraction technique to look for inositol 1,2-cyclic phosphate derivatives in [3H]inositol-labelled parotid gland slices stimulated with carbachol. The incubations were terminated by adding cold chloroform/methanol (1:2, v/v), the samples were dried under vacuum and inositol phosphates were extracted from the dried residues by phenol/chloroform/water partitioning. Water-soluble inositol metabolites were separated by h.p.l.c. at pH 3.7. 32P-labelled inositol phosphate standards (inositol 1-phosphate, inositol 1,2-cyclic phosphate, inositol 1,4,5-trisphosphate and inositol 1,2-cyclic 4,5-trisphosphate) were quantitively recovered through both extraction and chromatography steps. Treatment of inositol cyclic phosphate standards with 5% (w/v) HClO4 for 10 min prior to chromatography resulted in formation of the expected non-cyclic compounds. [3H]Inositol 1-phosphate and [3H]inositol 1,4,5-trisphosphate were both present in parotid gland slices and both increased during stimulation with 1 mM-carbachol. There was no evidence for significant quantities of [3H]inositol 1,2-cyclic phosphate or [3H]inositol 1,2-cyclic 4,5-trisphosphate in control or carbachol-stimulated glands. Parotid gland homogenates rapidly converted inositol 1,4,5-trisphosphate to inositol bisphosphate and inositol tetrakisphosphate, but metabolism of the inositol cyclic trisphosphate was much slower. The results suggest that inositol 1,4,5-trisphosphate, but not inositol 1,2-cyclic 4,5-trisphosphate, is the water-soluble product of muscarinic receptor-stimulated phospholipase C in rat parotid glands.


Thermogenesis in decomposing carcasses.
It is of fundamental importance in forensic entomology that the factors controlling carcass temperatures during decomposition are thoroughly understood. The thermal environment to which fly larvae are exposed is the primary influence on their growth rate, and hence affects any estimate of minimum time since death using such specimens in homicide investigations. To date, much of the entomological research on maggot masses has focused on their elevation of carcass temperatures, with very little focus on the bacteria associated with larval activity. The aim of this study was to investigate the heat associated with decay and the types of bacteria present during the decomposition of a carcass, both in the presence and in the absence of maggots. Three treatments were imposed: fresh, frozen and maggot-infested, each consisting of five replicate pig carcasses. Temperature measurements and bacterial swabs were taken from the gastro-intestinal region of each pig and temperatures and bacterial communities compared between treatments. All carcasses reached average maximum temperatures above 32 °C in a temperature controlled room set at 23 °C. Treatment had no statistically significant effect on the temperatures recorded in each carcass but did significantly affect the community structure of the bacteria. However, bacterial community structure varied across time. This study suggests that bacterial metabolism plays a significant role in carcass thermogenesis, and that maggot masses, while contributing to localised heating within the carcass, may have less of a role in elevating carcass temperatures than previously assumed.


Effects of naltrexone on cortisol levels in heavy drinkers.
The primary objectives of this study were to: (a) examine the neuroendocrine effects of naltrexone vs. placebo by comparing serum cortisol levels; and (b) test the biobehavioral correlates of naltrexone-induced changes in cortisol. Non-treatment seeking heavy drinkers (n=37) completed two intravenous alcohol administrations, one after naltrexone (50 mg) and one after placebo. Cortisol levels were measured at baseline and after alcohol intake (BrAC=0.06 g/dl) on both sessions, as were subjective responses to alcohol. Analyses revealed that naltrexone significantly raised overall cortisol levels compared to placebo. Cortisol levels decreased during alcohol administration and a stronger decrease was observed in the naltrexone condition. Cortisol levels were, in turn, inversely related to some of alcohol's the reinforcing effects (i.e., alcohol 'high,' vigor) and positively associated with some of its unpleasant effects (i.e., sedation and subjective intoxication). These results suggest that naltrexone alters cortisol levels in heavy drinkers and that its effects on subjective responses to alcohol may be related, in part, to naltrexone's ability to activate the HPA-axis.


Severe paraneoplastic hypereosinophilia in metastatic renal cell carcinoma.
Renal cell carcinoma can cause various paraneoplastic syndromes including metabolic and hematologic disturbances. Paraneoplastic hypereosinophilia has been reported in a variety of hematologic and solid tumors. We present the first case in the literature of severe paraneoplastic hypereosinophilia in a patient with renal cell carcinoma. A 46 year-old patient patient with a history of significant weight loss, reduced general state of health and coughing underwent radical nephrectomy for metastasized renal cell carcinoma. Three weeks after surgery, the patient presented with excessive peripheral hypereosinophilia leading to profound neurological symptoms due to cerebral microinfarction. Systemic treatment with prednisolone, hydroxyurea, vincristine, cytarabine, temsirolimus and sunitinib led to reduction of peripheral eosinophils but could not prevent rapid disease progression of the patient. At time of severe leukocytosis, a considerable increase of cytokines associated with hypereosinophilia was measurable. Paraneoplastic hypereosinophilia in patients with renal cell carcinoma might indicate poor prognosis and rapid disease progression. Myelosuppressive therapy is required in symptomatic patients.


Middle East Respiratory Syndrome: Emergence of a Pathogenic Human Coronavirus.
In 2012, a zoonotic coronavirus was identified as the causative agent of Middle East respiratory syndrome and was named MERS coronavirus (MERS-CoV). As of August 11, 2016, the virus has infected 1,791 patients, with a mortality rate of 35.6%. Although MERS-CoV generally causes subclinical or mild disease, infection can result in serious outcomes, including acute respiratory distress syndrome and multi-organ failure in patients with comorbidities. The virus is endemic in camels in the Arabian Peninsula and Africa and thus poses a consistent threat of frequent reintroduction into human populations. Disease prevalence will increase substantially if the virus mutates to increase human-to-human transmissibility. No therapeutics or vaccines are approved for MERS; thus, development of novel therapies is needed. Further, since many MERS cases are acquired in healthcare settings, public health measures and scrupulous attention to infection control are required to prevent additional MERS outbreaks.


Hypervariable loci that enhance the discriminatory ability of newly proposed 15-loci and 24-loci variable-number tandem repeat typing method on Mycobacterium tuberculosis strains predominated by the Beijing family.
The newly proposed 15- and 24-loci mycobacterial interspersed repetitive unit (MIRU)-variable-number tandem repeat (VNTR) typing method was evaluated for its ability to differentiate 181 Mycobacterium tuberculosis Beijing family strains. Compared with the original 12-loci MIRU-VNTR typing method, the 15-loci system dramatically improved the discriminatory power for Beijing strains; however, large clusters that could be further differentiated by IS6110 restriction fragment length polymorphism (RFLP) were still obtained. The clonal stability and allelic diversity of a total of 31 VNTR loci were evaluated. VNTRs 3232, 3820, and 4120 were identified as the effective hypervariable VNTR set for the second-line typing of clustered strains following the 15-loci based scheme. Consequently, the discriminatory power of the new scheme (18 loci) equaled that of IS6110 RFLP.


Network-enabled gene expression analysis.
Although genome-scale expression experiments are performed routinely in biomedical research, methods of analysis remain simplistic and their interpretation challenging. The conventional approach is to compare the expression of each gene, one at a time, between treatment groups. This implicitly treats the gene expression levels as independent, but they are in fact highly interdependent, and exploiting this enables substantial power gains to be realized. We assume that information on the dependence structure between the expression levels of a set of genes is available in the form of a Bayesian network (directed acyclic graph), derived from external resources. We show how to analyze gene expression data conditional on this network. Genes whose expression is directly affected by treatment may be identified using tests for the independence of each gene and treatment, conditional on the parents of the gene in the network. We apply this approach to two datasets: one from a hepatotoxicity study in rats using a PPAR pathway, and the other from a study of the effects of smoking on the epithelial transcriptome, using a global transcription factor network. The proposed method is straightforward, simple to implement, gives rise to substantial power gains, and may assist in relating the experimental results to the underlying biology.


Purification and properties of peptides which induce germination of blastospores of Candida albicans.
A glycopeptide and a peptide have been isolated from bovine seminal plasma which together will induce germination of Candida albicans blastospores at 37 degrees C and in the presence of glucose and Mn2+. ¿They have molecular weights of 2000 to 3000. Both peptides contain appreciable amounts of aspartic and glutamic acids, only the glycopeptide contains threonine, lysine, histidine and arginine, while only the peptide contains proline. Acid hydrolysates are fully active in inducing germination and a mixture of aspartic acid, lysine, histidine, threonine, proline and beta-alanine can replace them. Mn2+ is not then required. Amino acid mixtures are required to be present throughout the whole period in the incubation medium for full germination to take place, but the peptides can be removed after 1 h incubation and if the cells are resuspended in a buffered glucose medium full germination occurs after a further 3 h incubation.


Quantum and Dielectric Confinement Effects in Lower-Dimensional Hybrid Perovskite Semiconductors.
Hybrid halide perovskites are now superstar materials leading the field of low-cost thin film photovoltaics technologies. Following the surge for more efficient and stable 3D bulk alloys, multilayered halide perovskites and colloidal perovskite nanostructures appeared in 2016 as viable alternative solutions to this challenge, largely exceeding the original proof of concept made in 2009 and 2014, respectively. This triggered renewed interest in lower-dimensional hybrid halide perovskites and at the same time increasingly more numerous and differentiated applications. The present paper is a review of the past and present literature on both colloidal nanostructures and multilayered compounds, emphasizing that availability of accurate structural information is of dramatic importance to reach a fair understanding of quantum and dielectric confinement effects. Layered halide perovskites occupy a special place in the history of halide perovskites, with a large number of seminal papers in the 1980s and 1990s. In recent years, the rationalization of structure-properties relationship has greatly benefited from new theoretical approaches dedicated to their electronic structures and optoelectronic properties, as well as a growing number of contributions based on modern experimental techniques. This is a necessary step to provide in-depth tools to decipher their extensive chemical engineering possibilities which surpass the ones of their 3D bulk counterparts. Comparisons to classical semiconductor nanostructures and 2D van der Waals heterostructures are also stressed. Since 2015, colloidal nanostructures have undergone a quick development for applications based on light emission. Although intensively studied in the last two years by various spectroscopy techniques, the description of quantum and dielectric confinement effects on their optoelectronic properties is still in its infancy.


Laser annealing of Corning 7059 glass waveguides.
Corning 7059 glass thin film waveguides prepared by rf sputtering and vapor deposition were annealed with a CO(2) laser at various powers and scan velocities. Some reduction in optical loss was observed after laser annealing of the films. The results show a reduction in optical loss with the number of laser scans. Optical profilometer measurements indicated no change in surface roughness after laser annealing. RBS analysis of laser annealed samples show no change in elemental composition. We discuss possible optical loss reduction mechanisms and present data on the marking of thin films when annealing is done at higher CO(2) laser powers.


Development of a low cost microP-based blood gas monitor.
A low cost microprocessor-based system for continuous in-vivo measurement of blood pH and pCO2 using a biosensor is being developed. The biosensor is a pH Ti2O3 ISFET (Ion Sensitive Field Effect Transistor) with a sensitivity of -56 mV/pH and a linear response over physiologically meaningful blood pH range of 6.5 to 8.0. The ISFET chip is bonded onto a printed circuit board substrate to enable reliable and robust connections to three wires. The small sensor tip sized of 0.95 mm facilitates its incorporation into a catheter tip and its placement into a rat's artery. A microcontroller supervises preusage calibration, data logging, display of alphanumeric information on a LCD (liquid crystal display) unit, and resettable visual & audio alarm indicators. Preliminary clinical testing are underway to perfect the system and use it on a routine basis to monitor the physiological state of laboratory animals during neurophysiological experiments.


The bankruptcy of the Allegheny Health System and its consequences.
In the midst of the healthcare consolidation of the past decade, many have overlooked the inevitable: some of the consolidated systems are bound to fail. The following Commentary gives the reader a close look at the rapid decline of one such system, the Allegheny Health System, and the impact of that failure, the "rescue" of the System's facilities, and the System's ongoing bankruptcy upon delivery of healthcare in the Philadelphia area.


Public health financial management needs: report of a national survey.
The work reported here builds on the identification of public health financial management practice competencies by a national expert panel. The next logical step was to provide a validity check for the competencies and identify priority areas for educational programming. We developed a survey for local public health finance officers based on the public health finance competencies and field tested it with a convenience sample of officials. We asked respondents to indicate the importance of each competency area and the need for training to improve performance; we also requested information regarding respondent education, jurisdiction size, and additional comments. Our local agency survey sample drew on the respondent list from the National Association of County and City Health Officials 2005 local health department survey, stratified by agency size and limited to jurisdiction populations of 25,000 to 1,000,000. Identifying appropriate respondents was a major challenge. The survey was fielded electronically, yielding 112 responses from 30 states. The areas identified as most important and needing most additional training were knowledge of budget activities, financial data interpretation and communication, and ability to assess and correct the organization's financial status. The majority of respondents had some postbaccalaureate education. Many provided additional comments and recommendations. Health department finance officers demonstrated a high level of general agreement regarding the importance of finance competencies in public health and the need for training. The findings point to a critical need for additional training opportunities that are accessible, cost-effective, and targeted to individual needs.


A modified Delphi study to develop a practical guide for selecting patients with prostate cancer for active surveillance.
Active surveillance (AS) is a management option for men diagnosed with lower risk prostate cancer. There is wide variation in all aspects of AS internationally, from patient selection to investigations and follow-up intervals, and a lack of clear evidence on the optimal approach to AS. This study aimed to provide guidance for clinicians from an international panel of prostate cancer experts. A modified Delphi approach was undertaken, utilising two rounds of online questionnaires followed by a face-to-face workshop. Participants indicated their level of agreement with statements relating to patient selection for AS via online questionnaires on a 7-point Likert scale. Factors not achieving agreement were iteratively developed between the two rounds of questionnaires. Draft statements were presented at the face-to-face workshop for discussion and consensus building. 12 prostate cancer experts (9 urologists, 2 academics, 1 radiation oncologist) participated in this study from a range of geographical regions (4 USA, 4 Europe, 4 Australia). Complete agreement on statements presented to the participants was 29.4% after Round One and 69.0% after Round Two. Following robust discussions at the face-to-face workshop, agreement was reached on the remaining statements. PSA, PSA density, Multiparametric MRI, and systematic biopsy (with or without targeted biopsy) were identified as minimum diagnostic tests required upon which to select patients to recommend AS as a treatment option for prostate cancer. Patient factors and clinical parameters that identified patients appropriate to potentially receive AS were agreed. Genetic and genomic testing was not recommended for use in clinical decision-making regarding AS. The lack of consistency in the practice of AS for men with lower risk prostate cancer between and within countries was reflected in this modified Delphi study. There are, however, areas of common practice and agreement from which clinicians practicing in the current environment can use to inform their clinical practice to achieve the best outcomes for patients.


Cytokine targets in the brain: impact on neurotransmitters and neurocircuits.
Increasing attention has been paid to the role of inflammation in a host of illnesses including neuropsychiatric disorders such as depression and anxiety. Activation of the inflammatory response leads to release of inflammatory cytokines and mobilization of immune cells both of which have been shown to access the brain and alter behavior. The mechanisms of the effects of inflammation on the brain have become an area of intensive study. Data indicate that cytokines and their signaling pathways including p38 mitogen-activated protein kinase have significant effects on the metabolism of multiple neurotransmitters such as serotonin, dopamine, and glutamate through impact on their synthesis, release, and reuptake. Cytokines also activate the kynurenine pathway, which not only depletes tryptophan, the primary amino acid precursor of serotonin, but also generates neuroactive metabolites that can significantly influence the regulation of dopamine and glutamate. Through their effects on neurotransmitter systems, cytokines impact neurocircuits in the brain including the basal ganglia and anterior cingulate cortex, leading to significant changes in motor activity and motivation as well as anxiety, arousal, and alarm. In the context of environmental challenge from the microbial world, these effects of inflammatory cytokines on the brain represent an orchestrated suite of behavioral and immune responses that subserve evolutionary priorities to shunt metabolic resources away from environmental exploration to fighting infection and wound healing, while also maintaining vigilance against attack, injury, and further pathogen exposure. Chronic activation of this innate behavioral and immune response may lead to depression and anxiety disorders in vulnerable individuals.


Raynaud phenomenon and digital ulcers in systemic sclerosis.
Raynaud phenomenon is a symptom complex caused by impaired digital perfusion and can occur as a primary phenomenon or secondary to a wide range of underlying causes. Raynaud phenomenon occurs in virtually all patients with systemic sclerosis (SSc) and is often the earliest clinical manifestation to occur. Careful assessment is required in patients with Raynaud phenomenon to avoid missing secondary causes such as SSc. Digital ulcers are a painful and disabling visible manifestation of digital vascular injury in patients with SSc. Progress has been made in the classification and assessment of digital ulcers and in understanding ulcer pathogenesis, and there are a wide range of treatments available to both prevent and heal digital ulcers, some of which are also used in Raynaud phenomenon management. In this Review, the assessment of patients with Raynaud phenomenon is discussed, including 'red flags' that are suggestive of SSc. The pathogenesis, classification and assessment of SSc-associated digital ulcers are also covered, alongside an overview of management approaches for SSc-associated Raynaud phenomenon and digital ulcers. Finally, unmet needs are discussed and the concept of a unified vascular phenotype in which therapies that affect the vasculature to support disease modification strategies is introduced.


Bioleaching of metals from spent fluid catalytic cracking catalyst using adapted Acidithiobacillus caldus.
In this study, an adapted bioleaching strain of Acidithiobacillus caldus UVS10 was successfully developed. Batch tests and tests in bioreactor were conducted to evaluate the metals bioleaching performance of A. caldus UVS10 to spent FCC catalyst (SFCCC). Results of batch experiments showed the bioleaching efficiency of Ni, V, La, and Ce in SFCCC reached 19.40%, 22.06%, 53.75%, and 59.56%, respectively. High SFCCC pulp density inhibited the leaching of metals. Sb leaching was inhibited in acidic environment caused by A. caldus UVS10. Contents of Ni, V, La, and Ce in extracellular polymeric substances (EPS) were significantly higher than those intracellular. Accumulation of metal in EPS and cytosol increased with the increase of SFCCC pulp density. V was less intercepted by EPS than Ni, La, and Ce, because of lower toxicity. Experimental results in bioreactor showed that Ni, V, La, and Ce could be effectively leached by A. caldus UVS10 under 10% pulp density. The aeration and stirring operating environment in bioreactor improved the leaching efficiency of metals in SFCCC. After bioleached in bioreactor, the available fraction content of four metals in SFCCC decreased significantly. Ecological risk analysis demonstrated the environmental risks of bioleached SFCCC were significantly lower than raw SFCCC. Different reaction kinetic models were used to represent metals leaching behavior under bioleaching of A. caldus UVS10, leaching of La and Ce showed good agreement with the product layer diffusion model, while Ni and V leaching kinetics fit well with the surface chemical reaction models.


Microstructure, physical and mechanical properties of dental polychromic multilayer zirconia of uniform composition.
The present study aimed to compare the microstructure, physical, and mechanical properties of three commercially available dental polychromatic multilayer zirconia materials of uniform composition: Dima Mill Zirconia ML, VITA YZ/ST Multicolor, and VITA YZ/XT Multicolor (with 3, 4, and 5 mol% Y2 O3 , respectively); thus, the influence of Y2 O3 content on the above properties of the produced materials was experimentally studied. Homogeneous zirconia ceramics with a dense micro- and nanostructure, without pores or defects, were produced after milling the blocks and sintering, which resulted in yttrium-stabilized tetragonal and cubic zirconia. Statistical analysis of the results of measurable magnitudes was performed by the one-way ANOVA test. The increase of Y2 O3 content (from 3 to 5 mol%) favored larger grain and crystallite sizes and a decrease of the values of the mechanical properties; yet, the differences were statistically insignificant. Clinically, these differences are expected to have no impact on their function in the oral cavity, both in terms of their fracture propensity and the damage that can be caused to the opposing teeth. Accordingly, the experimental results qualify the polychromic multilayer zirconia ceramics of uniform composition fabricated by milling technology for use in dental restorations.


Understanding intestinal health in nursery pigs and the relevant nutritional strategies.
In the modern pig production, pigs are weaned at early age with immature intestine. Dietary and environmental factors challenge the intestine, specifically the jejunum, causing inflammation and oxidative stress followed by destruction of epithelial barrier and villus structures in the jejunum. Crypt cell proliferation increases to repair damages in the jejunum. Challenges to maintain the intestinal health have been shown to be related to changes in the profile of mucosa-associated microbiota in the jejunum of nursery pigs. All these processes can be quantified as biomarkers to determine status of intestinal health related to growth potential of nursery pigs. Nursery pigs with impaired intestinal health show reduced ability of nutrient digestion and thus reduced growth. A tremendous amount of research effort has been made to determine nutritional strategies to maintain or improve intestinal health and microbiota in nursery pigs. A large number of feed additives have been evaluated for their effectiveness on improving intestinal health and balancing intestinal microbiota in nursery pigs. Selected prebiotics, probiotics, postbiotics, and other bioactive compounds can be used in feeds to handle issues with intestinal health. Selection of these feed additives should aim modulating biomarkers indicating intestinal health. This review aims to define intestinal health and introduce examples of nutritional approaches to handle intestinal health in nursery pigs.


Targeted Metabolome Profiling of Indonesian Shallots and Japanese Long-Day/Short-Day Bulb Onions.
In this study, targeted metabolome analysis was applied to identify the discriminative metabolites between Indonesian shallot landraces, Japanese long-day onion (LDO) varieties, and Japanese short-day onion (SDO) varieties. In total, 172 metabolite signal intensities were subjected to multivariate PLS-DA, VIP, and random forest modeling to gain further insight into genotype-specific metabolites. PLS-DA divides the examined genotypes into three different clusters, implying that shallot landraces exhibited a distinct metabolite profile compared with Japanese LDO and SDO varieties. The PLS-DA, VIP, and random forest results indicated that the shallot and LDO are richer in metabolite constituents in comparison with the SDO. Specifically, amino acids and organosulfur compounds were the key characteristic metabolites in shallot and LDO genotypes. The analysis of S-alk(en)yl-L-cysteine sulfoxide (ACSO) compounds showed higher accumulation in the shallot landraces relative to LDO and SDO varieties, which explains the stronger pungency and odor in shallots. In addition, the LDO showed higher ACSO content compared with the SDO, implying that long-day cultivation might enhance sulfur assimilation in the Japanese onion. The LDO 'Super Kitamomiji' and the shallots 'Probolinggo' and 'Thailand' showed higher ACSO content than other varieties, making it useful for Allium breeding to improve the flavor and stress tolerance of onions.


Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial.
Our goal was to compare the safety and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, with clopidogrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). AZD6140 achieves higher mean levels of platelet inhibition than clopidogrel in patients with stable coronary artery disease. A total of 990 patients with NSTE-ACS, treated with aspirin and standard therapy for ACS, were randomized in a 1:1:1 double-blind fashion to receive either twice-daily AZD6140 90 mg, AZD6140 180 mg, or clopidogrel 300-mg loading dose plus 75 mg once daily for up to 12 weeks. The primary end point, the Kaplan-Meier rate of major or minor bleeding through 4 weeks, was 8.1% in the clopidogrel group, 9.8% in the AZD6140 90-mg group, and 8.0% in the AZD6140 180-mg group (p = 0.43 and p = 0.96, respectively, vs. clopidogrel); the major bleeding rates were 6.9%, 7.1%, and 5.1%, respectively (p = 0.91 and p = 0.35, respectively, vs. clopidogrel). Although not statistically significant, favorable trends were seen in the Kaplan-Meier rates of myocardial infarction (MI) over the entire study period (MI: 5.6%, 3.8%, and 2.5%, respectively; p = 0.41 and p = 0.06, respectively, vs. clopidogrel). In a post-hoc analysis of continuous electrocardiograms, mostly asymptomatic ventricular pauses >2.5 s were more common, especially in the AZD6140 180-mg group (4.3%, 5.5%, and 9.9%, respectively; p = 0.58 and p = 0.01, respectively, vs. clopidogrel). This initial experience with AZD6140 in patients with ACS showed no difference in major bleeding but an increase in minor bleeding at the higher dose with encouraging results on the secondary end point of MI. This agent is currently being studied in a large outcomes trial in 18,000 patients with ACS.


mRNA vaccines against COVID-19: a showcase for the importance of microbial biotechnology.
Pfizer-BioNTech and Moderna developed in record time mRNA vaccines against COVID-19 of high efficacy. The modest protection achieved with a similarly designed mRNA from CureVac underlines the importance of biotechnological details in formulation such as replacement of uridine by pseudouridine in the mRNA encoding the SARS-CoV-2 spike protein or the lipid composition of the nanoparticle coating the mRNA. Phase 3 vaccine trials and vaccine studies in special subject groups as well observational studies in whole populations confirmed the real-world vaccine efficacy against symptomatic disease, particularly against severe COVID-19 cases and to a lesser extent against mild SARS-CoV-2 infections. mRNA vaccine protection extended also to the alpha and beta variant viruses. The surge of delta variants led to an increase of infections and cases even in populations which achieved high vaccine coverage. This efficacy decline resulted to a lesser extent from a weaker neutralization of the delta variant but mostly from a waning vaccine protection over time. Data from Israel documented the efficacy of a third 'booster' injection 5 months after the second injection in older segments of the population. Adverse reactions consisted of transient injection site pain, headache, muscle pain, fatigue, fever and chills. Extensive surveillance studies documented a good safety profile revealing only a non-significant increase in transient facial nerve paralysis and a significant, but modest increase in myocarditis in vaccinated young males that was lower than the myocarditis risk induced by SARS-CoV-2 infection.


Leading together towards a stronger 'us': An experimental test of the effectiveness of the 5R Shared Leadership Program (5RS) in basketball teams.
Leadership has been suggested to be a key factor in gaining a competitive advantage as a team, with shared leadership being a better predictor of team functioning than vertical leadership. Although the benefits of shared leadership are well-documented, evidence about how to implement a shared leadership structure remains sparse. This leaves coaches with three key challenges: (1) identifying the best leaders; (2) defining what roles those leaders should fulfill; and (3) developing their leadership skills. Solutions to these challenges have been proposed in the 5R Shared Leadership Program (5RS) - a leadership development program that seeks to implement an effective structure of shared leadership within sports teams. To test the effectiveness of 5RS program, we conducted an experimental-comparison group intervention in which eight national-level basketball teams (N = 96) completed a questionnaire at two points in time (i.e., pre- and posttest). The teams in the intervention condition completed the 5RS program, in which we identified the leadership structure in their teams (through Shared Leadership Mapping), appointed the best leaders in their leadership role, and then developed their identity leadership skills. The results revealed that the 5RS program was successful in strengthening athlete leaders' identity leadership skills, and as a result also team members' identification with their team. Furthermore, in contrast to athletes in the comparison condition, athletes in the 5RS condition were able to maintain their levels of intrinsic motivation and commitment to team goals, while also reporting improved well-being. The present study provides encouraging evidence that, by implementing a structure of shared leadership and by promoting athlete leaders' identity leadership skills, the 5RS program is able to improve the team's functioning and the well-being of its members.


Yeast sterol C24-methyltransferase: role of highly conserved tyrosine-81 in catalytic competence studied by site-directed mutagenesis and thermodynamic analysis.
The role of Try-81 in the reaction catalyzed by Saccharomyces cerevisiae sterol 24-C-methyltransferase (Erg6p) was investigated kinetically and for product differences against a panel of position-81 mutants in which Tyr was substituted with Trp, Phe, Ile, Leu, Val and Ala. The residue chosen for mutation is one that was reported previously to accept fecosterol and yield a set 24-ethyl (idene) sterol products typical of plants, showing the amino acid residue is located close to the transient C25 carbocation intermediate in the active site. One group of mutants (aromatic) tested with the natural substrate zymosterol accelerated the C-methylation reaction (k(cat)/K(m)) whereas the other group of mutants (aliphatics) decreased catalytic competence as the amino acid side chain was downsized. Mutating to aromatic and assaying with the substrate analog designed as a suicide substrate 26,27-dehydrozymosterol favored C26-monol formation, whereas mutating to the aliphatic of smaller size favored C26-diol formation (a measure of enzyme alkylation). In no case was zymosterol converted to an intermediate that formed a C25-diol. Thermodynamic analysis (determination of E(a), DeltaG(double dagger), DeltaH(double dagger) and TDeltaS(double dagger)) for the C-methylation reaction performed by these enzymes assayed with the substrate and its analog or zymosterol paired with the "charged' high energy intermediate (HEI) analogs 24(R,S)25,epiminolanosterol and 25-azalanosterol or "neutral" membrane insert ergosterol showed that mutation to aromatics can reduce inhibitor potency (measured as K(m)/K(i)), yet catalysis can improve in Trp81 by the introduction of a gain in free energy associated with stabilization of the transition state of a rate-controlling step directed toward turnover. Alternatively, mutation to the smaller aliphatic amino acid side chains led to a destabilization in the active site structure which was accompanied by increases in the partition ratios associated with abortive complex formation. The results are explained by consideration of the functional differences attributed to Tyr81 substitution to aromatics and aliphatics of different size involved with cation-pi or hydrogen bonding interactions and in the activation barriers required of differing side chain conformations to orient the reactants in the direction of turnover versus enzyme inactivation.


Cellular congenital mesoblastic nephroma: case report.
Congenital Mesoblastic Nephroma (CMN) is a rare pediatric renal tumor. It comprises two histological subtypes, namely classic and cellular, with the second accounting for two thirds of all cases and being more often associated with poor prognosis. It remains a diagnostic challenge for pathologists due to its similarity with other more frequent pediatric kidney neoplasms. We describe the case of a 2-year- old girl who presented with a left renal mass. After nephrectomy, the specimen analysis showed, on gross examination, an extensive, granular and whitish tumor lesion occupying almost the entire kidney, invading the renal sinus, capsule and perirenal fat, with areas of hemorrhage and necrosis. Histologically, it was characterized by ovoid spindle cells, mitoses and no cell atypia, which led to a diagnosis of cellular mesoblastic nephroma. Adjuvant chemotherapy was carried out, but tumor recurrence occurred in the first year, presenting as an unresectable tumor that did not respond to adjuvant chemotherapy and the patient died at 4 years of age. The cellular variant tends to be more aggressive, with a survival rate of 85% versus 100% for the classic variant. Recurrence generally occurs in the first year, particularly with the cellular variant.


Real-world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease.
Vedolizumab is a gut-selective treatment approved for Crohn's disease (CD) and ulcerative colitis (UC). Recently, a subcutaneous formulation of vedolizumab was approved. The aims of this study were to evaluate efficacy, safety, pharmacokinetics, patient experience and costs following a switch from intravenous to subcutaneous vedolizumab treatment. Patients were switched from intravenous to subcutaneous vedolizumab maintenance treatment and followed prospectively for 6 months and a subgroup for 12 months. The primary endpoint was change in faecal calprotectin levels. Furthermore, we evaluated clinical disease activity, remission rates, plasma CRP, drug persistence, adverse events, local injection reactions, serum drug concentrations, patient satisfaction, quality-of-life and treatment costs. Eighty-nine patients were included (48 CD; 41 UC). Faecal calprotectin decreased significantly in CD but not in UC. Clinical indices, remission rates, plasma CRP levels and quality-of-life scores remained unchanged. Patients that had been on standard compared to optimised IV vedolizumab dosing displayed similar outcomes on standard SC dosing. Drug persistence at 6 and 12 months was 95.5% and 88.5%, respectively. Frequencies of adverse events were similar before and after the switch. No serious adverse events occurred. Transient severe local injection reactions were experienced by 1.2% of patients. Median vedolizumab trough levels were 2.3 times higher on subcutaneous compared to intravenous treatment. Patient satisfaction was generally high. Annualised treatment costs were reduced by 15% following the switch. The switch from intravenous to subcutaneous vedolizumab could be done with preserved therapeutic effectiveness, safety, high patient satisfaction and low discontinuation rate, at a reduced cost.


Painless osteoid osteoma in the maxilla of an elderly female patient.
Osteoid osteoma is an osteoblastic benign bone tumor more frequent in long bones of young male patients. It is the third most commonly diagnosed benign bone tumor and has distinctive symptomatology, nocturnal pain that relieves with nonsteroidal anti-inflammatory drugs. Nowadays, total resection is the preferred management. In the present paper, an unusual variant in the maxilla of a female elderly patient without previous symptomatology is exposed; it was surgically removed without signs of reappearance in 12 months of follow-up. Although it is not a common site of appearance, the manifestation of this tumor in the skull bones seems to be associated with a different pattern in contrast to the skeletal type as can be seen in the present case and others previously reported. The authors consider due to the clinical similarity between this and other tumors that it should be taken into consideration for future diagnosis dilemma.


Induction of micronuclei and chromosomal aberrations by the mycotoxin patulin in mammalian cells: role of ascorbic acid as a modulator of patulin clastogenicity.
Patulin is a mycotoxin produced by several species of Penicillium, Aspergillus and BYSSOCHLAMYS: Patulin is a common contaminant of ripe apples used for the production of apple juice concentrates and is also present in other fruits, vegetables and food products. Patulin has been reported to have mutagenic, carcinogenic and teratogenic properties. Nevertheless, these properties are still a matter of debate. In this report, we further investigated the genotoxicity of patulin in mammalian cells by two different approaches. Firstly, we evaluated the induction of micronuclei in cytokinesis-blocked human lymphocytes. This approach is important because available data concerning the genetic toxicity of patulin in human cells is sparse. Secondly, we chose an established model for patulin genotoxicity, i.e. the chromosomal aberration assay in V79 Chinese hamster cells, to clarify whether concomitant exposure to ascorbic acid with the mycotoxin modulates or not the clastogenicity of patulin. The results unequivocally show induction of DNA-damaged cells by patulin as assessed by both cytogenetic assays. In addition, an almost complete abolition of patulin (0.8 microM) clastogenicity was observed in the presence of 80 microM ascorbic acid (P < 0.05), showing that although a genetic risk is present, ascorbic acid could somehow partially modulate this problem.


Attentional processing of multiple targets and distractors.
We assessed the functioning of attention when multiple relevant objects are intermingled with multiple distractors, measuring two electrophysiological subcomponents of the N2pc that have been associated, respectively, with target selection and distractor suppression: the target negativity (Nt) and the distractor positivity (Pd). To this aim, we orthogonally manipulated the number of targets and distractors in an enumeration task. The Nt was modulated by target, but not distractor numerosity, suggesting that an increase in target numerosity leads to an increase in attentional resources needed to form individual representations of the targets. In contrast, the number of distractors did not differentially alter the Pd. We hypothesize that distractors sharing similar visual features can be processed (and possibly suppressed) as a set, without the need for individuation.


Risk assessment for HIV infection: validation study of a computer-assisted preliminary screen.
Development has been undertaken for microcomputer software intended to assess individual risk for HIV infection by analyzing personal case histories pertinent to drug abuse, receptive blood transfusion, and sexual behavior. The software performs interactive confidential interviews of individuals desiring expert assistance when deciding whether to commit to an antibody test. In the first phase of a validation study, 87 subjects responded to the computer interview. For each subject, human immunodeficiency virus (HIV) antibody status was on clinical record. This sample included 70 subjects, 29 of whom were HIV seropositive, recruited from the clientele of an AIDS antibody testing and counseling facility. In this phase, the software accurately assessed 28 of 29 seropositives (96.6%) to be at risk for HIV. The second phase was based upon participation of an additional 74 subjects who were undergraduates at the University of Oklahoma. In this presumed low-risk sample, 55 members reported never having previously tested for HIV antibodies. Seven members (12.7%) of the untested group were declared at risk in the course of receiving confidential computer screen advice. Of these 7, there were 3 members (42.9%) who were motivated by the computer to voluntarily seek HIV antibody testing. Of the 7 declared at risk, 2 members (3.9%) were among the 51 seronegative subjects classified as heterosexuals without specific and identified risks. All Phase II subjects seeking follow-up antibody tests were found seronegative.


Optimal medical therapy with or without percutaneous coronary intervention for patients with stable coronary artery disease and chronic kidney disease.
Chronic kidney disease (CKD) is a risk factor for poor outcomes in patients with coronary artery disease (CAD), but it is unknown whether CKD influences the efficacy of alternative CAD treatment strategies. Thus, we compared outcomes in stable CAD patients with and without CKD randomized to percutaneous coronary intervention (PCI) and optimal medical therapy (OMT) or OMT alone in a post hoc analysis of the 2,287 patient COURAGE study. At baseline, 320 patients (14%) had CKD defined as a glomerular filtration rate of <60 mL/min/1.73 m(2), as estimated by the abbreviated 4-variable Modification of Diet in Renal Disease equation. The patients with CKD were older (68 +/- 9 vs 61 +/- 10 years; p <0.001) and more often had diabetes mellitus (42% vs 33%; p = 0.002), hypertension (81% vs 65%; p <0.03), heart failure (13% vs 3.4%; p <001), and three-vessel CAD (37% vs 29%, p = 0.01). After adjustment for these differences, CKD remained an independent predictor of death or nonfatal myocardial infarction (hazard ratio 1.48, 95% confidence interval 1.15 to 1.90). PCI had no effect on these outcomes. Furthermore, at 36 months, a similar percentage of patients with CKD treated with OMT (70%) and PCI plus OMT (76%) were angina free compared to patients without CKD. In conclusion, CKD is an important determinant of clinical outcomes in patients with stable CAD, regardless of the treatment strategy. Although PCI did not reduce the risk of death or myocardial infarction when added to OMT for patients with CKD, it also was not associated with worse outcomes in this high-risk group.


Analyzing the Moving Parts of a Large-Scale Multi-Label Text Classification Pipeline: Experiences in Indexing Biomedical Articles.
Medical subject headings (MeSH) is a controlled hierarchical vocabulary used by the National Library of Medicine (NLM) to index biomedical articles. In the 2014 version of MeSH terminology there are a total of 27,149 terms. Librarians at the NLM tag each biomedical article to be indexed for the PubMed literature search system with terms from MeSH. This means the human indexers look at each article's full text and index it with a small set of descriptors, 13 on average, from over 27,000 descriptors available in MeSH. There have been many recent attempts to automate this process focused on using the article title and abstract text to predict MeSH terms for the corresponding article. There has also been an open automated biomedical indexing challenge, BioASQ [1], that started in 2013. The best general supervised learning framework in these challenges has been a pipeline with four different components: 1. pre-processing and feature extraction; 2. employing the binary relevance and/or nearest neighbor approaches to select a set of candidate terms; 3. ranking these candidate terms using corresponding informative features; and 4. applying label calibration to dynamically predict the number of top terms to be included in the final selection for the current instance. The specific details in how each of these components is implemented determines the performance variations of various entries in the challenge. In this paper, we analyze these moving parts of the MeSH indexing multi-label classification pipeline with experiments involving different combinations. Our best combination achieves ≈ 1% increase in micro F-score compared with the top performing team across the five weeks of the final batch of the BioASQ 2014 challenge. The main take away from our efforts is that small improvements/modifications to different components of the pipeline can offer moderate improvements to the overall performance of the method. Our experiences show that, at least thus far, top performances have resulted mostly due to these improvements rather than drastic changes of the core methodology.


A highly sensitive and adjustable colorimetric assay of hydrogen sulfide by signal amplification based on G-quadruplex-Cu2+ peroxidase mimetics.
This work reports the first example of a colorimetric H2S sensor constructed through G-quadruplex-Cu2+ (G4-Cu2+) peroxidase mimetics employing Cu2+ ions and G-rich DNA with signal amplification. In the hydrogen peroxide (H2O2)-mediated oxidation of 3,3',5,5'-tetramethylbenzidine (TMB), the catalytic capacity of Cu2+ can be greatly improved in the presence of 22AG DNA, where 22AG DNA acts as a signal amplifier. However, G4-Cu2+ peroxidase mimetics lose their catalytic abilities after reacting with H2S. This is employed to develop a colorimetric assay of H2S without complex synthesis and instrumentation, with a linear range from 0.01 μM to 150 μM and a detection limit of 7.5 nM. The sensitivity of the sensor can also be adjusted by changing the concentration of Cu2+. Moreover, the developed sensor is successfully applied for the quantitative determination of H2S in human serum samples.


Innate and adaptive immune responses of Arctic charr (Salvelinus alpinus, L.) during infection with Aeromonas salmonicida subsp. achromogenes and the effect of the AsaP1 toxin.
Aeromonas salmonicida subsp. achromogenes, the causative agent of atypical furunculosis in many fish species, secretes the toxic metalloendopeptidase AsaP1. This study aimed to analyze innate and adaptive immune parameters induced in Arctic charr (Salvelinus alpinus, L.) infected with wild type (wt) A. salmonicida subsp. achromogenes and its isogenic asaP1 deletion mutant (AsaP1-deficient). Head-kidney, liver and spleen were obtained from i.p. infected charr (wt, AsaP1-deficient), during a time schedule of 7 d post infection. Reverse transcription quantitative real-time PCR (RT-qPCR) was applied to study the expression of immune parameters: pro-inflammatory cytokines IL-1β and TNF-α; anti-inflammatory cytokine IL-10; chemokines CXCL-8 (IL-8) and CC-chemokine; the cytokines IFN-γ and IL-4/13A as tracers for Th1 and Th2 immune responses, respectively; and the cell markers CD8α and CD83. In addition, lymphoid organs were histopathologically examined at days 3 and 7 post infection, including B (IgM) and T (CD3ε) cell staining. The detected immune responses were initially driven by innate mechanisms represented by the up-regulation of pro-inflammatory cytokines and chemokines and later on by adaptive Th2 related responses cumulating in B-cell recruitment as shown by regulation of immune parameters in spleen and head-kidney, with significant differences between mutant and wt infected fish. Histological sections revealed IgM-positive cells around ellipsoid arterioles in spleen, while CD3ε positive cells were found in clusters scattered all over the section. However, histopathological differences were only detected between infected and non-infected fish, but not between AsaP1-deficient mutant and wt infected fish. This work represents the first study on innate and adaptive immune responses of Arctic charr induced by a bacterial infection.


D-penicillamine: chemistry and clinical use in rheumatic disease.
The discovery of D-penicillamine and its uses in medicine are reviewed. Chemical-physical properties are discussed, and the molecular structure of D-penicillamine and several of its reaction products are illustrated. Examples of its three main types of biochemical reactions--sulfhydryl-disulfide exchange, thiazolidine formation, and metal chelation are included. Trials of D-penicillamine in RA patients are reviewed critically. The administration of the drug is discussed in detail, including dosages, clinical and laboratory responses, patterns of adverse side effects or toxicity, drug-induced autoimmune diseases, indications and contraindications, and the monitoring and management of patients.


Day and Night Changes of Cardiovascular Complexity: A Multi-Fractal Multi-Scale Analysis.
Recently, a multifractal-multiscale approach to detrended fluctuation analysis (DFA) was proposed to evaluate the cardiovascular fractal dynamics providing a surface of self-similarity coefficients α(q,τ), function of the scale τ, and moment order q. We hypothesize that this versatile DFA approach may reflect the cardiocirculatory adaptations in complexity and nonlinearity occurring during the day/night cycle. Our aim is, therefore, to quantify how α(q, τ) surfaces of cardiovascular series differ between daytime and night-time. We estimated α(q,τ) with -5 ≤ q ≤ 5 and 8 ≤ τ ≤ 2048 s for heart rate and blood pressure beat-to-beat series over periods of few hours during daytime wake and night-time sleep in 14 healthy participants. From the α(q,τ) surfaces, we estimated short-term (<16 s) and long-term (from 16 to 512 s) multifractal coefficients. Generating phase-shuffled surrogate series, we evaluated short-term and long-term indices of nonlinearity for each q. We found a long-term night/day modulation of α(q,τ) between 128 and 256 s affecting heart rate and blood pressure similarly, and multifractal short-term modulations at q < 0 for the heart rate and at q > 0 for the blood pressure. Consistent nonlinearity appeared at the shorter scales at night excluding q = 2. Long-term circadian modulations of the heart rate DFA were previously associated with the cardiac vulnerability period and our results may improve the risk stratification indicating the more relevant α(q,τ) area reflecting this rhythm. Furthermore, nonlinear components in the nocturnal α(q,τ) at q ≠ 2 suggest that DFA may effectively integrate the linear spectral information with complexity-domain information, possibly improving the monitoring of cardiac interventions and protocols of rehabilitation medicine.


A Systematic Review of the Effectiveness of Antianxiety and Antidepressive Agents for Functional Dyspepsia.
Objective Functional dyspepsia (FD) is defined as persistent or recurrent pain or discomfort centered in the upper abdomen without organic disease. Psychosocial factors have been proposed as an important element in the pathophysiology of FD. Therefore, psychotropic agents having antianxiety or antidepressive action are expected to alleviate FD. We previously reported on the treatment of FD using such agents in a systematic review, wherein the effectiveness of the agents on FD was suggested, although there were several limitations. We searched for articles on this subject after our systematic review and re-reviewed them systematically. Methods Articles were searched for in MEDLINE from 2003 to 2014 using terms related to antianxiety or antidepressive agents. Clinical studies in which the effectiveness of such agents was clearly stated were selected from the retrieved articles. The newly selected and previously selected studies were combined, and statistical analyses were carried out. Results Nine studies were selected. Five of the studies indicated a significant symptomatic improvement using psychotropic drugs. A statistical analysis suggested a significant treatment effect of psychotropic agents having antianxiety or antidepressive action [pooled relative risk (PRR), 0.72; 95% confidence interval (95% CI), 0.52-0.99; p=0.0406] but did not show a significant benefit of treatment with agents having an antidepressive action alone (PRR, 0.63; 95% CI, 0.38-1.03; p=0.0665). Conclusion Our systematic review suggested that psychotropic drugs having antianxiety and antidepressive actions as a whole might be effective in alleviating FD symptoms, whereas those having only antidepressive action were not effective.


Bicentric validation of the navigated transcranial magnetic stimulation motor risk stratification model.
The authors sought to validate the navigated transcranial magnetic stimulation (nTMS)-based risk stratification model. The postoperative motor outcome in glioma surgery may be preoperatively predicted based on data derived by nTMS. The tumor-to-tract distance (TTD) and the interhemispheric resting motor threshold (RMT) ratio (as a surrogate parameter for cortical excitability) emerged as major factors related to a new postoperative deficit. In this bicentric study, a consecutive prospectively collected cohort underwent nTMS mapping with diffusion tensor imaging (DTI) fiber tracking of the corticospinal tract prior to surgery of motor eloquent gliomas. The authors analyzed whether the following items were associated with the patient's outcome: patient characteristics, TTD, RMT value, and diffusivity parameters (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]). The authors assessed the validity of the published risk stratification model and derived a new model. A new postoperative motor deficit occurred in 36 of 165 patients (22%), of whom 20 patients still had a deficit after 3 months (13%; n3 months = 152). nTMS-verified infiltration of the motor cortex as well as a TTD ≤ 8 mm were confirmed as risk factors. No new postoperative motor deficit occurred in patients with TTD > 8 mm. In contrast to the previous risk stratification, the RMT ratio was not substantially correlated with the motor outcome, but high RMT values of both the tumorous and healthy hemisphere were associated with worse motor outcome. The FA value was negatively associated with worsening of motor outcome. Accuracy analysis of the final model showed a high negative predictive value (NPV), so the preoperative application may accurately predict the preservation of motor function in particular (day of discharge: sensitivity 47.2%, specificity 90.7%, positive predictive value [PPV] 58.6%, NPV 86.0%; 3 months: sensitivity 85.0%, specificity 78.8%, PPV 37.8%, NPV 97.2%). This bicentric validation analysis further improved the model by adding the FA value of the corticospinal tract, demonstrating the relevance of nTMS/nTMS-based DTI fiber tracking for clinical decision making.


Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1.
Erythropoietin‑producing hepatocellular carcinoma cell surface type‑A receptor 3 (EPHA3) has been found to promote the proliferation and survival of prostate cancer (PCa) cell lines and prostate tumor development in nude mice. However, the regulation of EPHA3 in PCa remains largely unknown. This study is aimed to investigate the association between EPHA3 expression and androgen receptor (AR) signaling and the potential mechanism. We determined mRNA and protein levels of EPHA3 and AR signaling‑related genes in the PCa cell line 22Rv1 by reverse transcription‑polymerase chain reaction (RT‑PCR) and western blotting, respectively. The EPHA3 mRNA and protein levels were both found to be elevated by dihydrotestosterone (DHT) hormone in a dose‑ and time‑dependent manner, as AR and prostate‑specific antigen (PSA) expression were increased. Similarly, EPHA3 protein levels were also increased in the PCa cell line LNCaP stimulated with DHT or mibolerone (Mib). Overexpression of pEGFP‑AR in 22Rv1 cells significantly increased the EphA3 level, while AR knockdown with small interfering RNA (siRNA) for AR (siAR) markedly decreased the expression of EPHA3. The key EPHA3 promoter region associated with AR regulation was evaluated by co‑transfection of various pGL3‑basic‑luciferase reporter plasmids, containing EPHA3 core promoter fragments differing in length, with the AR plasmid or siAR into 22Rv1 cells. AR overexpression in 22Rvl cells raised the EphA3 promoter transcription activity of pGL3‑EPHA3‑Luc (EPHA3‑Luc)‑789, and vice versa. Similarly, luciferase activity of EPHA3‑Luc‑317 was also clearly affected. However, truncated EPHA3‑Luc‑237 without the transcription factor specific protein 1 (SP1) binding sites or EPHA3‑Luc‑789ΔSP1 with modified SP1 binding sites clearly decreased EPHA3 promoter activity regardless of whether AR was overexpressed or blocked. Treatment of 22Rv1 cells with 10 and 100 nM of the SP1 inhibitor mithramycin A for 24 and 48 h significantly reduced EPHA3 mRNA and protein levels. Additionally, selective inhibition of SP1 with siRNA SP1 (siSP1) at various concentration from 25 to 75 nM, reduced the EPHA3 protein level in PCa LNCaP cells, accordingly. Co‑immunoprecipitation (co‑IP) and chromatin IP (ChIP) assays were performed to determine whether AR forms a transcription factor complex with Sp1 that binds the EPHA3 core promoter region to sense androgen induction. The result suggests that the interaction of AR and SP1 contributes to regulate EPHA3 expression, and the SP1 binding sites (‑295~‑261) in the EPHA3 core promoter region is crucial to the regulation of EPHA3 expression in response to androgen hormone stimuli.


Musculoskeletal impairments after critical illness: A protocol for a qualitative study of the experiences of patients, family and health care professionals.
Survivors of critical care are at risk of long-term disability from musculoskeletal (MSK) impairments. These can have a biopsychosocial impact on the patient and their families with a reduction in health-related quality of life, increased health care utilization, caregiving roles and associated psychological distress. To understand the experiences of patients living with MSK impairments following critical illness, and family and health care professionals supporting them, to inform the development of a future intervention to improve MSK health following critical illness. A four-site qualitative case study approach will be taken, with each of the four hospital sites and associated community services representing a case site. We will conduct semi-structured interviews with 10-15 patients/family members and 10-15 health care professionals about their experiences of MSK impairment following critical illness. Interviews will be audio recorded, transcribed verbatim and analysed using reflexive thematic analysis within a descriptive phenomenological approach. Alongside interview data, analysis of publicly available policy documentation, patient-facing materials and information from service leads at the four sites will be conducted. Discourse analysis will be used for this case study documentation. This protocol describes a qualitative study exploring the experiences of patients living with MSK impairments following critical illness, and the family and health care professionals supporting them. Data analysis will illuminate their experiences and enable data richness to contribute to the qualitative body of evidence of intensive care unit (ICU) survivors. These findings will inform the development of a complex intervention for MSK rehabilitation after critical illness.


Pharmacokinetic and pharmaceutical properties of a novel buprenorphine/naloxone sublingual tablet for opioid substitution therapy versus conventional buprenorphine/naloxone sublingual tablet in healthy volunteers.
A novel sublingual buprenorphine/naloxone rapidly-dissolving tablet (BNX-RDT) for opioid substitution therapy has been developed for improved bioavailability, rapid disintegration and improved taste masking. We compared the bioavailability and pharmaceutical properties of BNX-RDT with conventional buprenorphine/naloxone sublingual tablets (BNX). Fasting, open-label, randomized, single-dose, two-cohort crossover study in healthy volunteers under naltrexone block. Cohort 1 (high-dose, N = 64) received BNX-RDT 11.4/2.9 mg and BNX 16/4 mg. Cohort 2 (low-dose, N = 61) received BNX-RDT 2.9/0.71 mg and BNX 4/1 mg. Plasma samples were collected over 72 h. Relative systemic exposures of buprenorphine and naloxone were assessed using standard statistical models for bioequivalence analysis. Pharmaceutical assessments included dissolve time, taste and mouthfeel assessments, and overall preference. BNX-RDT 11.4/2.9 mg provided equivalent buprenorphine and naloxone exposure to BNX 16/4 mg. BNX-RDT 2.9/0.71 mg provided ~20% lower buprenorphine and 35% lower naloxone exposure compared with BNX 4/1 mg. The comparison of BNX-RDT 2.9/0.71 mg with BNX 4/1 mg did not fully meet equivalence criteria. BNX-RDT was associated with improved dose proportionality across strengths compared with BNX (post hoc analysis), resulting in lower exposure from BNX-RDT relative to BNX at the lower strength. Median perceived dissolve times were significantly shorter for BNX-RDT than BNX at high (8.5 versus 16.2 min) and low (7.6 versus 9.1 min) doses. Taste and mouthfeel were rated significantly more pleasant than BNX, with ~78% of subjects preferring BNX-RDT. BNX-RDT provided improved buprenorphine absorption compared to a conventional sublingual tablet, with shorter dissolve times and improved taste and mouthfeel, resulting in a high preference for the novel formulation.


Benefit of Bilateral Cochlear Implantation on Phonological Processing Skills in Deaf Children.
Children with bilateral cochlear implants (CIs) would have better phonological processing skills than children with unilateral CIs because those with bilateral CIs have better speech perception abilities in noisy environments and higher levels of central auditory system development than those with unilateral CIs. Previous studies have focused on the performance of children with bilateral CIs on standardized clinical assessments. However, these tests are not sufficiently sensitive to explain better speech and language outcomes in children with bilateral CIs than children with unilateral CIs. Thus, this study focused on phonological processing skills at more central levels of analysis that reflect the operation of cognitive processes. Twenty children with bilateral CIs and 20 children with unilateral CIs, aged 4 to 6 years, participated in this study. The children completed the experience-dependent tasks and phonological processing tasks. The experience-dependent tasks involved the monosyllabic word, articulation, and receptive vocabulary tests. The phonological processing tasks involved the phonological awareness, phonological memory, and rapid automatic naming tasks. Task performance was compared between the unilateral and bilateral CI groups. Children with unilateral CIs performed similarly to children with bilateral CIs on all three experience-dependent tasks. However, children with bilateral CIs significantly outperformed children with unilateral CIs on all three phonological processing tasks. Among the phonological processing tasks, the rapid automatic naming task scores differentiated children with unilateral CIs from children with bilateral CIs. Bilateral cochlear implantation may positively impact the phonological processing skills of deaf children.


Promoting Creativity Through Transcranial Direct Current Stimulation (tDCS). A Critical Review.
Creativity, meant as the ability to produce novel, original and suitable ideas, has received increased attention by research in the last years, especially from neuroaesthetics and social neuroscience. Besides the research conducted on the neural correlates of such capacities, previous work tried to answer the question of whether it is possible to enhance creativity through cognitive and neural stimulation. In particular, transcranial direct current stimulation (tDCS) has been applied to increase neuronal excitability in those areas related to creativity. However, being a complex construct that applies to a huge variety of situations, available results are often confusing and inconsistent. Thus, in the present critical review, after selecting original research articles investigating creativity with tDCS, results will be reviewed and framed according to the different effects of tDCS and its underlying mechanisms, which can be defined as follows: the promotion of self-focused attention; the disruption of inhibiting mechanisms; the enhancement of creative thinking; the promotion of artistic enactment. Finally, a theoretical perspective, the creative on/off model, will be provided to integrate the reported evidence with respect to both anatomical and functional issues and propose a cognitive explanation of the emergence of creative thinking.


Identification of proteins regulated by PACAP in PC12 cells by 2D gel electrophoresis coupled to mass spectrometry.
The rat pheochromocytoma PC12 cell line has been widely used as a model to study neuronal differentiation. In particular, after serum depletion, PC12 cells stop to proliferate and undergo apoptosis. Under such conditions, treatment with pituitary adenylate cyclase-activating polypeptide (PACAP) promotes cell survival and induces neurite outgrowth. The identification of the proteins regulated by PACAP in PC12 cells under apoptotic conditions should provide valuable information concerning the mechanisms controlling neuronal cell survival and differentiation. To this aim, PC12 cells cultured in serum-free medium were treated with PACAP (10(-7) M), proteins were extracted, separated by two-dimensional gel electrophoresis (2-DE), and identified by MALDI-ToF mass spectrometry. The comparison between 16 2-DE maps led to the characterization of 110 proteins regulated by PACAP among which 22 have been identified by automatic query of the Mascot, Aldente, and Profound servers with the ProGeR-CDD database. Seventy-six percent of these proteins, including the p17 subunit of caspase-3, the heat shock protein hsp60, and the GTPase ran were found to be repressed whereas the others notably hsp27, tubulin beta-5, and calmodulin were overexpressed. Investigation of the putative functions indicated that some of the proteins regulated by PACAP and identified in the present article could control cell survival or differentiation.


The reliability and validity of the Turkish version of the Oxford Elbow Score.
Objective measures of outcome ensure reliable decisions with regard to treatment planning. Oxford Elbow Score (OES) is one of the common outcome measures used for assessing quality of life of patients with elbow disorders. OES consists of three domains: pain, elbow function and social/psychological. The aim of this study is to test the validity and reliability of the Turkish version of the OES. The study's sample includes 82 patients with elbow problems. The original version of the OES was translated into Turkish using the Isis Outcomes Translation and Linguistic Validation Process. The construct validity of the Turkish version of the OES was tested using a confirmatory factor analysis. For internal consistency, Cronbach's alpha was calculated. A Pearson correlation and a dependent sample t test were utilised for reproducibility of the OES. For convergent validity, the correlation coefficients were calculated between the domains of the OES and Short Form 36 (SF36). An independent sample t test was calculated to determine if there was a significant difference between the scores of the participants from the upper and lower groups. Confirmatory factor analysis (CFA) indicates that the three-factor structure of the OES was confirmed. Most of the fit indices are at the expected level, except for a root mean square error of approximation and an adjusted goodness of fit index. Cronbach's alpha was calculated as 0.91 for the whole scale. The results showed that there are positive and high correlations between the first and follow-up assessments (r = 0.89, p < 0.0001). The Turkish OES version and its dimensions have moderate and significant correlations with domains of SF36 in general. The test results indicated that the mean of each item on three domains of the OES was higher for the upper 27 %, and this difference was significant at the 0.01 level. The Turkish version of the OES is a reliable, valid, reproducible and practical tool. It can be used for patients with elbow disorders and is recommended for clinician use.


Establishing in-hospital geriatrics services in Africa: Insights from the University of Benin Teaching Hospital geriatrics project.
Unawareness of the peculiar healthcare needs of the elderly and resource constraints may be some reasons why until recently, Nigerian hospitals have not been equipped with the human and infrastructural resources required to meet older adults' special healthcare needs. There is paucity of specialized health services for the elderly in Africa. Nigeria, with a population of over 170 million, did not have any healthcare facility with dedicated services for the elderly until 2012. The University of Benin Teaching Hospital (UBTH) in Nigeria was established in 1973 and created its geriatrics unit in October 2013. A prepared environment and trained interdisciplinary teams are pivotal in providing effective healthcare services for the elderly. The ongoing UBTH geriatrics project aims to provide specialized interdisciplinary health services to older adults and to provide training and continuing professional development in geriatrics for healthcare staff. In developing our inpatient services, we adopted the acute care for elders (ACE) model and worked in tandem with the "ABCs" of implementing ACE units. In the face of limited resources, it was possible to establish a functional geriatrics unit with a trained interdisciplinary team. Family participation is central in our practice. Since October 2013, residents and house officers in internal medicine have been undertaking 4- and 12-weekly rotations, respectively. There is also a robust academic program, which includes once-weekly geriatric pharmacotherapy seminars, once-weekly interdisciplinary seminars, and 2-weekly journal club meetings alternating with seminars on geriatric assessment tools. It is possible to establish geriatric services and achieve best practices in resource-limited settings by investing on improving available human resources and infrastructure. We also make recommendations for setting up similar services in other parts of Africa.


Variable pulse repetition frequency output from an optically injected solid state laser.
An optically injected solid state laser (OISSL) system is known to generate complex nonlinear dynamics within the parameter space of varying the injection strength of the master laser and the frequency detuning between the master and slave lasers. Here we show that within these complex nonlinear dynamics, a system which can be operated as a source of laser pulses with a pulse repetition frequency (prf) that can be continuously varied by a single control, is embedded. Generation of pulse repetition frequencies ranging from 200 kHz up to 4 MHz is shown to be achievable for an optically injected Nd:YVO4 solid state laser system from analysis of prior experimental and simulation results. Generalizing this to other optically injected solid state laser systems, the upper bound on the repetition frequency is of order the relaxation oscillation frequency for the lasers. The system is discussed in the context of prf versatile laser systems more generally. Proposals are made for the next generation of OISSLs that will increase understanding of the variable pulse repetition frequency operation, and determine its practical limitations. Such variable prf laser systems; both low powered, and, higher powered systems achieved using one or more optical power amplifier stages; have many potential applications from interrogating resonance behaviors in microscale structures, through sensing and diagnostics, to laser processing.