How should we discuss genetic testing with women newly diagnosed with breast cancer? Design and implementation of a randomized controlled trial of two models of delivering education about treatment-focused genetic testing to younger women newly diagnosed with breast cancer.
Germline BRCA1 and BRCA2 mutation testing offered shortly after a breast cancer diagnosis to inform women's treatment choices - treatment-focused genetic testing 'TFGT' - has entered clinical practice in specialist centers and is likely to be soon commonplace in acute breast cancer management, especially for younger women. Yet the optimal way to deliver information about TFGT to younger women newly diagnosed with breast cancer is not known, particularly for those who were not suspected of having a hereditary breast cancer syndrome prior to their cancer diagnosis. Also, little is known about the behavioral and psychosocial impact or cost effectiveness of educating patients about TFGT. This trial aims to examine the impact and efficiency of two models of educating younger women newly diagnosed with breast cancer about genetic testing in order to provide evidence for a safe and effective future clinical pathway for this service. In this non-inferiority randomized controlled trial, 140 women newly diagnosed with breast cancer (aged less than 50 years) are being recruited from nine cancer centers in Australia. Eligible women with either a significant family history of breast and/or ovarian cancer or with other high risk features suggestive of a mutation detection rate of > 10% are invited by their surgeon prior to mastectomy or radiotherapy. After completing the first questionnaire, participants are randomized to receive either: (a) an educational pamphlet about genetic testing (intervention) or (b) a genetic counseling appointment at a family cancer center (standard care). Each participant is offered genetic testing for germline BRCA mutations. Decision-related and psychosocial outcomes are assessed over 12 months and include decisional conflict (primary outcome);uptake of bilateral mastectomy and/or risk-reducing salpingo-oophorectomy; cancer-specific- and general distress; family involvement in decision making; and decision regret. A process-oriented retrospective online survey will examine health professionals' attitudes toward TFGT; a health economic analysis will determine the cost effectiveness of the intervention. This trial will provide crucial information about the impact, efficiency and cost effectiveness of an educational pamphlet designed to inform younger women newly diagnosed with breast cancer about genetic testing. Issues regarding implementation of the trial are discussed.


Ras isoform-specific signaling: location, location, location.
The proteins that compose the Ras family of small guanosine triphosphatases share a remarkably high degree of sequence similarity, yet recent evidence indicates that they may have unique biological properties. How is it that similar proteins carry out different jobs in the cell? Wolfman addresses this question by surveying recent reports that indicate that different biological roles may be born out of distinct subcellular localizations of the Ras proteins. It appears that the small differences in their amino acid sequences and their different posttranslational modifications may be all that is necessary to direct various Ras proteins to different sites.


Microglial phospholipase D4 deficiency influences myelination during brain development.
Phospholipase D4 (PLD4) is expressed in activated microglia that transiently appear in white matter during postnatal brain development. Previous knockdown experiments using cultured microglia showed PLD4 involvement in phagocytosis and proliferation. To elucidate the role of PLD4 in vivo, PLD4-deficient mice were generated and the cerebella were examined at postnatal day 5 (P5) and P7, when PLD4 expression is highest in microglia. Wild type microglia showed strong immunoreactivity for microglial marker CD68 at P5, whereas CD68 signals were weak in PLD4-deficient microglia, suggesting that loss of PLD4 affects microglial activation. At P5 and P7, immunostaining for anti-myelin basic protein (MBP) antibody indicated a mild but significant delay in myelination in PLD4-deficient cerebellum. Similar change was also observed in the corpus callosum at P7. However, this difference was not apparent at P10, suggesting that microglial PLD4-deficiency primarily influences the early myelination stage. Thus, microglia may have a transient role in myelination via a PLD4-related mechanism during development.


Identification of Plant Enhancers and Their Constituent Elements by STARR-seq in Tobacco Leaves.
Genetic engineering of cis-regulatory elements in crop plants is a promising strategy to ensure food security. However, such engineering is currently hindered by our limited knowledge of plant cis-regulatory elements. Here, we adapted self-transcribing active regulatory region sequencing (STARR-seq)-a technology for the high-throughput identification of enhancers-for its use in transiently transformed tobacco (Nicotiana benthamiana) leaves. We demonstrate that the optimal placement in the reporter construct of enhancer sequences from a plant virus, pea (Pisum sativum) and wheat (Triticum aestivum), was just upstream of a minimal promoter and that none of these four known enhancers was active in the 3' untranslated region of the reporter gene. The optimized assay sensitively identified small DNA regions containing each of the four enhancers, including two whose activity was stimulated by light. Furthermore, we coupled the assay to saturation mutagenesis to pinpoint functional regions within an enhancer, which we recombined to create synthetic enhancers. Our results describe an approach to define enhancer properties that can be performed in potentially any plant species or tissue transformable by Agrobacterium and that can use regulatory DNA derived from any plant genome.


A pathway for conformational diversity in proteins mediated by intramolecular chaperones.
Conformational diversity within unique amino acid sequences is observed in diseases like scrapie and Alzheimer's disease. The molecular basis of such diversity is unknown. Similar phenomena occur in subtilisin, a serine protease homologous with eukaryotic pro-hormone convertases. The subtilisin propeptide functions as an intramolecular chaperone (IMC) that imparts steric information during folding but is not required for enzymatic activity. Point mutations within IMCs alter folding, resulting in structural conformers that specifically interact with their cognate IMCs in a process termed "protein memory." Here, we show a mechanism that mediates conformational diversity in subtilisin. During maturation, while the IMC is autocleaved and subsequently degraded by the active site of subtilisin, enzymatic properties of this site differ significantly before and after cleavage. Although subtilisin folded by Ile-48 --> Thr IMC (IMCI-48T) acquires an "altered" enzymatically active conformation (SubI-48T) significantly different from wild-type subtilisin (SubWT), both precursors undergo autocleavage at similar rates. IMC cleavage initiates conformational changes during which the IMC continues its chaperoning function subsequent to its cleavage from subtilisin. Structural imprinting resulting in conformational diversity originates during this reorganization stage and is a late folding event catalyzed by autocleavage of the IMC.


Serum Vitamin A Levels in Patients with Chalazion.
Chalazion is a chronic, localized lipogranulomatous inflammation of the sebaceous glands of the lids. Chalazion occurs often secondary to blockage of the sebaceous gland ducts. Some studies have reported vitamin A deficiency as a risk factor for chalazion. In this study, we determined the serum levels of vitamin A in patients with chalazion. The study involved a total of 107 subjects (52 patients with chalazion and 55 control healthy subjects). The study was conducted at the Ophthalmology Clinics of Imam Khomeini Hospital, Ahwaz Jundishapur University of Medical Sciences, Ahwaz, Iran between September 2014 and February 2015. The subjects were divided into three groups according to age: 7-12 years old, 13-19 years old, and more than 19 years old. Patients were further divided into four subgroups based on the type of chalazion: single, multiple, primary, and recurrent. Blood samples were collected and the serum was tested for levels of vitamin A using high-performance liquid chromatography (HPLC). The average serum vitamin A levels in patients with chalazion in the age groups of 7-12 and 13-19 years were significantly lower than in their control counterparts. Serum vitamin A levels in patients with recurrent, multiple chalazia were significantly lower than in patients with primary, multiple chalazia (P = 0.026) and patients with a recurrent, single chalazion (P = 0.029). In conclusion, chalazion could be one of the ocular presentations of vitamin A deficiency.


Patients' knowledge about 9 common health conditions: the DECISIONS survey.
To make informed decisions, patients must have adequate knowledge of key decision-relevant facts. To determine adults' knowledge about information relevant to common types of medication, screening, or surgery decisions they recently made. National sample of US adults identified by random-digit dialing. Cross-sectional survey conducted between November 2006 and May 2007. A total of 2575 English-speaking adults aged 40 y or older who reported having discussed the following medical decisions with a health care provider within the previous 2 y: prescription medications for hypertension, hypercholesterolemia, or depression; screening tests for colorectal, breast, or prostate cancer; or surgeries for knee/hip replacement, cataracts, or lower back pain. Participants answered knowledge questions and rated the importance of their health care provider, family/friends, and the media as sources of information. Accuracy rates varied widely across questions and decision contexts. For example, patients considering cataract surgery were more likely to correctly estimate recovery time than those patients considering lower back pain or knee/hip replacement (78% v. 29% and 39%, P < 0.001). Similarly, participants were more knowledgeable of facts about colorectal cancer screening than those who were asked about breast or prostate cancer. Finally, respondents were consistently more knowledgeable on comparable questions about blood pressure medication than cholesterol medication or antidepressants. The impact of demographic characteristics and sources of information also varied substantially. For example, blacks had lower knowledge than whites about cancer screening decisions (odds ratio [OR] = 0.57; 95% confidence interval [CI] = 0.43, 0.75; P = 0.001) and medication (OR = 0.77; 95% CI = 0.60, 0.97; P = 0.03) even after we controlled for other demographic factors. The same was not true for surgical decisions. The questions did not measure all knowledge relevant to informed decision making, were subject to recall biases, and may have assessed numeracy more than knowledge. Patient knowledge of key facts relevant to recently made medical decisions is often poor and varies systematically by decision type and patient characteristics. Improving patient knowledge about risks, benefits, and characteristics of medical procedures is essential to support informed decision making.


Photolon™ --photosensitization induces apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes.
The localization of photosensitizers in the subcellular compartments during photodynamic therapy (PDT) plays a major role in the cell destruction; therefore, the aim of this study was to investigate the intracellular localization of Chlorin e6-PVP (Photolon™) in malignant and normal cells. Our study involves the characterization of the structural determinants of subcellular localization of Photolon, and how subcellular localization affects the selective toxicity of Photolon towards tumor cells. Using confocal laser scanning microscopy (CLSM) and fluorescent organelle probes; we examined the subcellular localization of Photolon™ in the murine colon carcinoma CT-26 and normal fibroblast (NHLC) cells. Our results demonstrated that after 30 min of incubation, the distribution of Photolon was localized mainly in the cytoplasmic organelles including the mitochondria, lysosomes, Golgi apparatus, around the nuclear envelope and also in the nucleus but not in the endo-plasmic reticulum whereas in NHLC cells, Photolon was found to be localized minimally only in the nucleus not in other organelles studied. The relationship between subcellular localization of Photolon and PDT-induced apoptosis was investigated. Apoptotic cell death was judged by the formation of known apoptotic hallmarks including, the phosphatidylserine externalization (PS), PARP cleavage, a substrate for caspase-3 and the formation of apoptotic nuclei. At the irradiation dose of 1 J/cm2, the percentage of apoptotic cells was 80%, respectively. This study provided substantial evidence that Photolon preferentially localized in the subcellular organelles in the following order: nucleus, mitochondria, lysosomes and the Golgi apparatus and subsequent photodamage of the mitochondria and lyso-somes played an important role in PDT-mediated apoptosis CT-26 cells. Our results based on the cytoplasmic organelles and the intranuclear localization extensively enhance the efficacy of PDT with appropriate photosensitizer and light dose and support the idea that PDT can contribute to elimination of malignant cells by inducing apoptosis, which is of physiological significance.


Long-term regulation of neuronal high-affinity glutamate and glutamine uptake in Aplysia.
An increase in transmitter release accompanying long-term sensitization and facilitation occurs at the glutamatergic sensorimotor synapse of Aplysia. We report that a long-term increase in neuronal Glu uptake also accompanies long-term sensitization. Synaptosomes from pleural-pedal ganglia exhibited sodium-dependent, high-affinity Glu transport. Different treatments that induce long-term enhancement of the siphon-withdrawal reflex, or long-term synaptic facilitation increased Glu uptake. Moreover, 5-hydroxytryptamine, a treatment that induces long-term facilitation, also produced a long-term increase in Glu uptake in cultures of sensory neurons. The mechanism for the increase in uptake is an increase in the V(max) of transport. The long-term increase in Glu uptake appeared to be dependent on mRNA and protein synthesis, and transport through the Golgi, because 5,6-dichlorobenzimidazole riboside, emetine, and brefeldin A inhibited the increase in Glu uptake. Also, injection of emetine and 5,6-dichlorobenzimidazole into Aplysia prevented long-term sensitization. Synthesis of Glu itself may be regulated during long-term sensitization because the same treatments that produced an increase in Glu uptake also produced a parallel increase in Gln uptake. These results suggest that coordinated regulation of a number of different processes may be required to establish or maintain long-term synaptic facilitation.


Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors.
Foxp3(+)CD25(+)CD4(+) regulatory T cells are produced in the thymus (natural T regs) but can also differentiate from peripheral Foxp3(-)CD4(+) precursors (induced or adaptive T regs). We assessed antigen presenting cell (APC) requirements for the latter differentiation. With added transforming growth factor (TGF)-beta, both immature and mature populations of dendritic cells (DCs) induced antigen-specific Foxp3(+) T regs from Foxp3(-) precursors. Using endogenous TGF-beta, DCs from gut-associated mesenteric lymph nodes were capable of differentiating Foxp3(+)T regs. Spleen DCs were 100-fold more potent than DC-depleted APCs for the induction of T regs and required 10-fold lower doses of peptide antigen. Interleukin-2 (IL-2) was essential, but could be provided endogenously by T cells stimulated by DCs, but not other APCs. The required IL-2 was induced by DCs that expressed CD80/CD86 costimulatory molecules. The DC-induced Foxp3(+)T regs divided up to 6 times in 6 days and were comprised of CD62L and CD103 positive and negative forms. The induced Foxp3(+)T regs exerted suppression in vitro and blocked tumor immunity in vivo. These results indicate that DCs are specialized to differentiate functional peripheral Foxp3(+)T regs and help set the stage to use DCs to actively suppress the immune response in an antigen-specific manner.


Sero-Surveillance to Assess Immunity to Rubella and Assessment of Immunogenicity and Safety of a Single dose of Rubella Vaccine in School Girls.
Rubella vaccination is not yet included in National Immunization Schedule in India. Serosurvey is frequently used to assess epidemiologic pattern of Rubella in a community. Serosurveys in different parts of India have found that 6-47% of women are susceptible for Rubella infection. The present serosurveillance was conducted in Jammu, India, in two public schools. To determine serological status of Rubella antibodies of school girls and assessment of immunogenicity and reactogenicity of Rubella immunization in seronegative girls. The current study was conducted to determine Rubella serostatus in peripubertal schoolgirls aged 11-18 years and also to assess immunogenicity and safety of Rubella vaccine (R-Vac) of Serum Institute of India Ltd., Pune, in seronegative girls. For screening, pre-vaccination serum Rubella IgG antibodies were determined and to assess immunogenicity of the vaccine, post-vaccination IgG antibodies were compared with pre-vaccination levels. Safety assessment was done for a period of 8 weeks, post-vaccination. A total of 90 (32.7%) seronegative girls were vaccinated. All girls (100%) became seropositive, post-vaccination. Clinically relevant and statistically significant increase in anti-Rubella IgG titres was observed. The adverse events were mild and self-limiting. R-Vac vaccine used in the study demonstrated an excellent safety and immunogenicity profile.


Development of a Self-reported Olfactory Dysfunction Questionnaire (SODQ) to screen olfactory disorders in China.
The diagnosis of olfactory dysfunction is challenging given the negligence during routine physical examination, inconvenience of diagnosis in clinical practice, and the inattention to cross-cultural adaptability. The study aimed to develop and validate a simple and effective self-reported olfactory dysfunction questionnaire (SODQ) for the initial screening of clinical olfactory disorders in China. A total of 121 subjects participated in the study; of these, 96 subjects completed the T&T olfactometer test and 12-item questionnaire, and 25 participants were retested using the SODQ after one week. The T&T olfactometer test examined the olfactory function and the questionnaire measured the ability to perceive common odors in daily life. We evaluated the factor structure, reliability, validity, and discriminative ability of the SODQ. The final version of the SODQ consisted of 10 items with one factor. Test-retest and internal consistency were excellent. Convergent validity of the questionnaire with the T&T olfactory test was high. Furthermore, the discrimination ability was high for the questionnaire with an area under the curve of 0.95 and a cut-off point of 22. The SODQ is a brief, valid, and repeatable tool that has the potential to effectively screen for clinical olfactory disorders from a subjective perspective.


Mechanism of threonine ADP-ribosylation of F-actin by a Tc toxin.
Tc toxins deliver toxic enzymes into host cells by a unique injection mechanism. One of these enzymes is the actin ADP-ribosyltransferase TccC3, whose activity leads to the clustering of the cellular cytoskeleton and ultimately cell death. Here, we show in atomic detail how TccC3 modifies actin. We find that the ADP-ribosyltransferase does not bind to G-actin but interacts with two consecutive actin subunits of F-actin. The binding of TccC3 to F-actin occurs via an induced-fit mechanism that facilitates access of NAD+ to the nucleotide binding pocket. The following nucleophilic substitution reaction results in the transfer of ADP-ribose to threonine-148 of F-actin. We demonstrate that this site-specific modification of F-actin prevents its interaction with depolymerization factors, such as cofilin, which impairs actin network turnover and leads to steady actin polymerization. Our findings reveal in atomic detail a mechanism of action of a bacterial toxin through specific targeting and modification of F-actin.


Development of a gene knockout system using mobile group II introns (Targetron) and genetic disruption of acid production pathways in Clostridium beijerinckii.
Clostridium beijerinckii is a well-known solvent-producing microorganism with great potential for biofuel and biochemical production. To better understand and improve the biochemical pathway to solvents, the development of genetic tools for engineering C. beijerinckii is highly desired. Based on mobile group II intron technology, a targetron gene knockout system was developed for C. beijerinckii in this study. This system was successfully employed to disrupt acid production pathways in C. beijerinckii, leading to pta (encoding phosphotransacetylase)- and buk (encoding butyrate kinase)-negative mutants. In addition to experimental characterization, the mutant phenotypes were analyzed in the context of our C. beijerinckii genome-scale model. Compared to those of the parental strain (C. beijerinckii 8052), acetate production in the pta mutant was substantially reduced and butyrate production was remarkably increased, while solvent production was dependent on the growth medium. The pta mutant also produced much higher levels of lactate, suggesting that disrupting pta influenced the energy generation and electron flow pathways. In contrast, acetate and butyrate production in the buk mutant was generally similar to that of the wild type, but solvent production was consistently 20 to 30% higher and glucose consumption was more rapid and complete. Our results suggest that the acid and solvent production of C. beijerinckii can be effectively altered by disrupting the acid production pathways. As the gene disruption method developed in this study does not leave any antibiotic marker in a disrupted allele, multiple and high-throughput gene disruption is feasible for elucidating genotype and phenotype relationships in C. beijerinckii.


Relationship between renal function and circulating microparticles, soluble P-selectin and E-selectin levels in atrial fibrillation.
Atrial fibrillation (AF) and chronic kidney disease are closely related, and any associated risk of stroke and thromboembolism due to AF is increased by concurrent renal dysfunction. The mechanism(s) for this include abnormalities in platelets and endothelial cells. We hypothesized relationships between levels of circulating platelet microparticles (PMPs, defined by CD42b), soluble P selectin (both reflecting platelet activation), soluble E-selectin (reflecting endothelial activation) and endothelial/platelet microparticles (EPMPs, defined by CD31) with progressive renal dysfunction. Blood samples were obtained from 160 anticoagulated AF patients. Microparticles were measured by flow cytometry, soluble E and P selectin levels by ELISA. Renal function was determined by estimated glomerular filtration rate (eGFR). EPMP levels demonstrated a linear increased trend across quartiles of eGFR (p = 0.034) and CKD stage (p < 0.001), and correlated with eGFR and serum creatinine (p < 0.01). PMPs, P-selectin and E-selectin levels were not significantly different across groupings of renal dysfunction, and no significant correlations with eGFR were evident (p = 0.186, p = 0.561, p = 0.746 respectively). Stepwise multivariable regression analysis demonstrated that worsening renal function was an independent predictor of EPMP levels (p < 0.001). In well-anticoagulated AF patients, there is potential relationship between endothelial function (as judged by elevated EPMP levels, with no change in PMPs) and renal function. Other markers of prothombotic state or cellular activation (PMP, P-selectin and E-selectin levels) were not significantly different across the various degree of renal dysfunction. Renal function must be addressed when measuring EPMP levels.


Dynamics of Carbonium Ions Solvated by Molecular Hydrogen: CH5+(H2)n (n = 1, 2, 3).
The dynamics of the carbonium ion (CH(5)(+)), a highly reactive intermediate with no equilibrium structure, was studied by measuring the infrared spectra for internally cold CH(5)(+)(H(2))n(n = 1, 2, 3) stored in an ion trap. First-principle molecular dynamics methods were used to directly simulate the internal motion for these ionic complexes. The combined experimental and theoretical efforts substantiated the anticipated scrambling motion in the CH(5)(+) core and revealed the effect of the solvent molecular hydrogen in slowing down the scrambling. The results indicate the feasibility of using solvent molecules to stabilize the floppy CH(5)(+) ion in order to make it amenable to spectroscopic study.


Human embryonic stem cell derived astrocytes mediate non-cell-autonomous neuroprotection through endogenous and drug-induced mechanisms.
The glial environment is an important determinant of neuronal health in experimental models of neurodegeneration. Specifically, astrocytes have been shown, dependent on context, to be both injurious and protective. Human pluripotent stem cells offer a powerful new system to improve our understanding of the mechanisms underlying astrocyte-mediated neuroprotection. Here, we describe a human embryonic stem cell (HESC)-based system to assess the scope and mechanism of human astrocyte-mediated neuroprotection. We first report the generation of enriched and functional HESC-derived astrocytes, by combining BMP-mediated Smad and LIF-mediated JAK-STAT signalling. These astrocytes promote the protection of HESC-derived neurons against oxidative insults. Moreover, their neuroprotective capacity can be greatly enhanced by treatment with the nuclear factor-erythroid 2-related factor 2 (Nrf2)-activating triterpenoid 1[2-Cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoroethylamide (CDDO(TFEA)). Activation of the transcription factor Nrf2 in human astrocytes by CDDO(TFEA) treatment induced expression of the glutamate-cysteine ligase (GCL) catalytic subunit, leading to enhanced GCL activity and glutathione production, and strong neuroprotection against H(2)O(2). This enhanced neuroprotection was found to be dependent on astrocytic GCL activity, unlike the basal neuroprotection afforded by untreated astrocytes. Direct treatment of HESC-derived neurons with CDDO(TFEA) elicited no induction of Nrf2 target genes, nor any neuroprotection. Thus, human astrocytes can mediate neuroprotection through glutathione-dependent and glutathione-independent mechanisms, and represent a therapeutic target for human disorders associated with neuronal oxidative stress.


Microemulsion-made gadolinium carbonate hollow nanospheres showing magnetothermal heating and drug release.
Gadolinium carbonate (Gd2(CO3)3) hollow nanospheres and their suitability for drug transport and magnetothermally-induced drug release are presented. The hollow nanospheres are prepared via a microemulsion-based synthesis using tris(tetramethylcyclopentadienyl)gadolinium(iii) and CO2 as the starting materials. Size, structure and composition of the as-prepared Gd2(CO3)3 hollow nanospheres are comprehensively validated by several independent analytical methods (HRTEM, HAADF-STEM, DLS, EDXS, XRD, FT-IR, DTA-TG). Accordingly, they exhibit an outer diameter of 26 ± 4 nm, an inner cavity of 7 ± 2 nm, and a wall thickness of 9 ± 3 nm. As a conceptual study, the nanocontainer-functionality of the Gd2(CO3)3 hollow nanospheres is validated upon filling with the anti-cancerogenic agent doxorubicin (DOX), which is straightforward via the microemulsion (ME) strategy. The resulting DOX@Gd2(CO3)3 nanocontainers provide the option of multimodal imaging including optical and magnetic resonance imaging (OI, MRI) as well as magnetothermal heating and drug release. As a proof-of-concept, we could already prove the intrinsic DOX-based fluorescence, a low systemic toxicity according to in vitro studies as well as the magnetothermal effect and a magnetothermally-induced DOX release. In particular, the latter is new for Gd-containing nanoparticles and highly promising in view of theranostic nanocontainers and synergistic physical and chemical tumor treatment.


Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System.
Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D₁ and D₂ receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D₁ receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D₂ receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D₁ receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D₁ receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders.


Perceived and measured availability of tobacco to youths in 14 Minnesota communities: the TPOP Study. Tobacco Policy Options for Prevention.
Availability of tobacco to young people is believed to be an important factor in the onset of tobacco use. We still do not have a complete picture of how tobacco is obtained by youths or how access can be curtailed. This article describes tobacco availability to youths in 14 communities that are part of a randomized trial, known as TPOP (Tobacco Policy Options for Prevention). The data reported here were obtained from student surveys and tobacco-purchase attempts by underage confederates. Students who have smoked at least once were likely to cite social sources for cigarettes. However, more than half of weekly smokers and almost one third of tenth-grade ever smokers reported purchasing cigarettes in the last 30 days. Tobacco-purchase attempts by confederate buyers at all outlets resulted in an overall success rate of 40.8%, lower than previously reported for urban communities. Fifty-five percent of the over-the-counter outlets had no self-service displays of tobacco at baseline. Store factors that predicted purchase success include tobacco location; purchase success was lower when all tobacco was locked or behind a service counter. The percentage of smokers who reported purchasing their own tobacco soon after starting to smoke was highest in towns where purchase success by teenage study confederates was highest. These results suggest that sources of cigarettes shift from social to commercial with age and that sources of cigarettes for rural youths may be different than for urban youths.


Physiological and behavioural responses to weaning conflict in free-ranging primate infants.
Weaning, characterized by maternal reduction of resources, is both psychologically and energetically stressful to mammalian offspring. Despite the importance of physiology in this process, previous studies have reported only indirect measures of weaning stress from infants, because of the difficulties of collecting physiological measures from free-ranging mammalian infants. Here we present some of the first data on the relationship between weaning and energetic and psychological stress in infant mammals. We collected data on 47 free-ranging rhesus macaque infants on Cayo Santiago, Puerto Rico, showing that faecal glucocorticoid metabolite (fGCM) concentrations were directly related to the frequency of maternal rejection, with fGCM concentrations increasing as rates of rejection increased. Infants with higher fGCM concentrations also engaged in higher rates of mother following, and mother following was associated with increased time on the nipple, suggesting that infants that experienced greater weaning-related stress increased their efforts to maintain proximity and contact with their mothers. Infants experiencing more frequent rejection uttered more distress vocalizations when being rejected; however, there was no relationship between rates of distress vocalizations and fGCM concentrations, suggesting a disassociation between behavioural and physiological stress responses to weaning. Elevated glucocorticoid concentrations during weaning may function to mobilize energy reserves and prepare the infant for continued maternal rejection and shortage of energetic resources.


Verbal creativity, depression and alcoholism. An investigation of one hundred American and British writers.
An earlier study of 291 world famous men had shown that only visual artists and creative writers were characterised, in comparison with the general population, by a much higher prevalence of pathological personality traits and alcoholism. Depressive disorders, but not any other psychiatric conditions, had afflicted writers almost twice as often as men with other high creative achievements. The present investigation was undertaken to confirm these findings in a larger and more comprehensive series of writers, and to discover causal factors for confirmed high prevalences of affective conditions and alcoholism in writers. Data were collected from post-mortem biographies and, where applicable, translated into DSM diagnoses. The frequencies of various abnormalities and deviations were compared between poets, prose fiction writers, and playwrights. A high prevalence in writers of affective conditions and of alcoholism was confirmed. That of bipolar affective psychoses exceeded population norms in poets, who in spite of this had a lower prevalence of all kinds of affective disorders, of alcoholism, of personality deviations, and related to this, of psychosexual and marital problems, than prose fiction and play writers. A hypothesis is developed, which links the greater frequency of affective illnesses and alcoholism in playwrights and prose writers, in comparison with poets, to differences in the nature and intensity of their emotional imagination. This hypothesis could be tested by clinical psychologists collaborating with experts in literature on random samples of different kinds of writers.


Retrograde venous perfusion with hypothermic saline and adenosine for protection of the ischemic spinal cord.
Spinal cord injury and the resultant postoperative paraplegia are devastating complications of thoracic aortic surgery, for which no widely accepted protective interventions exist. We hypothesized that retrograde venous perfusion-cooling of the spinal cord with a hypothermic saline and adenosine solution would protect it from ischemic injury caused by thoracic aortic occlusion. Adult domestic swine of either sex (weight range, 20 to 30 kg) were intubated and ventilated. A left thoracotomy was performed. The accessory hemiazygous vein was divided, and a catheter was inserted distally. The aorta was clamped at the left subclavian artery. The venous catheter was not used in the animals in the control group (n = 7); in the animals in the experimental group (n = 7), a cold (4 degrees C) saline and adenosine solution was infused into the accessory hemiazygous vein. After 30 minutes, the clamp and catheter were removed, and the chest was closed. A blinded observer evaluated the animals' hind-leg motor activity 24 hours later. The Tarlov scale was used: 0, complete paralysis; 1, minimal movement; 2, stands with assistance; 3, stands alone; 4, weak walk; 5, normal gait. The animals' rectal temperatures were measured at the end of the experiment, and blood pressure was measured throughout. Two other groups were studied to assess the effect of the intervention on spinal cord temperature. The animals in the control group had a mean Tarlov score of 1.7 +/- 0.6; the animals in the experimental group had a mean Tarlov score of 4.9 +/- 0.1 (P <.01). The animals in the experimental group had a significantly greater drop in spinal cord temperature than those in the control group (4. 05 +/- 0.6 degrees C vs 0.58 +/- 0.12 degrees C; P <.01). No significant difference in rectal temperatures was found, nor did any arrhythmias or hypotensive episodes occur in either group. Perfusion of the spinal cord was confirmed with angiography by using this approach. Retrograde venous perfusion-cooling of the spinal cord with a hypothermic saline and adenosine solution protects the cord from ischemic injury caused by clamping of the thoracic aorta.


Internal urethrotomy versus plasmakinetic energy for surgical treatment of urethral stricture.
we aimed to compare the longterm outcome of surgical treatment of urethral stricture with the internal urethrotomy and plasmakinetic energy. 60 patients, who have been operated due to urethral stricture were enrolled in our clinic. None of the patients had a medical history of urethral stricture. The urethral strictures were diagnosed by clinical history, uroflowmetry, ultrasonography and urethrography. The patients were divided two groups. Group 1 consisted of 30 patients treated with plasmakinetic urethrotomy and group 2 comprised 30 men treated with cold knife urethrotomy. There were no statistically significant differences between two groups in terms of patient age, maximum flow rate (Qmax) and quality of life score (Qol) value. A statistical difference between the two groups was observed when we compared the 3rd-month uroflowmetry results. Group 1 patients had a mean postoperative Qmax value of 16,1 ± 2,3 ml/s, whereas group 2 had a mean postoperative Qmax value of 15,1 ± 2,2 ml/s (p < 0.05). In the cold knife group, 3 of 11 (27,7%) recurrences appeared within the first 3 months, whereas in the plasmakinetic group zero recurrences appeared within the first 3 months in our study. The urethral stricture recurrence rate up to the 12 month period was statistically significant for group 1 (n = 7, 23%) compared with group 2 (n = 11, 37%) (p < 0.05). We believe that plasmakinetic surgery is better method than the cold knife technique for the treatment of urethral stricture.


Evolution, homology conservation, and identification of unique sequence signatures in GH19 family chitinases.
The discovery of GH (Glycoside Hydrolase) 19 chitinases in Streptomyces sp. raises the possibility of the presence of these proteins in other bacterial species, since they were initially thought to be confined to higher plants. The present study mainly concentrates on the phylogenetic distribution and homology conservation in GH19 family chitinases. Extensive database searches are performed to identify the presence of GH19 family chitinases in the three major super kingdoms of life. Multiple sequence alignment of all the identified GH19 chitinase family members resulted in the identification of globally conserved residues. We further identified conserved sequence motifs across the major sub groups within the family. Estimation of evolutionary distance between the various bacterial and plant chitinases are carried out to better understand the pattern of evolution. Our study also supports the horizontal gene transfer theory, which states that GH19 chitinase genes are transferred from higher plants to bacteria. Further, the present study sheds light on the phylogenetic distribution and identifies unique sequence signatures that define GH19 chitinase family of proteins. The identified motifs could be used as markers to delineate uncharacterized GH19 family chitinases. The estimation of evolutionary distance between chitinase identified in plants and bacteria shows that the flowering plants are more related to chitinase in actinobacteria than that of identified in purple bacteria. We propose a model to elucidate the natural history of GH19 family chitinases.


Retrospective cohort study between selective and standard C3-7 laminoplasty. Minimum 2-year follow-up study.
A total of 64 patients with cervical spondylotic myelopathy (CSM) were assessed in this study. Forty-two patients underwent selective expansive open-door laminoplasty (ELAP). Twenty-two patients who underwent conventional C3-7 ELAP served as controls. There were no significant differences in recovery rate of JOA scores, C2-C7 angle or cervical range of motion between two groups. Incidence of axial symptoms and segmental motor paralysis in selective ELAP was significantly lower than those in the C3-7 ELAP. Size of anterior compression mass, postoperative spinal cord positions and decompression conditions were evaluated using preoperative or postoperative MRI in 50 of 64 patients. There was a positive correlation between number of expanded laminae and maximum anterior spaces of spinal cord. Incomplete decompression was developed in three of 37 patients in selective ELAP and in two of 13 patients in C3-7ELAP. Mean size of anterior compression mass at incomplete decompression levels was significantly greater than that at complete decompression levels. Since, there was less posterior movement of the spinal cord in selective ELAP than that in C3-7ELAP, minute concerns about size of anterior compression mass is necessary to decide the number of expanded laminae. Overall, selective ELAP was less invasive and useful in reducing axial symptoms and segmental motor paralysis. This new surgical strategy was effective in improving the surgical outcomes of CSM, and short-term results were satisfactory.


A unity of the self or a multiplicity of locations? How the graphesthesia task sheds light on the role of spatial perspectives in bodily self-consciousness.
Integrating multisensory stimuli from a self-centred perspective is crucial for the unity of the self. On the other hand, understanding external space and communicating spatial knowledge with others necessitate the adoption of decentred perspectives. How do we juggle these two requirements? In this article, we review those studies that have used the graphesthesia task in order to investigate the perspectives that people adopt when interpreting ambiguous tactile symbols (e.g., b, d, p, and q). With such ambiguous symbols, self-centred and decentred perspectives conflict with one another. The results reviewed here reveal that the perspectives adopted vary significantly with spatial, personal, and interpersonal factors. Such findings suggest that the self can adopt a multiplicity of spatial locations. However, the unity of the self can partly be explained by the predominance of a head-centred perspective. On the other hand, perspective-taking abilities contribute to the distinction between self and others, reinforcing self-consciousness.


Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study.
The long-term excess risk of death associated with diabetes following acute myocardial infarction is unknown. We determined the excess risk of death associated with diabetes among patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) after adjustment for comorbidity, risk factors and cardiovascular treatments. Nationwide population-based cohort (STEMI n=281 259 and NSTEMI n=422 661) using data from the UK acute myocardial infarction registry, MINAP, between 1 January 2003 and 30 June 2013. Age, sex, calendar year and country-specific mortality rates for the populace of England and Wales (n=56.9 million) were matched to cases of STEMI and NSTEMI. Flexible parametric survival models were used to calculate excess mortality rate ratios (EMRR) after multivariable adjustment. This study is registered at ClinicalTrials.gov (NCT02591576). Over 1.94 million person-years follow-up including 120 568 (17.1%) patients with diabetes, there were 187 875 (26.7%) deaths. Overall, unadjusted (all cause) mortality was higher among patients with than without diabetes (35.8% vs 25.3%). After adjustment for age, sex and year of acute myocardial infarction, diabetes was associated with a 72% and 67% excess risk of death following STEMI (EMRR 1.72, 95% CI 1.66 to 1.79) and NSTEMI (1.67, 1.63 to 1.71). Diabetes remained significantly associated with substantial excess mortality despite cumulative adjustment for comorbidity (EMRR 1.52, 95% CI 1.46 to 1.58 vs 1.45, 1.42 to 1.49), risk factors (1.50, 1.44 to 1.57 vs 1.33, 1.30 to 1.36) and cardiovascular treatments (1.56, 1.49 to 1.63 vs 1.39, 1.36 to 1.43). At index acute myocardial infarction, diabetes was common and associated with significant long-term excess mortality, over and above the effects of comorbidities, risk factors and cardiovascular treatments.


Evaluating the effects of IADHFL on inhibiting DPP-IV activity and expression in Caco-2 cells and contributing to the amount of insulin released from INS-1 cells in vitro.
Dipeptidyl peptidase-IV (DPP-IV) is a serine exo-peptidase that can inactivate incretins by removing N-terminal dipeptides. Currently, inhibiting the DPP-IV activity is a common treatment for type 2 diabetes (T2D). The goal of this study is to investigate whether IADHFL, a novel DPP-IV inhibitory peptide identified from bighead carp (Hypophthalmichthys nobilis), has the potential to modulate T2D. IADHFL remained stable after simulated gastrointestinal digestion and significantly decreased the activity and expression of both soluble and membrane-bound DPP-IV after 24 h and 48 h of treatment. Intact peptide absorption was observed, but a percentage of the peptide was degraded while passing through a monolayer of Caco-2 cells. In addition, a double-layered cell model showed that the peptide could increase insulin secretion from INS-1 cells after glucose treatments of 2.8 mM and 16.7 mM. Finally, IADHFL could regulate the expression levels of genes associated with insulin secretion and T2D in INS-1 cells.


An straightforward entry to new pyrazolo-fused dibenzo[1,4]diazepines.
A series of novel pyrazolodibenzo[1,4]diazepines has been synthesized with good overall yields. The diarylpyrazole intermediates, with structure similarity to biologically relevant compounds such as currently marketed drugs like rimonabant or celecoxib, were prepared by a tandem sequence amine-exchange/heterocyclization starting from readily available enaminones and arylhydrazines. The key step of this efficient methodology was C(aryl)-N bond construction, accomplished by a palladium-catalyzed intramolecular N-arylation reaction, which was conducted in both homogeneous and polymer-supported versions. Reaction scope of such protocols and recycling of the heterogeneous catalyst were also examined.


An improved statistical approach for reconstructing past climates from biotic assemblages.
Quantitative reconstructions of past climates are an important resource for evaluating how well climate models reproduce climate changes. One widely used statistical approach for making such reconstructions from fossil biotic assemblages is weighted averaging partial least-squares regression (WA-PLS). There is however a known tendency for WA-PLS to yield reconstructions compressed towards the centre of the climate range used for calibration, potentially biasing the reconstructed past climates. We present an improvement of WA-PLS by assuming that: (i) the theoretical abundance of each taxon is unimodal with respect to the climate variable considered; (ii) observed taxon abundances follow a multinomial distribution in which the total abundance of a sample is climatically uninformative; and (iii) the estimate of the climate value at a given site and time makes the observation most probable, i.e. it maximizes the log-likelihood function. This climate estimate is approximated by weighting taxon abundances in WA-PLS by the inverse square of their climate tolerances. We further improve the approach by considering the frequency ( fx) of the climate variable in the training dataset. Tolerance-weighted WA-PLS with fx correction greatly reduces the compression bias, compared with WA-PLS, and improves model performance in reconstructions based on an extensive modern pollen dataset.


Detection of parvovirus B19 in donated blood: a model system for screening by polymerase chain reaction.
A highly sensitive and rapid method for routinely screening large numbers of donated blood units for parvovirus B19 by the polymerase chain reaction (PCR) was developed. Over a 3-month trial period in Edinburgh, B19 DNA was detected in 6 of 20,000 consecutive units of blood (0.03%), in concentrations ranging from 2.4 x 10(4) to 5 x 10(10) copies of viral DNA per ml. Seroconversion for B19-specific immunoglobulin M and immunoglobulin G and disappearance of circulating B19 DNA occurred in the interval between donation and recall in four of the five implicated donors who could be recalled. B19 DNA was detected in 18 of 27 separate batches of non-heat-treated factor VIII and IX concentrate manufactured from donated plasma unscreened for B19 DNA. Dry-heat treatment at 80 degrees C for 72 h reduced but did not always eliminate detectable B19 from factor VIII concentrates, consistent with recent observations that current methods for virus inactivation during blood product manufacture are insufficient to entirely eliminate B19 infectivity. The methods developed in this study for PCR screening could be applied routinely to prevent transfusion of B19 in blood and blood products and could play an important role in the prevention of iatrogenic transmission of infection. PCR screening could also be used for detection and exclusion of a range of other transmission-associated viruses for which current serological detection methods are only partially effective.


Crosstalk between Notch and Sonic hedgehog signaling in a mouse model of amyotrophic lateral sclerosis.
The developmental morphogen Sonic hedgehog (Shh) may continue to play a sustaining role in adult motor neurons, of potential relevance to motor neuron diseases including amyotrophic lateral sclerosis. The Shh signaling pathway is incompletely understood and interactions with other signaling pathways are possible. We focus here on Notch, and first show that there is an almost linear reduction in light output from a Gli reporter in Shh Light II cells in the presence of increasing concentrations of the Notch inhibitor DAPT (r=0.982). Second, in the spinal cord of mutant superoxide dismutase mice, but not control mice, a key marker of Notch signaling changes with age. Before the onset of clinical signs, the Notch intracellular domain is expressed predominantly in motor neurons, but by 125 days of age, Notch intracellular domain expression is markedly reduced in motor neurons and increased in neighboring astroglia. Third, there is a parallel reduction in Gli protein expression in mutant superoxide dismutase mouse spinal motor neurons, consistent with the observed reduction in Notch signaling and also a redistribution of Gli away from the nucleus. Thus, there is a reduction in motor neuronal Notch signaling and associated changes in Shh signaling, occurring coincidentally with disease expression, that may contribute toward the dysfunction and death of motor neurons in amyotrophic lateral sclerosis.


Review on the Integration of Microelectronics for E-Textile.
Modern electronic textiles are moving towards flexible wearable textiles, so-called e-textiles that have micro-electronic elements embedded onto the textile fabric that can be used for varied classes of functionalities. There are different methods of integrating rigid microelectronic components into/onto textiles for the development of smart textiles, which include, but are not limited to, physical, mechanical, and chemical approaches. The integration systems must satisfy being flexible, lightweight, stretchable, and washable to offer a superior usability, comfortability, and non-intrusiveness. Furthermore, the resulting wearable garment needs to be breathable. In this review work, three levels of integration of the microelectronics into/onto the textile structures are discussed, the textile-adapted, the textile-integrated, and the textile-based integration. The textile-integrated and the textile-adapted e-textiles have failed to efficiently meet being flexible and washable. To overcome the above problems, researchers studied the integration of microelectronics into/onto textile at fiber or yarn level applying various mechanisms. Hence, a new method of integration, textile-based, has risen to the challenge due to the flexibility and washability advantages of the ultimate product. In general, the aim of this review is to provide a complete overview of the different interconnection methods of electronic components into/onto textile substrate.


Prevalence of Burnout in residents of obstetrics and gynecology: A systematic review and meta-analysis.
Burnout is currently a major concern among physicians due to their high level of stress at work. There are several reports on various levels of burnout in residency programs due to several predisposing factors. The aim of this systematic review was to estimate a more precise prevalence of burnout among residents of obstetrics and gynecology. PubMed, Science Direct and Scopus were searched to identify peer-reviewed Englishlanguage studies published from January 1974 to 2005 reporting burnout among residents of obstetrics and gynecology. The key words used in the search were as follows: Residents, gynecology and obstetrics, professional burnout, depersonalization, distress, anxiety, or emotional exhaustion. Relevant additional articles were identified from the lists of the retrieved articles. We identified 12 studies which met our criteria. A total of 2509 participants were included in this meta-analysis. The overall prevalence rate of burnout on all the three subscales was 44% (95% CI: 30 - 57) in this group of residents. This meta-analysis revealed a high prevalence of burnout syndrome in residents during obstetrics and gynecology residency program. Therefore, it is recommended to consider and address this important issue to develop solutions and interventions which could improve the work condition of the medical residents.


Method for determining the optical constants of semitransparent films.
It is demonstrated that the interference oscillations in the intensity of light reflected from a substrate during deposition of a semitransparent film allows one to determine the optical constants of the film by graphical techniques. The method assumes that the optical constants of the substrate are known, and that the optical constants of the film are not a function of film thickness. This technique is applicable in any wavelength region, although surface irregularities, which are more important at short wavelengths, will generally lead to an overestimate of k. A discussion of probable errors is presented. Because the method is dependent on multiple reflections through the deposited film it is useful only for small k, or, more precisely, 2pik/n < 1.


Carotid Webs: An Unusual Presentation of Fibromuscular Dysplasia.
Carotid webs are abnormal luminal projections at the carotid bulb associated with blood flow stasis, artery dissection, and subsequent complications. Carotid webs are considered to be a rare variant of fibromuscular dysplasia (FMD). Young individuals with symptomatic carotid webs are found to be associated with ischemic stroke. The incidence of the carotid web is low, and it is rarely reported. Only 150 cases of FMD have been reported so far. FMD is a non-inflammatory and non-atherosclerotic arteriopathy. The most common arterial beds involved are renal and extracranial carotids. Presentation varies depending on the location of the arterial bed involved and disease severity. Clinical presentations range from minor headaches to severe headaches, resistant hypertension, acute coronary syndrome, transient ischemic attack, and in some cases, stroke. Diagnosis can be made through non-invasive methods, such as computed tomographic angiography, magnetic resonance angiography, or duplex ultrasonography or invasive imaging methods like catheter-based angiography. Treatment of FMD varies with disease presentation and its location. Asymptomatic carotid or vertebral arteries FMD should be monitored clinically and prescribed aspirin 81 mg daily for primary stroke prevention. Endovascular and surgical therapy with stents or coils is reserved for patients with aneurysms. We present a rare and interesting case of a 54-year-old female who presented with acute ischemic stroke in the setting of right carotid artery web, right internal carotid artery (ICA) thrombus with dissection, and possible pseudoaneurysm.


Lack of association between LRRK2 G2385R and cognitive dysfunction in Korean patients with Parkinson's disease.
Aside from the glucocerebrosidase gene, the genetic risk factors for cognitive decline in Parkinson's disease (PD) are controversial. We investigated whether the G2385R polymorphism in leucine-rich repeat kinase 2 gene (LRRK2), a risk variant for the development of PD in East Asians, is associated with cognitive dysfunction in PD. We recruited 299 PD patients, consisting of 23 carriers and 276 non-carriers of LRRK2 G2385R, from 14 centers. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). PD with cognitive dysfunction was defined as an MMSE Z score that, adjusting for age at study entry and years of education, was below -1.0 standard deviations. In multivariate analysis, PD duration, age at study entry and depression were significant risk factors for cognitive dysfunction as assessed by MMSE performance or the MoCA. In linear regression analysis of the association between MMSE Z scores and PD duration, there was no significant difference associated with the LRRK2 G2385R genotype. The interaction terms between PD duration and the LRRK2 G2385R genotype were not significant for the MMSE Z score but were significant for the MoCA. In conclusion, the LRRK2 G2385R genotype may not be associated with cognitive dysfunction in PD.


How useful are systematic reviews for informing palliative care practice? Survey of 25 Cochrane systematic reviews.
In contemporary medical research, randomised controlled trials are seen as the gold standard for establishing treatment effects where it is ethical and practical to conduct them. In palliative care such trials are often impractical, unethical, or extremely difficult, with multiple methodological problems. We review the utility of Cochrane reviews in informing palliative care practice. Published reviews in palliative care registered with the Cochrane Pain, Palliative and Supportive Care Group as of December 2007 were obtained from the Cochrane Database of Systematic Reviews, issue 1, 2008. We reviewed the quality and quantity of primary studies available for each review, assessed the quality of the review process, and judged the strength of the evidence presented. There was no prior intention to perform any statistical analyses. 25 published systematic reviews were identified. Numbers of included trials ranged from none to 54. Within each review, included trials were heterogeneous with respect to patients, interventions, and outcomes, and the number of patients contributing to any single analysis was generally much lower than the total included in the review. A variety of tools were used to assess trial quality; seven reviews did not use this information to exclude low quality studies, weight analyses, or perform sensitivity analysis for effect of low quality. Authors indicated that there were frequently major problems with the primary studies, individually or in aggregate. Our judgment was that the reviewing process was generally good in these reviews, and that conclusions were limited by the number, size, quality and validity of the primary studies.We judged the evidence about 23 of the 25 interventions to be weak. Two reviews had stronger evidence, but with limitations due to methodological heterogeneity or definition of outcomes. No review provided strong evidence of no effect. Cochrane reviews in palliative care are well performed, but fail to provide good evidence for clinical practice because the primary studies are few in number, small, clinically heterogeneous, and of poor quality and external validity. They are useful in highlighting the weakness of the evidence base and problems in performing trials in palliative care.


Salicylic acid signalling: new insights and prospects at a quarter-century milestone.
The plant hormone salicylic acid (SA) plays an essential role in the regulation of diverse biological processes throughout the entire lifespan of the plant. Twenty-five years ago, SA first emerged as an endogenous signal capable of inducing plant defence responses both at the site of infection and in the systemic tissue of the plant. Since then, SA-mediated signalling pathways have been extensively characterized and dissected using genetic and biochemical approaches. Current research is largely focused on the identification of novel SA downstream signalling genes, in order to understand their precise contributions to the phytohormonal cross-talk and signalling network. This will subsequently help us to identify novel targets that are important for plant health, and contribute to advances in modern agriculture. In this chapter we highlight recent advances in the field of SA biosynthesis and the discovery of candidates for systemic mobile signals. We also discuss the molecular mechanisms underlying SA perception. In addition, we review the novel SA signalling components that expand the scope of SA functions beyond plant immunity to include plant growth and development, endoplasmic reticulum (ER) stress, DNA repair and homologous recombination. Finally, we shed light on the roles of SA in epigenetically controlled transgenerational immune memory that has long-term benefits for plants.


Beta Oscillation-Targeted Neurofeedback Training Based on Subthalamic LFPs in Parkinsonian Patients.
Increased oscillatory activities in the beta frequency band (13-30 Hz) in the subthalamic nucleus (STN), and in particular prolonged episodes of increased synchrony in this frequency band, have been associated with motor symptoms such as bradykinesia and rigidity in Parkinson's disease (PD). Numerous studies have investigated sensorimotor cortical beta oscillations either as a control signal for Brain Computer Interfaces (BCI) or as target signal for neurofeedback training (NFB). However, it still remains unknown whether patients with PD can gain control of the pathological oscillations recorded from a subcortical site - the STN - with neurofeedback training. We tried to address this question in the current study. Specifically, we designed a simple basketball game, in which the position of a basketball changes based on the occurrence of events of temporally increased beta power quantified in real-time. Participants practised in the game to control the position of the basketball, which requires modulation of the beta oscillations recorded from STN local field potentials (LFPs). Our results suggest that it is possible to use neurofeedback training for PD patients to downregulate pathological beta oscillations in STN LFPs, and that this can lead to a reduction of beta oscillations in the cortical-STN motor network.


The staphylococcal saeRS system coordinates environmental signals with agr quorum sensing.
sae is a two-component signal transduction system in Staphylococcus aureus that regulates the expression of many virulence factors at the transcriptional level and appears to act synergistically with agr in some cases. In this study, the interactions between sae and agr have been characterized in some detail. It was found that the sae locus is larger and more complex than originally envisioned, in that it is expressed from several promoters, giving rise to four or five transcripts, at least three of which are initiated upstream of saeRS and contain two additional reading frames, here designated saeP and saeQ, which are likely to have important roles in sae function. The upstream transcripts are induced during exponential phase concomitantly with the onset of RNAIII synthesis and their induction requires the agr effector, RNAIII, but is blocked by several environmental signals that override the effects of RNAIII. saeR is also required for the induction of these transcripts, so that the sae locus contains an autoinduction circuit. It is suggested that sae is downstream of agr in the exoprotein activation pathway (and also epistatic with agr), that it coordinates the effects of environmental signals with the agr quorum-sensing system, and therefore that it is a key intermediary in the overall regulatory strategy by which S. aureus senses and responds to its environment.


Protein disulfide topology determination through the fusion of mass spectrometric analysis and sequence-based prediction using Dempster-Shafer theory.
Disulfide bonds constitute one of the most important cross-linkages in proteins and significantly influence protein structure and function. At the state-of-the-art, various methodological frameworks have been proposed for identification of disulfide bonds. These include among others, mass spectrometry-based methods, sequence-based predictive approaches, as well as techniques like crystallography and NMR. Each of these frameworks has its advantages and disadvantages in terms of pre-requisites for applicability, throughput, and accuracy. Furthermore, the results from different methods may concur or conflict in parts. In this paper, we propose a novel and theoretically rigorous framework for disulfide bond determination based on information fusion from different methods using an extended formulation of Dempster-Shafer theory. A key advantage of our approach is that it can automatically deal with concurring as well as conflicting evidence in a data-driven manner. Using the proposed framework, we have developed a method for disulfide bond determination that combines results from sequence-based prediction and mass spectrometric inference. This method leads to more accurate disulfide bond determination than any of the constituent methods taken individually. Furthermore, experiments indicate that the method improves the accuracy of bond identification as compared to leading extant methods at the state-of-the-art. Finally, the proposed framework is extensible in that results from any number of approaches can be incorporated. Results obtained using this framework can especially be useful in cases where the complexity of the bonding patterns coupled with specificities of the fragmentation pattern or limitations of computational models impair any single method to perform consistently across a diverse set of molecules.


Male migration/mobility and HIV among married couples: cross-sectional analysis of nationally representative data from India.
This paper examines the associations between male migration and mobility with HIV among married couples in India. Cross-sectional analyses of a nationally representative household survey conducted across all 29 states of India from 2005 to 2006 via the National Family Health Survey-3 (NFHS-3) included a subsample of 27,771 married couples who were tested for HIV as a part of their participation. Both bi-variate and multi-variate analyses were conducted. About 0.5% of the total married couples in the current study included an HIV-infected partner; 0.11% were HIV concordant and 0.38% were HIV serodiscordant couples. Adjusted logistic regression analyses demonstrated that HIV infection in couples (seroconcordant or serodiscordant) was significantly more likely among those couples where the man was migrant but not mobile and those couples where the man was migrant as well as mobile, relative to those couples where the man was neither migrant nor mobile. Male migration increases the risk for HIV among married couples in India, largely in the form of serodiscordance in which men are HIV infected. These findings document the need for not only primary prevention efforts to reduce HIV acquisition among migrant male workers, particularly more mobile migrants, but also efforts are needed to reduce subsequent transmission to their wives.


The proposed mechanisms of action of CBD in epilepsy.
Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States and as EPIDYOLEX from the EU agency) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy. Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).


Do hormone-modulating chemicals impact on reproduction and development of wild amphibians?
Globally, amphibians are undergoing a precipitous decline. At the last estimate in 2004, 32% of the approximately 6000 species were threatened with extinction and 43% were experiencing significant declines. These declines have been linked with a wide range of environmental pressures from habitat loss to climate change, disease and pollution. This review evaluates the evidence that endocrine-disrupting contaminants (EDCs) - pollutants that affect hormone systems - are impacting on wild amphibians and contributing to population declines. The review is limited to anurans (frogs and toads) as data for effects of EDCs on wild urodeles (salamanders, newts) or caecilians (limbless amphibians) are extremely limited. Evidence from laboratory studies has shown that a wide range of chemicals have the ability to alter hormone systems and affect reproductive development and function in anurans, but for the most part only at concentrations exceeding those normally found in natural environments. Exceptions can be found for exposures to the herbicide atrazine and polychlorinated biphenyls in leopard frogs (Rana pipiens) and perchlorate in African clawed frogs (Xenopus laevis). These contaminants induce feminising effects on the male gonads (including 'intersex' - oocytes within testes) at concentrations measured in some aquatic environments. The most extensive data for effects of an EDC in wild amphibian populations are for feminising effects of atrazine on male gonad development in regions across the USA. Even where strong evidence has been provided for feminising effects of EDCs, however, the possible impact of these effects on fertility and breeding outcome has not been established, making inference for effects on populations difficult. Laboratory studies have shown that various chemicals, including perchlorate, polychlorinated biphenyls and bromodiphenylethers, also act as endocrine disrupters through interfering with thyroid-dependent processes that are fundamental for amphibian metamorphosis. Perchlorate has also been shown to induce these effects in wild anuran populations from perchlorate-contaminated environments. Overall, the published data available suggest that some health effects observed in wild anuran populations, most notably intersex, likely have a chemical aetiology; however they derive only from very few anuran species and for a few pesticides at field sites in the USA. To understand better the impacts of EDCs on wild anuran populations, as well as other amphibian groups, assessment of fertility in exposed animals are required. Development of non-destructive biomarkers that are indicative of specific EDC-effect mechanisms are also needed to allow the study of vulnerable populations. This will help to distinguish the effects of EDCs from other environmental and/or genetic influences on development and reproduction.


Stratospheric ozone with added water vapor: influence of high-altitude aircraft.
Simple, steady-state models for ozone photochemistry, radiative heat balance, and eddy-diffusive mass transport can be combined to estimate water-induced changes in the stratospheric ozone concentrations and temperatures, the integrated ozone column, the solar power transmitted to the earth's surface, and the surface temperature. These changes have been computed parametrically for mixing fractions of water vapor between 3 x 10(-6) and 6.5 x 10(-6). With added water from the exhausts of projected fleets of stratospheric aircraft, the ozone column may diminish by 3.8 percent, the transmitted solar power increase by 0.07 percent, and the surface temperature rise by 0.04 degrees K in the Northern Hemisphere. Due to a cancellation of terms, temperatures in the lower stratosphere remain essentially unchanged. These results are sensitive to the form of the water profile and emphasize the potential role of convective transients near 30 kilometers.


Spatial and temporal analysis of cumulative environmental effects of offshore wind farms in the North Sea basin.
The North Sea basin is one of the busiest maritime areas globally with a considerable number of anthropogenic pressures impacting the functioning of the marine ecosystem. Due to growing EU ambitions for the deployment of large offshore wind farm projects (OWF), as part of the 2050 renewable energy roadmap, there is a key need for a holistic understanding of OWF potential impacts on the marine ecosystem. We propose a holistic Cumulative Effect Assessment methodology, applied using a geo-spatial open-source software, to assess impacts of OWF related pressures on selected seabed habitats, fish, seabird and mammal species. We take into account pressures specific to the three OWF development phases, spanning 1999-2050, for the entire North Sea basin. Our results underline 2022 as the peak year of cumulative impacts for the approved OWFs, followed by a considerable increase in potential impacts of the planned 212GWs, by 2050. The spatio-temporal analysis of the OWF environmental impacts presents the shift between highly impacted areas over the studied timeline and distinguishes between concentrated areas of high impacts (S-E of UK) and dispersed areas of high impacts (Germany). Our results can inform decision-makers and the OWF industry in a joint effort to mitigate the environmental impacts of future large OWF developments.


CD4+ T cell responses in hepatitis C virus infection.
Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. Evidence that CD4+ T cell responses to HCV play an important role in the outcome of acute infection has been shown in several studies. However, the mechanisms behind viral persistence and the failure of CD4+ T cell responses to contain virus are poorly understood. During chronic HCV infection, HCV-specific CD4+ T cell responses are relatively weak or absent whereas in resolved infection these responses are vigorous and multispecific. Persons with a T-helper type I profile, which promotes cellular effector mechanisms are thought to be more likely to experience viral clearance, but the overall role of these cells in the immunopathogenesis of chronic liver disease is not known. To define this, much more data is required on the function and specificity of virus-specific CD4+ T cells, especially in the early phases of acute disease and in the liver during chronic infection. The role and possible mechanisms of action of CD4+ T cell responses in determining the outcome of acute and chronic HCV infection will be discussed in this review.


Quantitative nanoscale electrostatics of viruses.
Electrostatics is one of the fundamental driving forces of the interaction between biomolecules in solution. In particular, the recognition events between viruses and host cells are dominated by both specific and non-specific interactions and the electric charge of viral particles determines the electrostatic force component of the latter. Here we probe the charge of individual viruses in liquid milieu by measuring the electrostatic force between a viral particle and the Atomic Force Microscope tip. The force spectroscopy data of co-adsorbed ϕ29 bacteriophage proheads and mature virions, adenovirus and minute virus of mice capsids is utilized for obtaining the corresponding density of charge for each virus. The systematic differences of the density of charge between the viral particles are consistent with the theoretical predictions obtained from X-ray structural data. Our results show that the density of charge is a distinguishing characteristic of each virus, depending crucially on the nature of the viral capsid and the presence/absence of the genetic material.


Habitual Sleep Deprivation is Associated with Type 2 Diabetes: A Case-Control Study.
It is suggested that a minimum of eight hours of sleep per night is needed for metabolism to work normally. The aim of the study was to determine the association of habitual sleep deprivation and type 2 diabetes mellitus (T2DM). We conducted a case-control study comparing patients with T2DM with age and sex matched healthy controls. Standard sleep questionnaires (the Berlin and Epworth Sleepiness Scale) and a weekly diary were used by patients to self-report habitual sleep. A total of 172 diabetics and 188 healthy controls were enrolled in the study. There was a significant difference between T2DM and healthy controls in nocturnal sleep duration (p = 0.033). There was a significant association between nocturnal sleep duration of fewer than six hours and T2DM (χ2 = 14.0; p = 0.0001). There was no significant difference in daytime sleepiness and daytime naps between the T2DM and control groups (p = 0.452; p = 0.581, respectively). A nocturnal sleep duration < 6 hours is associated with T2DM.


Diagnosis of malaria in a remote area of the Philippines: comparison of techniques and their acceptance by health workers and the community.
To compare the efficacies of remote symptom-based diagnosis of malaria, rapid diagnostic tests and microscopy in an area of low endemicity in the Philippines. In Trial I, 350 symptomatic patients were tested within their villages using malaria Plasmodium falciparum (Pf)/Plasmodium vivax (Pv) immunochromatographic tests (ICT tests) and blood films stored and read under local conditions. The slides were later restained and read. In Trial II, unsupervised volunteer barangay health workers prepared ICT tests and slides after brief training. These slides were read at rural health units. Twenty-seven barangay health workers and 72 community members were later questioned about the three diagnostic strategies. A history of fever alone was sensitive (95.4%) but poorly specific (16.5%) for predicting parasitaemia. The inclusion of other symptoms reduced the sensitivity to below 85%, while specificity remained low. The axillary temperature was poorly predictive. ICT tests achieved high sensitivity (97.9%) but many cases indicated as positive by ICT tests were negative by microscopy. Further analysis of these cases in Trial I indicated that ICT tests were detecting low-level parasitaemias missed by microscopy, and that local microscopy had poor accuracy. ICT tests were well accepted and accurately performed by barangay health workers. These tests meet a strong desire in the community for blood-based diagnosis and may increase the compliance and treatment-seeking behaviour of patients.


A Novel Experimental Animal Model of Adult Chronic Hydrocephalus.
The pathogenesis of adult chronic hydrocephalus is not fully understood, and the temporal relationship between development of the radiological changes and neurological deterioration is unknown. To clarify the progression of radiological-histological changes and subsequent clinical manifestations of adult chronic hydrocephalus. Kaolin was injected bilaterally into the subarachnoid space overlying the cranial convexities in 20 adult rats. Magnetic resonance imaging (MRI) was obtained by using an 11.7 T scanner at 14, 60, 90, and 120 days after kaolin injection. Locomotor, gait, and cognitive evaluations were performed independently. Kaolin distribution and the associated inflammatory and fibrotic responses were histologically analyzed. Evans index of ventriculomegaly showed significant progressive growth in ventricular size over all time points examined. The greatest enlargement occurred within the first 2 months. Evans index also correlated with the extent of kaolin distribution by MRI and by pathological examination at all time points. First gait changes occurred at 69 days, anxiety at 80, cognitive impairment at 81, and locomotor difficulties after 120 days. Only locomotor deterioration was associated with Evans index or the radiological evaluation of kaolin extension. Inflammatory/fibrotic response was histologically confirmed over the cranial convexities in all rats, and its extension was associated with ventricular size and with the rate of ventricular enlargement. Kaolin injected into the subarachnoid space over the cerebral hemispheres of adult rats produces an inflammatory/fibrotic response leading in a slow-onset communicating hydrocephalus that is initially asymptomatic. Increased ventricular size eventually leads to gait, memory, and locomotor impairment closely resembling the course of human adult chronic hydrocephalus. NPH, normal pressure hydrocephalus.


If Not Now, When? An Absence of Neurocognitive and Postural Stability Deficits in Collegiate Athletes with One or More Concussions.
A history of concussion has been associated with decreased neurocognitive function and postural control. The purpose of our study was to compare neurocognitive function and postural control in collegiate athletes with and without varying histories of concussion. Collegiate athletes were divided into groups based on 0 (n = 129), 1 (n = 91), 2 (n = 52), and 3+ (n = 34) prior concussions. Participants in each group were carefully matched by sport, sex, height, weight, and age. Athletes were administered the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT™) and the Sensory Organization Test (SOT) as part of a standard of care pre-season assessment. Group ImPACT (Verbal and Visual Memory, Visual Motor Speed, and Reaction Time) and SOT (Equilibrium Score and Somatosensory, Visual, and Vestibular sensory ratios) outcome scores were compared using one-way analyses of variance (ANOVAs). Coefficients of variation (CVs) were also calculated for each outcome score and were compared using two-sample tests with 95% confidence intervals (CIs). Participants with and without a history of concussion were not significantly different for any ImPACT or SOT outcome score (p's > 0.10). Groups (0, 1, 2, and 3+ previous concussions) were not different from each other for any ImPACT or SOT outcome score (p's ≥ 0.11). Likewise, the CVs associated with each ImPACT and SOT outcome score did not vary significantly between outcome scores for any group comparison (p ≥ 0.09). Our findings suggest that a history of one or more concussions does not influence neurocognitive performance or postural stability in collegiate athletes at their pre-season baseline assessment.


Prognostic Effect of Guideline-Directed Therapy Is More Noticeable Early in the Course of Heart Failure.
There have been few studies to evaluate the prognostic implications of guideline-directed therapy according to the temporal course of heart failure. This study assessed the relationship between adherence to guideline-directed therapy at discharge and 60-day clinical outcomes in de novo acute heart failure (AHF) and acute decompensated chronic heart failure (ADCHF) separately. Among 5,625 AHF patients who were recruited from a multicenter cohort registry of Korean Acute Heart Failure, 2,769 patients with reduced ejection fraction were analyzed. Guideline-directed therapies were defined as the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), β-blocker, and mineralocorticoid receptor antagonist. In de novo AHF, ACEI or ARB reduced re-hospitalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.34-0.95), mortality (HR, 0.41; 95% CI, 0.24-0.69) and composite endpoint (HR, 0.52; 95% CI, 0.36-0.77) rates. Beta-blockers reduced re-hospitalization (HR, 0.62; 95% CI, 0.41-0.95) and composite endpoint (HR, 0.65; 95% CI, 0.47-0.90) rates. In ADCHF, adherence to ACEI or ARB was associated with only mortality and β-blockers with composite endpoint. The prognostic implications of adherence to guideline-directed therapy at discharge were more pronounced in de novo heart failure. We recommend that guideline-directed therapy be started as early as possible in the course of heart failure with reduced ejection fraction.


Sleep deprivation of working adolescents--a hidden work hazard.
This manuscript discusses the sleep deprivation of adolescents and young workers and its impact on their work and learning. Several studies have shown that working adolescents wake up earlier, have a shorter nocturnal sleep duration and a higher level of sleepiness during wake time during the week than nonworking students do. These studies indicate that working students may have their learning ability negatively affected by being tired and sleepy. Therefore, on the basis of these results, the authors recommend that educational programs geared to sleep hygiene should be one of the priorities of the curriculum. At the same time, the workhours of teenagers should be shortened in order to allow them to work and study during daytime and to have enough time at night for leisure and rest. These recommendations would improve the quality of life of the population that already is or will soon be participating in the job market.


Partial nitrification of non-ammonium-rich wastewater within biofilm filters under ambient temperature.
This study evaluated the partial nitrification performances of two biofilm filters over a synthetic non-ammonium-rich wastewater at a 20°C room temperature under both limited DO (∼2.0 mg/L) and unlimited DO (∼4.0 mg/L) conditions. The two filters were each of 80 cm long and used different biofilm carriers: activated carbon and ceramic granule. Results showed that partial nitrification was accomplished for both filters under the limited DO condition. However, the effluent NO(2)-N was higher in the ceramic granule filter than in the activated carbon filter, and was less susceptible to the influent COD/N changes. Further investigation into the water phase COD and NH(4)-N depth profiles and bacteria population within the two filters showed that by putting upper filter layer (upstream) to confront relatively higher influent COD/N ratios, the filtration process naturally put lower filter layers (downstream) relatively more favorable for nitrifying bacteria (ammonia oxidizing bacteria in this study) to prosper, making the filter depth left for nitrification a crucial factor for the effectiveness of nitrification with a filter. The potentially different porous flow velocities of the two filters might be the reason to cause their different partial nitrification performances, with a lower porous flow velocity (the ceramic granule filter) favoring partial nitrification more. In summation, DO, filter depth, and filtration speed should be played together to successfully operate a biofilm filter for partial nitrification.


Dopamine modulation of avoidance behavior in Caenorhabditis elegans requires the NMDA receptor NMR-1.
The nematode C. elegans utilizes a relatively simple neural circuit to mediate avoidance responses to noxious stimuli such as the volatile odorant octanol. This avoidance behavior is modulated by dopamine. cat-2 mutant animals that are deficient in dopamine biosynthesis have an increased response latency to octanol compared to wild type animals, and this defect can be fully restored with the application of exogenous dopamine. Because this avoidance behavior is mediated by glutamatergic signaling between sensory neurons and premotor interneurons, we investigated the genetic interactions between dopaminergic signaling and ionotropic glutamate receptors. cat-2 mutant animals lacking either the GLR-1 or GLR-2 AMPA/kainate receptors displayed an increased response latency to octanol, which could be restored via exogenous dopamine. However, whereas cat-2 mutant animals lacking the NMR-1 NMDA receptor had increased response latency to octanol they were insensitive to exogenous dopamine. Mutants that lacked both AMPA/kainate and NMDA receptors were also insensitive to exogenous dopamine. Our results indicate that dopamine modulation of octanol avoidance requires NMR-1, consistent with NMR-1 as a potential downstream signaling target for dopamine.


Holistic multitask regression network for multiapplication shape regression segmentation.
A holistic multitask regression approach was implemented to tackle the limitations of clinical image analysis. Standard practice requires identifying multiple anatomic structures in multiple planes from multiple anatomic regions using multiple modalities. The proposed novel holistic multitask regression network (HMR-Net) formulates organ segmentation as a multitask learning problem. Multitask learning leverages the strength of joint task problem solving from capturing task correlations. HMR-Net performs multitask regression by estimating an organ's class, regional location, and precise contour coordinates. The estimation of each coordinate point also corresponds to another regression task. HMR-Net leverages hierarchical multiscale and fused organ features to handle nonlinear relationships between image appearance and distinct organ properties. Simultaneously, holistic shape information is captured by encoding coordinate correlations. The multitask pipeline enables the capturing of holistic organ information (e.g. class, location, shape) to perform shape regression for medical image segmentation. HMR-Net was validated on eight representative datasets obtained from a total of 222 subjects. A mean average precision and dice score reaching up to 0.81 and 0.93, respectively, was achieved on the representative multiapplication database. The generalized model demonstrates comparable or superior performance compared to state-of-the-art algorithms. The high-performance accuracy demonstrates our model as an effective general framework to perform organ shape regression in multiple applications. This method was proven to provide high-contrast sensitivity to delineate even the smallest and oddly shaped organs. HMR-Net's flexible framework holds great potential in providing a fully automatic preliminary analysis for multiple types of medical images.


The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.
The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-associated deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.


Quantification, qualification, and microbial killing efficiencies of antimicrobial chlorine-based substances produced by iontophoresis.
The dependence of microbial killing on chloride ions present in solutions undergoing iontophoresis is addressed. A 400-microA current was applied to vials containing synthetic urine or saline, and the production of chlorine-based substances (CBSs) was detected by the N,N-diethyl-p-phenylene diamine colorimetric method. It was found that as the time of current application increased, the total concentration of CBSs also increased. The iontophoretic current converted (through oxidation) chloride ions present in the solutions into CBSs such as free chlorine, chlorine dioxide, chlorite, monochloramine, and dichloramine (the last two were produced by iontophoresis only when nitrogenous substances were present in the solution). Two of the CBSs (free Cl and ClO2), when they were separately added back to microbial suspensions (approximately 3 x 10(5) CFU/ml) at the same concentrations at which they were detected in either 0.46% (wt/vol) NaCl solution or synthetic urine iontophoresed for 4 h at 400 microA, reduced or eliminated bacterial genera and a fungus. However, when free Cl and ClO2 were jointly added back to microbial suspensions, bacterial and fungal killing was synergistic and more rapid and complete than when these chlorine-based biocides were added separately. Therefore, iontophoresis of solutions containing chloride ions produces chlorine-based biocides that are responsible for the antimicrobial effect of iontophoresis.


Retrospective monitoring of organotin compounds in marine biota from 1985 to 1999: results from the German Environmental Specimen Bank.
In archived samples from the German Environmental Specimen Bank, organotin compounds including tributyltin (TBT) and triphenyltin (TPT) as well as their degradation products were quantified. Biota samples from North Sea and Baltic Sea areas were analyzed by gas chromatography/atomic emission detection-coupling after extraction and Grignard or ethylborate derivatization. TBT and TPT were detected in nearly all samples. A decrease of TPT contamination was observed in bladder wrack, common mussels, and eelpout muscle tissues in the period 1985-1999. In this period, TPT concentrations in North Sea mussels decreased from 98 to 7 ng/g (as organotin cation concentration in wet tissue). Concentrations of TBT remained relatively constant with 17 +/- 3 ng/g for mussels from a site with nearby marine traffic and 8 +/- 2 ng/g for a more remote area. The results reflect that TBT is still used as a biocide in antifouling paints whereas the use of TPT as a co-toxicant in such preparations had been ceased in the 1980s. The fact that the use of TBT in antifouling paints was banned in 1991 for small boats within the European Community seems not to have resulted in a decrease of TBT levels in marine biota.


Racial and Ethnic Disparities in Mode of Anesthesia for Cesarean Delivery.
Racial and ethnic disparities have been identified in the provision of neuraxial labor analgesia. These disparities may exist in other key aspects of obstetric anesthesia care. We sought to determine whether racial/ethnic disparities exist in mode of anesthesia for cesarean delivery (CD). Women who underwent CD between 1999 and 2002 at 19 different obstetric centers in the United States were identified from the Maternal-Fetal Medicine Units Network Cesarean Registry. Race/ethnicity was categorized as: Caucasian, African American, Hispanic, and Non-Hispanic Others (NHOs). Mode of anesthesia was classified as neuraxial anesthesia (spinal, epidural, or combined spinal-epidural anesthesia) or general anesthesia. To account for obstetric and non-obstetric covariates that may have influenced mode of anesthesia, multiple logistic regression analyses were performed by using sequential sets of covariates. The study cohort comprised 50,974 women who underwent CD. Rates of general anesthesia among racial/ethnic groups were as follows: 5.2% for Caucasians, 11.3% for African Americans, 5.8% for Hispanics, and 6.6% for NHOs. After adjustment for obstetric and non-obstetric covariates, African Americans had the highest odds of receiving general anesthesia compared with Caucasians (adjusted odds ratio [aOR] = 1.7; 95% confidence interval [CI], 1.5-1.8; P < 0.001). The odds of receiving general anesthesia were also higher among Hispanics (aOR = 1.1; 95% CI, 1.0-1.3; P = 0.02) and NHOs (aOR = 1.2; 95% CI, 1.0-1.4; P = 0.03) compared with Caucasians, respectively. In our sensitivity analysis, we reconstructed the models after excluding women who underwent neuraxial anesthesia before general anesthesia. The adjusted odds of receiving general anesthesia were similar to those in the main analysis: African Americans (aOR = 1.7; 95% CI, 1.5-1.9; P < 0.001); Hispanics (aOR = 1.2; 95% CI, 1.1-1.4; P = 0.006); and NHOs (aOR = 1.2; 95% CI, 1.0-1.5; P = 0.05). Based on data from the Cesarean Registry, African American women had the highest odds of undergoing general anesthesia for CD compared with Caucasian women. It is uncertain whether this disparity exists in current obstetric practice.