Space radiation cancer risks and uncertainties for Mars missions.
Projecting cancer risks from exposure to space radiation is highly uncertain because of the absence of data for humans and because of the limited radiobiology data available for estimating late effects from the high-energy and charge (HZE) ions present in the galactic cosmic rays (GCR). Cancer risk projections involve many biological and physical factors, each of which has a differential range of uncertainty due to the lack of data and knowledge. We discuss an uncertainty assessment within the linear-additivity model using the approach of Monte Carlo sampling from subjective error distributions that represent the lack of knowledge in each factor to quantify the overall uncertainty in risk projections. Calculations are performed using the space radiation environment and transport codes for several Mars mission scenarios. This approach leads to estimates of the uncertainties in cancer risk projections of 400-600% for a Mars mission. The uncertainties in the quality factors are dominant. Using safety standards developed for low-Earth orbit, long-term space missions (>90 days) outside the Earth's magnetic field are currently unacceptable if the confidence levels in risk projections are considered. Because GCR exposures involve multiple particle or delta-ray tracks per cellular array, our results suggest that the shape of the dose response at low dose rates may be an additional uncertainty for estimating space radiation risks.


Place of death, care-seeking and care pathway progression in the final illnesses of children under five years of age in sub-Saharan Africa: a systematic review.
Half of all under-5 deaths occur in sub-Saharan Africa. Reducing child mortality requires understanding of the modifiable factors that contribute to death. Social autopsies collect information about place of death, care-seeking and care-provision, but this has not been pooled to learn wider lessons. We therefore undertook a systematic review to collect, evaluate, map, and pool all the available evidence for sub-Saharan Africa. We searched PubMed, Embase, Global Health, the Cochrane Library and grey literature for studies relating to under-5 deaths in sub-Saharan Africa with information on place of death and/or care-seeking during a child's final illness. We assessed study quality with a modified Axis tool. We pooled proportions using random effects meta-analysis for place of death and for each stage of the Pathways to Survival framework. Pre-specified subgroup analysis included age group, national income and user-fee policy. We explored heterogeneity with meta-regression. Our protocol was published prospectively (CRD42018111484). We included 34 studies from 17 countries. Approximately half of the children died at home, irrespective of age. More children died at home in settings with user-fees (69.1%, 95% confidence interval (CI) = 56.2-80.6, I2 = 98.4%) compared to settings without user-fees (43.8%, 95% CI = 34.3-53.5, I2 = 96.7%). Signs of illness were present in over 95% of children but care-seeking differed by age. 40.1% of neonates (95% CI = 20.7-61.3, I2 = 98.0%) died without receiving any care, compared to 6.4% of older children (95% CI = 4.2%-9.0%, I2 = 90.6%). Care-seeking outside the home was less common in neonatal deaths (50.5%, 95% CI = 35.6-65.3, I2 = 98.3%) compared to infants and young children (82.4%, 95% CI = 79.4%-85.2%, I2 = 87.5%). In both age groups, most children were taken for formal care. Healthcare facilities discharged 69.6% of infants and young children who arrived alive (95% CI = 59.6-78.7, I2 = 95.5%), of whom only 34.9% were referred for further care (95% CI = 15.1-57.9, I2 = 98.7%). Despite similar distributions in place of death for neonates and infants and young children, care-seeking behaviour differed by age groups. Poor illness recognition is implicated in neonatal deaths, but death despite care-seeking implies inadequate quality care and referral for older children. Understanding such care-seeking patterns enables targeted interventions to reduce under-5 mortality across the region.


Comparing treatment plan in all locations of esophageal cancer: volumetric modulated arc therapy versus intensity-modulated radiotherapy.
The aim of this study was to compare treatment plans of volumetric modulated arc therapy (VMAT) with intensity-modulated radiotherapy (IMRT) for all esophageal cancer (EC) tumor locations.This retrospective study from July 2009 to June 2014 included 20 patients with EC who received definitive concurrent chemoradiotherapy with radiation doses >50.4 Gy. Version 9.2 of Pinnacle with SmartArc was used for treatment planning. Dosimetric quality was evaluated based on doses to several organs at risk, including the spinal cord, heart, and lung, over the same coverage of gross tumor volume.In upper thoracic EC, the IMRT treatment plan had a lower lung mean dose (P = 0.0126) and lung V5 (P = 0.0037) compared with VMAT; both techniques had similar coverage of the planning target volumes (PTVs) (P = 0.3575). In middle thoracic EC, a lower lung mean dose (P = 0.0010) and V5 (P = 0.0145), but higher lung V20 (P = 0.0034), spinal cord Dmax (P = 0.0262), and heart mean dose (P = 0.0054), were observed for IMRT compared with VMAT; IMRT provided better PTV coverage. Patients with lower thoracic ECs had a lower lung mean dose (P = 0.0469) and V5 (P = 0.0039), but higher spinal cord Dmax (P = 0.0301) and heart mean dose (P = 0.0020), with IMRT compared with VMAT. PTV coverage was similar (P = 0.0858) for the 2 techniques.IMRT provided a lower mean dose and lung V5 in upper thoracic EC compared with VMAT, but exhibited different advantages and disadvantages in patients with middle or lower thoracic ECs. Thus, choosing different techniques for different EC locations is warranted.


Topical sulindac combined with hydrogen peroxide in the treatment of actinic keratoses.
Actinic keratoses (AKs) are a precancerous condition of the skin that have the potential to become squamous cell cancer (SCC). Sulindac is a Food and Drug Administration (FDA)-approved nonsteroidal anti-inflammatory drug (NSAID) that has been shown to have clinically significant anticancer effects. Malignant cells may have a different response to oxidative stress than normal cells. To establish a role of increased reactive oxygen species (ROS) in the mechanism of cancer killing by sulindac in the presence of an oxidizing agent. To assess the tolerability and efficacy of the combination of gels containing sulindac and hydrogen peroxide in the treatment of patients with AKs. Cell culture studies were performed using a skin SCC cell line and normal human epidermal keratinocytes. After treatment with sulindac and an oxidizing agent, cell viability, and intracellular ROS levels were measured. An open-label clinical trial was performed using sulindac and hydrogen peroxide gels daily for 3 weeks on AKs involving the upper extremities. In SCC cells, a combination of sulindac and an oxidizing agent lead to 400 to 500% increases in intracellular ROS, which resulted in significant cell death. In sharp contrast, normal keratinocytes did not show increases in ROS levels and were not killed. A clinical trial using the combination of sulindac and hydrogen peroxide therapy in 5 patients with AKs revealed that 60% of the treated AKs responded and 50% showed no residual AK on histopathology specimens after skin biopsy. The small number of patients and the lack of a placebo group. Increased levels of ROS appear to be important in the selective killing of cancer cells in the presence of sulindac and oxidizing agents. Further studies are necessary to define the role of the combination of sulindac and oxidizing agent therapy in patients with AKs and skin cancer.


Hot Speech and Exploding Bombs: Autonomic Arousal During Emotion Classification of Prosodic Utterances and Affective Sounds.
Emotional expressions provide strong signals in social interactions and can function as emotion inducers in a perceiver. Although speech provides one of the most important channels for human communication, its physiological correlates, such as activations of the autonomous nervous system (ANS) while listening to spoken utterances, have received far less attention than in other domains of emotion processing. Our study aimed at filling this gap by investigating autonomic activation in response to spoken utterances that were embedded into larger semantic contexts. Emotional salience was manipulated by providing information on alleged speaker similarity. We compared these autonomic responses to activations triggered by affective sounds, such as exploding bombs, and applause. These sounds had been rated and validated as being either positive, negative, or neutral. As physiological markers of ANS activity, we recorded skin conductance responses (SCRs) and changes of pupil size while participants classified both prosodic and sound stimuli according to their hedonic valence. As expected, affective sounds elicited increased arousal in the receiver, as reflected in increased SCR and pupil size. In contrast, SCRs to angry and joyful prosodic expressions did not differ from responses to neutral ones. Pupil size, however, was modulated by affective prosodic utterances, with increased dilations for angry and joyful compared to neutral prosody, although the similarity manipulation had no effect. These results indicate that cues provided by emotional prosody in spoken semantically neutral utterances might be too subtle to trigger SCR, although variation in pupil size indicated the salience of stimulus variation. Our findings further demonstrate a functional dissociation between pupil dilation and skin conductance that presumably origins from their differential innervation.


The combinatorics of neurite self-avoidance.
During neural development in Drosophila, the ability of neurite branches to recognize whether they are from the same or different neurons depends crucially on the molecule Dscam1. In particular, this recognition depends on the stochastic acquisition of a unique combination of Dscam1 isoforms out of a large set of possible isoforms. To properly interpret these findings, it is crucial to understand the combinatorics involved, which has previously been attempted only using stochastic simulations for some specific parameter combinations. Here we present closed-form solutions for the general case. These reveal the relationships among the key variables and how these constrain possible biological scenarios.


Drug-induced hypoglycaemia--new insight into an old problem.
To review the causes of drug-induced hypoglycaemia in patients not taking hypoglycaemic medications. Retrospective study. Regional hospitals in Hong Kong. Patients with suspected drug-induced hypoglycaemia without a known history of exposure to hypoglycaemic agents, referred to the Hospital Authority Toxicology Reference Laboratory from June 2005 to March 2006 inclusive. Rate of positive cases, laboratory findings, possible causes, age distribution, and final outcomes. A total of 51 such patients were referred, in whom the presence of oral hypoglycaemic agents was detected (or inferred) in 23 (45%). In 12 of the 23 patients, oral hypoglycaemic agents could only be detected by target analysis, not through broad-spectrum screening. Gliclazide and glibenclamide were detected in 14 and eight patients respectively, whereas glimepiride, nateglinide and rosiglitazone were detected in the remaining patient. Possible sources of oral hypoglycaemic agents included drug administration errors in residential care homes for the elderly (n=9), mistakenly taking medication of a family member or employer (n=6), taking stock medication by mistake (n=2), taking Chinese proprietary medicine adulterated with oral hypoglycaemic agents (n=1), taking unknown pills bought from a retail pharmacy (n=1), and unknown (n=4). Regarding these 23 patients, 17 (74%) were aged 70 years or above and 21 (91%) recovered uneventfully. Hypoglycaemia due to inadvertent use of oral hypoglycaemic agents is a recognised problem, particularly in cases where family members living in the same household are taking similar medications. Possible drug administration errors in residential care homes for the elderly should be investigated, and procedures rectified if confirmed. Health care providers should be vigilant to such potential errors, especially in cases of unexplained hypoglycaemia.


Parafoveal and foveal processing of abbreviations during eye fixations in reading: making a case for case.
The processing of abbreviations in reading was examined with an eye movement experiment. Abbreviations were of 2 distinct types: acronyms (abbreviations that can be read with the normal grapheme-phoneme correspondence [GPC] rules, such as NASA) and initialisms (abbreviations in which the GPCs are letter names, such as NCAA). Parafoveal and foveal processing of these abbreviations was assessed with the use of the boundary change paradigm (K. Rayner, 1975). Using this paradigm, previews of the abbreviations were either identical to the abbreviation (NASA or NCAA), orthographically legal (NUSO or NOBA), or illegal (NRSB or NRBA). The abbreviations were presented as capital letter strings within normal, predominantly lowercase sentences and also sentences in all capital letters such that the abbreviations would not be visually distinct. The results indicate that acronyms and initialisms undergo different processing during reading and that readers can modulate their processing based on low-level visual cues (distinct capitalization) in parafoveal vision. In particular, readers may be biased to process capitalized letter strings as initialisms in parafoveal vision when the rest of the sentence is normal, lowercase letters.


Light cigarette smoking impairs coronary microvascular functions as severely as smoking regular cigarettes.
Smoking is the most prevalent and most preventable risk factor for cardiovascular diseases. Smoking low-tar, low-nicotine cigarettes (light cigarettes) would be expected to be less hazardous than smoking regular cigarettes owing to the lower nicotine and tar yield. To compare the chronic and acute effects of light cigarette and regular cigarette smoking on coronary flow velocity reserve (CFVR). 20 regular cigarette smokers (mean (SD) age 24.8 (5.0)), 20 light cigarette smokers (mean age 25.6 (6.4)), and 22 non-smoker healthy volunteers (mean age 25.1 (4.2)) were included. First, each subject underwent echocardiographic examination, including CFVR measurement, after a 12 hour fasting and smokeless period. Two days later, each subject smoked two of their normal cigarettes in a closed room within 15 minutes. Finally, within 20-30 minutes, each subject underwent an echocardiographic examination, including CFVR measurement. Mean (SD) CFVR values were similar in light cigarette and regular cigarette smokers and significantly lower than in the controls (2.68 (0.50), 2.65 (0.61), 3.11 (0.53), p = 0.013). Before and after smoking a paired t test showed that smoking two light cigarettes acutely decreased the CFVR from 2.68 (0.50) to 2.05 (0.43) (p = 0.001), and smoking of two regular cigarettes acutely decreased CFVR from 2.65 (0.61) to 2.18 (0.48) (p = 0.001). Smoking low-tar, low-nicotine cigarettes impairs the CFVR as severely as smoking regular cigarettes. CFVR values are similar in light cigarette and regular cigarette smokers and significantly lower than in controls.


p24A, a type I transmembrane protein, controls ARF1-dependent resensitization of protease-activated receptor-2 by influence on receptor trafficking.
Protease-activated receptor-2 (PAR-2), the second member of the G protein-coupled PAR family, is irreversibly activated by trypsin or tryptase and then targeted to lysosomes for degradation. Intracellular presynthesized receptors stored at the Golgi apparatus repopulate the cell surface after trypsin stimulation, thereby leading to rapid resensitization to trypsin signaling. However, the molecular mechanisms of the exocytic trafficking of PAR-2 from the Golgi apparatus to the plasma membrane remain largely unclear. Here we show that p24A, a type I transmembrane protein, which is a crucial constituent of the Golgi apparatus, associates with PAR-2 at the Golgi apparatus. The protein interaction occurs between the N-terminal region of p24A (residues 1-105; p24A-GL (GOLD domain with a small linker)) and the second extracellular loop of PAR-2. After receptor activation, PAR-2 dissociates from p24A. Importantly, we found that ADP-ribosylation factor 1 regulated the dissociation process and initiated PAR-2 trafficking to the plasma membrane. Conversely, overexpression of the fragment p24A-GL, but not other mutants containing the functional coiled-coil domain of p24A, arrested PAR-2 at the Golgi apparatus and inhibited receptor trafficking to the plasma membrane, which consequently prevented resensitization of PAR-2. These findings identify a new function of p24A as a regulator of signal-dependent trafficking that regulates the life cycle of PAR-2, Thus, we reveal a new molecular mechanism underlying resensitization of PAR-2.


Perspectives on professional values among nurses in Taiwan.
The purpose of this study was to identify the most important contemporary professional nursing values for nursing clinicians and educators in Taiwan. Nursing values are constructed by members of political and social systems, including professional nursing organisations and educational institutions. Nurses' personal value systems shape the development of these professional values. An understanding of nurses' perceptions of professional values will enable the profession to examine consistencies with those reflected in existing and emerging educational and practice environments. A qualitative descriptive study was conducted using the focus-group discussion method. A purposive sample of 300 registered nurses in Taiwan, consisting of 270 nursing clinicians and 30 faculty members, participated in 22 focus-group interviews. Data were analysed using a systematic process of content analysis. Six prominent values related to professional nursing were identified: (a) caring for clients with a humanistic spirit; (b) providing professionally competent and holistic care; (c) fostering growth and discovering the meaning of life; (d) experiencing the 'give-and-take' of caring for others; (e) receiving fair compensation; and (f) raising the public's awareness of health promotion. Four background contexts framed the way participants viewed the appropriation of these values: (a) appraising nursing values through multiple perspectives; (b) acquiring nursing values through self-realisation; (c) recognising nursing values through professional competency and humanistic concerns and (d) fulfilling nursing values through coexisting self-actualisation. A conceptual framework was developed to represent this phenomenon. The most important professional nursing values according to the perspectives of nurses in Taiwan were identified. These values reflect benefits to society, to nurses themselves and to the interdisciplinary team. Nurses' awareness of their own values and of how these values influence their behaviour is an essential component of humanistic nursing care. Nursing educators need to develop better strategies for reflection and integration of both personal and professional philosophies and values.


Self-defending additively manufactured bone implants bearing silver and copper nanoparticles.
Effective preventive measures against implant-associated infection (IAI) are desperately needed. Therefore, the development of self-defending implants with intrinsic antibacterial properties has gained significant momentum. Biomaterials biofunctionalized with silver (Ag) have resulted in effective antibacterial biomaterials, yet regularly induce cytotoxicity. In this study, the use of both Ag and copper (Cu) nanoparticles (NPs) on TiO2 surfaces was investigated to generate antibacterial and osteoconductive biomaterials. Hence, additively manufactured Ti-6Al-4V volume-porous implants were biofunctionalized with plasma electrolytic oxidation (PEO) through the incorporation of varying ratios of Ag and/or Cu NPs in the TiO2 layer covering the implant surface. For all experimental groups, the surface morphology, chemical composition, ion release profile, generation of reactive ion species, antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in vitro and ex vivo, as well as the response of pre-osteoblastic MC3T3-E1 cells in metabolic activity and differentiation assays were determined. PEO biofunctionalization resulted in rough and highly porous surfaces that released Ag and Cu ions for 28 days and generated hydroxyl as well as methyl radicals. A strong synergistic bactericidal behavior between Ag and Cu ions was detected, which allowed to decrease the concentration of Ag ions by 10-fold, while maintaining the same level of antibacterial activity. Antibacterial agar diffusion and quantitative assays indicated strong antibacterial activity in vitro for the implants containing Ag and Ag/Cu, while no antibacterial activity was observed for implants bearing only Cu NPs. Moreover, the biofunctionalized implants with ratios of up to 75% Ag and 25% Cu NP totally eradicated all bacteria in an ex vivo model using murine femora. Meanwhile, the biofunctionalized implants did not show any signs of cytotoxicity, while implants bearing only Cu NPs improved the metabolic activity after 7 and 11 days. The biomaterials developed here, therefore, exploit the synergistic behavior of Ag and Cu to simultaneously offer strong antibacterial behavior while fully mitigating the cytotoxicity of Ag against mammalian cells.


Evolution of bilaterian central nervous systems: a single origin?
The question of whether the ancestral bilaterian had a central nervous system (CNS) or a diffuse ectodermal nervous system has been hotly debated. Considerable evidence supports the theory that a CNS evolved just once. However, an alternative view proposes that the chordate CNS evolved from the ectodermal nerve net of a hemichordate-like ancestral deuterostome, implying independent evolution of the CNS in chordates and protostomes. To specify morphological divisions along the anterior/posterior axis, this ancestor used gene networks homologous to those patterning three organizing centers in the vertebrate brain: the anterior neural ridge, the zona limitans intrathalamica and the isthmic organizer, and subsequent evolution of the vertebrate brain involved elaboration of these ancestral signaling centers; however, all or part of these signaling centers were lost from the CNS of invertebrate chordates. The present review analyzes the evidence for and against these theories. The bulk of the evidence indicates that a CNS evolved just once - in the ancestral bilaterian. Importantly, in both protostomes and deuterostomes, the CNS represents a portion of a generally neurogenic ectoderm that is internalized and receives and integrates inputs from sensory cells in the remainder of the ectoderm. The expression patterns of genes involved in medio/lateral (dorso/ventral) patterning of the CNS are similar in protostomes and chordates; however, these genes are not similarly expressed in the ectoderm outside the CNS. Thus, their expression is a better criterion for CNS homologs than the expression of anterior/posterior patterning genes, many of which (for example, Hox genes) are similarly expressed both in the CNS and in the remainder of the ectoderm in many bilaterians. The evidence leaves hemichordates in an ambiguous position - either CNS centralization was lost to some extent at the base of the hemichordates, or even earlier, at the base of the hemichordates + echinoderms, or one of the two hemichordate nerve cords is homologous to the CNS of protostomes and chordates. In any event, the presence of part of the genetic machinery for the anterior neural ridge, the zona limitans intrathalamica and the isthmic organizer in invertebrate chordates together with similar morphology indicates that these organizers were present, at least in part, at the base of the chordates and were probably elaborated upon in the vertebrate lineage.


Growth performance and carcass characteristics of female turkeys as affected by feeding programs.
A trial was conducted to evaluate the effects of different feeding programs on growth performance and carcass characteristics of Nicholas Large White female turkeys. Three different feeding programs were considered for a 12-wk period: 1) 3 diets fed for 4 wk each (starter 24% CP, grower 20% CP, and finisher diet 16% CP), 2) 2 diets fed for 6 wk each (starter-grower 22% CP and grower-finisher diet 18% CP), and 3) no change of diet for 12 wk (starter-grower-finisher diet 20% CP). From 0 to 4 wk of age, birds were fed an ad libitum common starter diet. Each dietary treatment was replicated 3 times, and feed and water were provided ad libitum. Body weight and feed consumption were measured every 2 wk, whereas carcass characteristics were evaluated at 16 wk of age. Feed intake increased as the frequency of dietary changes decreased, and feed conversion was not different between programs 1 and 3. There were no significant differences in final BW among experimental groups. For a single feeding program, the proportion of neck, bone, and feet decreased, and a greater percentage of edible meat was registered as compared with the other 2 groups. Mean carcass, breast, and thigh weights of turkeys reared under multiple diets were not different compared with other groups. Positive correlations were noted between live weight and weight of carcass, breast, thigh, drumstick, wing, and abdominal fat of turkeys. Thus, a single cycle feeding regimen in Nicholas Large White female turkeys results in similar growth performance and carcass characteristics compared with other conventional feeding programs considered in the present study.


Metaviromics of Namib Desert Salt Pans: A Novel Lineage of Haloarchaeal Salterproviruses and a Rich Source of ssDNA Viruses.
Viral communities of two different salt pans located in the Namib Desert, Hosabes and Eisfeld, were investigated using a combination of multiple displacement amplification of metaviromic DNA and deep sequencing, and provided comprehensive sequence data on both ssDNA and dsDNA viral community structures. Read and contig annotations through online pipelines showed that the salt pans harbored largely unknown viral communities. Through network analysis, we were able to assign a large portion of the unknown reads to a diverse group of ssDNA viruses. Contigs belonging to the subfamily Gokushovirinae were common in both environmental datasets. Analysis of haloarchaeal virus contigs revealed the presence of three contigs distantly related with His1, indicating a possible new lineage of salterproviruses in the Hosabes playa. Based on viral richness and read mapping analyses, the salt pan metaviromes were novel and most closely related to each other while showing a low degree of overlap with other environmental viromes.


Identification of differentially expressed genes in early stages of Eimeria tenella by suppression subtractive hybridization and cDNA microarray.
Avian coccidiosis, a major parasitic disease of poultry, is caused by Eimeria spp. infection. It inflicts severe economic losses on the poultry industry worldwide. To further understand the molecular basis of sporulation and invasion of Eimeria spp., suppression subtractive hybridization and microarray approaches were combined to identify novel and important genes involved in the development and invasion of the early stages of Eimeria tenella . Three subtractive cDNA libraries were constructed for 3 stages of E. tenella including unsporulated oocysts, sporulated oocysts, and sporozoites. A subset of clones was selected from the 3 subtractive libraries to construct cDNA microarrays. Microarray analysis was used to assay expression changes of these clones. A total of 657 valid expressed sequence tags (ESTs) was obtained, including 119 unique sequences, 31 from sporulated oocysts and 88 from sporozoites. Homology searches of the public sequence databases showed that, among the 119 ESTs, 32 genes encoded proteins homologous with previously reported proteins including microneme proteins and surface antigen proteins of E. tenella , small heat shock proteins, rhoptry proteins of Toxoplasma gondii , and calcium-dependent protein kinase of Plasmodium spp. Thus, the remaining 87 ESTs have not previously been reported. Further characterization of these differentially expressed genes will be useful in understanding those responsible for sporulation, invasion, growth, and development of E. tenella .


Imaging for abdominal involvement in amyloidosis.
Involvement of the abdominal organs has variable presentations mostly without specific findings. The objective of this pictorial essay was to illustrate the computed tomography and magnetic resonance imaging (MRI) findings of abdominal involvement in systemic amyloidosis. Heterogeneous appearance of the liver, periportal involvement, diffuse low signal intensity of spleen on T2-weighted MRI, and thickened bowel wall may be helpful imaging findings when accompanied by presence or history of chronic inflammatory disease and clinical suspicion for amyloidosis.


The biological significance of substrate inhibition: a mechanism with diverse functions.
Many enzymes are inhibited by their own substrates, leading to velocity curves that rise to a maximum and then descend as the substrate concentration increases. Substrate inhibition is often regarded as a biochemical oddity and experimental annoyance. We show, using several case studies, that substrate inhibition often has important biological functions. In each case we discuss, the biological significance is different. Substrate inhibition of tyrosine hydroxylase results in a steady synthesis of dopamine despite large fluctuations in tyrosine due to meals. Substrate inhibition of acetylcholinesterase enhances the neural signal and allows rapid signal termination. Substrate inhibition of phosphofructokinase ensures that resources are not devoted to manufacturing ATP when it is plentiful. In folate metabolism, substrate inhibition maintains reactions rates in the face of substantial folate deprivation. Substrate inhibition of DNA methyltransferase serves to faithfully copy DNA methylation patterns when cells divide while preventing de novo methylation of methyl-free promoter regions.


Nuclear-cytoskeletal linkages facilitate cross talk between the nucleus and intercellular adhesions.
The linker of nucleoskeleton and cytoskeleton (LINC) complex allows cells to actively control nuclear position by coupling the nucleus to the cytoplasmic cytoskeleton. Nuclear position responds to the formation of intercellular adhesions through coordination with the cytoskeleton, but it is not known whether this response impacts adhesion function. In this paper, we demonstrate that the LINC complex component SUN2 contributes to the mechanical integrity of intercellular adhesions between mammalian epidermal keratinocytes. Mice deficient for Sun2 exhibited irregular hair follicle intercellular adhesions, defective follicle structure, and alopecia. Primary mouse keratinocytes lacking Sun2 displayed aberrant nuclear position in response to adhesion formation, altered desmosome distribution, and mechanically defective adhesions. This dysfunction appeared rooted in a failure of Sun2-null cells to reorganize their microtubule network to support coordinated intercellular adhesion. Together, these results suggest that cross talk between the nucleus, cytoskeleton, and intercellular adhesions is important for epidermal tissue integrity.


Multiscale immunomagnetic enrichment of circulating tumor cells: from tubes to microchips.
We review the rare cancer cell sorting technologies, with a focus on multiscale immunomagnetic approaches. Starting from the conventional magnetic activated cell sorting system, we derive the scaling laws of immunomagnetic assay and justify the recent trend of using downscaled systems for CTC studies. Furthermore, we introduce recent work on combining the immunomagnetic assay with microfluidic technology for enhanced separation. We summarize different types of in-channel micro-magnetic structures that can further increase the local magnetic field without lowering the system throughput. Related design concepts, principles, and microfabrication techniques are presented and evaluated.


Mitotic block in HeLa cells by vinblastine: ultrastructural changes in kinetochore-microtubule attachment and in centrosomes.
Previous work from this laboratory has indicated that very low concentrations of vinblastine block HeLa cells at mitosis in the presence of a full complement of microtubules and without major disruption of spindle organization. In the present study we analyzed the structural organization of mitotic spindle microtubules, chromosomes and centrosomes by electron microscopy after incubating HeLa cells for one cell cycle with 2 nM vinblastine. We found that mitotic block of HeLa cells by vinblastine was associated with alterations of the fine structure of the spindle that were subtle but profound in their apparent consequences. The cell cycle was blocked in a stage that resembled prometaphase or metaphase; chromosomes had not undergone anaphase segregation. Neither the structure of the microtubules nor the structure of the kinetochores was detectably altered by the drug. However, the number of microtubules attached to kinetochores was decreased significantly. In addition, the centrosomes were altered; the normal close association of mother and daughter centriole was lost, numerous membranous vesicles were found in the centrosomal region, and many centrioles exhibited abnormal ultrastructure and had microtubules coursing through their interiors. These findings are consistent with our previous results and indicate that inhibition of the polymerization dynamics of mitotic spindle microtubules and perhaps of centriole microtubules, rather than microtubule depolymerization, is responsible for the mitotic inhibition by vinblastine.


Temporal work stressors and satisfaction with work, life and health among health professionals in Switzerland.
Working in a hospital can be both rewarding and stressful. Whether one or the other is dominant depends on a number of factors ranging from shift work, physical demands, responsibilities and time pressure to job autonomy, work climate and leisure time. This study aimed to examine associations between temporal work stressors and satisfaction with work, life and health among health professionals in general, and nurses and physicians in particular. Associations were further investigated for possible mediating and intervening factors. Cross-sectional survey data on 1232 health professionals at three public hospitals and two rehabilitation clinics were collected in 2015/2016. Stepwise multiple linear regression analyses were used to estimate the standardised effects (beta coefficients) of temporal work stressors (overtime and time pressure), and organisational and personal resources (job autonomy, work climate, internal control belief) on general stress as the assumed mediator and finally on satisfaction with work, life and health. Temporal work stressors were found to strongly predict general stress symptoms among health professionals (β = 0.25) and particularly physicians (β = 0.30), independently of the observed stress-buffering effects of organisational resources such as job autonomy (β = −0.09) or work climate (β = −0.22). Associations between temporal work stressors (as predictors) and satisfaction with work, life and health (as outcomes) turned out to be mostly indirect, mediated by general stress. General stress in turn was observed to be the strongest predictor of domain-specific satisfaction (β = −0.17 to −0.34), sometimes only surpassed by resources such as work climate or internal control belief. Explained variance of the three satisfaction outcomes in the fully specified regression or explanatory models ranged between 14% and 45% depending on the (sub-)sample (nurses, physicians, all health professionals) or the outcome. Control belief was revealed to be a strong and independent personal resource, particularly regarding satisfaction with life and health in general (β = 0.25/0.21). Satisfaction and well-being of health professionals are strongly affected by job stressors such as frequent or excessive overtime work or permanent time pressure at work. Negative consequences of temporal work stressors are attenuated by organisational and personal resources such as a high level of job autonomy, a good work climate or a strong internal control belief.


Parvovirus induced alterations in nuclear architecture and dynamics.
The nucleus of interphase eukaryotic cell is a highly compartmentalized structure containing the three-dimensional network of chromatin and numerous proteinaceous subcompartments. DNA viruses induce profound changes in the intranuclear structures of their host cells. We are applying a combination of confocal imaging including photobleaching microscopy and computational methods to analyze the modifications of nuclear architecture and dynamics in parvovirus infected cells. Upon canine parvovirus infection, expansion of the viral replication compartment is accompanied by chromatin marginalization to the vicinity of the nuclear membrane. Dextran microinjection and fluorescence recovery after photobleaching (FRAP) studies revealed the homogeneity of this compartment. Markedly, in spite of increase in viral DNA content of the nucleus, a significant increase in the protein mobility was observed in infected compared to non-infected cells. Moreover, analysis of the dynamics of photoactivable capsid protein demonstrated rapid intranuclear dynamics of viral capsids. Finally, quantitative FRAP and cellular modelling were used to determine the duration of viral genome replication. Altogether, our findings indicate that parvoviruses modify the nuclear structure and dynamics extensively. Intranuclear crowding of viral components leads to enlargement of the interchromosomal domain and to chromatin marginalization via depletion attraction. In conclusion, parvoviruses provide a useful model system for understanding the mechanisms of virus-induced intranuclear modifications.


Charge transport mechanism in thin cuticles holding nandi flame seeds.
Metal-sample-metal sandwich configuration has been used to investigate DC conductivity in 4 mum thick Nandi flame [Spathodea campanulata P. Beauv.] seed cuticles. J-V characteristics showed ohmic conduction at low fields and space charge limited current at high fields. Charge mobility in ohmic region was 4.06 x 10(-5) (m(2)V(-1)s(-1)). Temperature-dependent conductivity measurements have been carried out in the temperature range 320 K < T > 450 K. Activation energy within a temperature of 320 K-440 K was about 0.86 eV. Variable range hopping (VRH) is the main current transport mechanism at the range of 330-440 K. The VRH mechanism was analyzed based on Mott theory and the Mott parameters: density of localized states near the Fermi-level N(E(F)) approximately 9.04 x 10(19) (eV(-1)cm(-3)) and hopping distance R approximately 1.44 x 10(-7) cm, while the hopping energy (W) was in the range of 0.72 eV-0.98 eV.


Tissue cyst rupture in mice chronically infected with Toxoplasma gondii. An immunocytochemical and ultrastructural study.
The incidence and effect of tissue cyst rupture in the brains of mice chronically infected with Toxoplasma gondii was studied by immunocytochemistry and electron microscopy. Cyst rupture was extremely rare (2 of 750 tissue cysts) irrespective of the interval post-infection. The event was associated with a rapid cell-mediated immune response, giving rise to microglial or inflammatory nodules. Macrophages were observed to engulf and degrade the cystozoites and cyst debris. Initially, the nodules contained large amounts of immunologically reactive material, but this was degraded with the majority (94%) of lesions containing no recognizable parasites or Toxoplasma antigens. There was little evidence of parasite multiplication or new cyst formation associated with cyst rupture. This study shows that although intermittent cyst rupture occurs, in immunocompetent individuals the immune response limits the potential damage from the release of large numbers of infective organisms to small microglial/inflammatory nodules.


Patients' attitudes to the summary care record and HealthSpace: qualitative study.
To document the views of patients and the public towards the summary care record (SCR, a centrally stored medical record drawn from the general practice record) and HealthSpace (a personal health organiser accessible through the internet from which people can view their SCR), with a particular focus on those with low health literacy, potentially stigmatising conditions, or difficulties accessing health care. 103 semistructured individual interviews and seven focus groups. Three early adopter primary care trusts in England where the SCR and HealthSpace are being piloted. All were in areas of relative socioeconomic deprivation. Individual participants were recruited from general practice surgeries, walk-in centres, out of hours centres, and accident and emergency departments. Participants in focus groups were recruited through voluntary sector organisations; they comprised advocates of vulnerable groups and advocates of people who speak limited English; people with HIV; users of mental health services; young adults; elderly people; and participants of a drug rehabilitation programme. Participants were asked if they had received information about the SCR and HealthSpace and about their views on shared electronic records in different circumstances. Most people were not aware of the SCR or HealthSpace and did not recall receiving information about it. They saw both benefits and drawbacks to having an SCR and described a process of weighing the former against the latter when making their personal choice. Key factors influencing this choice included the nature of any illness (especially whether it was likely to lead to emergency care needs); past and present experience of healthcare and government surveillance; the person's level of engagement and health literacy; and their trust and confidence in the primary healthcare team and the wider NHS. Overall, people with stigmatising illness were more positive about the SCR than people who claimed to speak for "vulnerable groups." Misconceptions about the SCR were common, especially confusion about what data it contained and who would have access to it. Most people were not interested in recording their medical data or accessing their SCR via HealthSpace, but some saw the potential for this new technology to support self management and lay care for those with chronic illness. Despite an extensive information programme in early adopter sites, the public remains unclear about current policy on shared electronic records, though most people view these as a positive development. The "implied consent" model for creating and accessing a person's SCR should be revisited, perhaps in favour of "consent to view" at the point of access.


Characterization of a ricin fusion toxin targeted to the interleukin-2 receptor.
Fusion toxins are hybrid proteins consisting of peptide ligands linked through amide bonds to polypeptide toxins. The ligand directs the molecule to the surface of target cells and the toxin enters the cytosol and induces cell death. Ricin is an excellent candidate for use in fusion toxins because of its extreme potency, the extensive knowledge of its atomic structure and the lack of prior immunological exposure in patients. We synthesized a baculovirus transfer vector with the polyhedrin promoter followed sequentially from the 5' end with DNA encoding the gp67A leader sequence, the tripeptide ADP, IL-2 (interleukin-2), another ADP tripeptide and RTB (ricin toxin B chain) with lectin-site mutations W37S and Y248H. Recombinant baculovirus was generated in Sf9 insect cells and used to infect Sf9 cells. Recombinant IL-2-RTB[W37S/Y248H] protein (fusion protein of IL-2 with modifications W37S and Y248H) was recovered at high yields from day 6 insect cell supernatants, partially purified by affinity chromatography and reassociated with RTA (ricin toxin A chain). The fusion toxin was soluble, immunoreactive with antibodies to RTB, IL-2 and RTA and had a molecular weight of 80 kDa by SDS-PAGE. The molecule reacted poorly with asialofetuin, but bound strongly to IL-2 receptor based on selective cytotoxicity to IL-2 receptor bearing cells. The specific cytotoxicity could be blocked with IL-2 but not lactose. Thus, we report a novel targeted fusion toxin protein with full biological activity.


Factors relating to the infant's last sleep environment in sudden infant death syndrome in the Republic of Ireland.
To identify risk factors for sudden infant death syndrome (SIDS) in the sleeping environment of Irish infants. A five year population based case-control study with parental interviews conducted for each case and three controls matched for age, place of birth, and last sleep period. A total of 203 SIDS cases and 622 control infants born 1994-98 were studied. In a multivariate analysis, co-sleeping significantly increased the risk of SIDS both as a usual practice (adjusted OR 4.31; 95% CI 1.07 to 17.37) and during the last sleep period (adjusted OR 16.47; 95% CI 3.73 to 72.75). The associated risk was dependent on maternal smoking (OR 21.84; 95% CI 2.27 to 209.89), and was not significant for infants who were > or =20 weeks of age (OR 2.63; 95% CI 0.49 to 70.10) or placed back in their own cot/bed to sleep (OR 1.07; 95% CI 0.21 to 5.41). The use of pillows, duvets, and bedding with tog value > or =10 were not significant risk factors when adjusted for the effects of confounding variables, including maternal smoking and social disadvantage. However, the prone sleeping position remains a significant SIDS risk factor, and among infants using soothers, the absence of soother use during the last sleep period also significantly increased the SIDS risk (OR 5.83; CI 2.37 to 14.36). Co-sleeping should be avoided in infants who are <20 weeks of age, or whose mothers smoked during pregnancy. The prone position remains a factor in some SIDS deaths, and the relation between soother use and SIDS is a complex variable requiring further study.


Multiplex assay for simultaneous measurement of antibodies to multiple Plasmodium falciparum antigens.
Antibodies to Plasmodium falciparum are classically measured using the enzyme-linked immunosorbent assay (ELISA). Although highly sensitive, this technique is labor-intensive when large numbers of samples must be screened against multiple antigens. The suspension array technology (SAT) might be an alterative to ELISA, as it allows measurement of antibodies against multiple antigens simultaneously with a small volume of sample. This study sought to adapt the new SAT multiplex system for measuring antibodies against nine malarial vaccine candidate antigens, including recombinant proteins from two variants of merozoite surface protein 1, two variants of apical merozoite antigen 1, erythrocyte binding antigen 175, merozoite surface protein 3, and peptides from the circumsporozoite protein, ring erythrocyte surface antigen, and liver-stage antigen 1. Various concentrations of the antigens were coupled to microspheres with different spectral addresses, and plasma samples from Cameroonian adults were screened by SAT in mono- and multiplex formats and by ELISA. Optimal amounts of protein required to perform the SAT assay were 10- to 100-fold less than that needed for ELISA. Excellent agreement was found between the single and multiplex formats (R > or = 0.96), even when two variants of the same antigen were used. The multiplex assay was rapid, reproducible, required less than 1 mul of plasma, and had a good correlation with ELISA. Thus, SAT provides an important new tool for studying the immune response to malaria rapidly and efficiently in large populations, even when the amount of plasma available is limited, e.g., in studies of neonates or finger-prick blood.


Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.


Predicting Partition Coefficients of Neutral and Charged Solutes in the Mixed SLES-Fatty Acid Micellar System.
Sodium laureth sulfate (SLES) and fatty acids are common ingredients in many cosmetic products. Understanding how neutral and charged fatty acid compounds partition between micellar and water phases is crucial to achieve the optimal design of the product formulation. In this paper, we first study the formation of mixed SLES and fatty acid micelles using molecular dynamics (MD) simulations. Micelle/water partition coefficients of neutral and charged fatty acids are then calculated using COSMOmic as well as a MD approach based on the potential of mean force (PMF) calculations performed using umbrella sampling (US). The combined US/PMF approach was performed with both the additive, non-polarizable CHARMM general force field (CGenFF) and the classical Drude polarizable force field. The partition coefficients for the neutral solutes are shown to be accurately calculated with the COSMOmic and additive CGenFF US/PMF approaches, while only the US/PMF approach with the Drude polarizable force field accurately calculated the experimental partition coefficient of the charged solute. These results indicate the utility of the Drude polarizable force field as a tool for the rational development of mixed micelles.


Siblings' experiences of their brother's or sister's cancer death: a nationwide follow-up 2-9 years later.
The aim of this study was to examine siblings' experiences of their brother's or sister's cancer death and if these experiences influenced levels of anxiety 2-9 years later. This nationwide survey was conducted in Sweden in 2009. All siblings who had a brother/sister who was diagnosed with cancer before the age of 17 years and who died before the age of 25 years during 2000-2007 were invited. Of those, 174 siblings participated (participation rate: 73%). Mixed data from the survey about the siblings' experiences of death were included as well as data from the Hospital Anxiety and Depression Scale. To examine the experiences, descriptive statistics and content analysis were used. Mann-Whitney U-test was conducted to investigate if the experiences influenced anxiety 2-9 years later. The siblings reported poor knowledge and experienced a lack of communication about their brother's/sister's death, for example, about the time frame, bodily changes near death, and about their own experiences. Siblings who reported that no one talked with them about what to expect when their brother/sister was going to die reported higher levels of anxiety 2-9 years after the loss. Seventy percent reported that they witnessed their brother/sister suffering in the last hours in life. Many of those who were not present during the illness period and at the time of death expressed regret. It is important to prepare siblings for their brother's/sister's illness and death as it may decrease anxiety and regrets later on.


Long-term results of gamma knife surgery for craniopharyngioma.
One hundred seven cases of craniopharyngiomas were treated using gamma knife surgery (GKS) at Komaki City Hospital during the past 12 years. The authors report the long-term results obtained in 100 patients who were followed for 6 to 148 months (mean 65.5 months). All patients underwent GKS. The mean tumor diameter and volume were 18.8 mm and 5.8 ml, respectively; lesions were treated with a maximum dose of 21.8 Gy and marginal dose of 11.5 Gy (mean isocenters 4.5). Overall tumor responses were complete in 19, partial in 44, no change in 14, and disease progression in 23, yielding a complete response rate of 19%, overall response rate of 63%, control rate of 77%, and progression rate of 23%. Considering factors such as patient age, nature of the tumor (solid, mixed, cystic), frequency of previous treatments, and tumor size, the age and nature of the tumor were significant prognostic factors. Changes in neurological and pituitary-hypothalamic symptoms after GKS were evaluated in 91 patients. Overall improvement was demonstrated in 17 (18.7%), no change in 59 (64.8%), and deterioration in 15 (16.5%). Outcome was documented in 93 cases: excellent in 42, good in 23, fair in seven, poor in three, and dead in 18 patients. Stereotactic GKS is a safe and effective treatment as an adjuvant or boost therapy for postresection residual and/or recurrent craniopharyngiomas; the effects are durable and side effects acceptable.


Paradoxical helminthiasis and giardiasis in Cape Town, South Africa: epidemiology and control.
South Africa has endorsed a World Health Assembly (WHA) resolution calling for control of soil-transmitted helminths (STHs). In Cape Town, services and housing that exist in old-established suburbs should minimise the prevalence of intestinal parasitic infections, even when residents are poor. Where families live in shacks in densely-populated areas without effective sanitation, more than 90% of children can be infected by STHs. The humoral immune response to worms theoretically favours infection by Mycobacterium tuberculosis and HIV. Obtain estimates of gender-, age-, school-related and overall prevalence of helminthiasis and giardiasis in a low-income but well-serviced community. Assess possible sources of infection. Alert health services to the need for control measures and the threat from protozoal pathogens. Warn that the immune response to intestinal parasites may favour tuberculosis (TB) and HIV/AIDS. A cross-sectional study of the prevalence of helminthiasis and giardiasis was carried out in a large, non-selective sample of children attending nine schools. Gender, school and age effects were related to non-medical preventive services, sewage disposal practices and possible sources of infection. The overall STH infestation rate was 55.8%. Prevalence was influenced by school and age but not by gender. Eggs and cysts were seen at the following prevalences: Ascaris 24.8%; Trichuris 50.6%; Hymenolepis nana 2.2%; Enterobius 0.6%; Giardia 17.3%; hookworm 0.08%; and Trichostrongylus 0.1%. Approximately 60% of sewage sludge is used in a form that will contain viable eggs and cysts. Prevalence trends in this old community in Cape Town could indicate infection by swallowing eggs or cysts on food or in water, more than by exposure to polluted soil. Sewage sludge and effluent might be sources of infection. In adjacent, under-serviced, newer communities, promiscuous defaecation occurs. Probable vectors are discussed. The immune response to intestinal parasites might be a risk factor for HIV/AIDS and TB.


Network Approaches to Substance Use and HIV/Hepatitis C Risk among Homeless Youth and Adult Women in the United States: A Review.
During the United States economic recession of 2008-2011, the number of homeless and unstably housed people in the United States increased considerably. Homeless adult women and unaccompanied homeless youth make up the most marginal segments of this population. Because homeless individuals are a hard to reach population, research into these marginal groups has traditionally been a challenge for researchers interested in substance abuse and mental health. Network analysis techniques and research strategies offer means for dealing with traditional challenges such as missing sampling frames, variation in definitions of homelessness and study inclusion criteria, and enumeration/population estimation procedures. This review focuses on the need for, and recent steps toward, solutions to these problems that involve network science strategies for data collection and analysis. Research from a range of fields is reviewed and organized according to a new stress process framework aimed at understanding how homeless status interacts with issues related to substance abuse and mental health. Three types of network innovation are discussed: network scale-up methods, a network ecology approach to social resources, and the integration of network variables into the proposed stress process model of homeless substance abuse and mental health. By employing network methods and integrating these methods into existing models, research on homeless and unstably housed women and unaccompanied young people can address existing research challenges and promote more effective intervention and care programs.


New light on the systematics of fungi associated with attine ant gardens and the description of Escovopsis kreiselii sp. nov.
Since the formal description of fungi in the genus Escovopsis in 1990, only a few studies have focused on the systematics of this group. For more than two decades, only two Escovopsis species were described; however, in 2013, three additional Escovopsis species were formally described along with the genus Escovopsioides, both found exclusively in attine ant gardens. During a survey for Escovopsis species in gardens of the lower attine ant Mycetophylax morschi in Brazil, we found four strains belonging to the pink-colored Escovopsis clade. Careful examination of these strains revealed significant morphological differences when compared to previously described species of Escovopsis and Escovopsioides. Based on the type of conidiogenesis (sympodial), as well as morphology of conidiogenous cells (percurrent), non-vesiculated conidiophores, and DNA sequences, we describe the four new strains as a new species, Escovopsis kreiselii sp. nov. Phylogenetic analyses using three nuclear markers (Large subunit RNA; translation elongation factor 1-alpha; and internal transcribed spacer) from the new strains as well as available sequences in public databases confirmed that all known fungi infecting attine ant gardens comprise a monophyletic group within the Hypocreaceae family, with very diverse morphological characteristics. Specifically, Escovopsis kreiselii is likely associated with gardens of lower-attine ants and its pathogenicity remains uncertain.


Examining the consulting physician model to enhance the school nurse role for children with asthma.
The Centers for Disease Control and Prevention's Strategies for Addressing Asthma Within a Coordinated School Health Program recommends a consulting physician for schools to help manage asthma. The literature examines the effects when a school nurse is present, but the addition of a consulting physician is not well understood. The purpose of this study is to assess the effect of having a consulting physician on school absenteeism and children sent home due to health reasons for children with asthma and all children pooled together. A 2-year preimplementation group cohort and 1-year implementation group cohort of grades K-6 in an urban school district were used to determine the impact of a consulting physician on school absenteeism for children with asthma and all children pooled together. A consulting physician was significantly associated with reduced missed school days for children with asthma and all children as a group. All children pooled together were 44% more likely (OR = 1.44, 95% CI = 1.31-1.58) to be sent home without the consulting physician. There was a reduction from 13.8% to 12.6% of sent home events in children with asthma. Having consulting physicians in school districts appears to be associated with fewer days of school absence. The results provide additional evidence and suggest that more research is required to determine if this association is valid and to better understand the cause of such an association.


Television watching during lunch increases afternoon snack intake of young women.
Eating while watching television has been shown to increase food intake in part due to the distracting effects of television viewing. It is also known that enhancing memory for the specific attributes of foods eaten in the recent past decreases subsequent food intake. Because distraction at the time of encoding interferes with memory formation, we predicted that television watching during lunch would increase afternoon snack intake due to impaired memory for recent eating. Using a repeated-measures design, 16 young women undergraduate students visited the laboratory to eat a fixed lunch either while watching television or in the absence of television. Intake of cookies at a tasting session later that afternoon was measured and participants recalled eating the lunch and rated the memory for vividness. All participants ate all of the lunch and rated appetite during lunch did not differ according to condition. Participants ate significantly more cookies after they had eaten their lunch while watching television than when they had eaten their lunch while not watching television and this effect could not be attributed to an effect of television watching on rated mood or appetite before the snack session. Watching television while eating lunch was also associated with reduced vividness ratings of the memory of the lunch. These results suggest that the effects of television watching on food intake extend beyond the time of television watching to affect subsequent consumption. They further suggest that this effect may be related to an effect of television watching on encoding of the memory of the meal.


Expectation modulates repetition priming under high stimulus variability.
Neural responses to stimuli are often attenuated by repeated presentation. When observed in blood oxygen level-dependent signals, this attenuation is known as fMRI adaptation (fMRIa) or fMRI repetition suppression. According to a prominent account, fMRIa reflects the fulfillment of perceptual expectations during recognition of repeated items (Summerfield, Trittschuh, Monti, Mesulam, & Egner, 2008). Supporting this idea, expectation has been shown to modulate fMRIa under some circumstances; however, it is not currently known whether expectation similarly modulates recognition performance. To address this lacuna, we measured behavioral and fMRI responses to faces while varying the extent to which each stimulus was informative about its successor. Behavioral priming was greater when repetitions were more likely, suggesting that recognition was facilitated by the expectation than an item would repeat. Notably, this effect was only observed when stimuli were drawn from a broad set of faces including many ethnicities and both genders, but not when stimuli were drawn from a narrower face set, thus making repetitions less informative. Moreover, expectation did not modulate fMRIa in face-selective cortex, contrary to previous studies, although an exploratory analysis indicated that it did so in a medial frontal region. These results support the idea that expectation modulates recognition efficiency, but insofar as behavioral effects of expectation were not accompanied by fMRI effects in visual cortex, they suggest that fMRIa cannot be entirely explained in terms of fulfilled expectations.


Steered molecular dynamics studies of the potential of mean force of a Na+ or K+ ion in a cyclic peptide nanotube.
Potential of mean force (PMF) profiles of a single Na+ or K+ ion passing through a cyclic peptide nanotube, cyclo[-(D-Ala-Glu-D-Ala-Gln)2-], in water are calculated to provide insight into ion transport and to understand the conductance difference between these two ions. The PMF profiles are obtained by performing steered molecular dynamics (SMD) simulations that are based on the Jarzynski equality. The computed PMF profiles for both ions show barriers of around 2.4 kcal/mol at the channel entrances and exits and energy wells in the middle of the tube. The energy barriers, so-called dielectric energy barriers, arise due to the desolvation of water molecules when ions move across the nanotube, and the energy wells appear as a result of attractive interactions between the cations and negatively charged carbonyl oxygens on the backbone of the tube. We find more and deeper energy wells in the PMF profile for Na+ than for K+, which suggests that Na+ ions have a longer residence time inside the nanotube and that permeation of Na+ ions is reduced compared to K+ ions. Calculations of the radial distribution functions (RDF) between the ions and oxygens in the water molecules and in carbonyl groups on the tube and an investigation of the orientations of the carbonyl groups show that, in contrast with the dynamic carbonyl groups observed in the selectivity filter of the KcsA ion channel, the carbonyl groups in the cyclic peptide nanotube are relatively rigid, with only slight reorientation of the carbonyl groups as the cations pass through. The rigidity of the carbonyl groups in the cyclic peptide nanotube can be attributed to their role in hydrogen bonding, which is responsible for the tube structure. Comparison of the PMF profiles with the electrostatic energy profiles calculated from the Poisson-Boltzmann (PB) equation, a dielectric continuum model, reveals that the dielectric continuum model breaks down in the confined region within the tube that governs ion transport.


THE ELABORATION OF SPECIFIC SOLUBLE SUBSTANCE BY PNEUMOCOCCUS DURING GROWTH.
1. A specifically reacting substance of bacterial origin is present in the cell-free fluids of young cultures of pneumococcus. This substance is present when the organisms are growing at their maximum rate and undergoing little or no cell death, and consequently its. presence is not dependent upon cell disintegration but represents the extrusion of bacterial substance by the living organism. 2. The blood and urine of rabbits experimentally infected with pneumococcus contain a similar specific soluble substance during the early hours of the infectious process. 3. Human beings suffering from lobar pneumonia have in their blood and more frequently in their urine a specific soluble substance of pneumococcus origin. The amount of this substance present in the urine varies in different individuals and the presence of a large amount is of unfavorable prognostic import. This specific precipitin reaction in the urine is of diagnostic value. 4. Rabbits injected with soluble pneumococcus material continue to excrete this substance for a considerable period of time. 5. The specifically soluble substance obtained from bacterial cultures and from the urine during infection is not destroyed by boiling, by precipitation with alcohol, acetone, or ether, or by trypsin digestion. 6. Studies are in progress at this time on the degree of toxicity and on the antigenic properties of the substance.


Are depressive symptoms nonspecific in patients with acute stroke?
Some investigators have suggested that major depression might be overdiagnosed in stroke patients because of changes in appetite, sleep, or sexual interest caused by their medical illness; others have suggested that depression may be underdiagnosed in stroke patients who deny symptoms of depression because of anosognosia, neglect, or aprosody. The authors' goal was to determine how frequently depressive symptoms occur in acute stroke patients with and without depressed mood to estimate how often diagnostic errors of inclusion or exclusion may be made. They examined the rate of autonomic and psychological symptoms of depression in 205 patients who were consecutively hospitalized for acute stroke. Eighty-five (41%) of these patients had depressed mood, and 120 (59%) had no mood disturbance. Forty-six (54%) of the 85 patients with depressed mood (22% of all patients) were assigned the DSM-III diagnosis of major depression. The 120 patients without mood disturbance had a mean of one autonomic symptom, but the 85 patients with depressed mood had a mean of almost four. Tightening the diagnostic criteria to account for one more nonspecific autonomic symptom decreased the number of patients with major depression by only three; adding two more criteria decreased the number by only five. Thus, the rate of DSM-III major depression was 1% higher than the rate with one extra nonspecific autonomic symptom and 2% higher than the rate with two extra criteria. Conversely, loosening diagnostic criteria to account for denial of depressive illness increased the rate of major depression by only 5%. Both autonomic and psychological depressive symptoms are strongly associated with depressed mood in acute stroke patients.


Transradial approach to lower extremity interventions.
Percutaneous interventions of the coronary and peripheral vessels have historically been performed using a femoral artery approach. There has been increasing recognition of post-procedural bleeding complications and its impact on short- and long-term mortality. Because of its now recognized safety, the transradial approach has recently emerged as a preferred method compared to the transfemoral approach. The limitations associated with the distance from the puncture site to the lesion location are being addressed as new tools are developed for the endovascular treatment of peripheral arterial disease. In this review, we discuss the many facets of the transradial approach to lower extremity endovascular interventions, highlighting its safety and efficacy. Approaches to special populations including individuals with prior surgical bypass, Leriche's syndrome, and those committed to chronic anticoagulation are also reviewed.


Efficacy of venlafaxine compared with tricyclic antidepressants in depressive disorder: a meta-analysis.
With respect to the pharmacological characteristic, venlafaxine is comparable with tricyclic antidepressants (TCAs), and venlafaxine might be comparable in efficacy. We performed a systematic review investigating the relative efficacy and tolerability of venlafaxine compared with TCAs (imipramine, clomipramine, amitriptyline, nortriptyline and desipramine). Relevant double-blind randomised trials were identified from systematic searches of electronic databases. An exact analysis of the estimated odds ratios of response of the TCA relative to venlafaxine showed no overall significance of treatment effect (P = 0.38). The odds ratios were not homogenous across studies (P = 0.0213). The average dose of venlafaxine was 103.5 mg/day and for the TCA 106.1 mg/day. An exact analysis of the estimated odds ratios of the withdrawals and side effects in the trials with a TCA relative to venlafaxine showed no overall significance of withdrawal. From our review, no significant difference in treatment effect between low dose of both venlafaxine and the TCAs could be found. In our opinion, because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy.


Expression of the BabA adhesin during experimental infection with Helicobacter pylori.
The Helicobacter pylori babA gene encodes an outer membrane protein that mediates binding to fucosylated ABH antigens of the ABO blood group. We recently demonstrated that BabA expression is lost during experimental infection of rhesus macaques with H. pylori J166. We sought to test the generality of this observation by comparison of different H. pylori strains and different animal hosts. Challenge of macaques with H. pylori J99 yielded output strains that lost BabA expression, either by selection and then expansion of a subpopulation of J99 that had a single-base-pair mutation that encoded a stop codon or by gene conversion of babA with a duplicate copy of babB, a paralog of unknown function. Challenge of mice with H. pylori J166, which unlike J99, has 5' CT repeats in babA, resulted in loss of BabA expression due to phase variation. In the gerbil, Leb binding was lost by replacement of the babA gene that encoded Leb binding with a nonbinding allele that differed at six amino acid residues. Complementation experiments confirmed that change in these six amino acids of BabA was sufficient to eliminate binding to Leb and to gastric tissue. These results demonstrate that BabA expression in vivo is highly dynamic, and the findings implicate specific amino acid residues as critical for binding to fucosylated ABH antigens. We hypothesize that modification of BabA expression during H. pylori infection is a mechanism to adapt to changing conditions of inflammation and glycan expression at the epithelial surface.


Electrochemical biosensors for on-chip detection of oxidative stress from immune cells.
Seamless integration of biological components with electrochemical sensors is critical in the development of microdevices for cell analysis. The present paper describes the integration miniature Au electrodes next to immune cells (macrophages) in order to detect cell-secreted hydrogen peroxide (H(2)O(2)). Photopatterning of poly(ethylene glycol) (PEG) hydrogels was used to both immobilize horseradish peroxidase molecules onto electrodes and to define regions for cell attachment in the vicinity of sensing electrodes. Electrodes micropatterned in such a manner were enclosed inside poly(dimethylsiloxane) fluid conduits and incubated with macrophages. The cells attached onto the exposed glass regions in the vicinity of the electrodes and nowhere else on the non-fouling PEG hydrogel surface. A microfluidic device was converted into an electrochemical cell by placing flow-through Ag∕AgCl reference and Pt wire counter electrodes at the outlet and inlet, respectively. This microdevice with integrated H(2)O(2)-sensing electrodes had sensitivity of 27 μA∕cm(2) mM with a limit of detection of 2 μM. Importantly, this microdevice allowed controllable seeding of macrophages next to electrodes, activation of these cells and on-chip monitoring of H(2)O(2) release in real time. In the future, this biosensor platform may be utilized for monitoring of macrophage responses to pathogens or for the study of inflammatory signaling in micropatterned cell cultures.


Social networks, social support, and burden in relationships, and mortality after breast cancer diagnosis in the Life After Breast Cancer Epidemiology (LACE) study.
Larger social networks have been associated with lower breast cancer mortality. The authors evaluated how levels of social support and burden influenced this association. We included 2,264 women from the Life After Cancer Epidemiology study who were diagnosed with early-stage, invasive breast cancer between 1997 and 2000, and provided data on social networks (spouse or intimate partner, religious/social ties, volunteering, time socializing with friends, and number of first-degree female relatives), social support, and caregiving. 401 died during a median follow-up of 10.8 years follow-up with 215 from breast cancer. We used delayed entry Cox proportional hazards regression to evaluate associations. In multivariate-adjusted analyses, social isolation was unrelated to recurrence or breast cancer-specific mortality. However, socially isolated women had higher all-cause mortality (HR = 1.34, 95 % CI: 1.03-1.73) and mortality from other causes (HR = 1.79, 95 % CI: 1.19-2.68). Levels of social support and burden modified associations. Among those with low, but not high, levels of social support from friends and family, lack of religious/social participation (HR = 1.58, 95 % CI: 1.07-2.36, p = 0.02, p interaction = 0.01) and lack of volunteering (HR = 1.78, 95 % CI: 1.15-2.77, p = 0.01, p interaction = 0.01) predicted higher all-cause mortality. In cross-classification analyses, only women with both small networks and low levels of support (HR = 1.61, 95 % CI: 1.10-2.38) had a significantly higher risk of mortality than women with large networks and high levels of support; women with small networks and high levels of support had no higher risk of mortality (HR = 1.13, 95 % CI: 0.74-1.72). Social networks were also more important for caregivers versus noncaregivers. Larger social networks predicted better prognosis after breast cancer, but associations depended on the quality and burden of family relationships.


Ultrasound Image Representation Learning by Modeling Sonographer Visual Attention.
Image representations are commonly learned from class labels, which are a simplistic approximation of human image understanding. In this paper we demonstrate that transferable representations of images can be learned without manual annotations by modeling human visual attention. The basis of our analyses is a unique gaze tracking dataset of sonographers performing routine clinical fetal anomaly screenings. Models of sonographer visual attention are learned by training a convolutional neural network (CNN) to predict gaze on ultrasound video frames through visual saliency prediction or gaze-point regression. We evaluate the transferability of the learned representations to the task of ultrasound standard plane detection in two contexts. Firstly, we perform transfer learning by fine-tuning the CNN with a limited number of labeled standard plane images. We find that fine-tuning the saliency predictor is superior to training from random initialization, with an average F1-score improvement of 9.6% overall and 15.3% for the cardiac planes. Secondly, we train a simple softmax regression on the feature activations of each CNN layer in order to evaluate the representations independently of transfer learning hyper-parameters. We find that the attention models derive strong representations, approaching the precision of a fully-supervised baseline model for all but the last layer.


Displacement field analysis based on the combination digital speckle correlation method with radial basis function interpolation.
The digital speckle correlation method (DSCM) has been widely used to resolve displacement and deformation gradient fields. The computational time and the computational accuracy are still two challenging problems faced in this area. In this paper, we introduce the radial basis function (RBF) interpolation method to DSCM and propose a method for displacement field analysis based on the combination of DSCM with RBF interpolation. We test the proposed method on two computer-simulated and two experimentally obtained deformation measurements and compare it with the widely used Newton-Raphson iteration (NR method). The experimental results demonstrate that our method performs better than the NR method in terms of both quantitative evaluation and visual quality. In addition, the total computational time of our method is considerably shorter than that of the NR method. Our method is particularly suitable for displacement field analysis of large regions.


Plasma amino acids and neopterin in healthy persons with Down's syndrome.
In persons with Down's syndrome (DS) immunological abnormalities as well as hypothyroidism and Alzheimer type dementia are frequently observed. In addition, the activity of the enzyme cystathionine beta-synthase (CBS) is over-expressed which results in an altered homocysteine metabolism. In the present study, 48 older healthy DS persons without signs of dementia, psychiatric or somatic comorbidity and free of medication were analyzed for plasma levels of amino acids, neopterin and monoaminergic metabolites. Data were compared with those obtained from age and sex matched healthy controls. It was found that the spectrum of amino acids showed widespread differences in that levels of nearly all essential amino acids were lower in DS patients as compared to healthy controls. In addition, a significantly lower methionine and higher taurine concentration were observed which is in accordance with a disturbed homocysteine metabolism. With respect to the monoamine metabolites, the concentration of 5-hydroxyindoleacetic acid was not altered whereas that of homovanillic acid was significantly increased. Finally, the concentration of the immune activation marker neopterin was increased in persons with DS. It is concluded that healthy DS persons of older age show extensive biochemical abnormalities suggesting a compromised homocysteine metabolism, an activated cell-mediated immune response and an enhanced turnover of dopamine.


Papillary glioneuronal tumor growing slowly for 26 years: illustrative case.
Papillary glioneuronal tumors (PGNTs) are classified as a type of World Health Organization grade I mixed neuronal-glial tumor. Most PGNTs involve cystic formations with mural nodules and solid components in the cerebral hemispheres, and PGNTs occur mainly in young adults. The long-term prognosis of PGNTs remains unclear. A 38-year-old male had been diagnosed with an arachnoid cyst associated with epilepsy in a local hospital. The initial magnetic resonance imaging (MRI) study showed the tumor as a heterogeneously enhanced nodule in the left postcentral gyrus. Subsequent MRI studies showed slow growth of the tumor for 26 years. He underwent gross total resection to control his epilepsy. The histopathological findings revealed pseudopapillary structures involving hyalinized blood vessels with a single or pseudostratified layer of cuboidal glial cells with round nuclei and scant cytoplasm. At the periphery of the lesion, Rosenthal fibers and acidophilic granule bodies were observed in the gliotic brain tissue. Immunohistochemically, some interpapillary cells were positive for NeuN. On the basis of these findings, the tumor was diagnosed as a PGNT. This PGNT showed slow growth for 26 years. When recognizing a slowly growing tumor in the cerebral hemispheres of relatively young people that is associated with epileptic seizures, PGNT should be considered as a differential diagnosis.


Effect of a Novel Ashwagandha-based Herbomineral Formulation on Pro-inflammatory Cytokines Expression in Mouse Splenocyte Cells: A Potential Immunomodulator.
Herbomineral formulations are momentous in an audience of worldwide by virtue of their holistic approach to life. These formulations are widely used as complementary therapies in immunocompromised patients including cancer. Still, there is the need of cost-effective and safe herbomineral-based formulation that can modulate immune response by the regulation of cytokines cascades. Current study, we investigated immunomodulatory effect of TEBEH in LPS-induced cytokines expression levels in mouse splenocytes in vitro. The most effective and safe concentrations of TEBEH were chosen by determining the cell viability of splenocytes using MTT assay. The pro-inflammatory cytokines such as TNF-α, IL-1β, MIP-1α, and IFN-γ were measured in cell supernatants using ELISA. MTT data showed TEBEH formulation was found safe up to 10.53 μg/mL. At noncytotoxic concentrations (0.00001053-10.53 μg/mL), TEBEH significantly (P ≤ 0.001) inhibited the expressions of TNF-α, IL-1β, and MIP-1α in mouse splenocytes as compared with vehicle control. In summary, TEBEH may indeed promote an anti-inflammatory environment by suppression of pro-inflammatory cytokines. These observations indicated that TEBEH has potential effects in downregulating the immune system and might be developed as a useful anti-inflammatory product for various inflammatory disorders. The present study was undertaken to evaluate an immunomodulatory effect of the herbomineral formulation in LPS-induced mouse splenocytes with the measurement of cytokines expression such as TNF-α, IL-1β, MIP-1α and IFN-γ. The results showed that the expression of TNF-α, IL-1β, and MIP-1α was significantly down-regulated while, IFN-γ was significantly up-regulated in mouse splenocytes. It is hypothesized that modulation of the proinflammatory cytokines might occur via NF-κB pathway. Therefore, the herbomineral test formulation might act as an effective anti-inflammatory and immunomodulatory product, and this can be used as a complementary and alternative treatment for the prevention of various types of inflammatory and auto-immune disorders Abbreviations used: LPS: Lipopolysaccharide, IL: Interleukin; NF-κB: Nuclear factor kappa-B, TNF-α: Tumor necrosis factor alpha, MIP-1α: Macrophage inflammatory protein-1α, IFN-γ: Interferon, MTT: 3-(4,5-diamethyl-2-thiazolyl)-2, 5-diphenyl-2Htetrazolium), ELISA: Enzyme linked immune sorbent assay, ANOVA: Analysis of variance.


Ethics in human resource management: potential for burnout among healthcare workers in ART and community care centres.
This paper examines ethical dilemmas in providing care for people with HIV/AIDS. Healthcare providers in this sector are overworked, particularly in the high prevalence states. They are faced with the dual burden of the physical and the emotional risks of providing this care. The emotional risks result from their inability to control their work environment, while having to deal with the social and cultural dimensions of patients' experiences. The physical risk is addressed to some extent by post exposure prophylaxis. But the emotional risk is largely left to the individual and there is little by way of institutional responsibility for minimising this. The guidelines for training workers in care and support programmes do not include any detailed institutional mechanisms for reducing workplace stress. This aspect of the programme needs to be examined for its ethical justification. The omission of institutional mechanisms to reduce the emotional risks experienced by healthcare providers in the HIV/AIDS sector could be a function of lack of coordination across different stakeholders in programme development. This can be addressed in further formulations of the programme. Whatever the reasons may be for overlooking these needs, the ethics of this choice need to be carefully reviewed.


Conserved Molecular Underpinnings and Characterization of a Role for Caveolin-1 in the Tumor Microenvironment of Mature T-Cell Lymphomas.
Neoplasms of extra-thymic T-cell origin represent a rare and difficult population characterized by poor clinical outcome, aggressive presentation, and poorly defined molecular characteristics. Much work has been done to gain greater insights into distinguishing features among malignant subtypes, but there also exists a need to identify unifying characteristics to assist in rapid diagnosis and subsequent potential treatment. Herein, we investigated gene expression data of five different mature T-cell lymphoma subtypes (n = 187) and found 21 genes to be up- and down-regulated across all malignancies in comparison to healthy CD4(+) and CD8(+) T-cell controls (n = 52). From these results, we sought to characterize a role for caveolin-1 (CAV1), a gene with previous description in the progression of both solid and hematological tumors. Caveolin-1 was upregulated, albeit with a heterogeneous nature, across all mature T-cell lymphoma subtypes, a finding confirmed using immunohistochemical staining on an independent sampling of mature T-cell lymphoma biopsies (n = 65 cases). Further, stratifying malignant samples in accordance with high and low CAV1 expression revealed that higher expression of CAV1 in mature T-cell lymphomas is analogous with an enhanced inflammatory and invasive gene expression profile. Taken together, these results demonstrate a role for CAV1 in the tumor microenvironment of mature T-cell malignancies and point toward potential prognostic implications.


Levels of Human Immunodeficiency Virus DNA Are Determined Before ART Initiation and Linked to CD8 T-Cell Activation and Memory Expansion.
Initiation of antiretroviral therapy (ART) in early compared with chronic human immunodeficiency virus (HIV) infection is associated with a smaller HIV reservoir. This longitudinal analysis of 60 individuals who began ART during primary HIV infection (PHI) investigates which pre- and posttherapy factors best predict HIV DNA levels (a correlate of reservoir size) after treatment initiation during PHI. The best predictor of HIV DNA at 1 year was pre-ART HIV DNA, which was in turn significantly associated with CD8 memory T-cell differentiation (effector memory, naive, and T-bet-Eomes- subsets), CD8 T-cell activation (CD38 expression) and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) expression on memory T cells. No associations were found for any immunological variables after 1 year of ART. Levels of HIV DNA are determined around the time of ART initiation in individuals treated during PHI. CD8 T-cell activation and memory expansion are linked to HIV DNA levels, suggesting the importance of the initial host-viral interplay in eventual reservoir size.


Four-year longitudinal impact evaluation of the Action for Children UK Neglect Project: outcomes for the children, families, Action for Children, and the UK.
Neglect has a devastating impact on children and is the most pervasive form of child maltreatment in the United Kingdom. The study purpose was to establish outcomes for neglected children following structured assessment and intervention to ascertain what worked and why it worked. This prospective cohort study included 85 cases of neglected children under 8 years of age from 7 centers across the United Kingdom. Data were collected between 2008 and 2012 through serial quantitative recording of the level of concern about neglect. Serial review of qualitative case-file data was undertaken for detail of assessment, interventions, and evidence of outcomes for the child. Data analysis was undertaken by paired t-test, Chi Square, descriptive statics for categorical data, and, for narrative data, identification of recurring factors and patterns, with correlation of presenting factors, interventions, and outcomes. Paired t-test demonstrated significant decrease in overall Action for Children Assessment Tool scores between assessment (M=43.77, SD=11.09) and closing the case (M=35.47, SD=9.6, t(84)=6.77, p<0.01). Improvement in the level of concern about neglect was shown in 79% of cases, with only 21% showing no improvement. In 59% of cases, concern about neglect was removed completely. Use of the assessment tool fostered engagement by parents. The relationship between lack of parental engagement and children being taken into care was statistically significant, with a large effect size (χ(2) 10.66, df1, p=0.0001, OR=17.24). When parents refused or were unable to respond positively to the intervention, children benefited from an expedited move into care.


Integrating Cognitive Behavioral Group Therapy and Psychodrama for Social Anxiety Disorder: An Intervention Description and an Uncontrolled Pilot Trial.
Cognitive behavioral therapy (CBT) is generally considered to be the most effective psychological treatment for social anxiety disorder (SAD). Nevertheless, many patients with SAD are still symptomatic after treatment. The present pilot study aimed to examine integrating CBT, with a focus on cognitive and behavioral techniques, and psychodrama, which focuses more on experiential techniques into a combined treatment (CBPT) for social anxious patients in a group format. This new intervention for SAD is described session-by-session. Five adult female patients diagnosed with social anxiety disorder participated in a twelve-session CBPT in a group format. Pretest and posttest scores of social anxiety, avoidance, spontaneity, cost and probability estimates of negative social events, depression, and quality of life were compared, as were weekly assessments of fear of negative evaluation. Results demonstrated a significant reduction of the fear of negative evaluation and social anxiety symptoms. It is noteworthy that also the scores of the probability and cost estimates decreased. However, there were no significant differences between pre and post measures in any of other measures. The current study suggests that group CBPT might be an effective treatment for SAD. However, our sample size was small and this was an uncontrolled study. Therefore, it is necessary to test this intervention in a randomized controlled trial with follow-up assessments.


Effect of depression on mortality and cardiovascular morbidity in type 2 diabetes mellitus after 3 years follow up. The DIADEMA study protocol.
Type 2 diabetes mellitus and depression are highly prevalent diseases that are associated with an increased risk of cardiovascular disease and mortality. There is evidence about a bidirectional association between depressive symptoms and type 2 diabetes mellitus. However, prognostic implications of the joint effects of these two diseases on cardiovascular morbidity and mortality are not well-known. A three-year, observational, prospective, cohort study, carried out in Primary Health Care Centres in Madrid (Spain). The project aims to analyze the effect of depression on cardiovascular events, all-cause and cardiovascular mortality in patients with type 2 diabetes mellitus, and to estimate a clinical predictive model of depression in these patients.The number of patients required is 3255, all them with type 2 diabetes mellitus, older than 18 years, who regularly visit their Primary Health Care Centres and agree to participate. They are chosen by simple random sampling from the list of patients with type 2 diabetes mellitus of each general practitioner.The main outcome measures are all-cause and cardiovascular mortality and cardiovascular morbidity; and exposure variable is the major depressive disorder.There will be a comparison between depressed and not depressed patients in all-cause mortality, cardiovascular mortality, coronary artery disease and stroke using the Chi-squared test. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors that might alter the effect recorded will be taken into account in this analysis. To assess the effect of depression on the mortality, a survival analysis will be used comparing the two groups using the log-rank test. The control of potential confounding variables will be performed by the construction of a Cox regression model. Our study's main contribution is to evaluate the increase in the risk of cardiovascular morbidity and mortality, in depressed Spanish adults with type 2 diabetes mellitus attended in Primary Health Care Setting. It would also be useful to identify subgroups of patients for which the interventions could be more beneficial.


Notch Dosage: Jagged1 Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice.
Neural stem cells in the lateral ganglionic eminence (LGE) generate progenitors that migrate through the rostral migratory stream (RMS) to repopulate olfactory bulb (OB) interneurons, but the regulation of this process is poorly defined. The evolutionarily conserved Notch pathway is essential for neural development and maintenance of neural stem cells. Jagged1, a Notch ligand, is required for stem cell maintenance. In humans, heterozygous mutations in JAGGED1 cause Alagille syndrome, a genetic disorder characterized by complications such as cognitive impairment and reduced number of bile ducts in the liver, suggesting the presence of a JAGGED1 haploinsufficient phenotype. Here, we examine the role of Jagged1 using a conditional loss-of-function allele in the nervous system. We show that heterozygous Jagged1 mice possess a haploinsufficient phenotype that is associated with a reduction in size of the LGE, a reduced proliferative state, and fewer progenitor cells in the LGE and RMS. Moreover, loss of Jagged1 leads to deficits in periglomerular interneurons in the OB. Our results support a dose-dependent role for Jagged1 in maintaining progenitor division within the LGE and RMS.


Use of intravenous immunoglobulin in the Department of Neurology at Ninewells Hospital, 2008-2009: Indications for utilization and cost-effectiveness.
This study was designed to identify the indications for prescription of intravenous immunoglobulin (IVIg) in neurology and the cost effectiveness of this therapy. IVIg is a relatively costly therapy and the annual budget spent on providing this therapy for various indications at Ninewells Hospital was close to £1.5 million. In today's economic times, a cost-benefit analysis of all therapies is prudent. This is of relevance to countries in the developing world as well where perhaps not everybody could afford such cost-intensive therapy. We audited 2 time periods over 12 months each in 2004-2005 and 2008-2009 to look at the patterns of utilization of IVIg over these periods. We searched the literature for alternative and cost-effective therapies for the most common indications for use of IVIg. Fiscal costs on prescription of IVIg have rocketed up by almost 300% in this Neurology Department comparing data from 2004-2005 vs 2008-2009 and this is disproportionate to the increase in the annual admission rate (bed usage), partly because of the soaring costs of the drug available in the market and also because of the increased prescription of IVIg for numerous indications where clinical trials data are yet not so robust. We have looked at the cost of alternative therapies and offer some proposals that if implemented could potentially save £330,000 annually from the health budget at this NHS Trust. Perhaps similar models could evolve for better cost-effective utilization of IVIg in countries in the developing world where health budgeting is more acutely relevant.