Investigating the association of rs2910164 with cancer predisposition in an Irish cohort.
MicroRNAs (miRNAs) are small noncoding RNA molecules that exert post-transcriptional effects on gene expression by binding with cis-regulatory regions in target messenger RNA (mRNA). Polymorphisms in genes encoding miRNAs or in miRNA-mRNA binding sites confer deleterious epigenetic effects on cancer risk. miR-146a has a role in inflammation and may have a role as a tumour suppressor. The polymorphism rs2910164 in the MIR146A gene encoding pre-miR-146a has been implicated in several inflammatory pathologies, including cancers of the breast and thyroid, although evidence for the associations has been conflicting in different populations. We aimed to further investigate the association of this variant with these two cancers in an Irish cohort. The study group comprised patients with breast cancer (BC), patients with differentiated thyroid cancer (DTC) and unaffected controls. Germline DNA was extracted from blood or from saliva collected using the DNA Genotek Oragene 575 collection kit, using crystallisation precipitation, and genotyped using TaqMan-based PCR. Data were analysed using SPSS, v22. The total study group included 1516 participants. This comprised 1386 Irish participants; 724 unaffected individuals (controls), 523 patients with breast cancer (BC), 136 patients with differentiated thyroid cancer (DTC) and three patients with dual primary breast and thyroid cancer. An additional cohort of 130 patients with DTC from the South of France was also genotyped for the variant. The variant was detected with a minor allele frequency (MAF) of 0.19 in controls, 0.22 in BC and 0.27 and 0.26 in DTC cases from Ireland and France, respectively. The variant was not significantly associated with BC (per allele odds ratio = 1.20 (0.98-1.46), P = 0.07), but was associated with DTC in Irish patients (per allele OR = 1.59 (1.18-2.14), P = 0.002). The rs2910164 variant in MIR146A is significantly associated with DTC, but is not significantly associated with BC in this cohort.


Fabrication and optimization of uniform output couplers for far-infrared lasers.
An improved technique for the fabrication of uniform output couplers for far-infrared lasers has been developed. The technique includes a process for uniformly removing material from the back side of the coupler's substrate to tune the coupler's reflectivity precisely to the specified value for a particular laser line. Depending on the condition of the coupler after use, it can be retuned to another laser line, which lies within the coupler's reflectance envelope. Furthermore, when there is the possibility of lasing at two different laser wavelengths (as happens with some far-infrared lasers), it is possible to optimize the coupler for one wavelength while at the same time detuning the other wavelength. The fabrication and optimization of these devices are discussed.


The relationship between locus of control and depression: A cross-sectional survey with university students in Botswana.
Research has consistently revealed a positive association between external locus of control and depression. Little, if any, research has investigated locus of control and depression in the sociocultural context of Botswana. To explore the relationship between locus of control and depression among undergraduate students in Botswana and to determine the impact of age and gender on this relationship. University of Botswana. A sample of 272 students was surveyed through a self-administered questionnaire, which included the Levenson's multidimensional locus of control scale, the Beck Depression Inventory-II and demographic questions. Data analysis utilised descriptive statistics, correlation analysis, independent samples t-tests and standard multiple regression analysis. Of the 272 participants, 47.3% scored low (minimal) levels of depression, 23.4% scored mild levels, 18.0% scored moderate levels and 11.3% scored severe levels of depression. Students who believed that they were in control of events in their lives were less likely to present with depressive symptoms (r = -0.29, p = 0.000), while students who believed that chance (r = 0.45, p = 0.000) or powerful others (r = 0.40, p = 0.000) controlled their lives were more likely to have high depression scores. Both internal and external locus of control, together with age, explained 31% of the variance in depression scores; gender made no significant contribution to levels of depression. The study results draw attention to locus of control as one of the cognitive variables associated with depression. Further research is needed to determine how locus of control can be addressed in the treatment and prevention of depression in university contexts.


luxS in bacteria isolated from 25- to 40-million-year-old amber.
Interspecies bacterial communication is mediated by autoinducer-2, whose synthesis depends on luxS. Due to the apparent universality of luxS (present in more than 40 bacterial species), it may have an ancient origin; however, no direct evidence is currently available. We amplified luxS in bacteria isolated from 25- to 40-million-year-old amber. The phylogenies and molecular clocks of luxS and the 16S rRNA gene from ancient and extant bacteria were determined as well. Luminescence assays using Vibrio harveyi BB170 aimed to determine the activity of luxS. While the phylogeny of luxS was very similar to that of extant Bacillus spp., amber isolates exhibited unique 16S rRNA gene phylogenies. This suggests that luxS may have been acquired by horizontal transfer millions of years ago. Molecular clocks of luxS suggest slow evolutionary rates, similar to those of the 16S rRNA gene and consistent with a conserved gene. Dendograms of the 16S rRNA gene and luxS show two separate clusters for the extant and ancient bacteria, confirming the uniqueness of the latter group.


Raman Scattering in Carbon Nanosystems: Solving Polyacetylene.
Polyacetylene has been a paradigm conjugated organic conductor since well before other conjugated carbon systems such as nanotubes and graphene became front and center. It is widely acknowledged that Raman spectroscopy of these systems is extremely important to characterize them and understand their internal quantum behavior. Here we show, for the first time, what information the Raman spectrum of polyacetylene contains, by solving the 35-year-old mystery of its spectrum. Our methods have immediate and clear implications for other conjugated carbon systems. By relaxing the nearly universal approximation of ignoring the nuclear coordinate dependence of the transition moment (Condon approximation), we find the reasons for its unusual spectroscopic features. When the Kramers-Heisenberg-Dirac Raman scattering theory is fully applied, incorporating this nuclear coordinate dependence, and also the energy and momentum dependence of the electronic and phonon band structure, then unusual line shapes, growth, and dispersion of the bands are explained and very well matched by theory.


Role of tyrosine 337 in the binding of huperzine A to the active site of human acetylcholinesterase.
Huperzine A (HUP), a natural, potent, 'slow,' reversible inhibitor of antiacetylcholinesterase (AChE), has been suggested to be superior to antiacetylcholinesterase drugs now being used for management of Alzheimer's disease. To delineate the binding site of human AChE (HuAChE) for HUP, the biochemical constants kon, koff, and Ki were determined for complexes formed between HUP and single-site (Y337F, Y337A, F295A, W286A, and E202Q) or double-site (F295L/F297V) mutants of recombinant HuAChE (rHuAChE). The kinetic and dissociation constants were compared with those obtained for wild-type rHuAChE and AChE from Torpedo californica. Results demonstrate that the inhibition of AChE by HUP occurs through association with residues located inside the active site 'gorge,' rather than at the rim of the gorge. Tyrosine at position 337 (Y337) is essential for inhibition of rHuAChE by HUP (Ki = 26 nM). An aromatic array constituted from residues Y337, F295, and probably W86 is likely to offer a multicontact subsite that interacts with the ammonium group and with both the exo-and endocyclic double bond moieties of HUP. Lack of the aromatic side chain in the position homologous to Y337 explains the poor inhibitory potency of HUP toward human butyrylcholinesterase (Ki > 20,000 nM). Replacement of the carboxylate-containing E202 by glutamine had only marginal effect on the stability of the complex formed between HUP and rHuAChE. The pH-rate profiles suggest that destabilization of the complex after proton gain cannot be attributed solely to protonation of E202. These findings are expected to establish HUP as a lead compound for the design of new anti-AChE drugs.


Effects of Bach Flower Remedies on Menopausal Symptoms and Sleep Pattern: A Case Report.
Context • During the postmenopausal stage, women go through many remarkable changes, including physical, emotional, and hormonal. They also experience some unwanted effects, such as vasomotor symptoms, anxiety, and insomnia. The use of Bach flower remedies has been described as a supporting therapy for those symptoms. Objectives • The investigation aimed to evaluate the effects of the supplement on sleep pattern (ie, sleep perception and objective sleep) and on menopausal symptoms. Design • The research team created a case report. Setting • The study was conducted at the Menopause Transition and Postmenopause Sleep Disorder Clinic at the Department of Gynecology of the Federal University of São Paulo in São Paulo, Brazil. Participant • The participant was a 53-y-old, single woman, at the postmenopausal stage, who had been diagnosed with insomnia according to the criteria of the American Academy of Sleep Medicine and complained of climacteric symptoms. Intervention • The patient underwent treatment with a blend of the supplement for 4 mo. Outcome Measures • Sleep questionnaires were given and polysomnography was performed before and after treatment. Results • Both sleep perception and objective sleep were improved. The patient's anxiety and menopausal symptoms were reduced after the treatment with the supplement. Conclusion • The use of Bach flower remedies as a therapeutic strategy to relieve menopausal symptoms, such as anxiety, mood changes, and insomnia, seems worthy of further investigation.


Blueberry juice causes potent relaxation of rat aortic rings via the activation of potassium channels and the H₂S pathway.
The objective of this study was to investigate the in vitro effects of blueberry juice on healthy rat aortic rings, and to explore the roles of potassium channels and of the hydrogen sulphide (H(2)S) pathway in mediating the effects of blueberry juice. Firstly, the antioxidant capacity of blueberry juice was compared to other popular juice drinks using the Folin-Ciocalteu and the DPPH assays. Blueberry juice had significantly higher total polyphenol content than any of the other drinks studied (p < 0.01). The effect of blueberry juice on noradrenaline-contracted aortic rings was then observed, and the juice caused significant inhibition of noradrenaline-induced contractions (p < 0.01). Voltage-gated potassium channel (Kv) blockers 4-aminopyridine (1 mM) and 3,4-diaminopyridine (1 mM), as well as the cystathionine γ-lysase (CSE) inhibitor d,l-propargylglycine (2 mM) were then utilised to elucidate the role of Kv channels and the CSE/H(2)S pathway. Kv channel blocker 3,4-diaminopyridine caused significant blockade at 1/100 and 1/50 dilutions of juice (p < 0.01), whilst 4-aminopyridine caused significant blockade of the 1/100 dilution of blueberry juice (p < 0.05). In addition, d,l-propargylglycine potently inhibited the effect of 1/100 and 1/50 dilutions of blueberry juice (p < 0.01). This study indicates that blueberry juice has potent vasorelaxing properties, and thus may be a useful dietary agent for the prevention and treatment of hypertension. This study also provides strong evidence that Kv channels and the CSE/H(2)S pathway may be responsible, at least in part, for mediating the effects of blueberry juice.


Bridging from Goals to Tasks with Design Study Analysis Reports.
Visualization researchers and practitioners engaged in generating or evaluating designs are faced with the difficult problem of transforming the questions asked and actions taken by target users from domain-specific language and context into more abstract forms. Existing abstract task classifications aim to provide support for this endeavour by providing a carefully delineated suite of actions. Our experience is that this bottom-up approach is part of the challenge: low-level actions are difficult to interpret without a higher-level context of analysis goals and the analysis process. To bridge this gap, we propose a framework based on analysis reports derived from open-coding 20 design study papers published at IEEE InfoVis 2009-2015, to build on the previous work of abstractions that collectively encompass a broad variety of domains. The framework is organized in two axes illustrated by nine analysis goals. It helps situate the analysis goals by placing each goal under axes of specificity (Explore, Describe, Explain, Confirm) and number of data populations (Single, Multiple). The single-population types are Discover Observation, Describe Observation, Identify Main Cause, and Collect Evidence. The multiple-population types are Compare Entities, Explain Differences, and Evaluate Hypothesis. Each analysis goal is scoped by an input and an output and is characterized by analysis steps reported in the design study papers. We provide examples of how we and others have used the framework in a top-down approach to abstracting domain problems: visualization designers or researchers first identify the analysis goals of each unit of analysis in an analysis stream, and then encode the individual steps using existing task classifications with the context of the goal, the level of specificity, and the number of populations involved in the analysis.


Contiguous patterns of c-kit and steel expression: analysis of mutations at the W and Sl loci.
Mutations in either the dominant white-spotting (W) or Steel (Sl) loci of the mouse lead to coat color, primordial germ cell and hematopoietic defects. Consistent with the cell autonomous and microenvironmental nature of W and Sl mutations, respectively, it has recently been shown that W encodes the c-kit receptor tyrosine kinase while Sl encodes a ligand for this receptor. Previous in situ hybridization analysis has shown that both c-kit and steel are expressed in the embryo in anatomical sites known to be affected by W and Sl mutations and in various tissues in which no corresponding phenotype has been described. To investigate the possible involvement of the Kit transduction pathway in developmental processes, we compared the patterns of expression of c-kit and steel in wild-type embryos and in embryos homozygous for severe (lethal) and mild (viable) alleles at the W and Sl loci. In addition, we analyzed the patterns of expression of both genes in adult wild-type and mutant gonads and brain. Both c-kit and steel are contiguously expressed in a wide variety of anatomical locations in both the developing embryo and in the adult. In adult gonads, steel is expressed in the follicular cells of the ovary and in Sertoli cells of the testis, the layers that immediately surround the c-kit expressing germ cells. In adult brain, the complementary patterns are particularly striking in the olfactory bulb, cerebral cortex, hippocampus region and cerebellum. steel expression in brain is probably restricted to neurons in certain areas, while c-kit is expressed in neurons and in some glial cells. Severe mutations in the W or Sl loci result in dramatic reduction or absence of c-kit positive cells in lineages known to be affected by these mutations. In contrast, these mutations do not affect the number or histological organization of c-kit positive cells in the embryonic peripheral or central nervous systems, nor is the number or organization of c-kit positive cells detectably altered in Wv/Wv or Sld/Sld adult brain. Taken together, these results suggest that the Kit signaling pathway is not obligatory for the viability and/or migration of most c-kit expressing cells either because of functional redundancy with another signaling pathway or because the Kit pathway is involved in post-developmental processes of mature cells.


Supercoiling induces denaturation bubbles in circular DNA.
We present a theoretical framework for the thermodynamic properties of supercoiling-induced denaturation bubbles in circular double-stranded DNA molecules. We explore how DNA supercoiling, ambient salt concentration, and sequence heterogeneity impact on the bubble occurrence. An analytical derivation of the probability distribution to find multiple bubbles is derived and the relevance for supercoiled DNA discussed. We show that in vivo sustained DNA bubbles are likely to occur due to partial twist release in regions rich in weaker AT base pairs. Single DNA plasmid imaging experiments clearly demonstrate the existence of bubbles in free solution.


Light scattering by red blood cells in ektacytometry: Fraunhofer versus anomalous diffraction.
In the present literature on ektacytometry, small angle light scattering by ellipsoidal red blood cells is commonly approximated by Fraunhofer diffraction. Calculations on a sphere with the size and relative refractive index of a red cell, however, show that Fraunhofer diffraction deviates significantly from exact Mie theory. Anomalous diffraction is found to be a much better approximation. The anomalous diffraction theory is used to calculate the intensity distribution of the light scattered by an ellipsoidally deformed red blood cell. The derived expression shows that the ellipticity of isointensity curves in forward scattered light are equal to the ellipticity of the red blood cell. The theoretical expression is fitted to the intensity patterns measured with an ektacytometer. For the small observation angles used in ektacytometry, the experimental results confirm the validity of the anomalous diffraction approach.


Severe morbidity and mortality risk from malaria in the United States, 1985-2011.
Recent reports of Plasmodium vivax associated with severe syndromes and mortality from malaria endemic areas questions the "benign" course of non-falciparum malarias. We retrospectively analyzed data from patients reported to the US Centers for Disease Control and Prevention with a diagnosis of malaria parasite single-species infection between 1985 and 2011. Patients classified as having severe illness were further classified according to outcome (survival versus death) and clinical syndrome. Among all cases, .9% of Plasmodium falciparum cases resulted in death and 9.3% were classified as severe, whereas .09% of P. vivax cases resulted in death and 1.3% were classified as severe. The odds ratios for severe illness among 15 272 diagnoses of P. falciparum relative to patients diagnosed with P. vivax (n = 12 152), Plasmodium malariae (n = 1254), or Plasmodium ovale (n = 903) was 7.5, 5.7, and 5.0, respectively (P < .0001 for all); in contrast, the corresponding odds ratios for death among those severely ill was 1.6, 1.1, and .8 (P > .1 for all), respectively. Compared with P. vivax (n = 163), the odds of P. falciparum cases classified as severely ill (n = 1416) were 1.9 (P = .0006), .5 (P = .001), and 1.3 times (P = .1) as likely to present as cerebral, acute respiratory distress, and renal syndromes, respectively. Although less common, patients presenting with non-falciparum even in the United States can develop severe illness, and severe illness in patients having malaria of any species threatens life.


Formula tolerance in postbreastfed and exclusively formula-fed infants.
Perceived intolerance to infant formula is a frequently reported reason for formula switching. Formula intolerance may be related to perceived symptoms of constipation, fussiness, abdominal cramps, and excessive spit-up or vomit. Commercially available formulas differ from each other in processing and in sources and levels of protein, lipids, and micronutrients. These differences may affect tolerance. The objective of this article was to compare the tolerance of two commercially available powder infant formulas that differ in composition. Measures of tolerance in exclusively breastfed infants weaned to an infant formula and exclusively formula-fed infants were evaluated. Two clinical studies were conducted. In study 1, 82 healthy, full-term infants who were exclusively breastfed at the time of enrollment were randomized at weaning to formula A (commercially available Similac With Iron Powder) or formula B (previously available Enfamil With Iron Powder). Parents completed daily records of tolerance during exclusive breast milk feeding, during the weaning period, and for a 2-week exclusive formula-feeding period. In study 2, 87 healthy, full-term infants who were exclusively formula-fed at the time of study enrollment (by 2 weeks of age) were fed a standard cow milk-based formula (previously commercially available Similac With Iron Powder) and then randomized to receive formula A or B for a 2-week period. Parents completed daily records of tolerance throughout the study. Formula A was a cow milk-based formula with a whey:casein ratio of 48:52 and a fat blend of 42% high-oleic safflower, 30% coconut, and 28% soy oils. Formula B was a cow milk-based formula with a whey:casein ratio of 60:40 and a fat blend of 45% palm olein, 20% soy, 20% coconut, and 15% high-oleic sunflower oils. Both formulas had lactose as the source of carbohydrate and contained 12 mg of iron per liter. Only formula A contained nucleotides at the time of the study. Measures of tolerance included volume of each formula feeding, occurrences of spit-up and/or vomit, and the color (yellow, green, brown, or black) and consistency (water, loose/mushy, soft, formed, or hard) of each stool. In both studies, volume of formula intake, weight gain, and incidence of spit-up or vomit did not differ between feeding groups. In study 1, stool frequency decreased significantly from the exclusive breast milk period to weaning. Stools also became firmer as infants moved from breast milk to weaning and to exclusive formula feeding. When formula was introduced into the diet, stools became less yellow and more green. Infants weaned to formula B had less frequent stools, fewer brown stools, and more yellow stools than did infants fed formula A. In both studies, infants fed formula B experienced significantly firmer stools than did those fed formula A. The present clinical studies indicate that the composition and/or processing of milk-based powder iron-fortified infant formulas affect stool characteristics experienced by infants. The inclusion of palm olein oil in formula B may be the reason for the observed differences in stool characteristics. Palm olein is used in infant formulas to provide palmitic acid at a level similar to that found in breast milk. However, palmitic acid from palm olein is arranged differently from that in breast milk triglyceride and is poorly absorbed. Unabsorbed palmitic acid tends to react with calcium to form insoluble soaps, and the level of these soaps is correlated with stool hardness. The pattern of softer stools and greater frequency of stooling associated with formula A is similar to the stool pattern in the exclusively breastfed infant. Thus, the use of formula A may ease the transition from breast milk to formula feeding and ameliorate parents' perception that constipation is associated with iron-fortified formula.


Beyond transrectal ultrasound-guided prostate biopsies: available techniques and approaches.
Recent advances have led to the use of magnetic resonance imaging (MRI) alone or with fusion to transrectal ultrasound (TRUS) images for guiding biopsy of the prostate. Our group sought to develop consensus recommendations regarding MRI-guided prostate biopsy based on currently available literature and expert opinion. The published literature on the subject of MRI-guided prostate biopsy was reviewed using standard search terms and synthesized and analyzed by four different subgroups from among the authors. The literature was grouped into four categories-MRI-guided biopsy platforms, robotic MRI-TRUS fusion biopsy, template mapping biopsy and transrectal MRI-TRUS fusion biopsy. Consensus recommendations were developed using the Oxford Center for Evidence Based Medicine criteria. There is limited high level evidence available on the subject of MRI-guided prostate biopsy. MRI guidance with or without TRUS fusion can lead to fewer unnecessary biopsies, help identify high-risk (Gleason ≥ 3 + 4) cancers that might have been missed on standard TRUS biopsy and identify cancers in the anterior prostate. There is no apparent significant difference between MRI biopsy platforms. Template mapping biopsy is perhaps the most accurate method of assessing volume and grade of tumor but is accompanied by higher incidence of side effects compared to TRUS biopsy. Magnetic resonance imaging-guided biopsies are feasible and better than traditional ultrasound-guided biopsies for detecting high-risk prostate cancer and anterior lesions. Judicious use of MRI-guided biopsy could enhance diagnosis of clinically significant prostate cancer while limiting diagnosis of insignificant cancer.


Sound analysis of catathrenia: a vocal expiratory sound.
Catathrenia (nocturnal groaning) is a rare and relatively little-understood parasomnia. The characteristics of the sound and the recordings are not similar in all the relevant research papers. Indeed, there is currently some discussion regarding whether or not this is a single entity. For some authors, catathrenia is a particular form of parasomnia; for others, it may be a variant of snoring or a respiratory problem. The goal is to establish whether or not catathrenia may be regarded as an expiratory vocal sound. An attempt was made to classify the origin of this sound according to its sound structure. We present the sound analysis of two patients, a man and a woman, with clinically diagnosed catathrenia and we compared them with the analysis of snoring. We use the spectrogram and the oscillogram. We classified the sounds according to the Yanagihara criteria. The vocal nature of the sound was confirmed, and several significant differences to some snoring sounds were discovered. The analysis of the catathrenia samples demonstrated that these signals are type II according to Yanagihara classification; these signals had a very short jitter, and had formants and harmonics. However, snoring is a type III, very irregular and had formants but not harmonics. The oscillogram and the spectrogram in these patients show that the origins of the sounds are clearly different: catathrenia is laryngeal, while snoring is guttural. Catathrenia cannot be considered as expiratory snoring.


Using expert opinion to quantify unmeasured confounding bias parameters.
To develop and apply a method to quantify bias parameters in the case example of the association between alcohol use and HIV-serodiscordant condomless anal sex with potential confounding by sensation seeking among men who have sex with men (MSM), using expert opinion as an external data source. Through an online survey, we sought the input of 41 epidemiologist and behavioural scientists to quantify six parameters in the population of MSM: the proportion of high sensation seeking among heavy-drinking MSM, the proportion of sensation seeking among low-level drinking MSM, and the risk ratio (RR) of the association between sensation seeking and condomless anal sex, for HIV-positive and HIV-negative MSM. Eleven experts responded. For HIV-positive heavy drinkers, the proportion of high sensation seeking was 53.6% (beta distribution [α=5.50, β=4.78]), and 41.1% (beta distribution [α=3.10, β=4.46]) in HIV-negative heavy drinkers. In HIV-positive low-level alcohol drinkers, high sensation seeking was 26.9% (beta distribution [α=1.81, β=4.92]), similar to high sensation seeking among HIV-negative low-level alcohol drinkers (25.3%) (beta distribution [α=2.00, β=5.89]). The lnRR for the association between sensation seeking and condomless anal sex was ln(2.4) (normal distribution [μ=0.889, σ=0.438]) in HIV-positive and ln(1.5) (normal distribution [μ=0.625, σ=0.391]) in HIV-negative MSM. Expert opinion can be a simple and efficient method for deriving bias parameters to quantify and adjust for hypothesized confounding. In this test case, expert opinion confirmed sensation seeking as a confounder for the effect of alcohol on condomless anal sex and provided the parameters necessary for probabilistic bias analysis.


Voltammetry and molecular assembly of G-quadruplex DNAzyme on single-crystal Au(111)-electrode surfaces - hemin as an electrochemical intercalator.
DNA quadruplexes (qs) are a class of "non-canonical" oligonucleotides (OGNs) composed of stacked guanine (G) quartets stabilized by specific cations. Metal porphyrins selectively bind to G-qs complexes to form what is known as DNAzyme, which can exhibit peroxidase and other catalytic activity similar to heme group metalloenzymes. In the present study we investigate the electrochemical properties and the structure of DNAzyme monolayers on single-crystal Au(111)-electrode surfaces using cyclic voltammetry and scanning tunnelling microscopy under electrochemical potential control (in situ STM). The target DNAzyme is formed from a single-strand OGN with 12 guanines and iron(iii) porphyrin IX (hemin), and assembles on Au(111) through a mercapto alkyl linker. The DNAzyme monolayers exhibit a strong pair of redox peaks at 0.0 V (NHE) at pH 7 in acetate buffer, shifted positively by about 50 mV compared to free hemin weakly physisorbed on the Au(111)-electrode surface. The voltammetric hemin signal of DNAzyme is enhanced 15 times compared with that of hemin adsorbed directly on the Au(111)-electrode surface. This is indicative of both the formation of a close to dense DNAzyme monolayer and that hemin is strongly bound to the immobilized 12G-qs in well-defined orientation favorable for interfacial ET with a rate constant of 6.0 ± 0.4 s-1. This is supported by in situ STM which discloses single-molecule G-quartet structures with a size of 1.6 ± 0.2 nm.


EEG power and coherence during preschoolers' performance of an executive function battery.
The current study investigated a set of abilities collectively referred to as executive function (EF). Substantial improvement in EF ability occurs between 3 and 6 years of age (e.g., Carlson [2005] Developmental Neuropsychology, 28(2):595-616). This improvement is thought to reflect changes in brain development, especially in areas of prefrontal cortex and frontal cortex, which occur during this time period (e.g., Luu & Posner [2003] Brain 126:2119-2120). Little work has examined preschoolers' cortical activity during EF tasks, despite the frequent use of performance on such tasks as indirect measures of (pre)frontal functioning. The current study measured continuous EEG activity in 104 preschool aged children as they completed a battery of EF tasks. Changes from baseline to task performance in EEG activity (power, coherence) were used as predictors of EF ability. Results indicated that changes from baseline to task engagement in EEG coherence, but not EEG power, were significantly related to performance on the EF battery in our sample.


Spatial-domain low-coherence quantitative phase microscopy for cancer diagnosis.
A microscopy technique, spatial-domain low-coherence quantitative phase microscopy (SL-QPM) is proposed for speckle-free, quantitative phase imaging of subcellular structures with subnanometer sensitivity. We quantified, for the first time to our knowledge, the refractive index of the cell nuclei on original unmodified histology specimens. We demonstrate that the refractive index of cell nucleus is highly sensitive in detecting cancer, especially in histologically normal-appearing cells from cancer patients. Because this technique is sensitive and does not require special sample processing, it can be disseminated to all clinical settings.


NMDA-R1 subunit of the cerebral cortex co-localizes with neuronal nitric oxide synthase at pre- and postsynaptic sites and in spines.
The majority of nitric oxide's (NO) physiologic and pathologic actions in the brain has been linked to NMDA receptor activation. In order to determine how the NO-synthesizing enzyme within brain, neuronal NO synthase (nNOS), and NMDA receptors are functionally linked, previous studies have used in situ hybridization techniques in combination with light microscopic immunocytochemistry to show that the two are expressed within single neurons. However, this light microscopic finding does not guarantee that NMDA receptors are distributed sufficiently close to nNOS within single neurons to allow direct interaction of the two. Thus, in this study, dual immuno-electron microscopy was performed to determine whether nNOS and NMDA receptors co-exist within fine neuronal processes. We show that nNOS and the obligatory subunit of functional NMDA receptors, i.e. the NMDA-R1, co-exist within dendritic shafts, spines and terminals of the adult rat visual cortex. Axon terminals form asymmetric synaptic junctions with the dually labeled dendrites, suggesting that the presynaptic terminals release glutamate. Axons and dendrites expressing one without the other also are detected. These results indicate that it is possible for the generation of NO to be temporally coordinated with glutamatergic synaptic transmission at axo-dendritic and axo-axonic junctions and that NO may be generated independently of glutamatergic synaptic transmission. Together, our observations point to a greater complexity than previously recognized for glutamatergic neurotransmission, based on the joint versus independent actions of NO relative to NMDA receptors at pre- versus postsynaptic sites.


Urinary prostaglandin and sodium metabolism in patients with essential hypertension.
Urinary prostaglandin E (PGE) excretion as an indicator of renal PGE, urinary aldosterone excretion, plasma renin activity, urinary sodium excretion, and urinary potassium excretion were measured after sodium depletion in 15 patients with essential hypertension to investigate the interaction between renal PGE and sodium metabolism. Following sodium depletion, urinary PGE excretion decreased, whereas urinary aldosterone excretion and plasma renin activity increased. Significant positive correlations were found between urinary PGE excretion and urinary sodium excretion (r=0.41, p less than 0.01) or urinary sodium excretion-urinary potassium excretion ratio (r = 0.43, p less than 0.005). These results support the hypothesis that the renal PGE may play an important role in the regulation of sodium metabolism and this action of PGE is independent of the renin-aldosterone system.


Effect of Pt Nanoparticles on the Photocatalytic Activity of ZnO Nanofibers.
For this study, we originally realized ZnO nanofibers (∼50 nm in mean radius) mixed with Pt nanoparticles (∼30 nm in mean radius), prepared by pulsed laser ablation in liquid, and investigated their photocatalytic performance. The material was synthesized by the simple electrospinning method coupled with subsequent thermal treatments. Methylene blue was employed as a representative dye pollutant to evaluate the photocatalytic activity of the nanofibers. It was found that the Pt-ZnO fibers exhibit a photodegradation reaction rate that is ∼40 % higher than the one obtained for reference ZnO fibers. These encouraging results demonstrate that Pt-ZnO nanofibers can be fruitfully applied for environmental applications.


Beam propagation in gradient refractive-index media.
A generalized beam propagation method is described that uses the ABCD matrices to treat optical systems that have modest amounts of aberrations including gradient refractive-index elements. We can make calculations from any point in the near or far field to any other point by using appropriate numerical algorithms. The variation of the reduced length is discussed as a limitation to accuracy. The diffraction properties of a complex stigmatic system may be represented by those of an equivalent elementary system. This facilitates calculations using the standard diffraction operations for homogeneous media. The modified propagation technique replaces the large number of diffraction steps commonly used for the split-step solution of inhomogeneous media with one step for stigmatic media and in general no more than a few steps for aberrated media. Maxwell's fisheye lens is discussed in detail to show application of the method.


Effects of Arctium lappa L. (Burdock) root tea on inflammatory status and oxidative stress in patients with knee osteoarthritis.
This study was designed to examine the effect of Burdock root tea on inflammatory markers and oxidative stress indicators in patients with knee osteoarthritis (OA). Thirty-six patients (10 men and 26 women) aged 50-70 years old with knee osteoarthritis referred to the Physical Medicine and Rehabilitation Department of the Tabriz University of Medical Sciences Hospitals, were selected for the study and randomly divided into two groups. Anthropometric measurements, including height, weight and body mass index (BMI) were measured. For all individuals along the 42 days of study period, the same drug treatments, including two lots of 500 mg acetaminophen twice a day and one glucosamine 500 mg once a day,were considered. The intervention group received daily three cups of Burdock root tea (each cup containing 2 g/150 mL boiled water) half-hour after the meal. The control group received three cups containing 150 cc boiled water daily. We assessed inflammatory markers such as high sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) and oxidative stress indicators such as total antioxidants capacity (TAC), glutathione peroxidase (GPX), superoxide dismutase (SOD) and thiobarbituric acid reactive substances before and after the intervention. The results showed that burdock root tea significantly decreased the levels of serum IL-6 (P = 0.002), hs-CRP (P = 0.003) and malondialdehyde (P < 0.001), while the levels of serum TAC (P < 0.001) and activities of SOD (P = 0.009) were significantly increased. GPX activities increased but not significantly. The results suggested that Arctium lappa L. root tea improves inflammatory status and oxidative stress in patients with knee osteoarthritis.


c-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: an assessor-blind placebo-controlled randomized study.
To test the hypothesis that the c-Jun NH2-terminal kinase (JNK) inhibitor (JNKI) bentamapimod (AS602801/PGL5001) can reduce induced endometriosis in baboons. Prospective randomized placebo-controlled study. Nonhuman primate research center. Twenty baboons each underwent four laparoscopies. Initial screening laparoscopy (L1) was followed after one rest cycle by an endometriosis-induction laparoscopy (L2). Fifty days after L2, the baboons were randomized just before staging laparoscopy (L3). Treatment lasted for 60 days, followed by a post-treatment staging laparoscopy (L4). Randomization before a 60-day treatment in four groups: daily placebo (n = 5), daily oral administration of 20 mg/kg JNKI (n = 5), concomitant daily oral administration of 20 mg/kg JNKI and 10 mg medroxyprogesterone acetate (MPA; n = 5), or subcutaneous administration of 3 mg cetrorelix every 3 days (n = 5). Type, surface area and volume of endometriotic lesions, and revised American Society for Reproductive Medicine score and stage were recorded during L3 and L4. Menstrual cycle length and serum hormonal concentration were recorded before and after treatment. Compared with placebo, treatment with JNKI, JNKI + PMA, or cetrorelix resulted in lower total surface area and volume of endometriotic lesions. Remodeling of red active lesions into white lesions was observed more frequently in baboons treated with JNKI + MPA than in baboons treated with JNKI only. Menstrual cycle length and serum hormonal concentration were similar between placebo and JNKI groups. JNKI alone was as effective as JNKI + MPA or cetrorelix in reducing induced endometriosis in baboons, but without severe side effects or effect on cycle length or serum reproductive hormones.


A novel, diminutive Hemiphyllodactylus Bleeker, 1860 (Squamata: Gekkonidae) from a sacred grove in Odisha, eastern India.
We describe a distinct new species of Hemiphyllodactylus from a sacred grove near Humma in Ganjam District of Odisha state, eastern India. Hemiphyllodactylus minimus sp. nov. is the smallest member of the genus and can be diagnosed from all peninsular Indian congeners by its small body size (SVL ≤32.2 mm, n=11), having 15-18 dorsal scales and eight or nine ventral scales at mid-body contained within one longitudinal eye diameter, nine or ten precloacal pores separated by 4-6 poreless scales from a series of six or seven femoral pores on each thigh in males, lamellar formula of manus 2222 and of pes 2332 2333, as well as subtle colour pattern differences. Additionally, the new species is 16.0-22.7 % divergent from all other peninsular Indian Hemiphyllodactylus in uncorrected ND2 sequence data. The new species is the first member of the genus described from Odisha state and also the first Hemiphyllodactylus known from < 100 m asl. The discovery of Hemiphyllodactylus minimus sp. nov. from a low elevation coastal locality in the Eastern Ghats open ups the possibilities that the genus could be more widespread than currently understood and potentially harbour many more distinct undescribed lineages. Therefore, dedicated fine-scale sampling efforts are needed to uncover the true diversity and distribution of Hemiphyllodactylus in the region.


Manipulation of the primary breast tumor and the incidence of sentinel node metastases from invasive breast cancer.
The incidence of sentinel node (SN) metastases from invasive breast cancer might be affected by the technique used to obtain biopsy specimens from the primary tumor before sentinel lymph node dissection. Prospective database study. The John Wayne Cancer Institute. We identified 663 patients with biopsy-proven invasive breast cancer who underwent sentinel lymph node dissection between January 1, 1995, and April 30, 1999. Patients were divided into 3 groups based on type of biopsy: fine-needle aspiration (FNA), large-gauge needle core, and excisional. A logistic regression model was used to correlate tumor size, tumor grade, and type of biopsy with the incidence of SN metastases. Of the 676 cancers, 126 were biopsied by FNA, 227 by large-gauge needle core biopsy, and 323 by excisional biopsy before sentinel lymph node dissection. Mean patient age was 58 years (range, 28-96 years), and mean tumor size was 1.85 cm (range, 0.1-9.0 cm). In multivariate analysis based on known prognostic factors, the incidence of SN metastases was higher in patients whose cancer was diagnosed by FNA (odds ratio, 1.531; 95% confidence interval, 0.973-2.406; P =.07, Wald test) or large-gauge needle core biopsy (odds ratio, 1.484; 95% confidence interval, 1.018-2.164; P =.04, Wald test) than by excision. Tumor size (P<.001) and grade (P =.06) also were significant prognostic factors. Manipulation of an intact tumor by FNA or large-gauge needle core biopsy is associated with an increase in the incidence of SN metastases, perhaps due in part to the mechanical disruption of the tumor by the needle. The clinical significance of this phenomenon is unclear.


Evidence of parasympathetic activity of the angiotensin converting enzyme inhibitor, captopril, in normotensive man.
Captopril (50 mg orally) produced a significant fall in systolic and diastolic blood pressure in six normotensive sodium replete subjects, without a rise in heart rate. On captopril, there was no change in the expected normal increase in heart rate on standing. Supine plasma noradrenaline was not reduced by captopril and normal postural increases were maintained. Atropine (0.04 mg/kg i.v.) reduced the difference in blood pressure change between captopril and placebo. Facial immersion in water produced a bradycardia. This change was abolished by atropine and attenuated both by captopril and edrophonium (10 mg i.v.), a cholinesterase inhibitor. Lying down after 6 min standing produced an immediate transient tachycardia, which was abolished by atropine and attenuated by captopril. Blood pressure and heart rate rose after a cold pressor test on both captopril and placebo. The tachycardia during the Valsalva manoeuvre was inhibited by edrophonium and to a lesser extent by captopril. The effects of captopril and edrophonium were additive. Parasympathetic activity of captopril may contribute to its haemodynamic profile.


Postoperative imaging of orthopaedic hardware in the hand and wrist: is there an added value for tomosynthesis?
To prospectively investigate digital tomosynthesis (DTS) as an alternative to digital radiography (DR) for postoperative imaging of orthopaedic hardware after trauma or arthrodesis in the hand and wrist. Thirty-six consecutive patients (12 female, median age 36 years, range 19-86 years) were included in this institutional review board approved clinical trial. Imaging was performed with DTS in dorso-palmar projection and DR was performed in dorso-palmar, lateral, and oblique views. Images were evaluated by two independent radiologists for qualitative and diagnosis-related imaging parameters using a four-point Likert scale (1=excellent, 4not diagnostic) and nominal scale. Interobserver agreement between the two readers was assessed with Cohen's kappa (k). Differences between DTS and CR were tested with Wilcoxon's signed-rank test. A p-value <0.05 was considered statistically significant. Regarding image quality, interobserver agreement was higher for DTS compared to DR, especially for fracture-related parameters (delineation osteosynthesis material [OSM]: KDTS0.96 versus KDR0.45; delineation fracture margins: KDTS0.78 versus KDR0.35). Delineation of fracture margins and delineation of adjacent joint spaces scored significant better for DTS compared to DR (delineation fracture margins: DTS1.54, DR2.28, p0.001; delineation adjacent joint spaces: DTS1.31, DR2.24, p0.001). Regarding diagnosis-related findings, interobserver agreement was almost equal. DTS showed a significant higher sharpness of fracture margins (DTS1.94, DR2.33, p0.04). Mean dose area product (DAP) for DTS was significant higher compared to DR (mean DR0.219 Gy·cm2, mean DTS0.903 Gy·cm2, p0.001). Fracture healing is more visible and interobserver agreement is higher for DTS compared to DR in the postoperative assessment of orthopaedic hardware in the hand and wrist.


Eocene Epiphyllous Fungi.
Fossil fungi belonging to the Meliolaceae and Microthyriaceae were found in Eocene deposits in Tennessee. Germinated spores for each form of fungus were identified. One of the two forms of the genus Meliola, (Meliolaceae) appears to have parasitized the leaf upon which it grew. The vegetative, sexual, and asexual reproductive structures are preserved in a member of the genus Asterina (Microthyriaceae). The discovery of these fungi indicates that Western Tennessee was warm and humid during the Eocene.


A low-carbohydrate diet is more effective in reducing body weight than healthy eating in both diabetic and non-diabetic subjects.
Low-carbohydrate diets are effective for weight reduction in people without diabetes, but there is limited evidence for people with Type 2 diabetes. Aims To assess the impact of a low-carbohydrate diet on body weight, glycated haemoglobin (HbA(1c)), ketone and lipid levels in diabetic and non-diabetic subjects. Thirteen Type 2 diabetic subjects (on diet or metformin) and 13 non-diabetic subjects were randomly allocated to either a low-carbohydrate diet (< or = 40 g carbohydrate/day) or a healthy-eating diet following Diabetes UK nutritional recommendations and were seen monthly for 3 months. Subjects (25% male) were (mean +/- sd) age 52 +/- 9 years, weight 96.3 +/- 16.6 kg, body mass index 35.1 kg/m(2), HbA(1c) 6.6 +/- 1.1%, total cholesterol 5.1 +/- 1.1 mmol/l, high-density lipoprotein cholesterol 1.3 +/- 0.4 mmol/l, low-density lipoprotein cholesterol 3.1 +/- 0.9 mmol/l, triglycerides (geometric mean) 1.55 (1.10, 2.35) mmol/l and ketones range 0.0-0.2 mmol/l. Analysis was by intention to treat with last observation carried forward. Twenty-two of the participants (85%) completed the study. Weight loss was greater (6.9 vs. 2.1 kg, P = 0.003) in the low-carbohydrate group, with no difference in changes in HbA(1c), ketone or lipid levels. The diet was equally effective in those with and without diabetes.


Antiproliferative Acylated Glycerols from New Zealand Propolis.
Previous work has shown that a number of phenolic components of NZ propolis possess antiproliferative activity against certain human gastrointestinal cancer cell lines. Here we report on a series of acylglycerols isolated from the nonpolar fraction of propolis resin, which represent further bioactive constituents unrelated to the more usual phenolic compounds generally found in propolis. NZ propolis is sourced from poplar trees, and the acylglycerols have been shown to be present in the leaves and buds of some common poplars. The compounds are a series of monoglycerides containing 3,8-dihydroxy fatty acids, many of which are further acylated with acetic acid residues. The dihydroxy fatty acids are C18 to C24, with the most abundant being C20 and C22. These acylglycerols were found to have strong antiproliferative activity against three human gastrointestinal cell lines, particularly gastric cancer cell line NCI-N87, where one example shows an IC50 of less than 50 μM.


Assessment of Spinothalamic Tract Function Beyond Pinprick in Spinal Cord Lesions: A Contact Heat Evoked Potential Study.
Background Although a mainstay of clinical sensory examination after damage in the spinal cord, pinprick sensation represents only one afferent modality conveyed in the spinothalamic tract. As an objective outcome, complementary information regarding spinothalamic tract conduction may be elucidated by measuring contact heat evoked potentials (CHEPs). Objective To assess the value of CHEPs to measure spinothalamic tract function in spinal cord disorders compared with pinprick scoring. Methods CHEPs were examined using a standard (35°C) and increased baseline (42°C) contact heat temperature. Pinprick sensation was rated as absent, impaired, or normal according to the International Standards for the Neurological Classification of Spinal Cord Injury. Results Fifty-nine dermatomes above, at, and below the sensory level of impairment were analyzed in 37 patients with defined spinal cord disorder. In dermatomes with absent or impaired pinprick sensation, CHEPs using a standard baseline temperature were mainly abolished (3/16 and 8/35, respectively). However, when applying an increased baseline temperature, CHEPs became recordable (absent: 11/16; impaired: 31/35). Furthermore, CHEPs with increased baseline temperature allowed discerning between dermatomes with absent, impaired, and normal pinprick sensation when using an objective measure (ie, N2P2 amplitude). In contrast, the pain perception to contact heat stimulation was independent of pinprick scores. Conclusion Applying pinprick testing is of limited sensitivity to assess spinothalamic tract function in spinal cord disorders. The application of CHEPs (using standard and increased baseline temperatures) as an objective readout provides complementary information of spinothalamic tract functional integrity beyond pinprick testing.


A posteriori operation detection in evolving software models.
As every software artifact, also software models are subject to continuous evolution. The operations applied between two successive versions of a model are crucial for understanding its evolution. Generic approaches for detecting operations a posteriori identify atomic operations, but neglect composite operations, such as refactorings, which leads to cluttered difference reports. To tackle this limitation, we present an orthogonal extension of existing atomic operation detection approaches for detecting also composite operations. Our approach searches for occurrences of composite operations within a set of detected atomic operations in a post-processing manner. One major benefit is the reuse of specifications available for executing composite operations also for detecting applications of them. We evaluate the accuracy of the approach in a real-world case study and investigate the scalability of our implementation in an experiment.


PNPASE regulates RNA import into mitochondria.
RNA import into mammalian mitochondria is considered essential for replication, transcription, and translation of the mitochondrial genome but the pathway(s) and factors that control this import are poorly understood. Previously, we localized polynucleotide phosphorylase (PNPASE), a 3' --> 5' exoribonuclease and poly-A polymerase, in the mitochondrial intermembrane space, a location lacking resident RNAs. Here, we show a new role for PNPASE in regulating the import of nuclear-encoded RNAs into the mitochondrial matrix. PNPASE reduction impaired mitochondrial RNA processing and polycistronic transcripts accumulated. Augmented import of RNase P, 5S rRNA, and MRP RNAs depended on PNPASE expression and PNPASE-imported RNA interactions were identified. PNPASE RNA processing and import activities were separable and a mitochondrial RNA targeting signal was isolated that enabled RNA import in a PNPASE-dependent manner. Combined, these data strongly support an unanticipated role for PNPASE in mediating the translocation of RNAs into mitochondria.


Clinical utility of magnetic resonance imaging radiographs for suspected organic syndromes in adult psychiatry.
In psychiatric practice, adult patients are most commonly referred for magnetic resonance imaging (MRI) to screen for suspected organic medical diseases of the central nervous system that can mimic psychiatric syndromes. We identified the most common signs and symptoms prompting MRIs to establish the predictive value of these signs and symptoms for clinically pertinent organic syndromes. This study was a retrospective chart review of psychiatric patients at the Veterans Affairs Greater Los Angeles Health Care Center (Los Angeles, Calif.) who were referred for MRI of the brain between 1996 and 2002. Patients referred for evaluation of dementia were excluded. The specific indications leading clinicians to obtain MRI were identified and grouped. In order to offset the uncertain significance of many MRI findings, for this study, the predictive value of each indication was calculated based on the percentage of patients in whom clinical management changed in response to MRI findings rather than on the percentage with any abnormal MRI results. Of 253 patients who had MRIs, 38 (15%) incurred some degree of treatment modification as a result of MRI findings, including 6 patients in whom MRI identified a medical condition that became the focus of treatment. Six indications appeared most likely to prompt clinicians to obtain MRIs. Because pertinent results were associated with each of these indications, statistical evaluation did not reveal significant differences in their predictive values (chi(2) = 4.32, df = 5, p = .505). Unlike prior studies showing no value to screening radioimaging, this study shows MRI can be a useful screening test among patients suspected of having organic psychiatric disorders and that the common indications for MRI employed at one institution were predictive.


Dominance of Deleterious Alleles Controls the Response to a Population Bottleneck.
Population bottlenecks followed by re-expansions have been common throughout history of many populations. The response of alleles under selection to such demographic perturbations has been a subject of great interest in population genetics. On the basis of theoretical analysis and computer simulations, we suggest that this response qualitatively depends on dominance. The number of dominant or additive deleterious alleles per haploid genome is expected to be slightly increased following the bottleneck and re-expansion. In contrast, the number of completely or partially recessive alleles should be sharply reduced. Changes of population size expose differences between recessive and additive selection, potentially providing insight into the prevalence of dominance in natural populations. Specifically, we use a simple statistic, [Formula: see text], where xi represents the derived allele frequency, to compare the number of mutations in different populations, and detail its functional dependence on the strength of selection and the intensity of the population bottleneck. We also provide empirical evidence showing that gene sets associated with autosomal recessive disease in humans may have a BR indicative of recessive selection. Together, these theoretical predictions and empirical observations show that complex demographic history may facilitate rather than impede inference of parameters of natural selection.


Development of the retinotectal projection in zebrafish embryos under TTX-induced neural-impulse blockade.
The influence of neural activity on the morphology of retinal-axon-terminal arbors and the precision of the developing retinotectal projection in zebrafish embryos was explored. Terminal-arbor morphology and their distribution in the tectum was determined with anatomical fiber-tracing methods using the fluorescent dyes dil and diO. To allow development under activity-deprived conditions, TTX was injected into the eyes of 30-38-hr-old zebrafish embryos at concentrations that effectively blocked neural activity both in retinal ganglion cells and throughout the CNS. Much like axons with normal neural-activity patterns, activity-deprived axons from dorsal and ventral and from temporal and nasal regions in the retina terminated over retinotopically appropriate and nonoverlapping regions of the tectum. Even after ablation of 1 hemiretina at the time of axonal outgrowth, activity-deprived axons from the remaining hemiretina grew directed toward and arborized selectively within their retinotopically appropriate tectal half in the same way as would nondeprived axons. Besides being retinotopic, the area over which small populations of activity-deprived axons from neighboring ganglion cells arborize is as small as that of active axons. The size of terminal arbors of retinal ganglion cell axons was unaffected by blockade of neural activity. The mean terminal-arbor size was 27 x 18 microns for the TTX-injected and 31 x 22 microns for the control embryos. The tectal coverage of TTX-blocked and control axons was equally small, with values of 1.4% and 1.6%, respectively. These data show that a precisely organized retinotopic map in developing zebrafish forms independent of neural-impulse activity.


Resistance to Botrytis cinerea in Solanum lycopersicoides involves widespread transcriptional reprogramming.
Tomato (Solanum lycopersicum), one of the world's most important vegetable crops, is highly susceptible to necrotrophic fungal pathogens such as Botrytis cinerea and Alternaria solani. Improving resistance through conventional breeding has been hampered by a shortage of resistant germplasm and difficulties in introgressing resistance into elite germplasm without linkage drag. The goal of this study was to explore natural variation among wild Solanum species to identify new sources of resistance to necrotrophic fungi and dissect mechanisms underlying resistance against B. cinerea. Among eight wild species evaluated for resistance against B. cinerea and A. solani, S. lycopersicoides expressed the highest levels of resistance against both pathogens. Resistance against B. cinerea manifested as containment of pathogen growth. Through next-generation RNA sequencing and de novo assembly of the S. lycopersicoides transcriptome, changes in gene expression were analyzed during pathogen infection. In response to B. cinerea, differentially expressed transcripts grouped into four categories: genes whose expression rapidly increased then rapidly decreased, genes whose expression rapidly increased and plateaued, genes whose expression continually increased, and genes with decreased expression. Homology-based searches also identified a limited number of highly expressed B. cinerea genes. Almost immediately after infection by B. cinerea, S. lycopersicoides suppressed photosynthesis and metabolic processes involved in growth, energy generation, and response to stimuli, and simultaneously induced various defense-related genes, including pathogenesis-related protein 1 (PR1), a beta-1,3-glucanase (glucanase), and a subtilisin-like protease, indicating a shift in priority towards defense. Moreover, cluster analysis revealed novel, uncharacterized genes that may play roles in defense against necrotrophic fungal pathogens in S. lycopersicoides. The expression of orthologous defense-related genes in S. lycopersicum after infection with B. cinerea revealed differences in the onset and intensity of induction, thus illuminating a potential mechanism explaining the increased susceptibility. Additionally, metabolic pathway analyses identified putative defense-related categories of secondary metabolites. In sum, this study provided insight into resistance against necrotrophic fungal pathogens in the Solanaceae, as well as novel sequence resources for S. lycopersicoides.


MRI characteristics and scoring in HDLS due to CSF1R gene mutations.
To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan. Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.


Increased Risk of Acute Pancreatitis in Patients with Rheumatoid Arthritis: A Population-Based Cohort Study.
The study was conducted to determine whether patients with rheumatoid arthritis (RA) are at increased risk of acute pancreatitis compared with those without RA and to determine if the risk of acute pancreatitis varied by anti-RA drug use. We used the large population-based dataset from the National Health Insurance (NHI) program in Taiwan to conduct a retrospective cohort study. Patients newly diagnosed with RA between 2000 and 2011 were referred to as the RA group. The comparator non-RA group was matched with propensity score, using age and sex, in the same time period. We presented the incidence density by 100,000 person-years. The propensity score and all variables were analyzed in fully adjusted Cox proportional hazard regression. The cumulative incidence of acute pancreatitis was assessed by Kaplan-Meier analysis, with significance based on the log-rank test. From claims data of one million enrollees randomly sampled from the Taiwan NHI database, 29,755 adults with RA were identified and 119,020 non-RA persons were matched as a comparison group. The RA cohort had higher incidence density of acute pancreatitis (185.7 versus 119.0 per 100,000 person-years) than the non-RA cohort. The adjusted hazard ratio (HR) was 1.62 (95% CI [confidence interval] 1.43-1.83) for patients with RA to develop acute pancreatitis. Oral corticosteroid use decreased the risk of acute pancreatitis (adjusted HR 0.83, 95% CI 0.73-0.94) but without a dose-dependent effect. Current use of disease modifying anti-rheumatic drugs or tumor necrosis factor blockers did not decrease the risk of acute pancreatitis. In conclusion, patients with RA are at an elevated risk of acute pancreatitis. Use of oral corticosteroids may reduce the risk of acute pancreatitis.


Treatment of ovarian hyperstimulation syndrome: new insights.
Ovarian hyperstimulation syndrome is the most serious iatrogenic complication resulting from ovarian stimulation. Currently there is no clear evidence of absolute efficacy for most of standard preventive and curative methods. Recent studies indicate that human chorionic gonadotropin increases vascular endothelial growth factor, vascular endothelial cadherin and vascular permeability via endothelial adherence junctions. Vascular endothelial growth factor plays a pivotal role in the pathophysiology of the condition and therefore vascular endothelial factor antagonism has been suggested for the prevention of the syndrome. Since vascular endothelial growth factor is also a physiological regulator of folliculogenesis, progesterone secretion and endometrial angiogenesis, its complete inactivation by specific blockers could produce undesirable effects interfering with early pregnancy development and therefore they cannot be used clinically. Recently, low doses of dopamine agonists (cabergoline) have been shown to counteract vascular endothelial growth factor induced vascular hyperpermeability, reducing the incidence of the syndrome by prophylactic treatment without compromising pregnancy outcome. The absence of undesirable side effects could make cabergoline an effective and safe etiologic approach for the prevention and treatment of the syndrome. A novel approach has suggested that metformin may also be helpful in the syndrome prevention in women with or without polycystic ovary disease.


Bupropion differentially impacts acquisition of methamphetamine self-administration and sucrose-maintained behavior.
Bupropion reduces the subjective effects and cue-induced craving for methamphetamine in humans. Given these effects of bupropion on methamphetamine in humans and its widespread clinical use, a preclinical model of drug-taking was used to determine if pretreatment with bupropion would alter the acquisition of methamphetamine self-administration. During acquisition, rats were given saline or bupropion (30 or 60 mg/kg, IP) 5 min before a 60-min session. For the first 8 days, each response on the active lever produced an infusion of methamphetamine (0.025 mg/kg). Responding on the inactive lever had no programmed consequence. This FR1 schedule was then increased to an FR3 for 4 more days. In a parallel study, the identical procedures were used to test the impact of bupropion on sucrose-maintained responding. Bupropion pretreatment decreased the number of methamphetamine infusions and sucrose deliveries earned on an FR1 and FR3. However, bupropion pretreatment only delayed discrimination between the active and inactive levers in the methamphetamine self-administration rats. Discrimination between active and inactive levers was acquired in all groups in the sucrose experiment regardless of pretreatment condition. Combined, these results suggest that bupropion has a more general effect within the appetitive/reward system of the brain rather than having complete specificity for methamphetamine.


Mitochondrial protein 18 is a positive apoptotic regulator in cardiomyocytes under oxidative stress.
Accumulation of reactive oxygen species is a common phenomenon in cardiac stress conditions, for instance, coronary artery disease, aging-related cardiovascular abnormalities, and exposure to cardiac stressors such as hydrogen peroxide (H2O2). Mitochondrial protein 18 (Mtp18) is a novel mitochondrial inner membrane protein, shown to involve in the regulation of mitochondrial dynamics. Although Mtp18 is abundant in cardiac muscles, its role in cardiac apoptosis remains elusive. The present study aimed to detect the role of Mtp18 in H2O2-induced mitochondrial fission and apoptosis in cardiomyocytes. We studied the effect of Mtp18 in cardiomyocytes by modulating its expression with lentiviral construct of Mtp18-shRNA and Mtp18 c-DNA, respectively. We then analyzed mitochondrial morphological dynamics with MitoTracker Red staining; apoptosis with terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) and cell death detection assays; and protein expression with immunoblotting. Here, we observed that Mtp18 could regulate oxidative stress- mediated mitochondrial fission and apoptosis in cardiac myocytes. Mechanistically, we found that Mtp8 induced mitochondrial fission and apoptosis by enhancing dynamin-related protein 1 (Drp1) accumulation. Conversely, knockdown of Mtp18 interfered with Drp1-associated mitochondrial fission and subsequent activation of apoptosis in both HL-1 cells and primary cardiomyocytes. However, overexpression of Mtp18 alone was not sufficient to execute apoptosis when Drp1 was minimally expressed, suggesting that Mtp18 and Drp1 are interdependent in apoptotic cascade. Together, these data highlight the role of Mtp18 in cardiac apoptosis and provide a novel therapeutic insight to minimize cardiomyocyte loss via targetting mitochondrial dynamics.


The Hsp70-like StkA functions between T4P and Dif signaling proteins as a negative regulator of exopolysaccharide in Myxococcus xanthus.
Myxococcus xanthus displays a form of surface motility known as social (S) gliding. It is mediated by the type IV pilus (T4P) and requires the exopolysaccharide (EPS) to function. It is clear that T4P retraction powers S motility. EPS on a neighboring cell or deposited on a gliding surface is proposed to anchor the distal end of a pilus and trigger T4P retraction at its proximal end. Inversely, T4P has been shown to regulate EPS production upstream of the Dif signaling pathway. Here we describe the isolation of two Tn insertions at the stk locus which had been known to play roles in cellular cohesion and formation of cell groups. An insertion in stkA (MXAN_3474) was identified based on its ability to restore EPS to a pilA deletion mutant. The stkA encodes a DnaK or Hsp70 homolog and it is upstream of stkB (MXAN_3475) and stkC (MXAN_3476). A stkB insertion was identified in a separate genetic screen because it eliminated EPS production of an EPS(+) parental strain. Our results with in-frame deletions of these three stk genes indicated that the stkA mutant produced increased level of EPS while stkB and stkC mutants produced less EPS relative to the wild type. S motility and developmental aggregation were affected by deletions of stkA and stkB but only minimally by the deletion of stkC. Genetic epistasis indicated that StkA functions downstream of T4P but upstream of the Dif proteins as a negative regulator of EPS production in M. xanthus.


Homocysteinylated albumin promotes increased monocyte-endothelial cell adhesion and up-regulation of MCP1, Hsp60 and ADAM17.
The cardiovascular risk factor homocysteine is mainly bound to proteins in human plasma, and it has been hypothesized that homocysteinylated proteins are important mediators of the toxic effects of hyperhomocysteinemia. It has been recently demonstrated that homocysteinylated proteins are elevated in hemodialysis patients, a high cardiovascular risk population, and that homocysteinylated albumin shows altered properties. Aim of this work was to investigate the effects of homocysteinylated albumin - the circulating form of this amino acid, utilized at the concentration present in uremia - on monocyte adhesion to a human endothelial cell culture monolayer and the relevant molecular changes induced at both cell levels. Treated endothelial cells showed a significant increase in monocyte adhesion. Endothelial cells showed after treatment a significant, specific and time-dependent increase in ICAM1 and VCAM1. Expression profiling and real time PCR, as well as protein analysis, showed an increase in the expression of genes encoding for chemokines/cytokines regulating the adhesion process and mediators of vascular remodeling (ADAM17, MCP1, and Hsp60). The mature form of ADAM17 was also increased as well as Tnf-α released in the cell medium. At monocyte level, treatment induced up-regulation of ICAM1, MCP1 and its receptor CCR2. Treatment with homocysteinylated albumin specifically increases monocyte adhesion to endothelial cells through up-regulation of effectors involved in vascular remodeling.


Assessment of cytological criteria for diagnosing osteosarcoma in dogs.
To evaluate the specific cytological criteria of osteosarcomas in dogs. Significant cytological characteristics of osteosarcoma and benign mesenchymal bone proliferations were determined from imprint smears of 25 dogs with osteosarcoma (group 1) and 20 dogs admitted for removal of surgical bone implants after uncomplicated healing of bone fractures (group 2). Mild to moderate cellular necrosis occurred frequently in patients with osteosarcoma. The cytoplasm of osteoblasts was pale blue to blue with a more pronounced basophilia in group 2. In 48 per cent of the patients in group 1, but none in group 2, osteoblasts showed a slight to moderate eosinophilic cytoplasmic granulation. In both groups, osteoblasts contained one red to pale blue nucleus with one or two grey-red to blue nucleoli in group 2. Forty-four per cent of animals in group 1 had osteoblasts with more than two nucleoli per nucleus. The median nuclear:cytoplasmic ratio was higher in group 1 (1:2.0) than in group 2 (1:3.5). Osteoblasts in group I were frequently seen to have a clumped chromatin pattern and showed significantly more criteria of malignancy (median six criteria per patient) than those in group 2 (median two criteria per patient). In group 1, mitoses of osteoblasts were detectable in 23 of 25 dogs, whereas only one dog in group 2 had evidence of mitotic osteoblasts. Cytological criteria can be helpful in the diagnosis of canine osteosarcoma.


Impact of alcohol consumption on tuberculosis treatment outcomes: a prospective longitudinal cohort study protocol.
An estimated 10% of tuberculosis (TB) deaths are attributable to problematic alcohol use globally, however the causal pathways through which problem alcohol use has an impact on TB treatment outcome is not clear. This study aims to improve understanding of these mechanisms. Specifically, we aim to 1) assess whether poor TB treatment outcomes, measured as delayed time-to-culture conversion, are associated with problem alcohol use after controlling for non-adherence to TB pharmacotherapy; and 2) to determine whether pharmacokinetic (PK) changes in those with problem alcohol use are associated with delayed culture conversion, higher treatment failure/relapse rates or with increased toxicity. Our longitudinal, repeated measures, prospective cohort study aims to examine the associations between problem alcohol use and TB treatment outcomes and to evaluate the effect of alcohol on the PK and pharmacodynamics (PD) of TB drugs. We will recruit 438 microbiologically confirmed, pulmonary TB patients with evidence of rifampicin susceptibility in Worcester, South Africa with 200 HIV uninfected patients co-enrolled in the PK aim. Participants are followed for the six months of TB treatment and an additional 12 months thereafter, with sputum collected weekly for the first 12 weeks of treatment, alcohol consumption measures repeated monthly in concert with an alcohol biomarker (phosphatidylethanol) measurement at baseline, and in person directly observed therapy (DOT) using real-time mobile phone-based adherence monitoring. The primary outcome is based on time to culture conversion with the second objective to compare PK of first line TB therapy in those with and without problem alcohol use. Globally, an urgent need exists to identify modifiable drivers of poor TB treatment outcomes. There is a critical need for more effective TB treatment strategies for patients with a history of problem alcohol use. However, it is not known whether poor treatment outcomes in alcohol using patients are solely attributable to noncompliance. This study will attempt to answer this question and provide guidance for future TB intervention trials. Clinicaltrials.gov Registration Number: NCT02840877 . Registered on 19 July 2016.


Fetal Endoscopic Tracheal Intubation: A New Fetoscopic Procedure to Ensure Extrauterine Tracheal Permeability in a Case with Congenital Cervical Teratoma.
Congenital neck masses are associated with high perinatal mortality and morbidity secondary to airway obstruction due to a mass effect of the tumor with subsequent neonatal asphyxia and/or neonatal death. Currently, the only technique designed to establish a secure neonatal airway is the ex utero intrapartum treatment (EXIT) procedure, which involves neonatal tracheal intubation while fetal oxygenation is maintained by the uteroplacental circulation in a partial fetal delivery under maternal general anesthesia. We present a case with a giant cervical teratoma and huge displacement and compression of the fetal trachea that was treated successfully at 35 weeks of gestation with a novel fetoscopic procedure to ensure extrauterine tracheal permeability by means of a fetal endoscopic tracheal intubation (FETI) before delivery. The procedure consisted of a percutaneous fetal tracheoscopy under maternal epidural anesthesia using an 11-Fr exchange catheter covering the fetoscope that allowed a conduit to introduce a 3.0-mm intrauterine orotracheal cannula under ultrasound guidance. After FETI, a conventional cesarean section was performed uneventfully with no need for an EXIT procedure. This report is the first to illustrate that in cases with large neck tumors involving fetal airways, FETI is feasible and could potentially replace an EXIT procedure by allowing prenatal airway control.


Bioactive copper-doped glass scaffolds can stimulate endothelial cells in co-culture in combination with mesenchymal stem cells.
Bioactive glass (BG) scaffolds are being investigated for bone tissue engineering applications because of their osteoconductive and angiogenic nature. However, to increase the in vivo performance of the scaffold, including enhancing the angiogenetic growth into the scaffolds, some researchers use different modifications of the scaffold including addition of inorganic ionic components to the basic BG composition. In this study, we investigated the in vitro biocompatibility and bioactivity of Cu2+-doped BG derived scaffolds in either BMSC (bone-marrow derived mesenchymal stem cells)-only culture or co-culture of BMSC and human dermal microvascular endothelial cells (HDMEC). In BMSC-only culture, cells were seeded either directly on the scaffolds (3D or direct culture) or were exposed to ionic dissolution products of the BG scaffolds, kept in permeable cell culture inserts (2D or indirect culture). Though we did not observe any direct osteoinduction of BMSCs by alkaline phosphatase (ALP) assay or by PCR, there was increased vascular endothelial growth factor (VEGF) expression, observed by PCR and ELISA assays. Additionally, the scaffolds showed no toxicity to BMSCs and there were healthy live cells found throughout the scaffold. To analyze further the reasons behind the increased VEGF expression and to exploit the benefits of the finding, we used the indirect method with HDMECs in culture plastic and Cu2+-doped BG scaffolds with or without BMSCs in cell culture inserts. There was clear observation of increased endothelial markers by both FACS analysis and acetylated LDL (acLDL) uptake assay. Only in presence of Cu2+-doped BG scaffolds with BMSCs, a high VEGF secretion was demonstrated by ELISA; and typical tubular structures were observed in culture plastics. We conclude that Cu2+-doped BG scaffolds release Cu2+, which in turn act on BMSCs to secrete VEGF. This result is of significance for the application of BG scaffolds in bone tissue engineering approaches.


Structural and functional insights on the Myosin superfamily.
The myosin superfamily is a versatile group of molecular motors involved in the transport of specific biomolecules, vesicles and organelles in eukaryotic cells. The processivity of myosins along an actin filament and transport of intracellular 'cargo' are achieved by generating physical force from chemical energy of ATP followed by appropriate conformational changes. The typical myosin has a head domain, which harbors an ATP binding site, an actin binding site, and a light-chain bound 'lever arm', followed often by a coiled coil domain and a cargo binding domain. Evolution of myosins started at the point of evolution of eukaryotes, S. cerevisiae being the simplest one known to contain these molecular motors. The coiled coil domain of the myosin classes II, V and VI in whole genomes of several model organisms display differences in the length and the strength of interactions at the coiled coil interface. Myosin II sequences have long-length coiled coil regions that are predicted to have a highly stable dimeric interface. These are interrupted, however, by regions that are predicted to be unstable, indicating possibilities of alternate conformations, associations to make thick filaments, and interactions with other molecules. Myosin V sequences retain intermittent regions of strong and weak interactions, whereas myosin VI sequences are relatively devoid of strong coiled coil motifs. Structural deviations at coiled coil regions could be important for carrying out normal biological function of these proteins.


An fMRI study of imitation: action representation and body schema.
Recent neuropsychological investigations of apraxia have led to new hypotheses about the representational defects associated with imitation impairments in neurological patients. This fMRI experiment investigated the relation between imitation and the body schema in healthy subjects. Experimental conditions were derived from a factorial plan, and participants were asked to watch a human model performing bodily gestures and then to execute either an identical or a different action, with the same or different limbs. Brain areas activated when subjects imitated the model were traced to the representation of the action (main effect of performing an identical action regardless of limb), to the body schema (using the same limb regardless of action), or to both. The first set of analyses yielded a network associated with visual perception, indicating that action representation is primarily visuospatial not motor, while the second analysis highlighted regions involved in body schema including the inferior parietal cortex and the insula. It is suggested that imitation of simple body gestures requires both a visuospatial description of the observed model, sustained by visual perception areas in the right occipitotemporal and superior parietal cortices and a visuospatial description of one's own body, supported by the left inferior parietal lobule. These results favor a model of praxis proposing that imitation deficits in left inferior parietal lobe patients with apraxia reflect primarily an impairment of the body schema, while deficits of praxis in right parietal patients are limited to gestures demanding in terms of visuospatial analysis.


Enhancement of heat transfer and entropy generation analysis of nanofluids turbulent convection flow in square section tubes.
In this article, developing turbulent forced convection flow of a water-Al2O3 nanofluid in a square tube, subjected to constant and uniform wall heat flux, is numerically investigated. The mixture model is employed to simulate the nanofluid flow and the investigation is accomplished for particles size equal to 38 nm.An entropy generation analysis is also proposed in order to find the optimal working condition for the given geometry under given boundary conditions. A simple analytical procedure is proposed to evaluate the entropy generation and its results are compared with the numerical calculations, showing a very good agreement.A comparison of the resulting Nusselt numbers with experimental correlations available in literature is accomplished. To minimize entropy generation, the optimal Reynolds number is determined.


DNA methylation in anal intraepithelial lesions and anal squamous cell carcinoma.
Anal intraepithelial neoplasia is associated with human papillomavirus infection and may progress to invasive squamous cell carcinoma (SCC), which is increasing in immunocompromised patients. We hypothesize that anal intraepithelial neoplasia is associated with abnormal DNA methylation and that detection of these events may be used to improve screening programs. Seventy-six patients were identified who underwent anal cytology screening and subsequent biopsy at our institution between 1999 and 2004. The specimens from these patients included 184 anal biopsies [normal, n = 57; low-grade squamous intraepithelial lesion (LSIL), n = 74; high-grade squamous intraepithelial lesion (HSIL), n = 41; and invasive SCC, n = 12] and 37 residual liquid-based anal cytology specimens (normal, n = 11; LSIL, n = 12; HSIL, n = 14). The methylation status of the following genes was determined for each biopsy and cytology sample using real-time methylation-specific PCR: HIC1, RASSF1, RARB, CDKN2A, p14, TP73, APC, MLH1, MGMT, DAPK1, and IGSF4. Methylation-specific PCR analysis of biopsy samples revealed that DNA methylation was more common in SCC and HSIL than LSIL and normal mucosa. Specifically, methylation of IGSF4 and DAPK1 was prevalent in SCC (75% and 75% of cases, respectively) and HSIL (59% and 71%, respectively) but was absent in LSIL and normal biopsy samples. Methylation profiles of cytologic samples were similar to those found in the biopsy samples. Aberrant DNA methylation is a frequent event in anal HSIL and SCC. Methylation of IGSF4 and DAPK1 is specific for HSIL and SCC, and may serve as a useful molecular biomarker.


Physicians' experiences of SBIRT training and implementation for SUD management in primary care in the UAE: a qualitative study.
AimThe objective of this paper is to present a qualitative study of introducing substance misuse screening using the Screening Brief Intervention and Referral to Treatment (SBIRT) model, in primary care in Abu Dhabi. Substance misuse in the UAE is an increasing problem. However religious beliefs and fear of legal consequences have prevented this topic from being openly discussed, risk levels identified through screening and treatment options offered. A controlled trial was undertaken which included a qualitative process study which is reported here. Qualitative interviews with primary care physicians from two intervention clinics were undertaken to explore their views, experiences and attitudes towards substance misuse management in their clinic. Physicians were trained on SBIRT and on the research project process and documentation. At completion of the project, 10 months after the training, physicians (n=17) were invited to participate in an interview to explore their experiences of training and implementation of SBIRT. Interviews were recorded and transcribed. Inductive thematic coding was applied.FindingsIn total, 11 physicians were interviewed and three main themes emerged: (1) The SBIRT screening project, (2) cultural issues and (3) patient follow-up. Findings revealed a general willingness toward the concept of screening and delivering brief interventions in primary care although increased workload and uncertainties about remuneration for the service may be a barrier to future implementation. There was a perceived problem of substance misuse that was not currently being met and a strong perception that patients were not willing to reveal substance use due cultural barriers and fear of police involvement. In conclusion this qualitative process evaluation provided essential insight into implementing SBIRT in the Middle East. In conclusion, despite physician willingness and a clinical need for a substance misuse care pathway, the reluctance among patients to admit to substance use in this culture needs to be addressed to enable successful implementation.


A comparison of postcochlear implantation speech scores in an adult population.
The vast majority of cochlear implant recipients realize significant improvement in speech perception. However, there continue to be a small group that does not realize such a benefit. In an effort to identify possible predictors for this, we have compared pre- and postimplant audiologic data using Hearing In Noise Test (HINT), City University of New York (CUNY), or Central Institute for the Deaf (CID) scores for 445 consecutive English-speaking adult patients followed for a minimum of 1 year postimplantation in two distinct groups, poor versus excellent performers. Retrospective. Poor performers were those who realized a worsening, no improvement, or an improvement of less than 10%. This group numbered 58 (13%). High performers consisted of a cadre of 194 (44%) patients who scored between 91 and 100% postimplantation. Demographic data relating to onset of deafness, education exposure, etiology, etc., were evaluated. Of the poor performers, 33 (57%) were pre-/perilingually deafened. Of these, 79% had not received any auditory/oral training in childhood. On the other hand, a total of 109 implant recipients were individuals who were pre-/perilingually deafened. Of these, 24 were in the excellent performer category. All were identified early and were recipients of a strong auditory/oral education. Of the high performers, 170 (88%) were deafened late. Other findings such as preoperative electronystagmography with caloric testing, hearing aid use, device type, and high-resolution computed tomography scan of the temporal bone will be discussed for both groups. A high preimplant speech score, auditory verbal therapy, and postlingual deafness statistically correlate with higher postimplant speech scores 1 year after cochlear implantation. Device type, caloric response and hearing aid use preimplantation, age at surgery, and sex do not statistically correlate with either poor or excellent speech discrimination scores postcochlear implantation.


Generalized Information Theory Meets Human Cognition: Introducing a Unified Framework to Model Uncertainty and Information Search.
Searching for information is critical in many situations. In medicine, for instance, careful choice of a diagnostic test can help narrow down the range of plausible diseases that the patient might have. In a probabilistic framework, test selection is often modeled by assuming that people's goal is to reduce uncertainty about possible states of the world. In cognitive science, psychology, and medical decision making, Shannon entropy is the most prominent and most widely used model to formalize probabilistic uncertainty and the reduction thereof. However, a variety of alternative entropy metrics (Hartley, Quadratic, Tsallis, Rényi, and more) are popular in the social and the natural sciences, computer science, and philosophy of science. Particular entropy measures have been predominant in particular research areas, and it is often an open issue whether these divergences emerge from different theoretical and practical goals or are merely due to historical accident. Cutting across disciplinary boundaries, we show that several entropy and entropy reduction measures arise as special cases in a unified formalism, the Sharma-Mittal framework. Using mathematical results, computer simulations, and analyses of published behavioral data, we discuss four key questions: How do various entropy models relate to each other? What insights can be obtained by considering diverse entropy models within a unified framework? What is the psychological plausibility of different entropy models? What new questions and insights for research on human information acquisition follow? Our work provides several new pathways for theoretical and empirical research, reconciling apparently conflicting approaches and empirical findings within a comprehensive and unified information-theoretic formalism.


Coeliac disease: the path to diagnosis and the reality of living with the disease.
Coeliac disease (CD) is an under-diagnosed and often misunderstood disease, yet is one of the most common food intolerance disorders. The only treatment available to prevent the health impacts of CD is a lifelong, strict gluten-free diet (GFD). There are few studies that explore the experiences of diagnosis and the everyday experiences of living with this chronic condition. Utilising a qualitative study design, and purposive sampling, the present study describes the experiences of 10 women with coeliac disease in Victoria, Australia. Individual interviews were conducted with women aged between 31 and 60 years who had been diagnosed with CD for at least 2 years. A thematic analysis of the interview transcripts highlighted a number of issues for those living with the disease. Reactions to diagnosis, transition to a GFD and the changes needed to live with CD are discussed. A range of recommendations including the need to increase CD awareness and education and further research on the impacts of living with the disease are made.


Genetics of testicular germ cell tumors.
Understanding the molecular basis underlying testicular germ cell tumors (TGCTs) may help improve patient outcomes, particularly for patients with poorer risk or chemoresistant disease. Here, we review the major contemporary advances in elucidating TGCT genetics by discussing patterns of TGCT inheritance, recent genomic and transcriptomic discoveries in TGCT, and the role of genetics in predicting therapeutic resistance and in guiding treatment. In the absence of a major high-penetrance TGCT susceptibility gene, inheritance is likely driven by a complex polygenic model with considerable variation. The most common genomic alterations found in TGCTs include gains in chromosome 12p and mutations in KIT, KRAS, and NRAS, particularly in seminomas. Sensitivity to cisplatin-based chemotherapy likely relies on intact TP53, reciprocal loss of heterozygosity, and high mitochondrial priming. Targetable mutations are uncommon in TGCTs, however, posing a challenge for the development of effective personalized therapies. Consistent with the characteristically low tumor mutational burden, immune checkpoint inhibitors do not appear to be effective for most TGCTs. Refinements in next-generation sequencing techniques over the last few years have enabled considerable advances in elucidating the genomic, transcriptomic, and epigenetic landscape of TGCTs. Future efforts focused on developing novel treatment modalities are needed.


A hamster-derived West Nile virus isolate induces persistent renal infection in mice.
West Nile virus (WNV) can persist long term in the brain and kidney tissues of humans, non-human primates, and hamsters. In this study, mice were infected with WNV strain H8912, previously cultured from the urine of a persistently infected hamster, to determine its pathogenesis in a murine host. We found that WNV H8912 was highly attenuated for neuroinvasiveness in mice. Following a systemic infection, viral RNA could be detected quickly in blood and spleen and much later in kidneys. WNV H8912 induced constitutive IL-10 production, upregulation of IFN-β and IL-1β expression, and a specific IgM response on day 10 post-infection. WNV H8912 persisted preferentially in kidneys with mild renal inflammation, and less frequently in spleen for up to 2.5 months post infection. This was concurrent with detectable serum WNV-specific IgM and IgG production. There were also significantly fewer WNV- specific T cells and lower inflammatory responses in kidneys than in spleen. Previous studies have shown that systemic wild-type WNV NY99 infection induced virus persistence preferentially in spleen than in mouse kidneys. Here, we noted that splenocytes of WNV H8912-infected mice produced significantly less IL-10 than those of WNV NY99-infected mice. Finally, WNV H8912 was also attenuated in neurovirulence. Following intracranial inoculation, WNV persisted in the brain at a low frequency, concurrent with neither inflammatory responses nor neuronal damage in the brain. WNV H8912 is highly attenuated in both neuroinvasiveness and neurovirulence in mice. It induces a low and delayed anti-viral response in mice and preferentially persists in the kidneys.