Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells.
Lysophosphatidylcholine (lyso-PC) is a major phospholipid component of atherogenic lipoproteins (e.g., oxidized LDL and beta-VLDL) and also can be generated through the action of leukocyte-secreted phospholipase A2 at sites of inflammation. We have previously reported that lyso-PC can activate cultured endothelia, resulting in the selective upregulation of adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. In this study, we have found that lyso-PC increased steady state mRNA levels for two smooth muscle/fibroblast-directed growth factors, the A and B chains of PDGF and heparin-binding EGF-like protein (HB-EGF), in cultured human endothelial cells. Lyso-PC did not upregulate the expression of certain other inducible endothelial genes, including E-selectin, IL-8, or monocyte chemoattractant protein-1 in the same cells, in contrast to the coordinate pattern of activation typically observed with other stimuli, such as TNF alpha, bacterial endotoxin, or PMA. Nuclear runoff assays documented an increased transcriptional rate for the HB-EGF gene in lyso-PC-treated cells. Northern blot analyses, after actinomycin D treatment, further indicated that the increased amounts of mRNA for HB-EGF, PDGF A and B chains, and intercellular adhesion molecule-1 were not dependent upon message stabilization. We conclude that lyso-PC can induce growth factor gene expression in cultured endothelial cells and thus may contribute to the migration and proliferation of smooth muscle cells and fibroblasts in various response-to-injury settings in vivo.


Beyond the Ligand: Extracellular and Transcellular G Protein-Coupled Receptor Complexes in Physiology and Pharmacology.
G protein-coupled receptors (GPCRs) remain one of the most successful targets of U.S. Food and Drug Administration-approved drugs. GPCR research has predominantly focused on the characterization of the intracellular interactome's contribution to GPCR function and pharmacology. However, emerging evidence uncovers a new dimension in the biology of GPCRs involving their extracellular and transcellular interactions that critically impact GPCR function and pharmacology. The seminal examples include a variety of adhesion GPCRs, such as ADGRLs/latrophilins, ADGRBs/brain angiogenesis inhibitors, ADGRG1/GPR56, ADGRG6/GPR126, ADGRE5/CD97, and ADGRC3/CELSR3. However, recent advances have indicated that class C GPCRs that contain large extracellular domains, including group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8), γ-aminobutyric acid receptors, and orphans GPR158 and GPR179, can also participate in this form of transcellular regulation. In this review, we will focus on a variety of identified extracellular and transcellular GPCR-interacting partners, including teneurins, neurexins, integrins, fibronectin leucine-rich transmembranes, contactin-6, neuroligin, laminins, collagens, major prion protein, amyloid precursor protein, complement C1q-likes, stabilin-2, pikachurin, dystroglycan, complement decay-accelerating factor CD55, cluster of differentiation CD36 and CD90, extracellular leucine-rich repeat and fibronectin type III domain containing 1, and leucine-rich repeat, immunoglobulin-like domain and transmembrane domains. We provide an account on the diversity of extracellular and transcellular GPCR complexes and their contribution to key cellular and physiologic processes, including cell migration, axon guidance, cellular and synaptic adhesion, and synaptogenesis. Furthermore, we discuss models and mechanisms by which extracellular GPCR assemblies may regulate communication at cellular junctions. SIGNIFICANCE STATEMENT: G protein-coupled receptors (GPCRs) continue to be the prominent focus of pharmacological intervention for a variety of human pathologies. Although the majority of GPCR research has focused on the intracellular interactome, recent advancements have identified an extracellular dimension of GPCR modulation that alters accepted pharmacological principles of GPCRs. Herein, we describe known endogenous allosteric modulators acting on GPCRs both in cis and in trans.


Psychosocial correlates of harassment, threats and fear of violence in the workplace.
The purpose of this study was to investigate work climate factors and structural job aspects as predictors of workplace violence, with particular attention to the relative influence of both sets of factors. Telephone survey data collected by a large midwestern insurance company were analyzed. Interviewers asked 598 full-time workers about their work climate, structural job aspects, and subject and workplace demographics, all of which were used as predictor variables in regression analyses. The participants were also asked about incidents of threats, harassment, physical attacks, and fear of becoming a victim of workplace violence, all of which were used as outcome measures. Separate logistic regressions were carried out for each of the outcome measures. The study identified a variety of factors which appear to place workers at risk of nonfatal occupational violence. Work climate variables, such as co-worker support and work group harmony, were predictive of threats, harassment, and fear of becoming a victim of violence. Structural aspects of the job, such as work schedule, were also significant in predicting threats and fear of becoming a victim of violence, but they were not predictive of harassment. This is the first study which suggests that both work climate and structural aspects of work may be important in promoting workplace violence. This finding suggests that intervention strategies should consider organizational and climate issues in addition to basic security measures.


Cyanidin inhibits glioma stem cells proliferation through the Wnt signaling pathway.
Cyanidin has a protective effect on the nervous system and has been reported to treat tumor effectively. However, its impact on glioma stem cells (GSC) is unknown. Using seven GSC lines, the anti-tumor effect of cyanidin is tested. The effect of cyanidin on the cell viability in each cell line is evaluated. Wnt signaling pathway-related genes are checked after treatment of cyanidin. Cytoplasmic/nuclear β-catenin protein levels post cyanidin treatment is detected. Protein levels of c-Myc after cyanidin treatment are determined. Twist1 and Snail1 protein levels after cyanidin treatment are checked as well. Cyanidin significantly reduces the cell viability of all GSCs, and exhibited the most substantial effect in GBM2 but no apparent effect in 293T cells. It can regulate the Wnt signaling pathway of all GSC lines. In the GBM2, GBM7, G166, and G179 cell lines, there is upregulation of WNT1 and MYC genes, while in the G144 and GliNS2 cell line, these two genes are down-regulated after cyanidin treatment. Cytoplasmic and nuclear protein levels of β-catenin in all cell lines are down-regulated. Cyanidin treatment significantly decreases the protein level for c-Myc in the GBM2 cell line compared with untreated cells, not in G144 or GliNS2 cells. Furthermore, cyanidin strongly reduces the expression of Twist1 and Snail1 in GBM2, G179, and G144 cell lines, while the GliNS2 cells show an opposite change in the cytoplasm and no change in nuclear. Cyanidin exerts an anti-tumor effect in glioma stem cell lines, probably through the Wnt signaling pathway.


Genome-wide transcriptome analysis to further understand neutrophil activation and lncRNA transcript profiles in Kawasaki disease.
Kawasaki disease (KD) is the most common cause of acquired cardiac disease in children in developed countries. However, little is known regarding the role of transcriptomic targets of KD in the disease progression and development of complications, especially coronary artery aneurysms (CAA). The aim of our study was to identify transcripts affected by KD and their potential role in the disease. We enrolled 37 KD patients and collected blood samples along a comprehensive time-course. mRNA profiling demonstrated an abundance of CD177 transcript in acute KD, and in the intravenous immunoglobulin (IVIG)-resistant group compared to in the IVIG-sensitive group. lncRNA profiling identified XLOC_006277 as the most highly expressed molecule. XLOC_006277 expression in patients at acute stage was 3.3-fold higher relative to patients with convalescent KD. Moreover, XLOC_006277 abundance increased significantly in patients with CAA. XLOC_006277 knockdown suppressed MMP-8 and MMP-9 expression, both associated with heart lesions. Our result suggested that the increase of CD177pos neutrophils was associated with KD. Moreover, this study provided global long non-coding RNA transcripts in the blood of patients with KD, IVIG-resistant KD, or CAA. Notably, XLOC_006277 abundance was associated with CAA, which might contribute to further understanding of CAA pathogenesis in KD.


Force-inhibiting effect of Ser/Thr protein phosphatase 2A inhibitors on bovine ciliary muscle.
Ciliary muscle is a smooth muscle characterized by a rapid response to muscarinic receptor stimulation and sustained contraction. Although it is evident that these contractions are Ca(2+)-dependent, detailed molecular mechanisms are still unknown. In order to elucidate the role of Ser/Thr protein phosphatase 2A (PP2A) in ciliary muscle contraction, we examined the effects of okadaic acid and other PP2A inhibitors on contractions induced by carbachol (CCh) and ionomycin in bovine ciliary muscle strips (BCM). Okadaic acid inhibited ionomycin-induced contraction, while it did not cause significant changes in CCh-induced contraction. Fostriecin showed similar inhibitory effects on the contraction of BCM. On the other hand, rubratoxin A inhibited both ionomycin- and CCh-induced contractions. These results indicated that PP2A was involved at least in ionomycin-induced Ca(2+)-dependent contraction, and that BCM had a unique regulatory mechanism in CCh-induced contraction.


Effectiveness and safety of risankizumab in HIV patients with psoriasis: A case series.
Biological therapies represent the gold-standard treatment of severe forms of plaque psoriasis. However, people living with HIV are often under-treated for psoriasis because very limited data are available on the use of biologics in this population. We report four cases of patients affected by HIV and moderate-to-severe plaque psoriasis, all treated with risankizumab, a monoclonal antibody that selectively targets interleukin-23. After 16 weeks, all patients experienced complete or almost complete skin clearance without any adverse events. Data on the effectiveness and safety of biological therapies in people living with HIV are limited to case reports or small case series, especially for the most recently approved inhibitors of interleukin-23. Our experienced, although limited, supports the role of risankizumab as a safe and effective therapy for psoriasis amongst patients living with HIV.


Treatment of patients with traumatic subdural effusion and concomitant hydrocephalus.
Traumatic subdural effusion (TSE) is a common sequela of traumatic brain injury. Surgical intervention is suggested only when TSE exerts mass effect. The authors have found that many patients with TSE exerting mass effect have concomitant hydrocephalus. Patient experiencing this occurrence were studied, and the pathogenesis of this phenomenon was discussed in the context of recent advances in the understanding of CSF circulation. During a 2-year period, the authors' institution treated 14 patients with TSE who developed hydrocephalus, after 1 of the patients suffered subdural drainage and other 13 received subdural peritoneal shunt (SPSs). Thirteen of those who had SPSs received programmable ventriculoperitoneal shunts (VPSs) for the hydrocephalus. The clinical characteristics as well as the imaging and operative findings of these patients were reviewed. All patients with symptomatic TSE exerting mass effect received SPSs. All of these patients had a modified Frontal Horn Index of more than 0.33 at presentation, and high opening pressure on durotomy. Following a brief period (4-7 days) of clinical improvement, the condition of all patients deteriorated due to hydrocephalus. Programmable VPSs were inserted with the initial pressure set at approximately 8-10 cm H(2)O according to opening pressure at ventriculostomy. Shunt valve pressure was gradually decreased to 5-7 cm H(2)O, according to clinical and radiological follow-up. Elevated modified Frontal Horn Index in patients with TSE is suggestive of concomitant hydrocephalus. The authors propose that tearing of the dura-arachnoid plane following trauma contributes to TSE and may also impede CSF circulation, causing hydrocephalus. Shunt pressure was adjusted to relative low pressure, indicating the old age of the patients and poor reexpansion of brain parenchyma after the mass effect. Subdural peritoneal shunts and VPSs are indicated in those patients with TSE exerting mass effect with concomitant hydrocephalus.


Antibiotics in ingested human blood affect the mosquito microbiota and capacity to transmit malaria.
Malaria reduction is most efficiently achieved by vector control whereby human populations at high risk of contracting and transmitting the disease are protected from mosquito bites. Here, we identify the presence of antibiotics in the blood of malaria-infected people as a new risk of increasing disease transmission. We show that antibiotics in ingested blood enhance the susceptibility of Anopheles gambiae mosquitoes to malaria infection by disturbing their gut microbiota. This effect is confirmed in a semi-natural setting by feeding mosquitoes with blood of children naturally infected with Plasmodium falciparum. Antibiotic exposure additionally increases mosquito survival and fecundity, which are known to augment vectorial capacity. These findings suggest that malaria transmission may be exacerbated in areas of high antibiotic usage, and that regions targeted by mass drug administration programs against communicable diseases may necessitate increased vector control.


Dynamic changes in human-gut microbiome in relation to a placebo-controlled anthelminthic trial in Indonesia.
Microbiome studies suggest the presence of an interaction between the human gut microbiome and soil-transmitted helminth. Upon deworming, a complex interaction between the anthelminthic drug, helminths and microbiome composition might occur. To dissect this, we analyse the changes that take place in the gut bacteria profiles in samples from a double blind placebo controlled trial conducted in an area endemic for soil transmitted helminths in Indonesia. Either placebo or albendazole were given every three months for a period of one and a half years. Helminth infection was assessed before and at 3 months after the last treatment round. In 150 subjects, the bacteria were profiled using the 454 pyrosequencing. Statistical analysis was performed cross-sectionally at pre-treatment to assess the effect of infection, and at post-treatment to determine the effect of infection and treatment on microbiome composition using the Dirichlet-multinomial regression model. At a phylum level, at pre-treatment, no difference was seen in microbiome composition in terms of relative abundance between helminth-infected and uninfected subjects and at post-treatment, no differences were found in microbiome composition between albendazole and placebo group. However, in subjects who remained infected, there was a significant difference in the microbiome composition of those who had received albendazole and placebo. This difference was largely attributed to alteration of Bacteroidetes. Albendazole was more effective against Ascaris lumbricoides and hookworms but not against Trichuris trichiura, thus in those who remained infected after receiving albendazole, the helminth composition was dominated by T. trichiura. We found that overall, albendazole does not affect the microbiome composition. However, there is an interaction between treatment and helminths as in subjects who received albendazole and remained infected there was a significant alteration in Bacteroidetes. This helminth-albendazole interaction needs to be studied further to fully grasp the complexity of the effect of deworming on the microbiome. ISRCTN Registy, ISRCTN83830814.


International policies toward parental leave and child care.
The pleasures and pressures of parenting a newborn are universal, but the supports surrounding parents vary widely from country to country. In many nations, decades of attention to benefits and services for new parents offer lessons worthy of attention in this country. This article describes policies regarding parental leave, child care, and early childhood benefits here and in 10 industrial nations in North America and Europe. The sharpest contrast separates the United States from the other countries, although differences among the others also are instructive: The right to parental leave is new to American workers; it covers one-half of the private-sector workforce and is relatively short and unpaid. By contrast, other nations offer universal, paid leaves of 10 months or more. Child care assistance in Europe is usually provided through publicly funded programs, whereas the United States relies more on subsidies and tax credits to reimburse parents for part of their child care expenses. Nations vary in the emphasis they place on parental leave versus child care supports for families with children under age three. Each approach creates incentives that influence parents' decisions about employment and child care. Several European nations, seeking flexible solutions for parents, are testing "early childhood benefits" that can be used to supplement income or pay for private child care. Based on this review, the author urges that the United States adopt universal, paid parental leave of at least 10 months; help parents cover more child care costs; and improve the quality of child care. She finds policy packages that support different parental choices promising, because the right mix of leave and care will vary from family to family, and child to child.


Human Capital Theory and Internal Migration: Do Average Outcomes Distort Our View of Migrant Motives?
By modelling the distribution of percentage income gains for movers in Sweden, using multinomial logistic regression, this paper shows that those receiving large pecuniary returns from migration are primarily those moving to the larger metropolitan areas and those with higher education, and that there is much more variability in income gains than what is often assumed in models of average gains to migration. This suggests that human capital models of internal migration often overemphasize the job and income motive for moving, and fail to explore where and when human capital motivated migration occurs.


Effects of periodontal cell grafts and enamel matrix proteins on the implant-connective tissue interface: a pilot study in the minipig.
We have developed an experimental model to help identify and characterize factors necessary for periodontal connective tissue attachment formation on dental implants. In this pilot study, we report the effect of autogenous periodontal cell grafts, with and without the a pplication of enamel matrix derivative (EMD), on the implant-connective tissue interface. Periodontal ligament (PDL) and gingival connective tissue (GCT) cultures were established from an adult minipig. Implants were placed in osteotomies prepared with exaggerated countersinks that served as recipient sites for autogenous cell grafts in bilateral edentulated posterior mandibular sextants. In addition, 1 side received an application of EMD before placement of the autogenous cell grafts. A bioabsorbable membrane covering the coronal portion of the implants was placed before closure. After 8 weeks, quantitative histomorphometric and qualitative light microscopic analyses revealed that the implants that received gelatin vehicle alone were surrounded by bone, whereas the implants that received GCT cell grafts were mostly surrounded by fibrous connective tissue. In contrast, implants that received PDL cells without the application of EMD demonstrated good bone contact, but strands of epithelium were observed in the implant-connective tissue interface. Implants that received PDL cells and EMD also had good bone contact but without evidence of epithelium. A cementum-like interface was not observed in any of the groups. Results of this pilot study suggest that EMD and the type of cell populations present in the implant wound-healing environment may alter the implant-connective tissue interface.


Role of the proneural gene, atonal, in formation of Drosophila chordotonal organs and photoreceptors.
The Drosophila gene atonal encodes a basic helix-loop-helix protein similar to those encoded by the proneural genes of the achaete-scute complex (AS-C). The AS-C are required in the Drosophila PNS for the selection of neural precursors of external sense organs. We have isolated mutants of atonal, which reveal that this gene encodes the proneural gene for chordotonal organs and photoreceptors. In atonal mutants, all observable adult chordotonal organs, and almost all embryonic chordotonal organs fail to form; all adult photoreceptors are missing. For both types of sense organ, this defect is already apparent at the level of precursor formation. Therefore it is a failure in the epidermal-neural decision process i.e. a proneural defect. The failure to form photoreceptors results in atrophy of the atonal mutant imaginal disc, due to apoptosis and lack of stimulation of division. Lack of photoreceptors should also eliminate signalling that arises from differentiating photoreceptors and is required for morphogenetic furrow movement in the wild-type eye disc. Nevertheless, a remnant morphogenetic furrow is still observed in the atonal mutant disc. This presumably reflects the process of furrow initiation, which would not depend on signals from developing photoreceptors.


Evidence summaries tailored to health policy-makers in low- and middle-income countries.
To describe how the SUPPORT collaboration developed a short summary format for presenting the results of systematic reviews to policy-makers in low- and middle-income countries (LMICs). We carried out 21 user tests in six countries to explore users' experiences with the summary format. We modified the summaries based on the results and checked our conclusions through 13 follow-up interviews. To solve the problems uncovered by the user testing, we also obtained advisory group feedback and conducted working group workshops. Policy-makers liked a graded entry format (i.e. short summary with key messages up front). They particularly valued the section on the relevance of the summaries for LMICs, which compensated for the lack of locally-relevant detail in the original review. Some struggled to understand the text and numbers. Three issues made redesigning the summaries particularly challenging: (i) participants had a poor understanding of what a systematic review was; (ii) they expected information not found in the systematic reviews and (iii) they wanted shorter, clearer summaries. Solutions included adding information to help understand the nature of a systematic review, adding more references and making the content clearer and the document quicker to scan. Presenting evidence from systematic reviews to policy-makers in LMICs in the form of short summaries can render the information easier to assimilate and more useful, but summaries must be clear and easy to read or scan quickly. They should also explain the nature of the information provided by systematic reviews and its relevance for policy decisions.


Potent and specific inhibition of glycosidases by small artificial binding proteins (affitins).
Glycosidases are associated with various human diseases. The development of efficient and specific inhibitors may provide powerful tools to modulate their activity. However, achieving high selectivity is a major challenge given that glycosidases with different functions can have similar enzymatic mechanisms and active-site architectures. As an alternative approach to small-chemical compounds, proteinaceous inhibitors might provide a better specificity by involving a larger surface area of interaction. We report here the design and characterization of proteinaceous inhibitors that specifically target endoglycosidases representative of the two major mechanistic classes; retaining and inverting glycosidases. These inhibitors consist of artificial affinity proteins, Affitins, selected against the thermophilic CelD from Clostridium thermocellum and lysozyme from hen egg. They were obtained from libraries of Sac7d variants, which involve either the randomization of a surface or the randomization of a surface and an artificially-extended loop. Glycosidase binders exhibited affinities in the nanomolar range with no cross-recognition, with efficient inhibition of lysozyme (Ki = 45 nM) and CelD (Ki = 95 and 111 nM), high expression yields in Escherichia coli, solubility, and thermal stabilities up to 81.1°C. The crystal structures of glycosidase-Affitin complexes validate our library designs. We observed that Affitins prevented substrate access by two modes of binding; covering or penetrating the catalytic site via the extended loop. In addition, Affitins formed salt-bridges with residues essential for enzymatic activity. These results lead us to propose the use of Affitins as versatile selective glycosidase inhibitors and, potentially, as enzymatic inhibitors in general.


Phylogenetic analysis of erythritol catabolic loci within the Rhizobiales and proteobacteria.
The ability to use erythritol as a sole carbon source is not universal among the Rhizobiaceae. Based on the relatedness to the catabolic genes in Brucella it has been suggested that the eryABCD operon may have been horizontally transferred into Rhizobium. During work characterizing a locus necessary for the transport and catabolism of erythritol, adonitol and L-arabitol in Sinorhizobium meliloti, we became interested in the differences between the erythritol loci of S. meliloti and R. leguminosarum. Utilizing the Ortholog Neighborhood Viewer from the DOE Joint Genome Institute database it appeared that loci for erythritol and polyol utilization had distinct arrangements that suggested these loci may have undergone genetic rearrangements. A data set was established of genetic loci containing erythritol/polyol orthologs for 19 different proteobacterial species. These loci were analyzed for genetic content and arrangement of genes associated with erythritol, adonitol and L-arabitol catabolism. Phylogenetic trees were constructed for core erythritol catabolic genes and contrasted with the species phylogeny. Additionally, phylogenetic trees were constructed for genes that showed differences in arrangement among the putative erythritol loci in these species. Three distinct erythritol/polyol loci arrangements have been identified that reflect metabolic need or specialization. Comparison of the phylogenetic trees of core erythritol catabolic genes with species phylogeny provides evidence that is consistent with these loci having been horizontally transferred from the alpha-proteobacteria into both the beta and gamma-proteobacteria. ABC transporters within these loci adopt 2 unique genetic arrangements, and although biological data suggests they are functional erythritol transporters, phylogenetic analysis suggests they may not be orthologs and probably should be considered analogs. Finally, evidence for the presence of paralogs, and xenologs of erythritol catabolic genes in some of the genomes included in the analysis is provided.


Dynamic pattern generation in behavioral and neural systems.
In the search for principles of pattern generation in complex biological systems, an operational approach is presented that embraces both theory and experiment. The central mathematical concepts of self-organization in nonequilibrium systems (including order parameter dynamics, stability, fluctuations, and time scales) are used to show how a large number of empirically observed features of temporal patterns can be mapped onto simple low-dimensional (stochastic, nonlinear) dynamical laws that are derivable from lower levels of description. The theoretical framework provides a language and a strategy, accompanied by new observables, that may afford an understanding of dynamic patterns at several scales of analysis (including behavioral patterns, neural networks, and individual neurons) and the linkage among them.


What distinguishes cyanobacteria able to revive after desiccation from those that cannot: the genome aspect.
Filamentous cyanobacteria are the main founders and primary producers in biological desert soil crusts (BSCs) and are likely equipped to cope with one of the harshest environmental conditions on earth including daily hydration/dehydration cycles, high irradiance and extreme temperatures. Here, we resolved and report on the genome sequence of Leptolyngbya ohadii, an important constituent of the BSC. Comparative genomics identified a set of genes present in desiccation-tolerant but not in dehydration-sensitive cyanobacteria. RT qPCR analyses showed that the transcript abundance of many of them is upregulated during desiccation in L. ohadii. In addition, we identified genes where the orthologs detected in desiccation-tolerant cyanobacteria differs substantially from that found in desiccation-sensitive cells. We present two examples, treS and fbpA (encoding trehalose synthase and fructose 1,6-bisphosphate aldolase respectively) where, in addition to the orthologs present in the desiccation-sensitive strains, the resistant cyanobacteria also possess genes with different predicted structures. We show that in both cases the two orthologs are transcribed during controlled dehydration of L. ohadii and discuss the genetic basis for the acclimation of cyanobacteria to the desiccation conditions in desert BSC.


Distinct role of spatial frequency in dissociative reading of ideograms and phonograms: an fMRI study.
It has been proposed that distinct neural circuits are activated by reading Japanese ideograms (Kanji) and phonograms (Kana). By measuring high-density event-related potentials, we recently reported that spatial frequency (SF) information is responsible for the dissociation between Kanji and Kana reading. In particular, we found close links between Kana and low SF (LSF) information and between Kanji and high SF (HSF) information. However, it remains unclear which brain regions contribute to this dissociation. To determine this, we performed functional magnetic resonance imaging while presenting unfiltered or spatially filtered Kanji and Kana word stimuli to healthy native Japanese subjects. Fourier analysis revealed that Kanji and Kana stimuli were characterized by HSF and LSF information, respectively. When presented with either type of unfiltered stimulus (Kanji or Kana), the bilateral inferior temporal (IT, BA 37) regions were activated compared to the resting condition. Kana but not Kanji reading also activated the bilateral inferior parietal lobules (IPL, BA 40). When we compared Kanji and Kana reading directly, the left IT region was significantly activated by Kanji reading, while significant activation of the left IPL was observed during Kana reading. In response to filtered HSF stimuli, the Kanji reading minus Kana reading comparison revealed significant activation of the left IT region but not the left IPL. Conversely, significant activation of the left IPL but not the left IT region occurred in the Kana reading minus Kanji reading comparison for filtered LSF stimuli. These results suggest that Kanji and Kana engage a relatively overlapping network, within which the left IT is more involved in Kanji processing, while the left IPL contributes more to Kana processing. The preferential engagements of these brain regions could reflect the close links between Kana and LSF information, and between Kanji and HSF information. Therefore, this study provides further evidence that SF contributes to the dissociation between Kanji and Kana reading.


Role of mask pattern in intelligibility of ideal binary-masked noisy speech.
Intelligibility of ideal binary masked noisy speech was measured on a group of normal hearing individuals across mixture signal to noise ratio (SNR) levels, masker types, and local criteria for forming the binary mask. The binary mask is computed from time-frequency decompositions of target and masker signals using two different schemes: an ideal binary mask computed by thresholding the local SNR within time-frequency units and a target binary mask computed by comparing the local target energy against the long-term average speech spectrum. By depicting intelligibility scores as a function of the difference between mixture SNR and local SNR threshold, alignment of the performance curves is obtained for a large range of mixture SNR levels. Large intelligibility benefits are obtained for both sparse and dense binary masks. When an ideal mask is dense with many ones, the effect of changing mixture SNR level while fixing the mask is significant, whereas for more sparse masks the effect is small or insignificant.


Possible correlation of sonic hedgehog signaling with epithelial-mesenchymal transition in muscle-invasive bladder cancer progression.
To investigate the role of sonic hedgehog (Shh) signaling and epithelial-mesenchymal transition (EMT) in bladder cancer progression and invasion. We cultured three bladder cancer cell lines, muscle-invasive T24 and 5637, and non-muscle-invasive KK47, in the presence of a recombinant-Shh (r-Shh) protein or cyclopamine, a Shh signaling inhibitor, to investigate proliferation and expression of EMT markers. Wound-healing assays and transwell assay were performed to evaluate cell invasion and migration. Mice were then inoculated with bladder cancer cells and treated with cyclopamine. Mouse tumor samples were stained for Shh signaling and EMT markers. R-Shh protein enhanced cell proliferation, whereas cyclopamine significantly suppressed cell proliferation, especially in invasive cancer (5637 and T24) (p < 0.05). R-Shh protein promoted EMT, suppressed E-cadherin and enhanced N-cadherin and vimentin and Gli1, an Shh downstream molecule, while cyclopamine blocked EMT, especially in 5637 and T24. Cyclopamine also inhibited cell invasion and migration in vitro. In the animal study, intraperitoneal injection of cyclopamine significantly suppressed tumor growth in 5637 and T24 in mice (p = 0.01 and p = 0.004, respectively) and slightly suppressing KK47 tumor growth (p = 0.298). Significant cyclopamine-induced suppression of Gli1 in 5637 and T24 mouse tumors (both p = 0.03) was seen, suggesting that muscle-invasive bladder cancer may be more dependent on Shh signaling than non-muscle-invasive bladder cancer. Shh signaling and EMT were especially enhanced in muscle-invasive bladder cancer progression and invasion, and suppressed by the inhibition of Shh signaling.


Application of antibody to synthetic peptides for characterization of the intact and truncated alpha 22 protein specified by herpes simplex virus 1 and the R325 alpha 22- deletion mutant.
The alpha 22 protein is one of five proteins synthesized immediately after infection of permissive cells with herpes simplex virus 1 and 2 (HSV-1 and HSV-2). On the basis of the reported nucleotide sequence of the HSV-1 gene, we synthesized two peptides containing the predicted amino acids 12 through 23 (12 residues) and 21 through 36 (16 residues) in two hydrophilic domains near the N terminus of the protein. Rabbit antisera made against these peptides were then used to characterize the alpha 22 protein made by wild-type HSV-1(F) strain and by an HSV-1 mutant, R325, carrying a 500-base-pair deletion within the coding domain of the gene. The results were as follows. (i) Both antisera reacted with HSV-1(F) alpha 22 protein in lysates electrophoretically separated in denaturing polyacrylamide gels and electrically transferred to a nitrocellulose sheet; neither antiserum reacted with the corresponding HSV-2 protein. The protein accumulated at 34 and 39 degrees C in the nucleus of infected permissive HEp-2 and baby hamster kidney (BHK) cells. The protein formed at least five spots differing in charge, mobility, and extent of phosphorylation on two-dimensional electrophoretic separation. (ii) The antisera reacted with a truncated nuclear protein (33,700 apparent molecular weight) in permissive HEp-2 and restrictive BHK cells infected with R325 and incubated at 39 degrees C but not at 34 degrees C. The truncated protein represents, therefore, the product of the undeleted 5' domain of the alpha 22 gene in R325. (iii) The presence of identical as well as slower migrating, reactive proteins in infected BHK cell lysates indicated that wild-type and truncated alpha 22 proteins are processed differently in BHK and HEp-2 cells.


A chemical approach to perovskite solar cells: control of electron-transporting mesoporous TiO2 and utilization of nanocarbon materials.
Over the past several years, organometal halide perovskite solar cells (PSCs) have attracted considerable interest from the scientific research community because of their potential as promising photovoltaic devices for use in renewable energy production. To date, high power conversion efficiencies (PCEs) of more than 20% have been primarily achieved with mesoscopic-structured PSCs, where a mesoporous TiO2 (mTiO2) layer is incorporated as an electron-transporting mesoporous scaffold into the perovskite crystal, in addition to a compact TiO2 (cTiO2) as an electron-transporting layer (ETL). In this Perspective, we first summarize recent research on the preparation strategies of the mTiO2 layer with a high electron transport capability by facile sol-gel methods instead of the conventional nanoparticle approach. The importance of the control of the pore size and grain boundaries of the mTiO2 in achieving high PCEs for PSCs is discussed. In addition, an alternative method to improve the electron transport in the mTiO2 layer via the incorporation of highly conductive nanocarbon materials, such as two-dimensional (2D) graphene and one-dimensional (1D) carbon nanotubes, is also summarized. Finally, we highlight the utilization of zero-dimensional (0D) nanocarbon, i.e., fullerenes, as an n-type semiconducting material in mesostructure-free planar PSCs, which avoids high-temperature sintering during the fabrication of an ETL.


Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide.
Like all other secretory proteins, the HIV-1 envelope glycoprotein gp160 is targeted to the endoplasmic reticulum (ER) by its signal peptide during synthesis. Proper gp160 folding in the ER requires core glycosylation, disulfide-bond formation and proline isomerization. Signal-peptide cleavage occurs only late after gp160 chain termination and is dependent on folding of the soluble subunit gp120 to a near-native conformation. We here detail the mechanism by which co-translational signal-peptide cleavage is prevented. Conserved residues from the signal peptide and residues downstream of the canonical cleavage site form an extended alpha-helix in the ER membrane, which covers the cleavage site, thus preventing cleavage. A point mutation in the signal peptide breaks the alpha helix allowing co-translational cleavage. We demonstrate that postponed cleavage of gp160 enhances functional folding of the molecule. The change to early cleavage results in decreased viral fitness compared to wild-type HIV.


Absence of interferon-λ 4 enhances spontaneous clearance of acute hepatitis C virus genotypes 1-3 infection.
Absence of a functional interferon-λ 4 (IFN-λ4) gene (IFNL4) predicts spontaneous resolution of acute hepatitis C virus (HCV) infections in regions with a predominance of genotype 1, whereas variants of the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) entailing reduced activity associate with increased sustained virologic response rates following some therapeutic regimens. This study aimed at investigating the impact of IFNL4 on acute HCV genotype 2 or 3 infections, and whether ITPase activity influenced outcome. Two hundred and seven people who injected drugs (PWID) with documented anti-HCV seroconversion, and 57 PWID with reinfection with HCV were analyzed regarding IFNL4 (rs368234815 and rs12979860) and ITPA (rs1127354 and rs7270101), and longitudinally followed regarding HCV RNA. The spontaneous clearance of HCV infection in anti-HCV seronegative PWID was enhanced when IFN-λ4 was absent (44% vs. 20% for IFNL4 TT/TTrs1368234815 and ΔGrs1368234815 respectively, p < .001; OR 3.2) across genotypes 1-3. The proportion lacking IFN-λ4 was further increased following resolution of repeated re-exposure to HCV (74% among re-infected participants who had cleared at least two documented HCV infections). ITPA genetic variants did not independently impact on the outcome, but among males lacking IFN-λ4, reduced ITPase activity markedly augmented the likelihood of resolution (65% vs. 29% for <100% and 100% ITPase activity, p = .006). Absence of IFN-λ4 entails an enhanced likelihood of spontaneous resolution both following primary acute infection and repeated re-exposure to HCV across genotypes 1-3. Among men lacking IFN-λ4, reduced ITPase activity improved outcome.


Single dose antidepressant administration modulates the neural processing of self-referent personality trait words.
Drugs which inhibit the re-uptake of monoamines in the brain are effective in the treatment of depression; however, the neuropsychological mechanisms which lead to the resolution of depressive symptomatology are unclear. Behavioral studies in healthy volunteers suggest that acute administration of the selective norepinephrine reuptake inhibitor reboxetine modulates emotional processing. The current study therefore explored the neural basis of this effect. A single dose of reboxetine (4 mg) or placebo was administered to 24 healthy volunteers in a double-blind between-group design. Neural responses during categorisation and recognition of self-referent personality trait words were assessed using event-related functional Magnetic Resonance Imaging (fMRI). Reboxetine had no effect on neuronal response during self-referent categorisation of positive or negative personality trait words. However, in a subsequent memory test, reboxetine reduced neuronal activation in a fronto-parietal network during correct recognition of positive target words vs. matched distractors. This was combined with increased speed to recognize positive vs. negative words compared to control subjects and suggests facilitated memory for positive self-referent material. These results support the hypothesis that antidepressants have early effects on the neural processing of emotional material which may be important in their therapeutic actions.


Vps factors are required for efficient transcription elongation in budding yeast.
There is increasing evidence that certain Vacuolar protein sorting (Vps) proteins, factors that mediate vesicular protein trafficking, have additional roles in regulating transcription factors at the endosome. We found that yeast mutants lacking the phosphatidylinositol 3-phosphate [PI(3)P] kinase Vps34 or its associated protein kinase Vps15 display multiple phenotypes indicating impaired transcription elongation. These phenotypes include reduced mRNA production from long or G+C-rich coding sequences (CDS) without affecting the associated GAL1 promoter activity, and a reduced rate of RNA polymerase II (Pol II) progression through lacZ CDS in vivo. Consistent with reported genetic interactions with mutations affecting the histone acetyltransferase complex NuA4, vps15Δ and vps34Δ mutations reduce NuA4 occupancy in certain transcribed CDS. vps15Δ and vps34Δ mutants also exhibit impaired localization of the induced GAL1 gene to the nuclear periphery. We found unexpectedly that, similar to known transcription elongation factors, these and several other Vps factors can be cross-linked to the CDS of genes induced by Gcn4 or Gal4 in a manner dependent on transcriptional induction and stimulated by Cdk7/Kin28-dependent phosphorylation of the Pol II C-terminal domain (CTD). We also observed colocalization of a fraction of Vps15-GFP and Vps34-GFP with nuclear pores at nucleus-vacuole (NV) junctions in live cells. These findings suggest that Vps factors enhance the efficiency of transcription elongation in a manner involving their physical proximity to nuclear pores and transcribed chromatin.


Latent Dirichlet Allocation reveals spatial and taxonomic structure in a DNA-based census of soil biodiversity from a tropical forest.
High-throughput sequencing of amplicons from environmental DNA samples permits rapid, standardized and comprehensive biodiversity assessments. However, retrieving and interpreting the structure of such data sets requires efficient methods for dimensionality reduction. Latent Dirichlet Allocation (LDA) can be used to decompose environmental DNA samples into overlapping assemblages of co-occurring taxa. It is a flexible model-based method adapted to uneven sample sizes and to large and sparse data sets. Here, we compare LDA performance on abundance and occurrence data, and we quantify the robustness of the LDA decomposition by measuring its stability with respect to the algorithm's initialization. We then apply LDA to a survey of 1,131 soil DNA samples that were collected in a 12-ha plot of primary tropical forest and amplified using standard primers for bacteria, protists, fungi and metazoans. The analysis reveals that bacteria, protists and fungi exhibit a strong spatial structure, which matches the topographical features of the plot, while metazoans do not, confirming that microbial diversity is primarily controlled by environmental variation at the studied scale. We conclude that LDA is a sensitive, robust and computationally efficient method to detect and interpret the structure of large DNA-based biodiversity data sets. We finally discuss the possible future applications of this approach for the study of biodiversity.


A pilot point prevalence study of antimicrobial drugs in indoor patients of a teaching hospital in Central India.
To evaluate the point prevalence of antimicrobial drug use by using point prevalence survey method. A cross-sectional point prevalence study was done on patients admitted in AIIMS Bhopal hospital. This study included all inpatients receiving an antimicrobial that were on the ward at 8 AM on a specific day in May 2018. Information regarding age, gender, occupation, income group, diagnosis, patient's present/past medical history, treatment, any adverse drug reactions, and investigations are recorded in a pro forma. A total of 77 patients (31.95%) were included out of total 241 patients who received at least one antimicrobial. Of patients who received at least one antimicrobial, diagnosis was mentioned in 83.11% of prescriptions. Targeted treatment was given to 10.38% of patients. Reasons for antimicrobial were recorded in 12.98% of patients. Most common healthcare infection recorded was catheter-associated urinary tract infections followed by postoperative surgical site infections. Penicillin with beta lactamase inhibitors was most commonly prescribed antibiotic group followed by third generation cephalosporins and fluoroquinolones. Stop or review date was recorded in 19.48% of patients. Parenteral administration was given to 30.55% of patients. Compliance to guidelines was followed in 64.11% of patients. Local antibiotic guideline and antibiogram were available in hospital. Biomarkers were utilized in 9.77% of patients to guide the choice of therapy. Availability of antibiotic policy, antibiogram, local antibiotic guidelines, drugs, and therapeutic committee were some of the encouraging findings. Diagnosis was mentioned in majority of prescriptions. Most patients were prescribed oral antimicrobial drugs, which can reduce complications with parenteral route. Underutilizations of microbiological facilities, prolonged use of antibiotics for surgical prophylaxis, and polypharmacy were areas of concern.


Non-steroidal anti-inflammatory drugs for acute low back pain.
Acute low back pain (LBP) is a common health problem. Non-steroidal anti-inflammatory drugs (NSAIDs) are often used in the treatment of LBP, particularly in people with acute LBP. In 2008, a Cochrane Review was published about the efficacy of NSAIDs for LBP (acute, chronic, and sciatica), identifying a small but significant effect in favour of NSAIDs compared to placebo for short-term pain reduction and global improvement in participants with acute LBP. This is an update of the previous review, focusing on acute LBP. To assess the effects of NSAIDs compared to placebo and other comparison treatments for acute LBP. We searched CENTRAL, MEDLINE, Embase, PubMed, and two trials registers for randomised controlled trials (RCT) to 7 January 2020. We also screened the reference lists from relevant reviews and included studies. We included RCTs that assessed the use of one or more types of NSAIDs compared to placebo (the main comparison) or alternative treatments for acute LBP in adults (≥ 18 years); conducted in both primary and secondary care settings. We assessed the effects of treatment on pain reduction, disability, global improvement, adverse events, and return to work. Two review authors independently selected trials to be included in this review, evaluated the risk of bias, and extracted the data. If appropriate, we performed a meta-analysis, using a random-effects model throughout, due to expected variability between studies. We assessed the quality of the evidence using the GRADE approach. We used standard methodological procedures recommended by Cochrane. We included 32 trials, with a total of 5356 participants (age range 16 to 78 years). Follow-up ranged from one day to six months. Studies were conducted across the globe, the majority taking place in Europe and North-America. Africa and the Eastern Mediterranean region were not represented. We considered seven studies at low risk of bias. Performance and attrition were the most common biases. There was often a lack of information on randomisation procedures and allocation concealment (selection bias); studies were prone to selective reporting bias, since most studies did not register their trials. Almost half of the studies were industry-funded. There is moderate quality evidence that NSAIDs are slightly more effective in short-term (≤ 3 weeks) reduction of pain intensity (visual analogue scale (VAS), 0 to 100) than placebo (mean difference (MD) -7.29 (95% confidence interval (CI) -10.98 to -3.61; 4 RCTs, N = 815). There is high quality evidence that NSAIDs are slightly more effective for short-term improvement in disability (Roland Morris Disability Questionnaire (RMDQ), 0 to 24) than placebo (MD -2.02, 95% CI -2.89 to -1.15; 2 RCTs, N = 471). The magnitude of these effects is small and probably not clinically relevant. There is low quality evidence that NSAIDs are slightly more effective for short-term global improvement than placebo (risk ratio (RR) 1.40, 95% CI 1.12 to 1.75; 5 RCTs, N = 1201), but there was substantial heterogeneity (I² 52%) between studies. There is very low quality evidence of no clear difference in the proportion of participants experiencing adverse events when using NSAIDs compared to placebo (RR 0.86, 95% CI 0.63 to 1.18; 6 RCTs, N = 1394). There is very low quality evidence of no clear difference between the proportion of participants who could return to work after seven days between those who used NSAIDs and those who used placebo (RR 1.48, 95% CI 0.98 to 2.23; 1 RCT, N = 266). There is low quality evidence of no clear difference in short-term reduction of pain intensity between those who took selective COX-2 inhibitor NSAIDs compared to non-selective NSAIDs (mean change from baseline -2.60, 95% CI -9.23 to 4.03; 2 RCTs, N = 437). There is moderate quality evidence of conflicting results for short-term disability improvement between groups (2 RCTs, N = 437). Low quality evidence from one trial (N = 333) reported no clear difference between groups in the proportion of participants experiencing global improvement. There is very low quality evidence of no clear difference in the proportion of participants experiencing adverse events between those who took COX-2 inhibitors and non-selective NSAIDs (RR 0.97, 95% CI 0.63 to 1.50; 2 RCTs, N = 444). No data were reported for return to work. This updated Cochrane Review included 32 trials to evaluate the efficacy of NSAIDs in people with acute LBP. The quality of the evidence ranged from high to very low, thus further research is (very) likely to have an important impact on our confidence in the estimates of effect, and may change the estimates. NSAIDs seemed slightly more effective than placebo for short-term pain reduction (moderate certainty), disability (high certainty), and global improvement (low certainty), but the magnitude of the effects is small and probably not clinically relevant. There was no clear difference in short-term pain reduction (low certainty) when comparing selective COX-2 inhibitors to non-selective NSAIDs. We found very low evidence of no clear difference in the proportion of participants experiencing adverse events in both the comparison of NSAIDs versus placebo and selective COX-2 inhibitors versus non-selective NSAIDs. We were unable to draw conclusions about adverse events and the safety of NSAIDs for longer-term use, since we only included RCTs with a primary focus on short-term use of NSAIDs and a short follow-up. These are not optimal for answering questions about longer-term or rare adverse events.


An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors.
Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell-like phenotypes shown by many tumors.


Canine atopic dermatitis: validation of recorded diagnosis against practice records in 335 insured Swedish dogs.
A cross-sectional study of insured Swedish dogs with a recorded diagnosis of canine atopic dermatitis (CAD) was performed. In order to validate the correctness of this specific diagnosis in the insurance database, medical records were requested by mail from the attending veterinarians. All dogs with a reimbursed claim for the disease during 2002 were included in the original study sample (n = 373). Medical records were available for 335 individuals (response rate: 89.8%). By scrutinizing the submitted records it was determined that all dogs had been treated for dermatologic disease, and that 327 (97.6%) could be considered to have some allergic skin disease. However, as information regarding dietary trial testing was missing in many dogs the number that were truly atopic could not be determined. The clinical presentation and nature of test diet for dogs with or without response to dietary trial testing was compared for a subset of 109 individuals that had undergone such testing. The only significant difference between these two groups was that the proportion of dogs with reported gastrointestinal signs was higher in the group that subsequently responded to a diet trial. In conclusion, the agreement between the recorded diagnosis in the insurance database and the clinical manifestations recorded in the submitted medical records was considered acceptable. The concern was raised that many attending veterinarians did not exclude cutaneous adverse food reactions before making the diagnosis of CAD.


Alterations in the Transcriptional Profile of the Liver Tissue and the Therapeutic Effects of Propolis Extracts in Alcohol-induced Steatosis in Rats.
The hepatoprotective effects of the ethanolic extracts of propolis (EEP) on alcohol-induced liver steatosis were investigated in Wistar rats. Chronic alcoholic fatty liver was induced by administration of 52% alcohol to male Wistar rats at the dose of 1% body weight for 7 weeks. Then animals were simultaneously treated with 50% ethanol solutions of EEP or normal saline at the dose of 0.1% body weight for 4 further weeks. Serological analyses and liver histopathology studies were performed to investigate the development of steatosis. Microarray analysis was conducted to investigate the alterations of hepatic gene expression profiling. Our results showed that 4-week treatment of EEP helped to restore the levels of various blood indices, liver function enzymes and the histopathology of liver tissue to normal levels. Results from the microarray analysis revealed that the hepatic expressions of genes involved in lipogenesis were significantly down-regulated by EEP treatment, while the transcriptional expressions of functional genes participating in fatty acids oxidation were markedly increased. The ability of EEP to reduce the negative effects of alcohol on liver makes propolis a potential natural product for the alternative treatment of alcoholic fatty liver.


Family environment, glycemic control, and the psychosocial adaptation of adults with diabetes.
To evaluate whether the family system variables of adults with diabetes relate to the adequacy of metabolic control or the psychosocial adaptation to the illness. A total of 150 insulin-requiring adults were assessed on a single occasion. They completed two family system measures (the Family Environment Scale [FES] and the Diabetes Family Behavior Checklist [DFBC]), two quality-of-life measures (the Diabetes Quality of Life Scale and the Medical Outcomes Study Health Survey-36), and one measure of cognitive appraisal (the Appraisal of Diabetes Scale). Glycemic control was assessed using HbA1c results. Demographic data (age, sex, diabetes type, duration of diabetes, and number of diabetes-related medical complications) were gathered from the patients' charts. Concerning glycemic control, none of the family system measures were significant predictors of HbA1c. Older age and longer duration of diabetes predicted higher HbA1c values. For psychosocial adaptation, when family members behaved in ways that supported the diabetes care regimen (measured by the DFBC), the individual with diabetes was more satisfied with his or her adaptation to the illness and reported less interference in role function due to emotional problems. Family cohesion (measured by the FES) also related to better physical function. Women reported higher levels of diabetes satisfaction. The Appraisal of Diabetes Scale predicted glycemic control and psychosocial adaptation. For insulin-treated adults with diabetes, family system variables do not relate to glycemic control, but they do relate to psychosocial adaptation. Future work should explore the impact of family-centered interventions on adaptation, sex differences in adaptation, and the use of the Appraisal of Diabetes Scale as a first-line clinical screening tool.


Detailed analysis of operating time learning curves in robotic prostatectomy by a novice surgeon.
Structured mentor-led training programmes permit the safe introduction of novice trainees to robotic-assisted laparoscopic prostatectomy (RALP). We outline the first description of parallel learning curves for individual surgical steps and quantify the relative difficulty of each step to propose an order of training in our structured mentoring programme. A prospective ethically approved database was used to evaluate the operating times of each individual surgical step, in the first 150 RALP cases performed independently by a robotic-naive laparoscopic surgeon. Linear regression analysis was used to quantify the effect of surgeon experience on the operating time for each individual surgical step. Univariate linear regression analysis revealed significant reductions in operating time over the first 150 cases for all of the RALP steps, with the exception of the Rocco stitch. Multivariate linear regression analysis compensated for confounding variables and led to the identification of five surgical steps in which the operating time of each was significantly influenced by experience of the procedure. The most substantial improvement in operating time was seen in the bladder take down step. After taking into account the multivariate regression model, standardized univariate coefficients allowed an order of training to be identified for future RALP novices, of increasing complexity rather than order of surgery, beginning with the bladder take down step and ending with the vesico-urethral anastomosis. We can begin the training of new robotic-naive surgeons at simpler surgical steps, in which the greatest gains in expediency are made. We anticipate that identifying the more challenging surgical steps from this study and targeting training towards them may expedite our future trainees' proficiency at RALP.


A new look at an old problem: the survival and organ-specific growth of metastases.
Despite improvements in cancer detection and therapy, metastatic disease is largely incurable. Recent research indicates that tumor cells disseminate widely early in the process of pathogenesis, and that the survival and proliferation of these cells--and thus the development of metastases--depend on interactions between the disseminated cells and their particular microenvironment. Proliferative signals and the inhibition of proapoptotic responses are both critically involved in the development of clinically significant metastases. Identification of the underlying signaling cascades may provide additional targets for antimetastatic therapy.


Liquid atomic layer deposition as emergent technology for the fabrication of thin films.
Atomic layer deposition (ALD) is widely recognized as a unique chemical vapor deposition technique for the fabrication of thin films with high conformality and precise thickness control down to the Ångstrom level, thereby allowing surface and interface nanoengineering. However, several challenges such as the availability of chemical precursors for ALD and the use of vacuum conditions have hampered its widespread adoption and scalability for mass production. In recent years, the liquid phase homolog of ALD, liquid atomic layer deposition (LALD), has emerged as a much simpler and versatile strategy to overcome some of the current constraints of ALD. This perspective describes the different strategies that have been explored to achieve conformality and sub-nanometer thickness control with LALD, as well as the current challenges it faces to become a part of the thin-film community toolbox, in particular its automation and compatibility with different types of substrates. In this regard, the important role of LALD as complementary technology to ALD is emphasized by comparing the different pathways to deposit the same material and the precursors used to do so.


Evaluating the Effectiveness of Repricing for Market Expansion in the Japanese Drug Pricing System.
In 1994, the "Repricing for Market Expansion" system (the repricing system) was introduced to the pharmaceutical market in Japan to improve the financial performance of the national health insurance system. In 2010, the "Reward Premiums for the Promotion of Innovative Drug Discovery and the Resolution of Off-Label Use Issue, Etc." system (the reward system) was introduced to promote the development of new drugs. This study evaluates the effectiveness of these systems from an empirical perspective. The data set used in this study was created using publicly available information from the Ministry of Health, Labour and Welfare (MHLW) website and a market database maintained by IMS Japan Pharmaceutical Market Sales. Anticancer or immunomodulating drugs were the most frequently affected by the repricing system. The sales of similar drugs did not exceed double the sales forecast, and to begin with, the repricing system was not applied to these drugs, unintentionally reducing the profitability of pharmaceutical companies. In addition, we found that pharmaceutical expenditures have been steadily and significantly increasing, although this aspect is just one of the circumstances surrounding the Japanese pharmaceutical market. On the basis of these results, we propose that the current repricing system be replaced with one using a market mechanism that can evaluate the value of drugs from an economic perspective and help improving the financial performance of the national health insurance system. We also suggest that the number of generic medications on the market in Japan be increased to a ratio equivalent to those of the US and EU. We hope that the perspectives on Japan's unique drug pricing system obtained from this article are utilized by pharmaceutical companies in developing their businesses in Japan.


mecA gene is widely disseminated in Staphylococcus aureus population.
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important causes of hospital infections worldwide. High-level resistance to methicillin is caused by the mecA gene, which encodes an alternative penicillin-binding protein, PBP 2a. To determine the clonal relationships between methicillin-susceptible S. aureus (MSSA) and MRSA, we typed 1,069 S. aureus isolates (493 MSSA isolates and 576 MRSA isolates), collected mainly in North American and European hospitals between the 1960s and the year 2000, using pulsed-field gel electrophoresis and ribotyping. Of 10 widespread S. aureus lineages recognized, 8 had corresponding mecA-positive strains. Multiresistant MRSA strains are found in hospitals worldwide, while unrelated and more susceptible strains represent less than 1% of the MRSA population. This supports the hypothesis that horizontal transfer plays an important role in the dissemination of the mecA gene in the S. aureus population.


Single-crystal sapphire tubes as economical probes for optical pyrometry in harsh environments.
One-end-sealed single-crystal sapphire tubes are presented as a simple, robust, and economical alternative for bulky lightpipe probes. Thermal radiation from a blackbody cavity created at the inner surface of the sealed end is gathered by a simple lens-based collecting system and transmitted via optical fiber to the remote detection unit. Simplicity and applicability of the concept are demonstrated by the combination of commercially available sapphire tubes with a common optical pyrometer. Radiation thermometers with sapphire tubes as invasive probes can be useful for applications requiring immunity to electromagnetic interference, resistance to harsh environments, simple replacement in the case of failure, and enhanced mechanical firmness, enabling wider range probe positioning inside the medium of interest.


Interstitial lung disease more than 40 years after a 5 year occupational exposure to talc.
A 62 yr old woman was initially diagnosed with sarcoidosis until a thoracoscopic biopsy revealed the presence of numerous birefringent particles in fibrotic areas of the centrilobular lung zones. These particles were examined by electron microscopy and X-ray spectrometry and characterized as impure talc. Further inquiry into her occupational history revealed that she had worked from the age of 14-18 yrs in a factory making rubber hoses, where she had had an intense exposure to talc. There was no evidence of silicosis or asbestosis, and other significant causes of interstitial lung disease were excluded. This case emphasizes the importance of a thorough occupational history, which may reveal a remote and forgotten exposure to a significant cause of interstitial lung disease. Although this presentation of talcosis is unusual, this case suggests that even a relatively short, but presumably intense exposure to talc more than 40 yrs previously may be a cause of progressive lung fibrosis.


Evaluation of Human Epidermal Growth Factor Receptor 2 (HER2) Gene Status in Human Breast Cancer Formalin-Fixed Paraffin-Embedded (FFPE) Tissue Specimens by Fluorescence In Situ Hybridization (FISH).
Current standard of care requires that HER2 gene testing be performed on all newly diagnosed invasive breast cancers in order to determine eligibility for anti-HER2 antibody therapy and should be performed in accordance with current ASCO-CAP guidelines (Hammond et al., J Clin Oncol 29(15):e458, 2011; Wolff et al., J Clin Oncol 31(31):3997-4013, 2013). Here we describe a HER2 FISH methodology to evaluate HER2 gene status in FFPE breast tumor specimens.


Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5.
To study innate immune pathways in patients undergoing hepatopancreaticobiliary surgery to understand mechanisms leading to enhanced inflammatory responses and identifying biomarkers of adverse clinical consequences. Patients undergoing major abdominal surgery are at risk of life-threatening systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of at-risk patients would allow tailored postoperative care and improve survival. Two separate cohorts of patients undergoing major hepatopancreaticobiliary surgery were studied (combined n = 69). Bloods were taken preoperatively, on day 1 and day 2 postoperatively. Peripheral blood mononuclear cells and serum were separated and immune phenotype and function assessed ex vivo. Early innate immune dysfunction was evident in 12 patients who subsequently developed SIRS (postoperative day 6) compared with 27 who did not, when no clinical evidence of SIRS was apparent (preoperatively or days 1 and 2). Serum interleukin (IL)-6 concentration and monocyte Toll-like receptor (TLR)/NF-κB/IL-6 functional pathways were significantly upregulated and overactive in patients who developed SIRS (P < 0.0001). Interferon α-mediated STAT1 phosphorylation was higher preoperatively in patients who developed SIRS. Increased TLR4 and TLR5 gene expression in whole blood was demonstrated in a separate validation cohort of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14CD16 monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89 to 1.0 (areas under receiver operator curves). These data demonstrate the mechanism for IL-6 overproduction in patients who develop postoperative SIRS and identify markers that predict patients at risk of SIRS 5 days before the onset of clinical signs.


Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000.
The objective of this study was to estimate the global distribution and regional spread of different HIV-1 genetic subtypes and circulating recombinant forms (CRFs) in the year 2000. These estimates were made based on data derived from global HIV/AIDS surveillance and molecular virology studies. HIV-1 incidence during the year 2000 was estimated in defined geographic regions, using a country-specific model developed by WHO-UNAIDS. The proportion of new infections caused by different HIV-1 subtypes in the same geographic regions was estimated by experts from the WHO-UNAIDS Network for HIV Isolation and Characterization, based on results generated by HIV molecular epidemiology studies in 1998 to 2000. The absolute numbers and relative proportions of new infections due to different genetic subtypes of HIV-1 by different geographic regions were calculated using these two sets of estimated data. The results of the study demonstrated that the epidemiology of HIV-1 subtypes and CRFs is characterized by their differential distribution and varying significance as a driving cause of the pandemic on regional and global basis. The largest proportion of HIV-1 infections in the year 2000 was due to subtype C strains (47.2%). Subtype A/+CRF02_AG was estimated to be the second leading cause of the pandemic (27%), followed by subtype B strains (12.3%). The same analysis confirmed an increasing role of HIV-1 CRFs in the pandemic. The authors conclude that combined analysis of data based on the global HIV/AIDS surveillance and molecular virology studies provides for a useful model to monitor the dynamics of the global spread of HIV-1 subtypes and CRFs on regional and country levels-the information of potential importance for diagnosis and treatment of HIV/AIDS, as well as for the development globally effective HIV vaccines.


Empathy gaps for social pain: why people underestimate the pain of social suffering.
In 5 studies, the authors examined the hypothesis that people have systematically distorted beliefs about the pain of social suffering. By integrating research on empathy gaps for physical pain (Loewenstein, 1996) with social pain theory (MacDonald & Leary, 2005), the authors generated the hypothesis that people generally underestimate the severity of social pain (ostracism, shame, etc.)--a biased judgment that is only corrected when people actively experience social pain for themselves. Using a social exclusion manipulation, Studies 1-4 found that nonexcluded participants consistently underestimated the severity of social pain compared with excluded participants, who had a heightened appreciation for social pain. This empathy gap for social pain occurred when participants evaluated both the pain of others (interpersonal empathy gap) as well as the pain participants themselves experienced in the past (intrapersonal empathy gap). The authors argue that beliefs about social pain are important because they govern how people react to socially distressing events. In Study 5, middle school teachers were asked to evaluate policies regarding emotional bullying at school. This revealed that actively experiencing social pain heightened the estimated pain of emotional bullying, which in turn led teachers to recommend both more comprehensive treatment for bullied students and greater punishment for students who bully.


The effects of optimism, religion, and hope on mood and anxiety disorders in women with the FMR1 premutation.
The FMR1 premutation, caused by a CGG trinucleotide repeat expansion on the FMR1 gene, has been identified as a genetic risk factor for mood and anxiety disorders. Building on recent studies identifying increased risk for mood and affective disorders in this population, we examined effects of potential protective factors (optimism, religion, hope) on depression and anxiety diagnoses in a prospective, longitudinal cohort. Eighty-three women with the FMR1 premutation participated in the Structured Clinical Interview for DSM-IV-TR Disorders at two-time points, 3 years apart. Participants also completed measures of optimism, religion, personal faith, hope, and child and family characteristics. We used logistic regression to examine correlates of major depressive disorder (MDD) and anxiety disorders at the initial assessment, as well as predictors of the diagnostic course over time. Lower optimism and higher religious participation relevant to fragile X syndrome at the initial assessment were associated with a lifetime history of MDD. Lower optimism also predicted the occurrence and reoccurrence of an anxiety disorder 3 years later. In women with the FMR1 premutation, elevated optimism may reduce the occurrence or severity of MDD and anxiety disorders. These findings underscore the importance of supporting mental health across the FMR1 spectrum of involvement.


Basal cell proliferations of the prostate other than usual basal cell hyperplasia: a clinicopathologic study of 23 cases, including four carcinomas, with a proposed classification.
Basaloid proliferations of the prostate with morphologic patterns other than usual basal cell hyperplasia are rare, and the distinction between benign and malignant lesions has been difficult. We describe 23 such lesions and classify them into two groups: adenoid cystic-like hyperplasia and adenoid cystic or basaloid carcinoma. Adenoid cystic-like hyperplasia (n = 19) was characterized by an older age at presentation (mean, 71.8 years), transition zone location with background of nodular hyperplasia, multifocality, lobulation, circumscription, and small acini with occasional hyalinization. A cribriform pattern limited to small- and medium-sized glands, squamous metaplasia, and hypercellular myxoid stroma were occasionally seen. Adenoid cystic carcinoma (n = 3) was characterized by a younger age at presentation (mean, 46.0 years), peripheral zone involvement, and large acini that were often dilated and exhibited extensive interanastomoses, prominent intraglandular hyalinization, perineural invasion, and extraprostatic extension. Basaloid carcinoma (n = 1) showed infiltration between normal glands, perineural invasion, and extraprostatic extension but lacked a cribriform architecture. The degree of cytologic atypia and mitotic rate overlapped between the hyperplasia and carcinoma cases. Both hyperplastic lesions and adenoid cystic carcinomas showed a basal cell phenotype with strong immunoreactivity to cytokeratins 14 and 34betaE12, but the basaloid carcinoma was negative for these markers. In all cases, the proliferating basal cells were nonreactive for myoepithelial and prostatic secretory cell markers. The 8 patients with adenoid cystic-like hyperplasia with available follow-up information had no progression of disease (mean follow-up period, 8.6 years). One patient with adenoid cystic carcinoma died with widespread metastases, but the 3 other patients with carcinomas had no disease progression (mean follow-up period, 7.0 years). In conclusion, most florid basaloid proliferations of the prostate fall into one of two categories. In the first, there is a clear association with nodular hyperplasia (adenoid cystic-like hyperplasia) and, although cytologic atypia and mitoses may be seen, they are present within a lesion that retains an orderly, vaguely nodular (noninfiltrative) pattern. The second group of cases (adenoid cystic and basaloid carcinoma) shows a widespread, haphazard infiltrative growth pattern. This study suggests that adenoid cystic carcinomas are biologically indolent following prostatectomy but have a low risk of distant metastasis.


An overview on fermentation, downstream processing and properties of microbial alkaline proteases.
Microbial alkaline proteases dominate the worldwide enzyme market, accounting for a two-thirds share of the detergent industry. Although protease production is an inherent property of all organisms, only those microbes that produce a substantial amount of extracellular protease have been exploited commercially. Of these, strains of Bacillus sp. dominate the industrial sector. To develop an efficient enzyme-based process for the industry, prior knowledge of various fermentation parameters, purification strategies and properties of the biocatalyst is of utmost importance. Besides these, the method of measurement of proteolytic potential, the selection of the substrate and the assay protocol depends upon the ultimate industrial application. A large array of assay protocols are available in the literature; however, with the predominance of molecular approaches for the generation of better biocatalysts, the search for newer substrates and assay protocols that can be conducted at micro/nano-scale are becoming important. Fermentation of proteases is regulated by varying the C/N ratio and can be scaled-up using fed-batch, continuous or chemostat approaches by prolonging the stationary phase of the culture. The conventional purification strategy employed, involving e.g., concentration, chromatographic steps, or aqueous two-phase systems, depends on the properties of the protease in question. Alkaline proteases useful for detergent applications are mostly active in the pH range 8-12 and at temperatures between 50 and 70 degrees C, with a few exceptions of extreme pH optima up to pH 13 and activity at temperatures up to 80-90 degrees C. Alkaline proteases mostly have their isoelectric points near to their pH optimum in the range of 8-11. Several industrially important proteases have been subjected to crystallization to extensively study their molecular homology and three-dimensional structures.


Modification of sand fly biting behavior by Leishmania leads to increased parasite transmission.
To attempt rodent-sand fly-rodent transmission of Leishmania major, laboratory-reared Phlebotomus doboscqi were fed on L. major-infected mice and then refed on uninfected mice 21 days later. Flies which refed either probed 1-2 times and took a full blood meal in less than 10 min or probed 3 or more times and took little or no blood during a period of 15 min or more. When dissected, 7 of 8 flies which experienced difficulty in obtaining a blood meal had flagellates in their cibaria, an observation supporting the hypothesis that parasites in this part of the alimentary canal modify normal blood feeding behavior. None of the infected females which probed 1-2 times had similar anterior station infections. Infected sand flies transmitted L. major to uninfected mice and a single fly, transferred from 1 mouse to the next while repeatedly attempting to take blood, infected 5 mice. During a year-long survey in Baringo District, Kenya, we collected 9,182 female sand flies. Only 2 of the 278 P. duboscqi captured during this collection were infected with L. major; however, 18 of the 789 small rodents from this area were infected with L. major. Parasite interference with normal blood feeding may explain how a relatively small population of P. duboscqi, only a few of which are infected with L. major, can amplify parasite transmission thereby maintaining a disproportionately large reservoir in local rodents.


Estrogen receptor antagonism exacerbates cardiac structural and functional remodeling in female rats.
We have previously demonstrated the cardioprotective effects of ovarian hormones against adverse ventricular remodeling imposed by chronic volume overload. Here, we assess the estrogen receptor dependence of this cardioprotection. Four groups of female rats were studied: sham-operated (Sham), volume overloaded [aortocaval fistula (ACF)], Sham treated with estrogen receptor antagonist ICI 182,780 (Sham + ICI), and ACF treated with ICI. Cardiac function was assessed temporally using echocardiogram, and tissue samples were collected at 5 days and 6 wk postsurgery. All rats with volume overload had significantly increased cardiac output (96 ± 32 ml/min for ACF and 108 ± 11 ml/min for ACF + ICI vs. 31 ± 2 for Sham, P < 0.05). At 6 wk, volume overload induced significant left ventricular (LV) hypertrophy in both untreated and treated ACF groups. Both ACF groups developed significantly increased LV end-diastolic diameter (LVEDD), indicating LV dilatation, with the ACF + ICI group having the greatest increase (340%, relative to Sham). Ejection fraction was significantly reduced in the ACF + ICI group (23% reduction) at 6 wk postsurgery compared with untreated ACF (P < 0.05). Interstitial collagen staining was significantly reduced by volume overload, with estrogen receptor antagonism causing greater collagen loss at both 5 days and 6 wk postsurgery. Furthermore, volume overload induced a significant increase in LV wall stress only in rats treated with estrogen antagonist. These data indicate that estrogen receptor signaling is essential for sex hormone-dependent cardioprotection against adverse remodeling. The maintenance of myocardial extracellular matrix collagen appears to play a key role in this cardioprotection. We assessed the estrogen receptor (ER) dependence of female-specific cardioprotection using a rat model of chronic volume-overload stress. ER antagonism worsened ventricular wall stress, ventricular dilation, and cardiac dysfunction induced by volume overload. Further, blocking ERs resulted in cardiac remodeling and functional changes similar to that previously found in ovariectomized rats.


Association between maternal exposure to major phthalates, heavy metals, and persistent organic pollutants, and the neurodevelopmental performances of their children at 1 to 2years of age- CHECK cohort study.
Exposure of the developing fetus and infants to toxic substances can cause serious lifelong health consequences. Several chemicals have been associated with adverse neurodevelopmental disorders in the early life stages of humans. However, most epidemiological studies have focused on a limited number of chemicals, and hence may exclude important chemicals from consideration or result in conclusions built on associations by chance. In the present study, we investigated the chemical exposure profile of the women, and associated these with the early neurodevelopmental performance of their offspring at 13-24months of age. The chemicals assessed include four phthalates, bisphenol A, three heavy metals, 19 polychlorinated biphenyls (PCBs), 19 organochlorine pesticides, and 19 polybrominated diphenyl ethers, which were measured from urine, whole blood, serum, and/or breastmilk of the pregnant or lactating women. For neurodevelopmental performance, the Bayley Scales of Infant Development-II (BSID-II), Social Maturity Scale (SMS), and Child Behavior Checklist (CBCL) were measured from a total of 140 toddlers. Among the measured chemicals, monoethyl phthalate (MEP) in maternal urine was significantly associated with early mental, psychomotor, and social development. In addition, breast milk di-ethylhexyl phthalate (DEHP) metabolite and blood lead concentrations were inversely associated with mental and psychomotor development indices, respectively. Maternal blood PCB153, heavy metals, and urinary MEP levels were also higher among the children with behavioral problems, as indicated by the CBCL range. Taken together, maternal exposure to several EDCs such as PCBs and DEHP was associated with adverse neurodevelopmental performances among the children aged 1-2years. Confirmation of these association in larger populations, as well as longer-term consequences of such exposure warrant further investigation.


Social-distancing Fatigue: Evidence from Real-time Crowd-sourced Traffic Data.
To mitigate the COVID-19 pandemic and prevent overwhelming the healthcare system, social-distancing policies such as school closure, stay-at-home orders, and indoor dining closure have been utilized worldwide. These policies function by reducing the rate of close contact within populations and results in decreased human mobility. Adherence to social distancing can substantially reduce disease spread. Thus, quantifying human mobility and social-distancing compliance, especially at high temporal resolution, can provide great insight into the impact of social distancing policies. We used the movement of individuals around New York City (NYC), measured via traffic levels, as a proxy for human mobility and the impact of social-distancing policies (i.e., work from home policies, school closure, indoor dining closure etc.). By data mining Google traffic in real-time, and applying image processing, we derived high resolution time series of traffic in NYC. We used time series decomposition and generalized additive models to quantify changes in rush hour/non-rush hour, and weekday/weekend traffic, pre-pandemic and following the roll-out of multiple social distancing interventions. Mobility decreased sharply on March 14, 2020 following declaration of the pandemic. However, levels began rebounding by approximately April 13, almost 2 months before stay-at-home orders were lifted, indicating premature increase in mobility, which we term social-distancing fatigue. We also observed large impacts on diurnal traffic congestion, such that the pre-pandemic bi-modal weekday congestion representing morning and evening rush hour was dramatically altered. By September, traffic congestion rebounded to approximately 75% of pre-pandemic levels. Using crowd-sourced traffic congestion data, we described changes in mobility in Manhattan, NYC, during the COVID-19 pandemic. These data can be used to inform human mobility changes during the current pandemic, in planning for responses to future pandemics, and in understanding the potential impact of large-scale traffic interventions such as congestion pricing policies.


Psychiatric illness in patients with persistent somatisation.
This study explores the incidence and nature of mental illness among persistent somatisers, and analyses their use of mental health services. Individuals with at least ten admissions to non-psychiatric departments during an 8-year period were studied. Persistent somatisers (n = 56) were compared with other frequent users (n = 57) of non-psychiatric services. Of the persistent somatisers, 82% had been examined by a psychiatrist at least once (median, 3 times). Sixteen per cent were mentally retarded, 48% were dependent on alcohol or drugs, and 48% had DSM-III-R personality disorder. The most prevalent ICD-10 diagnoses were anxiety states (54%), depressions (30%), phobias (18%) and psychoses (20%). Persistent somatisation is associated with severe mental illness and a broad spectrum of heterogeneous psychiatric diagnoses and syndromes. Persistent somatisers impose a serious burden on the mental health care system.


Veratrum poisoning.
Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. These alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. Increased stimulation, associated with the vagal nerve results in a reflex that causes the triad of responses known as the Bezold-Jarisch reflex: hypotension, bradycardia and apnoea. Clinically, various Veratrum extracts were marketed for clinical use as antihypertensive drugs, but because of their narrow therapeutic index were withdrawn from the market. Following the ingestion of Veratrum alkaloids, expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension and cardiac conduction abnormalities and death. Similar symptoms arise in other mammalian species ingesting these alkaloids; teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. Treatment consists of supportive care, with an emphasis on haemodynamic stability with fluid replacement, atropine and vasopressors. The onset of symptoms occurs between 30 minutes and 4 hours, and the duration of the illness can range from 1 to 10 days; however, with prompt supportive care, patients typically make a full recovery within 24 hours.


Acquired immunodeficiency syndrome: cerebral computed tomographic manifestations.
CT examination of the central nervous system was performed in 19 patients with acquired immunodeficiency syndrome (AIDS). Eighteen patients were homosexuals, and five drug abusers. Parenchymal and meningeal inflammations were seen in patients with intracranial manifestations of the disease. The most common demonstrable lesion in the parenchyma was toxoplasmosis, which produced ring enhancement, solid enhancement, and nonenhancing focal edema. The most common meningeal inflammation was cryptococcosis, which was diagnosed by examination of the cerebrospinal fluid and did not show specific CT changes. It is concluded that toxoplasmosis and cryptococcosis should be the first diagnostic consideration in patients with neurologic findings who have a history of homosexuality and/or intravenous drug abuse and previous unusual infections or anergy. A delayed contrast scan, single or double dose, appears to be the most accurate method of outlining the total extent of disease thereby helping to locate the best biopsy site for pretreatment diagnosis. Empirical institution of toxoplasmosis therapy is recommended in those cases in which CT findings are consistent with toxoplasmosis and the biopsy shows only nonspecific encephalitis. A biopsy of every parenchymal lesion is not considered necessary.


Birth preparedness and complication readiness in pregnant women attending urban tertiary care hospital.
Birth preparedness and complication readiness (BP/CR) is a strategy to promote the timely use of skilled maternal and neonatal care and is based on the theory that preparing for childbirth and being ready for complications reduce delay in obtaining care. The objective of this study was to evaluate the incidence and predictors of birth preparedness, knowledge on danger signs, and emergency readiness among pregnant women attending outpatient clinic of a tertiary care hospital. Six hundred pregnant women attending the outpatient department of a tertiary care hospital for the first time in an urban setting were interviewed using a tool adapted from the "Monitoring BP/CR-tools and indicators for maternal and new born health" of the "JHPIEGO." The outcomes of the study were birth preparedness, knowledge of severe illness, and emergency readiness. Six hundred pregnant women were in the study. Mean age of respondents was 25.2 (±4) years. The mean gestation at enrolment was 18.7 ± 8 weeks. Among the women who participated in the survey, 20% were illiterate, 70% were homemakers and nearly 70% had a monthly family income >Rs. 15,197 (n = 405). Three hundred and sixteen mothers (52%) were primigravida. As defined in the study, 71.5% were birth prepared. However, 59 women (9.8%) did not identify a place of delivery, 102 (17%) had not started saving money, and 99 mothers (16.5%) were not aware of purchasing materials needed for delivery. The predictors of birth preparedness are multiparity (odds ratio [OR]: 2.2, 95% confidence interval [CI]: 1.4-3.1), registration in the antenatal clinic in the first trimester (OR: 3.7, 95% CI: 2.2-6.1), educational status of women (OR: 1.9, 95% CI: 1.2-3.0), and pregnancy supervison by a doctor (OR: 5, 95% CI: 2.8-6.6). One hundred and sixty-four women (27%) made no arrangements in the event of an emergency, 376 women (63%) were not aware of their blood group, and 89% (n = 531) did not identify any blood donor. Only 20% (n = 120), 15.8% (n = 95), and 12% (n = 73) of the respondents had knowledge of at least 3 danger signs of pregnancy, labor, and severe illness in newborn, respectively. Nearly three-fourth pregnant women attending a tertiary care hospital in an urban area are birth prepared. However, emergency readiness and awareness of danger signs are very poor. Maternal education and early booking have an independent association with birth preparedness.


Community nurses', home carers' and patients' perceptions of factors affecting venous leg ulcer recurrence and management of services.
This study examines the feasibility of utilizing social service home carers (SSHC) to provide a collaborative approach with community nurses for the provision of leg ulcer aftercare in four National Health Service (NHS) Trusts. The purpose of this study was to gain insight into what community nurses and people with healed venous leg ulcers felt influenced leg ulcer recurrence. Studies have demonstrated that provision of community-based leg ulcer clinics has improved healing rates of venous leg ulcers, yet recurrence remains a problem. The reasons for this are far from clear, and further research is required before unequivocal support can be given to one approach to the provision of care for this client group. Collaborative approaches to the provision of leg ulcer aftercare are beginning to receive more attention. It has been recognized that social service health carers could be co-opted to provide essential aftercare once healing has occurred, although the logistics of this approach have not been fully explored. This study was conducted in four NHS Trusts. Stage one used focus groups to explore the perceptions of district nurses (n = 15) and social service health carers (n = 15) of a leg ulcer shared care project and to gain insight into factors that they felt influenced recurrence. The second stage used semistructured interviews (n = 12) to explore the perceptions that people with healed leg ulcers have about factors influencing ulcer recurrence. Key themes emerging from this study were: health promotion is perceived by community nurses and patients to be ineffective and leg ulcer aftercare services are fragmented. Organizational factors such as time constraints and limited resources were cited by community nurses and home carers as being responsible for high leg ulcer recurrence rates. Community nurses expressed a desire to delegate preventative aspects of leg ulcer care to home carers rather than participate in health promotion strategies to support healing behaviours. A strategy aimed at supporting healing behaviour in elderly people has the potential to reduce the recurrence of leg ulceration and improve quality of life. The findings suggest that such a strategy needs to rationalize delivery of leg ulcer aftercare to provide seamless care. It needs to improve carers' and patients' understanding of factors influencing leg ulcer recurrence and facilitate development of a more balanced professional--patient relationship.