The touch that heals: the uses and meanings of touch in the clinical encounter.
This paper investigates the healer's touch in contemporary medical practice, with attention to both allopathic and alternative modalities. Healing is understood as the recovery of an integrated relationship between the self and its body, others, and the surrounding world-the relationship that illness has rendered problematic. In this context, touch can play a crucial role in the clinical encounter. Unlike other modes of sensory apprehension, which tend to involve distance and/or objectification, touch unfolds through an impactful, expressive, reciprocity between the toucher and the touched. For the ill person this can serve to reestablish human connection and facilitate healing changes at the prelinguistic level. The healer's touch involves a blending of attention, compassion, and skill. The clinical efficacy of touch is also dependent upon the patient's active receptivity, aspects of which are explored. All too often, modern medical practice is characterized predominately by the "objectifying touch" of the physical examination, or the "absent touch" wherein technological mediation replaces embodied contact. This paper explores the unique properties of touch as a medium of perception, action, and expression that can render touch a healing force within the clinical encounter.


Chlorhexidine vaginal and infant wipes to reduce perinatal mortality and morbidity: a randomized controlled trial.
To estimate the effects of chlorhexidine vaginal and baby wipes on fetal and neonatal mortality, respectively, and infection-related morbidity. We performed a placebo-controlled, randomized trial of chlorhexidine vaginal and neonatal wipes to reduce neonatal sepsis and mortality in three hospitals in Pakistan. The primary study outcome was a composite of neonatal sepsis or 7-day perinatal mortality. From 2005 to 2008, 5,008 laboring women and their neonates were randomly assigned to receive either chlorhexidine wipes (n=2,505) or wipes with a saline placebo (n=2,503). The primary outcome was similar in the chlorhexidine and control groups (3.1% compared with 3.4%; relative risk 0.91, 95% confidence interval 0.67-1.24) as was the composite rate of neonatal sepsis or 28-day perinatal mortality (3.8% compared with 3.9%, relative risk 0.96, 95% confidence interval 0.73-1.27). At day 7, the chlorhexidine group had a lower rate of neonatal skin infection (3.3% compared with 8.2%, P<.001). With the exception of less frequent 7-day hospitalization in the chlorhexidine group, there were no significant differences in maternal outcomes between the groups. Using maternal chlorhexidine vaginal wipes during labor and neonatal chlorhexidine wipes does not reduce maternal and perinatal mortality or neonatal sepsis. The finding of reduced superficial skin infections on day 7 without change in sepsis or mortality suggests that this difference, although statistically significant, may not be of major importance. I.


Improved data pages for an interference-based cryptosystem.
In this paper, we propose a novel input wave front modulation method to enhance the security level of a Mach-Zender interferometer-based Fourier encryption system. The input data is encoded in the two wave fronts propagated in the arms of the interferometer. Both arms contain a 4f setup, and two independent Fourier keys are used to encrypt these wave fronts. During decryption the encrypted wave fronts are propagated through the interferometer. In the case when correct Fourier keys are used for decryption, the reconstructed data page is shown by the interference pattern of the output. We propose a method to synthesize two phase modulated input images for this cryptosystem. The modulation method has a user defined phase parameter. We prove that the security level of the proposed cryptosystem can be significantly improved compared with previous solutions, by using an optimally chosen phase parameter.


ABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)-Groupe d'Étude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial.
For early-stage Hodgkin lymphoma (HL), optimal chemotherapy regimen and the number of cycles to be delivered remain to settle down. The H9-U trial compared three modalities of chemotherapy followed by involved-field radiotherapy (IFRT) in patients with stage I-II HL and risk factors (NCT00005584). Patients aged 15-70 years with untreated supradiaphragmatic HL with at least one risk factor (age ≥ 50, involvement of 4-5 nodal areas, mediastinum/thoracic ratio ≥ 0.35, erythrocyte sedimentation rate (ESR) ≥ 50 without B-symptoms or ESR ≥ 30 and B-symptoms) were eligible for the randomised, open label, multicentre, non-inferiority H9-U trial. The limit of non-inferiority was set at 10% for the difference between 5-year event-free survival (EFS) estimates. From October 1998 to September 2002, 808 patients were randomised to receive either the control arm 6-ABVD-IFRT (n = 276), or one of the two experimental arms: 4-ABVD-IFRT (n = 277) or 4-BEACOPPbaseline-IFRT (n = 255). Results in the 4-ABVD-IFRT (5-year EFS, 85.9%) and the 4-BEACOPPbaseline-IFRT (5-year EFS, 88.8%) were not inferior to 6-ABVD-IFRT (5-year EFS, 89.9%): difference of 4.0% (90%CI, -0.7%-8.8%) and of 1.1% (90%CI,-3.5%-5.6%) respectively. The 5-year overall survival estimates were 94%, 93%, and 93%, respectively. Patients treated with combined modality treatment chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vincristine (Oncovin), cyclophosphamide, procarbazine, etoposide and prednisone (BEACOPP)baseline more often developed serious adverse events requiring supportive measures and hospitalisation compared with patients receiving the chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD). The trial demonstrates that 4-ABVD followed by IFRT yields high disease control in patients with early-stage HL and risk factors responding to chemotherapy. Although non-inferior in terms of efficacy, four cycles of BEACOPPbaseline were more toxic than four or six cycles of ABVD.


Micromanipulated bivalents can trigger mini-spindle formation in Drosophila melanogaster spermatocyte cytoplasm.
Single (individual) bivalents in cultured Drosophila melanogaster primary spermatocytes were detached from the spindle with a micromanipulation needle and placed in the cytoplasm. Such bivalents are prevented from rejoining the spindle by a natural membrane barrier that surrounds the spindle, but they quickly orient as if on a spindle of their own and the half-bivalents separate in anaphase. Serial section electron microscopy shows that a mini-spindle forms around the cytoplasmic bivalent, i.e., the microtubule density in the vicinity of the bivalent is much greater than in other cytoplasmic regions. This microtubule population cannot be accounted for solely by kinetochore nucleation and/or capture of microtubules. Furthermore, the mini-spindles frequently form at odd angles to the main spindle, so that at least one pole has no relationship to the poles of the main spindle. We conclude that a bivalent, or factors that become associated with the bivalent as a result of the manipulation, can either stabilize microtubules or promote their assembly. The bivalent activates latent microtubule organizing centers, or alternatively, polar organizing material has been passively transported from the main spindle to the cytoplasm by the micromanipulation procedure.


Ultrasmooth surface polishing based on the hydrodynamic effect.
This study will examine the feasibility of applying the hydrodynamic effect to ultrasmooth surface polishing. Differing from conventional pad polishing, hydrodynamic effect polishing is noncontact, as the polishing wheel is floated on the workpiece under the hydrodynamic effect. The material removal mechanism and the removal contour are analyzed in detail. Dynamic pressure and shear stress distribution on the workpiece are numerically simulated in three dimensions under different clearances between the polishing wheel and the workpiece, showing that the dynamic pressure distribution and the magnitude of shear stress on the workpiece are greatly influenced by the clearance. It is clearly demonstrated from fixed-point polishing experiments that material removal rates and contours are determined by the combined action of dynamic pressure and shear stress. A material removal analytic model is presented with the hydrodynamic effect polishing method. Finally, a polishing experiment is conducted on a quartz glass and the plastic scratches, cracks, and bumpy structures on the initial surface are clearly removed. Moreover, the processed surface roughness is improved to 0.145 nm rms, 0.116 nm Ra.


Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia.
The existence of water-selective channels has been postulated to explain the high water permeability of erythrocytes and certain epithelial cells. The aquaporin CHIP (channel-forming integral membrane protein of 28 kDa), a molecular water channel, is abundant in erythrocytes and water-permeable segments of the nephron. To determine whether CHIP may mediate transmembrane water movement in other water-permeable epithelia, membranes of multiple organs were studied by immunoblotting, immunohistochemistry, and immunoelectron microscopy using affinity-purified anti-CHIP IgG. The apical membrane of the choroid plexus epithelium was densely stained, implying a role for CHIP in the secretion of cerebrospinal fluid. In the eye, CHIP was abundant in apical and basolateral domains of ciliary epithelium, the site of aqueous humor secretion, and also in lens epithelium and corneal endothelium. CHIP was detected in membranes of hepatic bile ducts and water-resorptive epithelium of gall bladder, suggesting a role in bile secretion and concentration. CHIP was not detected in glandular epithelium of mammary, salivary, or lacrimal glands, suggesting the existence of other water-channel isoforms. CHIP was also not detected within the epithelium of the gastrointestinal mucosa. CHIP was abundant in membranes of intestinal lacteals and continuous capillaries in diverse tissues, including cardiac and skeletal muscle, thus providing a molecular explanation for the known water permeability of certain lymphatics and capillary beds. These studies underscore the hypothesis that CHIP plays a major role in transcellular water movement throughout the body.


Hormonal control of cell proliferation requires PASTICCINO genes.
PASTICCINO (PAS) genes are required for coordinated cell division and differentiation during plant development. In loss-of-function pas mutants, plant aerial tissues showed ectopic cell division that was specifically enhanced by cytokinins, leading to disorganized tumor-like tissue. To determine the role of the PAS genes in controlling cell proliferation, we first analyzed the expression profiles of several genes involved in cell division and meristem function. Differentiated and meristematic cells of the pas mutants were more competent for cell division as illustrated by the ectopic and enlarged expression profiles of CYCLIN-DEPENDENT KINASE A and CYCLIN B1. The expression of meristematic homeobox genes KNOTTED-LIKE IN ARABIDOPSIS (KNAT2, KNAT6), and SHOOT MERISTEMLESS was also increased in pas mutants. Moreover, the loss of meristem function caused by shoot meristemless mutation can be suppressed by pas2. The KNAT2 expression pattern defines an enlarged meristematic zone in pas mutants that can be mimicked in wild type by cytokinin treatment. Cytokinin induction of the primary cytokinin response markers, ARABIDOPSIS RESPONSE REGULATOR (ARR5 and ARR6), was enhanced and lasted longer in pas mutants, suggesting that PAS genes in wild type repress cytokinin responses. The expression of the cytokinin-regulated cyclin D, cyclin D3.1, was nonetheless not modified in pas mutants. However, primary auxin response genes were down-regulated in pas mutants, as shown by a lower auxin induction of IAA4 and IAA1 genes, demonstrating that the auxin response was also modified. Altogether, our results suggest that PAS genes are involved in the hormonal control of cell division and differentiation.


Waiting for two mutations: with applications to regulatory sequence evolution and the limits of Darwinian evolution.
Results of Nowak and collaborators concerning the onset of cancer due to the inactivation of tumor suppressor genes give the distribution of the time until some individual in a population has experienced two prespecified mutations and the time until this mutant phenotype becomes fixed in the population. In this article we apply these results to obtain insights into regulatory sequence evolution in Drosophila and humans. In particular, we examine the waiting time for a pair of mutations, the first of which inactivates an existing transcription factor binding site and the second of which creates a new one. Consistent with recent experimental observations for Drosophila, we find that a few million years is sufficient, but for humans with a much smaller effective population size, this type of change would take > 100 million years. In addition, we use these results to expose flaws in some of Michael Behe's arguments concerning mathematical limits to Darwinian evolution.


The deubiquitinase ubiquitin-specific protease 20 is a positive modulator of myocardial β1-adrenergic receptor expression and signaling.
Reversible ubiquitination of G protein-coupled receptors regulates their trafficking and signaling; whether deubiquitinases regulate myocardial β1-adrenergic receptors (β1ARs) is unknown. We report that ubiquitin-specific protease 20 (USP20) deubiquitinates and attenuates lysosomal trafficking of the β1AR. β1AR-induced phosphorylation of USP20 Ser-333 by protein kinase A-α (PKAα) was required for optimal USP20-mediated regulation of β1AR lysosomal trafficking. Both phosphomimetic (S333D) and phosphorylation-impaired (S333A) USP20 possess intrinsic deubiquitinase activity equivalent to WT activity. However, unlike USP20 WT and S333D, the S333A mutant associated poorly with the β1AR and failed to deubiquitinate the β1AR. USP20-KO mice showed normal baseline systolic function but impaired β1AR-induced contractility and relaxation. Dobutamine stimulation did not increase cAMP in USP20-KO left ventricles (LVs), whereas NKH477-induced adenylyl cyclase activity was equivalent to WT. The USP20 homolog USP33, which shares redundant roles with USP20, had no effect on β1AR ubiquitination, but USP33 was up-regulated in USP20-KO hearts suggesting compensatory regulation. Myocardial β1AR expression in USP20-KO was drastically reduced, whereas β2AR expression was maintained as determined by radioligand binding in LV sarcolemmal membranes. Phospho-USP20 was significantly increased in LVs of wildtype (WT) mice after a 1-week catecholamine infusion and a 2-week chronic pressure overload induced by transverse aortic constriction (TAC). Phospho-USP20 was undetectable in β1AR KO mice subjected to TAC, suggesting a role for USP20 phosphorylation in cardiac response to pressure overload. We conclude that USP20 regulates β1AR signaling in vitro and in vivo Additionally, β1AR-induced USP20 phosphorylation may serve as a feed-forward mechanism to stabilize β1AR expression and signaling during pathological insults to the myocardium.


Ultra-brief intervention for problem drinkers: research protocol.
Helping the large number of problem drinkers who will never seek treatment is a challenging issue. Public health initiatives employing educational materials or mass media campaigns have met with mixed success. However, clinical research has developed effective brief interventions to help problem drinkers. This project will employ an intervention that has been validated in clinical settings and then modified into an ultra-brief format suitable for use as a public health intervention. The major objective of this study is to conduct a randomized controlled trial to establish the effectiveness of an ultra-brief, personalized feedback intervention for problem drinkers. Problem drinkers recruited on a baseline population telephone survey conducted in a major metropolitan city in Canada will be randomized to one of three conditions - a personalized feedback pamphlet condition, a control pamphlet condition, or a no intervention control condition. In the week after the baseline survey, households in the two pamphlet conditions will be sent their respective pamphlets. Changes in drinking will be assessed post intervention at three-month and six-month follow-ups. Drinking outcomes will be compared between experimental conditions using Structural Equation Modeling. The primary hypothesis is that problem drinkers from households who receive the personalized feedback pamphlet intervention will display significantly improved drinking outcomes at three and six-month follow-ups as compared to problem drinkers from households in the no intervention control condition. Secondary hypotheses will test the impact of the intervention on help seeking, and explore the mediating or moderating role of perceived drinking norms, perceived alcohol risks and the problem drinker's social reasons for drinking. This trial will provide information on the effectiveness of a pamphlet-based personalized feedback intervention for problem drinkers in a community setting. ClinicalTrials.gov registration #NCT00688584.


Sentinel nematodes of land-use change and restoration in tallgrass prairie.
Changes in land use and the associated changes in land cover are recognized as the most important component of human-induced global change. Much attention has been focused on deforestation, but grasslands are among the most endangered ecosystems on Earth. The North American tallgrass prairie is a dramatic example, exhibiting a greater than 95% decline in historical area. Renewed interest in prairie conservation and restoration has highlighted the need for ecological indicators of disturbance and recovery in native systems, including the belowground component. The tallgrass prairie differs from the agricultural systems that have replaced it in having greater diversity and heterogeneity of resources, less physical soil disturbance (although other disturbances, such as fire and grazing, are prominent), and greater nitrogen limitation. Understanding the responses of nematode taxa to these characteristic differences is crucial to the development and improvement of community indices, but while knowledge of disturbance responses by individual taxa is accumulating, the level of necessary taxonomic resolution remains in question. Although nematode communities generally are better described for temperate grasslands than for other natural ecosystems, identification of sentinel taxa is further confounded by high levels of diversity, and both spatial and temporal heterogeneity.


Strong accumulation of chloroplast DNA in the Y chromosomes of Rumex acetosa and Silene latifolia.
Chloroplast DNA (cpDNA) sequences are often found in plant nuclear genomes, but patterns of their chromosomal distribution are not fully understood. The distribution of cpDNA on the sex chromosomes can only be studied in dioecious plant species possessing heteromorphic sex chromosomes. We reconstructed the whole chloroplast genome of Rumex acetosa (sorrel, XY1Y2 system) from next generation sequencing data. We systematically mapped the chromosomal localization of various regions of cpDNA in R. acetosa and in Silene latifolia (white campion, XY system) using fluorescence in situ hybridization. We found that cpDNA was accumulated on the Y chromosomes of both studied species. In R. acetosa, the entire Y chromosome gathered all parts of cpDNA equally. On the contrary, in S. latifolia, the majority of the cpDNA, corresponding to the single copy regions, was localized in the centromere of the Y chromosome, while the inverted repeat region was present also in other loci. We found a stronger accumulation of cpDNA on the more degenerated Y1 and Y2 chromosomes of R. acetosa than in evolutionary younger S. latifolia Y chromosome. Our data stressed the prominent role of the Y chromosome centromere in cpDNA accumulation.


Tuning photoresponse through size control of Cu nanoparticles deposited on multi wall carbon nanotubes.
In this paper we illustrate a simple method for the production of multiwall carbon nanotubes thin films decorated with copper metal nanoparticles. The structural information obtained from the transmission electron microscopy study performed on samples differing in the quantity of deposited Copper was linked to the opto-electronic properties evaluated with photo-electrochemical measurements. The photo-response evaluated in terms of incident photon-to-charge carrier generation efficiency varied for different sized-Cu-multiwall carbon nanotubes samples across all the visible and near-ultraviolet photon energy range with respect to the response of bare carbon tubes. The photo-response from the sample covered with of 0.5 nm Cu nominal thickness, reached 10.2%, a value 2 times higher than that measured for bare carbon tubes of 5.9%. While this value decreased to 2.8% when the Cu nominal coverage thickened up to 3 nm. The increase in the photo-response found was interpreted as being the result of a remarkable charge transfer between the Cu metal nanoparticles and the carbon atoms in the tube due to the formation of a strong ionic bond at their interface. The results obtained prove that the metal nanoparticle-carbon nanotube composites have optical, electrical and structural properties that can be applied in a variety of nanoscale architectures for novel photo-electrochemical devices.


ZnO particulate matter requires cell contact for toxicity in human colon cancer cells.
There is ongoing concern regarding the toxicity of nanoparticles with sizes less than 100 nm as compared to larger particles of the same nominal substance. Two commercial ZnO types, one sold as a 8-10 nm powder and the other described as -325 mesh (<44 mum) powder, were evaluated in human colon-derived RKO cells. The powders had a volume-to-surface area ratio equivalent to 40 and 330 nm spheres, respectively. Both materials formed micrometer-sized agglomerates in cell culture media. The nanosized ZnO was more cytotoxic than the micrometer-sized ZnO with LC(50) values of 15 +/- 1 and 29 +/- 4 mug/cm(2), respectively. Transfer of Zn from the solid phase to the cell culture media in the presence of RKO cells was time- and concentration-dependent. However, direct particle-cell contact was required for RKO cell cytotoxicity, and the toxicity of particles was independent of the amount of soluble Zn in the cell culture media. The mechanism of cell death includes the disruption of mitochondrial function. Robust markers of apoptosis, Annexin V staining, loss of mitochondrial potential, and increased generation of superoxide were observed when cells were treated with ZnO particulate matter but not when treated with comparable concentration of a soluble Zn salt. Both ZnO samples induced similar mechanisms of toxicity, but there was a statistically significant increase in potency per unit mass with the smaller particles.


Reducing aluminum: an occupation possibly associated with bladder cancer.
A case-control study, undertaken to identify reasons for the exceptionally high incidence of bladder cancer among men in the Chicoutimi census division of the province of Quebec, revealed an increased risk associated with employment in the electrolysis department of an aluminum reduction plant. The estimated relative risk was 2.83 (95% confidence interval; 1.06 to 7.54). An interaction was found between such employment and cigarette smoking, resulting in a combined relative risk of 5.70 (95% confidence interval: 2.00 to 12.30). These findings suggest that employment in an aluminum reduction plant accounts for part of the excess of bladder cancer in the region studied.


Does inferior oblique recession cause overcorrections in laterally incomitant small hypertropias due to superior oblique palsy?
To evaluate the effects of inferior oblique muscle recession (IOR) in cases of laterally incomitant hypertropia <10 prism dioptres (PD) in central gaze thact 2t are clinically consistent with superior oblique palsy (SOP). We retrospectively reviewed patients with SOP and hypertropias <10 PD in central gaze who underwent graded IOR. Primary outcomes were reduction of lateral incomitance and number of overcorrections in central gaze. Twenty-five patients were included. Mean follow-up was 13.8 months (range 1.4-66). Mean central gaze hypertropia decreased from 5.6±2.1 to 0.2±1.6 PD (p<0.001). Contralateral gaze hypertropia decreased from 15.9±7.6 to 2.3±3.3 PD (p<0.001). Lateral incomitance (central vs contralateral gaze) was 10.3±6.9 PD preoperatively and 2.0±3.0 PD postoperatively (p<0.001). There were two patients overcorrected in central gaze, and one patient overcorrected in downgaze. One patient necessitated further surgery for overcorrection. Although small hypertropias can be treated with prisms or small, adjustable inferior rectus recessions, IOR collapses incomitance without causing much overcorrection. IOR is a reasonable treatment for small, laterally incomitant hypertropia due to SOP.


The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications.
The promoter region of the UDP glucuronosyltransferase 1 gene (UGT1A1) contains a run of thymine-adenine (TA) repeats, usually six (TA)(6). As well as its relationship to Gilbert's syndrome, homozygosity for the extended sequence, (TA)(7) (TA)(7), has been found to be an important risk factor for hyperbilirubinemia and gallstones in patients with hemoglobin E-beta-thalassemia and other intermediate forms of beta thalassemia. To assess the importance of this polymorphism in these common disorders a wide-scale population study of the relative frequency of the size alleles of the UGT1A1 promoter has been carried out. Homozygosity for the (TA)(7) allele occurs in 10-25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurs at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations show a much greater diversity of length alleles than other populations. These findings define those populations with a high frequency of hemoglobin E-beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gall bladder disease and provide evolutionary insights into how these polymorphisms have arisen and are so unequally distributed among human populations.


Racing performance of Swedish Standardbred trotting horses with proximal palmar/plantar first phalangeal (Birkeland) fragments compared to fragment free controls.
The aim of this study was to determine whether horses with a proximal palmar/plantar first phalangeal osteochondral fragment (POF) had comparable racing careers (prior to and following surgery) to horses without this fracture. A retrospective cohort study included 174 Swedish Standardbred trotters with osteochondral fragmentation in the palmar/plantar fetlock joint and 613 radiographically negative control horses presented for prepurchase examinations. Medical records and radiographs were examined for each horse. Racing data were retrieved from online Swedish Standardbred harness racing records. The effect of having a POF on race speed compared to radiographically negative control horses was examined using generalised estimating equations. Multivariable regression was used to examine differences in money earned and career longevity. The horses raced a total of 16,448 races. Horses gained speed as a function of race number. There was no difference in racing speed between horses with POF fractures that raced before surgery and control horses. Horses did not slow before, nor speed up after, surgery. There was no difference in the number of days between the last race prior to, or the first race after, the hospital visit between POF and control horses. Career earnings and lifetime starts were not significantly different between groups. The results of this study suggest the need to reevaluate the previously reported benefits of surgical intervention for POF.


Enzyme kinetics by directly imaging a porous silicon microfluidic reactor using desorption/ionization on silicon mass spectrometry.
Enzyme kinetics were obtained in a porous silicon microfluidic channel by combining an enzyme and substrate droplet, allowing them to react and deposit a small amount of residue on the channel walls, and then analyzing this residue by directly ionizing the channel walls using a matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) laser source. The porous silicon of the channel walls functions in a manner analogous to the matrix in MALDI-MS, and is referred to as a desorption/ionization on silicon mass spectrometry (DIOS-MS) target when used in this configuration. Mass spectrometry signal intensity of substrate residue correlates with relative concentration, and position in the microchannel correlates with time, thus allowing determination of kinetic parameters. The system is especially suitable for initial reaction velocity determination. This microreactor is broadly applicable to time-resolved kinetic assays as long as at least one substrate or product of the reaction is ionizable by DIOS-MS.


Dose-dependent alteration in zif/268 and preprodynorphin mRNA expression induced by amphetamine or methamphetamine in rat forebrain.
The dose-related effects of a single injection of D-amphetamine (AMPH) or methamphetamine (METH) on the mRNA expression of the immediate early gene zif/268 and the opioid peptide preprodynorphin, in rat forebrain, were investigated with quantitative in situ hybridization histochemistry 3 h after injection. Both drugs at equimolar doses (3.75, 7.5, 15 and 30 mumol/kg) up-regulated zif/268 mRNA expression in cerebral cortex in a dose-dependent fashion. In the "nose" area of the sensory cortex, all doses of METH, but not AMPH, induced a substantial, dose-dependent increase in zif/268 mRNA. Dose-dependent induction of zif/268 mRNA also occurred in caudoputamen after injection of AMPH at all doses. However, dose-dependent increases in zif/268 mRNA in caudoputamen in METH-treated rats and in nucleus accumbens in AMPH-treated and METH-treated rats were seen only after the three lower doses. Injection of 30 mumol/kg actually decreased zif/268 mRNA induction in these areas to or below that detected after 3.75 mumol/kg. Preprodynorphin mRNA expression in the striatum was dose-dependently increased by either drug at all doses. These results demonstrate a clear dose-related responsiveness of zif/268 and preprodynorphin gene expression in cortical and/or striatal neurons that is positively correlated with a dose-dependent motor-stimulating effect of AMPH and METH. METH is a more potent psychostimulant than AMPH in eliciting behavioral and genomic activity at equimolar doses, and METH elicits a qualitatively different pattern of genomic activity in some forebrain regions, especially in the higher dose range.


Targeted disruption of outer limiting membrane junctional proteins (Crb1 and ZO-1) increases integration of transplanted photoreceptor precursors into the adult wild-type and degenerating retina.
Diseases culminating in photoreceptor loss are a major cause of untreatable blindness. Transplantation of rod photoreceptors is feasible, provided donor cells are at an appropriate stage of development when transplanted. Nevertheless, the proportion of cells that integrate into the recipient outer nuclear layer (ONL) is low. The outer limiting membrane (OLM), formed by adherens junctions between Müller glia and photoreceptors, may impede transplanted cells from migrating into the recipient ONL. Adaptor proteins such as Crumbs homologue 1 (Crb1) and zona occludins (ZO-1) are essential for localization of the OLM adherens junctions. We investigated whether targeted disruption of these proteins enhances donor cell integration. Transplantation of rod precursors in wild-type mice achieved 949 +/- 141 integrated cells. By contrast, integration is significantly higher when rod precursors are transplanted into Crb1(rd8/rd8) mice, a model of retinitis pigmentosa and Lebers congenital amaurosis that lacks functional CRB1 protein and displays disruption of the OLM (7,819 +/- 1,297; maximum 15,721 cells). We next used small interfering (si)RNA to transiently reduce the expression of ZO-1 and generate a reversible disruption of the OLM. ZO-1 knockdown resulted in similar, significantly improved, integration of transplanted cells in wild-type mice (7,037 +/- 1,293; maximum 11,965 cells). Finally, as the OLM remains largely intact in many retinal disorders, we tested whether transient ZO-1 knockdown increased integration in a model of retinitis pigmentosa, the rho(-/-) mouse; donor cell integration was significantly increased from 313 +/- 58 cells without treatment to 919 +/- 198 cells after ZO-1 knockdown. This study shows that targeted disruption of OLM junctional proteins enhances integration in the wild-type and degenerating retina and may be a useful approach for developing photoreceptor transplantation strategies.


Focal subarachnoid haemorrhage mimicking transient ischaemic attack--do we really need MRI in the acute stage?
Acute non-traumatic focal subarachnoid haemorrhage (fSAH) is a rare transient ischaemic attack (TIA)-mimic. MRI is considered to be indispensable by some authors in order to avoid misdiagnosis, and subsequent improper therapy. We therefore evaluated the role of CT and MRI in the diagnosis of fSAH patients by comparing our cases to those from the literature. From 01/2010 to 12/2012 we retrospectively identified seven patients with transient neurological episodes due to fSAH, who had received unenhanced thin-sliced multiplanar CT and subsequent MRI within 3 days on a 1.5 T scanner. MRI protocol included at least fast-field-echo (FFE), diffusion-weighted imaging (DWI), T2-weighted fluid-attenuated inversion recovery (FLAIR) and time-of-flight (TOF) MRA sequences. By using MRI as gold-standard, we re-evaluated images and data from recent publications regarding the sensitivity to detect fSAH in unenhanced CT. fSAH was detected by CT and by FFE and FLAIR on MRI in all of our own cases. However, DWI and T2w-spin-echo sequences revealed fSAH in 3 of 7 and 4 of 6 cases respectively. Vascular imaging was negative in all cases. FFE-MRI revealed additional multiple microbleeds and superficial siderosis in 4 of 7 patients and 5 of 7 patients respectively. Including data from recently published literature CT scans delivered positive results for fSAH in 95 of 100 cases (95%), whereas MRI was positive for fSAH in 69 of 69 cases (100%). Thin-sliced unenhanced CT is a valuable emergency diagnostic tool to rule out intracranial haemorrhage including fSAH in patients with acute transient neurological episodes if immediate MRI is not available. However, MRI work-up is crucial and mandatorily has to be completed within the next 24-72 hours.


Point mutations in the conserved box 1 region inactivate the human granulocyte colony-stimulating factor receptor for growth signal transduction and tyrosine phosphorylation of p75c-rel.
The human granulocyte colony-stimulating factor receptor (hG-CSFR) belongs to the cytokine receptor superfamily. As with other members of this family, the cytoplasmic domain of hG-CSFR lacks intrinsic tyrosine kinase activity. To identify critical regions mediating growth signal transduction by hG-CSFR, deletions or site-directed amino acid substitutions were introduced into the cytoplasmic domain of hG-CSFR, and the mutant cDNAs were transfected into the murine interleukin-3 (IL-3)-dependent Ba/F3 and FDCP cell lines. Truncation of the carboxy-terminal end of the receptor to the membrane-proximal 53 amino acids of the cytoplasmic domain, which retained the conserved Box 1 and Box 2 sequence motifs, decreased the ability of hG-CSFR to transduce G-CSF-mediated growth signals without an associated loss in receptor binding affinity. Substitution of proline by alanine at amino acid positions 639 and 641 within Box 1 completely abolished the G-CSF-mediated growth signal. Rapid induction of tyrosine phosphorylation of several cellular proteins, including a 75-kD protein (p75) identified as c-rel, was an early event associated with transduction of proliferative signals by hG-CSFR in Ba/F3 transfectants. Mutant receptors containing Pro-to-Ala substitutions that inactivated the receptor for mitogenic activity also inactivated the receptor for tyrosine-specific phosphorylation of p75. These results show that the conserved Box 1 sequence motif (amino acids 634 to 641) is critical for mitogenesis and activation of cellular tyrosine kinases by hG-CSFR.


The anti-cancer effects of carotenoids and other phytonutrients resides in their combined activity.
Epidemiological studies have consistently shown that regular consumption of fruits and vegetables is strongly associated with reduced risk of developing chronic diseases, such as cancer. It is now accepted that the actions of any specific phytonutrient alone do not explain the observed health benefits of diets rich in fruits and vegetables as nutrients that were taken alone in clinical trials did not show consistent preventive effects. The considerable cost and complexity of such clinical trials requires prudent selection of combinations of ingredients rather than single compounds. Indeed, synergistic inhibition of prostate and mammary cancer cell growth was evident when using combinations of low concentrations of various carotenoids or carotenoids with retinoic acid and the active metabolite of vitamin-D. In this study we aimed to develop simple and sensitive in vitro methods which provide information on potent combinations suitable for inclusion in clinical studies for cancer prevention. We, thus, used reporter gene assays of the transcriptional activity of the androgen receptor in hormone-dependent prostate cancer cells and of the electrophile/antioxidant response element (EpRE/ARE) transcription system. We found that combinations of several carotenoids (e.g., lycopene, phytoene and phytofluene), or carotenoids and polyphenols (e.g., carnosic acid and curcumin) and/or other compounds (e.g., vitamin E) synergistically inhibit the androgen receptor activity and activate the EpRE/ARE system. The activation of EpRE/ARE was up to four fold higher than the sum of the activities of the single ingredients, a robust hallmark of synergy. Such combinations can further be tested in the more complex in vivo models and human studies.


On a new schedule: transitions to adulthood and family change.
Frank Furstenberg examines how the newly extended timetable for entering adulthood is affecting, and being affected by, the institution of the Western, particularly the American, family. He reviews a growing body of research on the family life of young adults and their parents and draws out important policy implications of the new schedule for the passage to adulthood. Today, says Furstenberg, home-leaving, marriage, and the onset of childbearing take place much later in the life span than they did during the period after World War II. After the disappearance of America's well-paying unskilled and semi-skilled manufacturing jobs during the 1960s, youth from all economic strata began remaining in school longer and marrying and starting their own families later. Increasing numbers of lower-income women did not marry at all but chose, instead, non-marital parenthood-often turning to their natal families for economic and social support, rather than to their partners. As the period of young adults' dependence on their families grew longer, the financial and emotional burden of parenthood grew heavier. Today, regardless of their income level, U.S. parents provide roughly the same proportion of their earnings to support their young adult children. Unlike many nations in Europe, the United States, with its relatively underdeveloped welfare system, does not invest heavily in education, health care, and job benefits for young adults. It relies, instead, on families' investments in their own adult children. But as the transition to adulthood becomes more protracted, the increasing family burden may prove costly to society as a whole. Young adults themselves may begin to regard childbearing as more onerous and less rewarding. The need to provide greater support for children for longer periods may discourage couples from having additional children or having children at all. Such decisions could lead to lower total fertility, ultimately reduce the workforce, and furthdr aggravate the problem of providing both for increasing numbers of the elderly and for the young. U.S. policy makers must realize the importance of reinforcing the family nest and helping reduce the large and competing demands that are being placed on today's parents.


Making a difference together: reciprocal interactions in C. elegans and zebrafish asymmetric neural development.
Brain asymmetries are thought to increase neural processing capacity and to prevent interhemispheric conflict. In order to develop asymmetrically, neurons must be specified along the left-right axis, assigned left-side versus right-side identities and differentiate appropriately. In C. elegans and zebrafish, the cellular and molecular mechanisms that lead to neural asymmetries have recently come to light. Here, we consider recent insights into the mechanisms involved in asymmetrical neural development in these two species. Although the molecular details are divergent, both organisms use iterative cell-cell communication to establish left-right neuronal identity.


Natriuresis induced by localized perfusion within the third cerebral ventricle of sheep.
Push-pull perfusion was performed at four different sites in the third cerebral ventricle of conscious sheep. The recovery of the infused solution was 75-90%, suggesting a localized change in the ionic composition and osmolality restricted to a relatively small area in the cerebrospinal fluid (CSF). Sodium and potassium excretion and urine flow were studied before, during, and after perfusion of 200, 150, and 100 mM Na-CSF. Localized perfusion in the anterior dorsal third ventricle (AD3V) of 200 mM Na-CSF caused an increase in sodium and potassium excretion, in urine flow, and a decrease in free water clearance. Perfusion of 200 mM Na-CSF at the other three perfusion sites, i.e., anterior ventral third ventricle, posterior dorsal third ventricle, and posterior ventral third ventricle, did not influence sodium excretion and urine flow. Perfusions with 150 and 100 mM Na-CSF did not cause any change in sodium, potassium excretion, or urine flow at any of the four perfusion sites. These results suggest that sensors sensitive to changes of sodium concentration are located close to the ventricular surface in the anterior dorsal part of the third cerebral ventricle. When stimulated with increased sodium concentration they will initiate increased sodium excretion.


Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity.
Many compounds that appear promising in preclinical species, fail in human clinical trials due to safety concerns. The FDA has strongly encouraged the application of modeling in drug development to improve product safety. This study illustrates how DILIsym, a computational representation of liver injury, was able to reproduce species differences in liver toxicity due to PF-04895162 (ICA-105665). PF-04895162, a drug in development for the treatment of epilepsy, was terminated after transaminase elevations were observed in healthy volunteers (NCT01691274). Liver safety concerns had not been raised in preclinical safety studies. DILIsym, which integrates in vitro data on mechanisms of hepatotoxicity with predicted in vivo liver exposure, reproduced clinical hepatotoxicity and the absence of hepatotoxicity observed in the rat. Simulated differences were multifactorial. Simulated liver exposure was greater in humans than rats. The simulated human hepatotoxicity was demonstrated to be due to the interaction between mitochondrial toxicity and bile acid transporter inhibition; elimination of either mechanism from the simulations abrogated injury. The bile acid contribution occurred despite the fact that the IC50 for bile salt export pump (BSEP) inhibition by PF-04895162 was higher (311 µmol/L) than that has been generally thought to contribute to hepatotoxicity. Modeling even higher PF-04895162 liver exposures than were measured in the rat safety studies aggravated mitochondrial toxicity but did not result in rat hepatotoxicity due to insufficient accumulation of cytotoxic bile acid species. This investigative study highlights the potential for combined in vitro and computational screening methods to identify latent hepatotoxic risks and paves the way for similar and prospective studies.


Azithromycin in early infancy and pyloric stenosis.
Use of oral erythromycin in infants is associated with infantile hypertrophic pyloric stenosis (IHPS). The risk with azithromycin remains unknown. We evaluated the association between exposure to oral azithromycin and erythromycin and subsequent development of IHPS. A retrospective cohort study of children born between 2001 and 2012 was performed utilizing the military health system database. Infants prescribed either oral erythromycin or azithromycin as outpatients in the first 90 days of life were evaluated for development of IHPS. Specific diagnostic and procedural codes were used to identify cases of IHPS. A total of 2466 of 1 074 236 children in the study period developed IHPS. Azithromycin exposure in the first 14 days of life demonstrated an increased risk of IHPS (adjusted odds ratio [aOR], 8.26; 95% confidence interval [CI], 2.62-26.0); exposure between 15 and 42 days had an aOR of 2.98 (95% CI, 1.24-7.20). An association between erythromycin and IHPS was also confirmed. Exposure to erythromycin in the first 14 days of life had an aOR of 13.3 (95% CI, 6.80-25.9), and 15 to 42 days of life, aOR 4.10 (95% CI, 1.69-9.91). There was no association with either macrolide between 43 and 90 days of life. Ingestion of oral azithromycin and erythromycin places young infants at increased risk of developing IHPS. This association is strongest if the exposure occurred in the first 2 weeks of life, but persists although to a lesser degree in children between 2 and 6 weeks of age.


Zero-tillage is a proven technology for sustainable wheat intensification in the Eastern Indo-Gangetic Plains: what determines farmer awareness and adoption?
In India, there is increasing recognition among policy-makers of the largely untapped potential of the Eastern Indo-Gangetic Plains (IGP) for meeting state- and national-level food needs. Zero-tillage (ZT) is a proven technology for enhancing wheat productivity and, hence, food security in the IGP, while reducing production costs - a 'win-win' scenario that should support rapid technology scaling even though adoption remains modest to date. In order to inform policies and derive recommendations for a more effective extension strategy, this study investigated determinants of ZT adoption in the Eastern IGP using a random sample of 1000 wheat-growing households from Bihar, stratified by ZT adoption status. We corrected for potential non-exposure bias by using a two-stage estimation procedure that differentiates between factors affecting farmers' awareness of ZT and those affecting adoption conditional on awareness. Owing to the relatively nascent stage of ZT diffusion in the area, we emphasized the role of information in the adoption process, including social networks, whereby we allowed for endogenous and exogenous network effects. Only 44% of sample households knew about ZT technology, and there was substantial scale bias in favor of larger scale farmers both with respect to awareness and adoption. Both the adoption behavior and characteristics of the respondents' network members influenced their own awareness and adoption of ZT, particularly among farmers in the smallest landholding tercile. Farmers valued the time-saving potential of ZT, especially under conditions of increasingly unreliable monsoon rains resulting in a delayed rice crop and, consequently, late establishment of wheat which reduces yield. The fact that most farmers accessed ZT via custom-hire services was accounted for in the model, and the importance of proximate service providers confirmed. We conclude that there is need for further awareness-raising campaigns for ZT technology, where-by, apart from mass media, agricultural extension should use contact farmers belonging to different social strata for effective within-village diffusion of messages, especially to the poorer farmers. The social inclusiveness of ZT use can be enhanced by supporting the emergence of more ZT service providers and by developing business models that lower the transaction costs of servicing smaller farms. JEL Classifications O33 . Q55.


On-Treatment Blood Pressure and Cardiovascular Outcomes in Older Adults With Isolated Systolic Hypertension.
Our aim was to assess optimal on-treatment blood pressure (BP) at which cardiovascular disease (CVD) and all-cause mortality risks are minimized in Japanese older adults with isolated systolic hypertension. We used data from the VALISH study (Valsartan in Elderly Isolated Systolic Hypertension) that recruited older adults (n=3035; mean age, 76 years) with systolic BP (SBP) of ≥160 mm Hg and diastolic BP of <90 mm Hg. Patients were treated by valsartan. Patients were also categorized into 3 groups based on achieved on-treatment SBP of <130 mm Hg (n=317), 130 to <145 mm Hg (n=2025), or ≥145 mm Hg (n=693). The primary outcome was composite CVD (coronary heart disease, stroke, heart failure, cardiovascular deaths, other vascular diseases, and kidney diseases) with secondary outcome being all-cause mortality. Cox proportional hazards models were used to assess the CVD risk for each group. Over a median 3-year follow-up (8022 person-years), 93 CVD events and 52 deaths occurred. Using the on-treatment SBP of 130 to <145 mm Hg as reference stratum, the multivariable-adjusted hazard ratios and 95% confidence intervals of CVD and all-cause mortality risks for those with SBP<130 mm Hg were 2.08 (1.12-3.83) and 2.09 (0.93-4.71) and for those with SBP≥145 mm Hg were 2.29 (1.44-3.62) and 2.51 (1.35-4.66), respectively. On-treatment diastolic BP yielded no relationships with CVD or all-cause mortality risk. In conclusion, among Japanese older adults with isolated systolic hypertension, SBP in the range between 130 and 144 mm Hg was associated with minimal adverse outcomes and a reduction in CVD and all-cause mortality. The BP range will need to be confirmed in randomized controlled trials. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00151229.


Prediction of graft-versus-host disease by phenotypic analysis of early immune reconstitution after CD6-depleted allogeneic bone marrow transplantation.
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). Because GVHD is frequently refractory to treatment, the early identification of high-risk patients could have significant clinical value. To identify such patients, we examined early immunologic recovery in 136 patients with hematologic malignancies who received anti-T12 (CD6)-purged allogeneic bone marrow over a 9-year period. The majority of patients received marrow from HLA-matched sibling donors after ablation with cyclophosphamide and total body irradiation. No patients received any immune suppressive medications for GVHD prophylaxis. The fraction and absolute numbers of peripheral blood lymphocytes (PBL) expressing the CD3, CD4, CD8, and CD56 surface antigens were determined weekly by immunofluorescence analysis in patients beginning 8 to 14 days (week 2) after marrow infusion. Results in patients who did or did not subsequently develop GVHD post-BMT were compared. Within 2 weeks of marrow infusion, patients who developed grades 2-4 GVHD had significantly higher percentages and absolute numbers of CD8+ T cells and a lower fraction of CD56+ natural killer (NK) cells than individuals who remained free of GVHD. Thirty-five percent of patients whose PBL were greater than 25% CD8+ in the second posttransplant week developed GVHD, compared with only 3% of patients who had < or = 25% CD8+ cells (odds ratio 37.8; 95% confidence interval [CI] 4.1 to 397). A subgroup of patients at very high risk for GVHD could be identified based on the combined frequency of CD8+ T cells and NK cells in blood. Seventy-five percent of patients with greater than 25% CD8+ cells and < or = 45% CD56+ cells during week 2 post-BMT developed GVHD, compared with only 11% of the remaining patients (odds ratio 24.9; 95% CI, 5.3 to 117.0). None of the 23 patients with both less than 25% CD8+ cells and greater than 45% CD56+ cells in the second posttransplant week developed grades 2-4 GVHD. Our findings indicate that CD8+ T cells play an important role in the pathogenesis of GVHD in humans. Analysis of immune reconstitution early after BMT is useful in predicting the onset of GVHD and can help direct the implementation of treatment strategies before the appearance of clinical manifestations. Such interventions may decrease the morbidity and mortality associated with allogeneic BMT and ultimately improve overall survival.


Modulation of intracellular protein degradation by SSB1-SIS1 chaperon system in yeast S. cerevisiae.
In prokaryotes, DnaK-DnaJ chaperon is involved in the protein degradation catalyzed by proteases La and ClpA/B complex as shown in E. coli. To extend this into eukaryotic cells, we examined the effects of hsp70 genes, SSA1 and SSB1, and DnaJ genes, SIS1 and YDJ1, on the growth of proteasome subunit mutants of the yeast S. cerevisiae. The results identified SSB1 and SIS1 as a pair of chaperon genes specifically involved in efficient protein turnover in the yeast, whose overexpression suppressed the growth defects caused by the proteasome mutations. Moreover, a single amino acid substitution in the putative peptide-binding site of SSB1 protein profoundly enhanced the suppression activity, indicating that the activity is mediated by the peptide-binding activity of this chaperon. Thus SSB1, with its partner DnaJ, SIS1, modulates the efficiency of protein turnover through its chaperon activity.


Reducing user fees for primary health care in Kenya: Policy on paper or policy in practice?
Removing user fees in primary health care services is one of the most critical policy issues being considered in Africa. User fees were introduced in many African countries during the 1980s and their impacts are well documented. Concerns regarding the negative impacts of user fees have led to a recent shift in health financing debates in Africa. Kenya is one of the countries that have implemented a user fees reduction policy. Like in many other settings, the new policy was evaluated less that one year after implementation, the period when expected positive impacts are likely to be highest. This early evaluation showed that the policy was widely implemented, that levels of utilization increased and that it was popular among patients. Whether or not the positive impacts of user fees removal policies are sustained has hardly been explored. We conducted this study to document the extent to which primary health care facilities in Kenya continue to adhere to a 'new' charging policy 3 years after its implementation. Data were collected in two districts (Kwale and Makueni). Multiple methods of data collection were applied including a cross-sectional survey (n = 184 households Kwale; 141 Makueni), Focus Group Discussions (n = 12) and patient exit interviews (n = 175 Kwale; 184 Makueni). Approximately one third of the survey respondents could not correctly state the recommended charges for dispensaries, while half did not know what the official charges for health centres were. Adherence to the policy was poor in both districts, but facilities in Makueni were more likely to adhere than those in Kwale. Only 4 facilities in Kwale adhered to the policy compared to 10 in Makueni. Drug shortage, declining revenue, poor policy design and implementation processes were the main reasons given for poor adherence to the policy. We conclude that reducing user fees in primary health care in Kenya is a policy on paper that is yet to be implemented fully. We recommend that caution be taken when deciding on how to reduce or abolish user fees and that all potential consequences are carefully considered.


Bioremediation of the tobacco waste-contaminated soil by Pseudomonas sp. HF-1: nicotine degradation and microbial community analysis.
The highly effective nicotine-degrading bacterium Pseudomonas sp. HF-1 was augmented into the tobacco waste-contaminated soil to degrade nicotine and evaluate the effect of the bioremediation. Comparing with non-adding (NA) systems, the treatments with addition of strain HF-1 (TA) exhibited considerably stronger pollution disposal abilities and higher stability of pH value and moisture content, especially in groups containing a large quantity of tobacco waste. The denaturing gradient gel electrophoresis (DGGE) profiles showed that the Shannon-Wiener index decreased with increasing wastes in the NA treatments, while a gradual increase was found in the TA groups. A comparison of sequences from DGGE bands demonstrated that there were differences in the dominant microbial species between the two treatments, suggesting that strain HF-1 could persist in the soil and enhance the efficiency of tobacco waste disposal. The results of real-time fluorescence quantitative PCR (RT-qPCR) also indicated that strain HF-1 existed in the TA systems and grew with relative high quantities. In conclusion, the nicotine-degrading strain HF-1 played a leading role in the bioremediation of the tobacco waste-contaminated soil and influenced the dynamics and structure of the microbial community.


Failure of male pronucleus formation is the major cause of lack of fertilization and embryo development in pig oocytes subjected to intracytoplasmic sperm injection.
The objectives of this study were 1) to compare the efficiency of intracytoplasmic sperm injection (ICSI) with and without additional artificial stimulation using frozen-thawed sperm and in vitro-matured porcine oocytes and 2) to determine the nuclear anomalies of ICSI oocytes that failed to fertilize or develop. In experiments 1 and 2, we evaluated the effects of additional activation treatments, e.g., electrical stimulus, Ca ionophore (A23187), and/or cycloheximide, on fertilization and development of ICSI porcine oocytes. Significantly higher fertilization, cleavage, and blastocyst rates were obtained for oocytes treated with a combination of ICSI and electrical activation (EA) (P < 0.05) than for those treated with ICSI alone. However, different combinations of electrical and chemical activation treatments did not further improve the rates of fertilization, cleavage, and blastocyst development for ICSI embryos. To elucidate the association between sperm head decondensation and oocyte activation and to investigate the cause of embryonic development failure, in experiment 3 we evaluated the nuclear morphology of oocytes 16-20 h after ICSI. Nearly 100% of oocytes showed female pronucleus formation after ICSI regardless of activation treatment. However, failure of male pronucleus formation with intact or swelling sperm heads was observed in some ICSI embryos, suggesting that these embryos underwent cell division with the female pronucleus only. Artificial activation (EA and A23187) had a beneficial effect on embryonic development, sperm decondensation was independent of the resumption of meiosis, and the failure of formation of a male pronucleus was the major cause for fertilization failure in porcine ICSI embryos.


Can computerized clinical decision support systems improve practitioners' diagnostic test ordering behavior? A decision-maker-researcher partnership systematic review.
Underuse and overuse of diagnostic tests have important implications for health outcomes and costs. Decision support technology purports to optimize the use of diagnostic tests in clinical practice. The objective of this review was to assess whether computerized clinical decision support systems (CCDSSs) are effective at improving ordering of tests for diagnosis, monitoring of disease, or monitoring of treatment. The outcome of interest was effect on the diagnostic test-ordering behavior of practitioners. We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for eligible articles published up to January 2010. We included randomized controlled trials comparing the use of CCDSSs to usual practice or non-CCDSS controls in clinical care settings. Trials were eligible if at least one component of the CCDSS gave suggestions for ordering or performing a diagnostic procedure. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of test ordering outcomes. Thirty-five studies were identified, with significantly higher methodological quality in those published after the year 2000 (p = 0.002). Thirty-three trials reported evaluable data on diagnostic test ordering, and 55% (18/33) of CCDSSs improved testing behavior overall, including 83% (5/6) for diagnosis, 63% (5/8) for treatment monitoring, 35% (6/17) for disease monitoring, and 100% (3/3) for other purposes. Four of the systems explicitly attempted to reduce test ordering rates and all succeeded. Factors of particular interest to decision makers include costs, user satisfaction, and impact on workflow but were rarely investigated or reported. Some CCDSSs can modify practitioner test-ordering behavior. To better inform development and implementation efforts, studies should describe in more detail potentially important factors such as system design, user interface, local context, implementation strategy, and evaluate impact on user satisfaction and workflow, costs, and unintended consequences.


Perceived blur in amblyopia.
The well-documented fact that visual acuity and contrast sensitivity in amblyopia are attenuated at high spatial frequencies predicts that amblyopes should perceive objects as blurred, because they do not have the high spatial frequency information necessary to represent sharp edges adequately. In the current study, the representation of blur in amblyopia with blur-discrimination and blur-matching tasks was explored in a series of experiments. Monocular blur-discrimination thresholds were measured in a spatial two-alternative forced-choice procedure. Observers were required to discriminate which edge (right or left) appeared to be the lesser blurred. Observers also interocularly matched edges that were identical with those used in the blur-discrimination tasks, with the exception that they were viewed dichoptically at all times. Blur-discrimination thresholds were elevated in both the amblyopic and fellow fixing eyes but were within the normal range for interocular matching thresholds. The results suggest that blur is veridically represented in the amblyopic visual system. The surprising result is that all amblyopes, even those with the most severe visual loss, veridically matched all blurred edges, including the sharpest ones. This implies that amblyopes are able to represent levels of blur that are defined by spatial structure beyond their resolution limit.


Overcoming efficiency and stability limits in water-processing nanoparticular organic photovoltaics by minimizing microstructure defects.
There is a strong market driven need for processing organic photovoltaics from eco-friendly solvents. Water-dispersed organic semiconducting nanoparticles (NPs) satisfy these premises convincingly. However, the necessity of surfactants, which are inevitable for stabilizing NPs, is a major obstacle towards realizing competitive power conversion efficiencies for water-processed devices. Here, we report on a concept for minimizing the adverse impact of surfactants on solar cell performance. A poloxamer facilitates the purification of organic semiconducting NPs through stripping excess surfactants from aqueous dispersion. The use of surfactant-stripped NPs based on poly(3-hexylthiophene) / non-fullerene acceptor leads to a device efficiency and stability comparable to the one from devices processed by halogenated solvents. A record efficiency of 7.5% is achieved for NP devices based on a low-band gap polymer system. This elegant approach opens an avenue that future organic photovoltaics processing may be indeed based on non-toxic water-based nanoparticle inks.


The use of drug provocation testing in the investigation of suspected immediate perioperative allergic reactions: current status.
Suspected perioperative allergic reactions are often severe. To avoid potentially life-threatening re-exposure to the culprit drug, establishing a firm diagnosis and identifying the culprit is crucial. Drug provocation tests are considered the gold standard in drug allergy investigation but have not been recommended in the investigation of perioperative allergy, mainly because of the pharmacological effects of drugs such as induction agents and neuromuscular blocking agents. Some specialised centres have reported benefits of provocation testing in perioperative allergy investigation, but the literature on the subject is limited. Here we provide a status update on the use of drug provocation testing in perioperative allergy, including its use in specific drug groups. This review is based on a literature search and experiences of the authors comprising anaesthesiologists and allergists with experience in perioperative allergy investigation. In addition, 19 participating centres in the International Suspected Perioperative Allergic Reaction Group were surveyed on the use of provocation testing in perioperative allergy investigation. A response was received from 13 centres in eight European countries, New Zealand, and the USA. Also, 21 centres from the Australian and New Zealand Anaesthetic Allergy Group were surveyed. Two centres performed provocation routinely and seven centres performed no provocations at all. Nearly half of the centres reported performing provocations with induction agents and neuromuscular blocking agents. Drug provocation testing is being used in perioperative allergy investigation in specialised centres, but collaborations between relevant specialties and multicentre studies are necessary to determine indications and establish common testing protocols.


Sex differences in electric signaling in an electric fish.
The electric discharge of Sternopygus macrurus is distinctly different from the discharges of ten sympatric species of electric fish in Guyana, South America. Sternopygus is the first known example of a fish with sexually different electric discharges. Males and females differ in the steady-state frequency of their discharges, and males produce variations in their discharge during courtship. Playback experiments demonstrate that species and sex differences in electric discharges have communicative significance.


Molecular trait indicators: moving beyond phylogeny in arbuscular mycorrhizal ecology.
Arbuscular mycorrhizal (AM) fungi form symbiotic associations with the roots of most plants, thereby mediating nutrient and carbon fluxes, plant performance, and ecosystem dynamics. Although considerable effort has been expended to understand the keystone ecological position of AM symbioses, most studies have been limited in scope to recording organism occurrences and identities, as determined from morphological characters and (mainly) ribosomal sequence markers. In order to overcome these restrictions and circumvent the shortcomings of culture- and phylogeny-based approaches, we propose a shift toward plant and fungal protein-encoding genes as more immediate indicators of mycorrhizal contributions to ecological processes. A number of candidate target genes, involved in the uptake of phosphorus and nitrogen, carbon cycling, and overall metabolic activity, are proposed. We discuss the advantages and disadvantages of future protein-encoding gene marker and current (phylo-) taxonomic approaches for studying the impact of AM fungi on plant growth and ecosystem functioning. Approaches based on protein-encoding genes are expected to open opportunities to advance the mechanistic understanding of ecological roles of mycorrhizas in natural and managed ecosystems.


Effects of aerobic exercise on lipid profiles and high molecular weight adiponectin in Japanese workers.
The metabolic syndrome is characterized by the accumulation of several metabolic risk factors. It is important to improve physical activity and dietary habits to reduce the risk of cardiovascular disease in humans. The study participants participated in a weekly aerobic exercise program that included a session composed of a brief meeting, warm-up exercises, and primary exercises (low and high impact, stretch, muscle training, and cooling down). To evaluate the effect of this intervention we measured body fat composition, holding power, and quality of life assessment. Blood tests were also carried out before and every 3 months during the study. Of the 37 participants enrolled in the exercise group, 31 (83.8%) completed the 12-week program. The control group consisted of 42 subjects, 36 (85.7%) of whom were available for follow-up at the end of the 12-week study period. In the exercise group, weight, body fat percentage, waist circumference, the World Health Organization quality of life 26 (WHO-QOL 26) score, triglyceride, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol had improved significantly at the end of three months. The high molecular weight adiponectin concentration of the participants in the exercise group increased during the 9-month period of the study, although this change did not reach statistical significance compared with pre-exercise. Aerobic exercise led to an improvement in body composition and lipid profiles. High molecular weight adiponectin concentrations tended to improve compared with pre-aerobic exercise levels.


A global assessment of knowledge of dental students about nicotine replacement therapy: findings from 43 countries.
Knowledge of nicotine replacement therapy (NRT) is a competency that is expected from receiving training in the treatment for tobacco dependence. This study therefore assessed the knowledge of dental students in 43 countries about NRT. The 2005-2011 dental Global Health Professions Student Survey data were analysed for 13,040 third-year dental students from 43 countries. Knowledge about NRT was self-reported and country-specific prevalence estimates were calculated. To assess for correlates of knowledge about NRT amongst dental students, a multivariate logistic regression model was fitted (P < 0.05), with pooled data from all 43 countries. The model assessed for geographical location, gross national income, tobacco cessation training in school, sex, current tobacco use and survey year. Amongst all dental students, the proportion that knew about NRT ranged from 37.0% (Mongolia) to 97.6% (Slovakia). The odds of knowing about NRT were lower amongst dental students in the Eastern Mediterranean region (aOR = 0.52; 95% CI: 0.34-0.79) compared to those in the European region. Dental students in upper-middle-income (aOR = 2.46; 95% CI: 1.57-3.85) and high-income countries (aOR=4.55; 95% CI: 2.28-9.09) both had higher odds of knowing about NRT compared to dental students in low-income countries. Also, current use of any tobacco product and receipt of tobacco cessation training in school were both associated with higher likelihood of knowing about NRT. No significant gender differences in knowledge of NRT were observed. A large proportion of dental students in several countries knew about NRT. However, disparities in knowledge existed across regions. Enhanced efforts are needed to formally train dental students on tobacco cessation techniques.


More from less - bottom-up reconstitution of cell biology.
The ultimate goal of bottom-up synthetic biology is recreating life in its simplest form. However, in its quest to find the minimal functional units of life, this field contributes more than its main aim by also offering a range of tools for asking, and experimentally approaching, biological questions. This Review focusses on how bottom-up reconstitution has furthered our understanding of cell biology. Studying cell biological processes in vitro has a long tradition, but only recent technological advances have enabled researchers to reconstitute increasingly complex biomolecular systems by controlling their multi-component composition and their spatiotemporal arrangements. We illustrate this progress using the example of cytoskeletal processes. Our understanding of these has been greatly enhanced by reconstitution experiments, from the first in vitro experiments 70 years ago to recent work on minimal cytoskeleton systems (including this Special Issue of Journal of Cell Science). Importantly, reconstitution approaches are not limited to the cytoskeleton field. Thus, we also discuss progress in other areas, such as the shaping of biomembranes and cellular signalling, and prompt the reader to add their subfield of cell biology to this list in the future.


Generation and characterization of transgenic mice with the full-length human DMD gene.
We report the generation of mice with an intact and functional copy of the 2.3-megabase human dystrophin gene (hDMD), the largest functional stretch of human DNA thus far integrated into a mouse chromosome. Yeast spheroplasts containing an artificial chromosome with the full-length hDMD gene were fused with mouse embryonic stem cells and were subsequently injected into mouse blastocysts to produce transgenic hDMD mice. Human-specific PCR, Southern blotting, and fluorescent in situ hybridization techniques demonstrated the intactness and stable chromosomal integration of the hDMD gene on mouse chromosome 5. Expression of the transgene was confirmed by RT-PCR and Western blotting. The tissue-specific expression pattern of the different DMD transcripts was maintained. However, the human Dp427p and Dp427m transcripts were expressed at 2-fold higher levels and human Dp427c and Dp260 transcripts were expressed at 2- and 4-fold lower levels than their endogenous counterparts. Ultimate functional proof of the hDMD transgene was obtained by crossing of hDMD mice with dystrophin-deficient mdx mice and dystrophin and utrophin-deficient mdx x Utrn-/- mice. The hDMD transgene rescued the lethal dystrophic phenotype of the mdx x Utrn-/- mice. All signs of muscular dystrophy disappeared in the rescued mice, as demonstrated by histological staining of muscle sections and gene expression profiling experiments. Currently, hDMD mice are extensively used for preclinical testing of sequence-specific therapeutics for the treatment of Duchenne muscular dystrophy. In addition, the hDMD mouse can be used to study the influence of the genomic context on deletion and recombination frequencies, genome stability, and gene expression regulation.


A model of protein association based on their hydrophobic and electric interactions.
The propensity of many proteins to oligomerize and associate to form complex structures from their constituent monomers, is analyzed in terms of their hydrophobic (H), and electric pseudo-dipole (D) moment vectors. In both cases these vectors are defined as the product of the distance between their positive and negative centroids, times the total hydrophobicity or total positive charge of the protein. Changes in the magnitudes and directions of H and D are studied as monomers associate to form larger complexes. We use these descriptors to study similarities and differences in two groups of associations: a) open associations such as polymers with an undefined number of monomers (i.e. actin polymerization, amyloid and HIV capsid assemblies); b) closed symmetrical associations of finite size, like spherical virus capsids and protein cages. The tendency of the hydrophobic moments of the monomers in an association is to align in parallel arrangements following a pattern similar to those of phospholipids in a membrane. Conversely, electric dipole moments of monomers tend to align in antiparallel associations. The final conformation of a given assembly is a fine-tuned combination of these forces, limited by steric constraints. This determines whether the association will be open (indetermined number of monomers) or closed (fixed number of monomers). Any kinetic, binding or molecular peculiarities that characterize a protein assembly, comply with the vector rules laid down in this paper. These findings are also independent of protein size and shape.


Quantifying the Speed of Chromatophore Activity at the Single-Organ Level in Response to a Visual Startle Stimulus in Living, Intact Squid.
The speed of adaptive body patterning in coleoid cephalopods is unmatched in the natural world. While the literature frequently reports their remarkable ability to change coloration significantly faster than other species, there is limited research on the temporal dynamics of rapid chromatophore coordination underlying body patterning in living, intact animals. In this exploratory pilot study, we aimed to measure chromatophore activity in response to a light flash stimulus in seven squid, Doryteuthis pealeii. We video-recorded the head/arms, mantle, and fin when squid were presented with a light flash startle stimulus. Individual chromatophores were detected and tracked over time using image analysis. We assessed baseline and response chromatophore surface area parameters before and after flash stimulation, respectively. Using change-point analysis, we identified 4,065 chromatophores from 185 trials with significant surface area changes elicited by the flash stimulus. We defined the temporal dynamics of chromatophore activity to flash stimulation as the latency, duration, and magnitude of surface area changes (expansion or retraction) following the flash presentation. Post stimulation, the response's mean latency was at 50 ms (± 16.67 ms), for expansion and retraction, across all body regions. The response duration ranged from 217 ms (fin, retraction) to 384 ms (heads/arms, expansion). While chromatophore expansions had a mean surface area increase of 155.06%, the retractions only caused a mean reduction of 40.46%. Collectively, the methods and results described contribute to our understanding of how cephalopods can employ thousands of chromatophore organs in milliseconds to achieve rapid, dynamic body patterning.


Chronic stress targets posttranscriptional mechanisms to rapidly upregulate α1C-subunit of Cav1.2b calcium channels in colonic smooth muscle cells.
Chronic stress elevates plasma norepinephrine, which enhances expression of the α(1C)-subunit of Ca(v)1.2b channels in colonic smooth muscle cells within 1 h. Transcriptional upregulation usually does not explain such rapid protein synthesis. We investigated whether chronic stress-induced release of norepinephrine utilizes posttranscriptional mechanisms to enhance the α(1C)-subunit. We performed experiments on colonic circular smooth muscle strips and in conscious rats, using a 9-day chronic intermittent stress protocol. Incubation of rat colonic muscularis externa with norepinephrine enhanced α(1C)-protein expression within 45 min, without a concomitant increase in α(1C) mRNA, indicating posttranscriptional regulation of α(1C)-protein by norepinephrine. We found that norepinephrine activates the PI3K/Akt/GSK-3β pathway to concurrently enhance α(1C)-protein translation and block its polyubiquitination and proteasomal degradation. Incubation of colonic muscularis externa with norepinephrine or LiCl, which inhibits GSK-3β, enhanced p-GSK-3β and α(1C)-protein time dependently. Using enrichment of phosphoproteins and ubiquitinated proteins, we found that both norepinephrine and LiCl decrease α(1C) phosphorylation and polyubiquitination. Concurrently, they suppress eIF2α (Ser51) phosphorylation and 4E-BP1 expression, which stimulates gene-specific translation. The antagonism of two upstream kinases, PI3K and Akt, inhibits the induction of α(1C)-protein by norepinephrine. Cyanopindolol (β(3)-AR-antagonist) almost completely suppresses and propranolol (β(1/2)-AR antagonist) partially suppresses norepinephrine-induced α(1C)-protein expression, whereas phentolamine and prazosin (α-AR and α(1)-AR antagonist, respectively) have no significant effect. Experiments in conscious animals showed that chronic stress activates the PI3K/Akt/GSK-3β signaling. We conclude that norepinephrine released by chronic stress rapidly enhances the protein expression of α(1C)-subunit of Ca(v)1.2b channels by concurrently suppressing its degradation and enhancing translation of existing transcripts to maintain homeostasis.


A prebiotic intervention study in children with autism spectrum disorders (ASDs).
Different dietary approaches, such as gluten and casein free diets, or the use of probiotics and prebiotics have been suggested in autistic spectrum disorders in order to reduce gastrointestinal (GI) disturbances. GI symptoms are of particular interest in this population due to prevalence and correlation with the severity of behavioural traits. Nowadays, there is lack of strong evidence about the effect of dietary interventions on these problems, particularly prebiotics. Therefore, we assessed the impact of exclusion diets and a 6-week Bimuno® galactooligosaccharide (B-GOS®) prebiotic intervention in 30 autistic children. The results showed that children on exclusion diets reported significantly lower scores of abdominal pain and bowel movement, as well as lower abundance of Bifidobacterium spp. and Veillonellaceae family, but higher presence of Faecalibacterium prausnitzii and Bacteroides spp. In addition, significant correlations were found between bacterial populations and faecal amino acids in this group, compared to children following an unrestricted diet. Following B-GOS® intervention, we observed improvements in anti-social behaviour, significant increase of Lachnospiraceae family, and significant changes in faecal and urine metabolites. To our knowledge, this is the first study where the effect of exclusion diets and prebiotics has been evaluated in autism, showing potential beneficial effects. A combined dietary approach resulted in significant changes in gut microbiota composition and metabolism suggesting that multiple interventions might be more relevant for the improvement of these aspects as well as psychological traits. NCT02720900 ; registered in November 2015.


Characteristics of long non-coding RNA and its relation to hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with high prevalence and lethality. However, the underlying mechanism for HCC has not been entirely elucidated. Recent studies have highlighted the roles of long non-coding RNAs (lncRNAs) in carcinogenesis, and it is suggested that they might play critical roles in HCC progression. Here, we will briefly introduce the biology of lncRNAs, emphasizing the mechanisms and emerging roles of HCC-related lncRNAs. To date, HCC-related lncRNAs are demonstrated to influence the life cycle of genes by various means including epigenetic silencing, splicing regulation, lncRNA-miRNA interaction, lncRNA-protein interaction and genetic variation. Moreover, they can participate in diverse biological processes involved in HCC progression through impacts upon cell proliferation, apoptosis, invasion and metastasis and angiogenesis. Since lncRNA can present in body fluid and have good specificity and accessibility, some HCC-related lncRNAs are suggested to be useful as novel potential biomarkers for HCC diagnosis, prognosis and prediction of response to therapy. Those HCC-related lncRNAs may provide potential novel therapeutic targets for HCC and other diseases.


Nucleation and growth of a helical nanofilament (B4) liquid-crystal phase confined in nanobowls.
The B4 helical nanofilament (HNF) liquid crystal (LC) phase is a three-dimensional (3D) helical structure composed of 2D smectic layers. Because of the complex shape of the HNF phase, it is difficult to understand the generation mechanism of HNFs in the bulk as well as in the thin-film condition. Here, we directly investigated the nucleation and growth of HNFs in nanobowls. A combination of electron microscopy and X-ray diffraction was used to reveal the transitional surface structures, in which barrel-like structures as well as short HNFs with random handedness were observed, depending on the LC film thickness. These results will be useful in achieving a better understanding of thin film structures of complex chiral structures in soft matter.


Endoscopic orbital decompression for Graves' ophthalmopathy.
In patients with Graves' ophthalmopathy, orbital decompression surgery is indicated for compressive optic neuropathy, severe corneal exposure, or for cosmetic deformity due to proptosis. Traditionally this has been performed through a transantral approach, but the associated complication rate is high. More recently, endoscopic orbital decompression has been performed successfully with significantly fewer postoperative complications. To report our experience of endoscopic orbital decompression in patients with severe Graves' ophthalmopathy. Three patients (five eyes) underwent endoscopic orbital decompression for Graves' ophthalmopathy at Soroka Medical Center between the years 2000 and 2002. The indications for surgery were compressive optic neuropathy in three eyes, severe corneal exposure in one eye, and severe proptosis not cosmetically acceptable for the patient in one case. An intranasal endoscopic approach with the removal of the medial orbital wall and medial part of the floor was performed. In all five eyes an average reduction of 5 mm in proptosis was achieved. Soon after surgery, visual acuity improved in the three cases with compressive optic neuropathy, and exposure keratopathy and cosmetic appearance also improved. The diplopia remained unchanged. No complications were observed postoperatively. Endoscopic orbital decompression with removal of the medial orbital wall and medial part of the floor in the five reported eyes was an effective and safe procedure for treatment of severe Graves' ophthalmopathy. A close collaboration between ophthalmologists and otorhinolaryngologists skilled in endoscopic sinus surgery is crucial for the correct management of these patients.


Zero-field nuclear magnetic resonance of chemically exchanging systems.
Zero- to ultralow-field (ZULF) nuclear magnetic resonance (NMR) is an emerging tool for precision chemical analysis. In this work, we study dynamic processes and investigate the influence of chemical exchange on ZULF NMR J-spectra. We develop a computational approach that allows quantitative calculation of J-spectra in the presence of chemical exchange and apply it to study aqueous solutions of [15N]ammonium (15N[Formula: see text]) as a model system. We show that pH-dependent chemical exchange substantially affects the J-spectra and, in some cases, can lead to degradation and complete disappearance of the spectral features. To demonstrate potential applications of ZULF NMR for chemistry and biomedicine, we show a ZULF NMR spectrum of [2-13C]pyruvic acid hyperpolarized via dissolution dynamic nuclear polarization (dDNP). We foresee applications of affordable and scalable ZULF NMR coupled with hyperpolarization to study chemical exchange phenomena in vivo and in situations where high-field NMR detection is not possible to implement.


[Self-rated health and social inequalities, Buenos Aires, Argentina, 2005].
Self-rated health is a quality-of-life indicator. This study investigates the impact of individual-level and neighborhood-level socioeconomic characteristics, considered simultaneously, on the state of self-rated health at the individual level in Buenos Aires, Argentina. The study employs a two-level (individual and neighborhood) multilevel analysis, and the data sources were the 2005 Argentina National Risk Factor Survey (multistage probabilistic sample) and the 2001 Population Census. Linear regression shows that higher schooling and income, as well as occupational category, are related to better self-rated health, and increasing age with worse health. In the multilevel analysis, an increase in the proportion (per census tract) of individuals with less schooling was associated with an increase in the proportion of individuals with worse self-rated health. Improving the general health of the population requires strategies and action that reduce the levels of social inequalities in their multiple dimensions, including the individual and neighborhood levels.


Bioaccumulation and toxicity of dissolved heavy metals from the Guadalquivir Estuary after the Aznalcóllar mining spill using Ruditapes philippinarum.
The shore clam Ruditapes philippinarum was used as a biomonitoring organism to measure the potential impact that the mining spill in the Guadalquivir Estuary (SW, Spain) in 1998 may have exerted on local biota. Individuals were exposed to dissolved cadmium, copper, and zinc at concentrations found in local waters after the spill (3 microg x L(-1) Cd, 15 microg x L(-1) Cu, 700 microg x L(-1) Zn) at two salinity values: 10 and 35. Residues of metals were measured in gill and digestive gland, together with metallothioneins in the digestive gland and histopathological lesions in gill, digestive gland, and gonad tissues over time. Heavy metals Zn and Cd associated with the mining spill, were bioaccumulated in clam tissues, associated with the activation of metallothioneins, and related to the histopathological lesions measured at all the clam tissues. The heavy metal Cu not related to the spill was not directly associated with effects measured. The bioaccumulation and adverse effects associated with Cd and Zn were significantly higher at low salinity (10) than at high salinity (35) values.


Physicians' Use of Online Clinical Evidence in Mashhad University of Medical Sciences, Iran.
The Internet is an important source of medical information. It is expected that the use of online sources will improve clinical decisions. This study aims to evaluate online information seeking behavior of physicians of Mashhad University of Medical Sciences on the use of online clinical evidence. A cross-sectional, questionnaire-based study was carried out between November and December 2014 in the five academic hospitals. A total of 252 physicians completed the questionnaire. The majority of physicians (63.6 of specialists and 58.5% of residents) had no internet access in their consultation and visit rooms. The majority of physicians (77.8% of specialists and 80% of residents) respectively used Google, as well as 67.5% specialists and 52.2% residents always used Medline or PubMed, among electronic sources, to searching for information. The main reasons for physicians' dissatisfaction with the Internet, as a source of health information, were lack of access to medical sources owing to the non-targeted filtering (61% specialists and 74.6% residents) and very slow connection of the Internet (75.6% specialists and 83.1% residents). It is recommended that medical informatics training programs should be incorporated, where physicians are required to search for health information in the Internet.


Diet-induced obesity and mammary tumor development in MMTV-neu female mice.
Obesity is a risk factor for postmenopausal breast cancer and is associated with shortened latency and/or increased mammary tumor (MT) incidence in animals. Elevated body weight is usually associated with hormone-responsive tumors. In agreement with these data we previously showed that latency of hormone-responsive MTs in MMTV-TGF-alpha mice with diet-induced obesity was significantly shortened. Here, we used the same protocol to determine the impact of diet-induced obesity on estrogen receptor-negative MT development in MMTV-neu (strain 202) mice. Mice were fed a low-fat diet (n=20) or a high-fat diet (n=54) from 10 wk of age. Body weight at 19 wk of age was used to assign high-fat mice to obesity-prone, overweight, and obesity-resistant groups. Mice were euthanized due to MT size or at 85 wk of age. Final body weights of obesity-prone mice were heaviest, and those of obesity-resistant and low-fat groups were similar. Fat pad weights were heaviest in obesity-prone mice followed by overweight and obesity-resistant groups, and lightest in low-fat mice. Serum IGF-I levels were similar for low-fat and high-fat mice, whereas leptin was higher in high-fat mice (P <0.0001). MT latency, incidence, metastasis, and burden were similar for all groups. These findings support that obesity is not a risk factor for development of estrogen-negative breast cancer.


Rare coding variants associated with blood pressure variation in 15 914 individuals of African ancestry.
Hypertension is a major risk factor for all cardiovascular diseases, especially among African Americans. This study focuses on identifying specific blood pressure (BP) genes using 15 914 individuals of African ancestry from eight cohorts (Africa America Diabetes Mellitus, Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in young Adults, Genetics Network, Genetic Epidemiology Network of Arteriopathy, Howard University Family Study, Hypertension Genetic Epidemiology Network, and Loyola University Chicago Cohort) to further genetic findings in this population which has generally been underrepresented in BP studies. We genotyped and performed various single variant and gene-based exome-wide analyses on 15 914 individuals on the Illumina HumanExome Beadchip v1.0 or v1.1 to test association with SBP and DBP long-term average residuals that were adjusted for age, age-squared, sex, and BMI. We identified rare variants affecting SBP and DBP in 10 genes: AFF1, GAPDHS, SLC28A3, COL6A1, CRYBA2, KRBA1, SEL1L3, YOD1, CCDC13, and QSOX1. Prior experimental evidence for six of these 10 candidate genes supports their involvement in cardiovascular mechanisms, corroborating their potential roles in BP regulation. Although our results require replication or validation due to their low numbers of carriers, and an ethnicity-specific genotyping array may be more informative, this study, which has identified several candidate genes in this population most susceptible to hypertension, presents one of the largest African-ancestry BP studies to date and the largest including analysis of rare variants.


Different optimal offspring sizes for sons versus daughters may favor the evolution of temperature-dependent sex determination in viviparous lizards.
Temperature-dependent sex determination (TSD) has evolved independently in at least two lineages of viviparous Australian scincid lizards, but its adaptive significance remains unclear. We studied a montane lizard species (Eulamprus heatwolei) with TSD. Our data suggest that mothers can modify the body sizes of their offspring by selecting specific thermal regimes during pregnancy (mothers with higher and more stable temperatures produced smaller offspring), but cannot influence sons versus daughters differentially in this way. A field mark-recapture study shows that optimal offspring size differs between the sexes: larger body size at birth enhanced the survival of sons but reduced the survival of daughters. Thus, a pregnant female can optimize the fitness of either her sons or her daughters (via yolk allocation and thermoregulation), but cannot simultaneously optimize both. One evolutionary solution to reduce this fitness cost is to modify the sex-determining mechanism so that a single litter consists entirely of either sons or daughters; TSD provides such a mechanism. Previous work has implicated a sex difference in optimal offspring size as a selective force for TSD in turtles. Hence, opposing fitness determinants of sons and daughters may have favored evolutionary transitions from genetic sex determination to TSD in both oviparous turtles and viviparous lizards.


Conceptualization of Idle (Laghw) and its relation to medical futility.
A major debate in medical ethics is the request for futile treatment. The topic of medical futility requires discrete assessment in Iran for at least two reasons. First, the common principles and foundations of medical ethics have taken shape in the context of Western culture and secularism. Accordingly, the implementation of the same guidelines and codes of medical ethics as Western societies in Muslim communities does not seem rational. Second, the challenges arising in health service settings are divergent across different countries. The Quranic concept of idle (laghw) and its derivatives are used in 11 honorable verses of the Holy Quran. Among these verses, the 3rd verse of the blessed Al-Muminūn Surah was selected for its closer connection to the concept under examination. The selected verse was researched in the context of all dictionaries presented in Noor Jami` al-Tafasir 2 (The Noor Collection of Interpretations 2) software. "Idle" is known as any insignificant speech, act, or thing that is not beneficial; an action from which no benefit is gained; any falsehood (that is not stable or realized); an entertaining act; any foul, futile talk and action unworthy of attention; loss of hope; and something that is not derived from method and thought. The word has also been used to refer to anything insignificant. The notes and derived interpretations were placed in the following categories: A) Having no significant benefit (When medical care does not benefit the patient (his body and/or soul and his life in this world and/or the Hereafter), it is wrong to proceed with that medical modality; B) Falsehood (Actions that fail to provide, maintain, and improve health are clearly futile); C) Unworthy of attention (An action that neither improves health nor threatens it is wrong and impermissible).