Impact of alternative metrics on estimates of extent of occurrence for extinction risk assessment.
In International Union for Conservation of Nature (IUCN) Red List assessments, extent of occurrence (EOO) is a key measure of extinction risk. However, the way assessors estimate EOO from maps of species' distributions is inconsistent among assessments of different species and among major taxonomic groups. Assessors often estimate EOO from the area of mapped distribution, but these maps often exclude areas that are not habitat in idiosyncratic ways and are not created at the same spatial resolutions. We assessed the impact on extinction risk categories of applying different methods (minimum convex polygon, alpha hull) for estimating EOO for 21,763 species of mammals, birds, and amphibians. Overall, the percentage of threatened species requiring down listing to a lower category of threat (taking into account other Red List criteria under which they qualified) spanned 11-13% for all species combined (14-15% for mammals, 7-8% for birds, and 12-15% for amphibians). These down listings resulted from larger estimates of EOO and depended on the EOO calculation method. Using birds as an example, we found that 14% of threatened and near threatened species could require down listing based on the minimum convex polygon (MCP) approach, an approach that is now recommended by IUCN. Other metrics (such as alpha hull) had marginally smaller impacts. Our results suggest that uniformly applying the MCP approach may lead to a one-time down listing of hundreds of species but ultimately ensure consistency across assessments and realign the calculation of EOO with the theoretical basis on which the metric was founded.


The effect of ultra-low sodium dialysate in CAPD. A kinetic and clinical analysis.
In peritoneal dialysis, sodium (Na) passes through the peritoneal membrane to a lesser extent than H2O and thus hypotonic fluid is removed indicating that Na removal is inefficient. Therefore we developed an ultra-low Na dialysate (ULNaD) [Na 98 mmol/liter, osmolality 340 mOsm/kg, glucose (G), 2.48%] to facilitate trans-peritoneal Na removal. The aim of the study was to examine (a) the fluid and Na kinetics of this solution, and (b) the clinical effect in the overhydrated patient. Regarding the former, in six cases, changes in the effluent Na levels during a 240-minute dwell of ULNaD were measured at 60-minute intervals. In eighteen cases, the transperitoneal net-Na removal (Na removal) and drained ultrafiltration (UF) volume after a 240-minute dwell of ULNaD were measured and compared to two types of standard Na dialysate (SNaD) [Na 132 mmol/liter, 1.36% G (348 mOsm/kg) and 2.27% G (396 mOsm/kg)]. The effluent Na levels increased gradually until the end of the dwelling. Drained UF volume of ULNaD (224 +/- 25 ml) was more than 1.36% G SNaD (77 +/- 33 ml, p < 0.01), but it was less than 2.27% G SNaD (341 +/- 32 ml, p < 0.01). However, a significant increase in Na removal by ULNaD (78.1 +/- 5.6 mmol) was found compared with both SNaD solutions (12.6 +/- 6.4 mmol in 1.36% G solution, p < 0.001; 27.8 +/- 5.1 mmol in 2.27% G solution, p < 0.001, respectively). Regarding the latter study aim, in six overhydrated patients with a Na excess, SNaD was replaced with ULNaD once a day for 7 consecutive days. At the end of the study as compared to the pre-values, a significant reduction in body weight (-2.5 +/- 1.0%, p < 0.05) and mean arterial pressure (-12.3 +/- 3.5%, p < 0.001) was observed. An increased drainage of daily UF volume (+86.5 +/- 31.1%, p < 0.05) and a markedly increased daily Na removal (+131.1 +/- 24.2%, p < 0.01) were also observed. The results of this study suggest that ULNaD actually facilitates trans-peritoneal Na removal mainly by diffusion force, and that ULNaD could benefit overhydrated patients with a Na excess.


Isolation of developmentally regulated genes from Toxoplasma gondii by a gene trap with the positive and negative selectable marker hypoxanthine-xanthine-guanine phosphoribosyltransferase.
Within its intermediate host, Toxoplasma gondii switches between two forms: a rapidly replicating tachyzoite and an encysted bradyzoite. Bradyzoites persist within the host throughout its life, hidden from antimicrobial agents and the immune system. The signals that mediate switching are poorly understood. A gene trap was employed to isolate genes whose expression is up-regulated early in the switching of bradyzoites via the negative and positive selectable marker hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT). T. gondii was transfected with promoterless HXGPRT and negatively selected with 6-thioxanthine to inhibit the growth of tachyzoites expressing HXGPRT. The surviving tachyzoites were then induced for in vitro bradyzoite formation and treated with mycophenolic acid and xanthine to positively select for parasites in which the construct had integrated downstream of a bradyzoite-specific gene. Strains were checked for their ability to differentiate by using Dolichos biflorus agglutinin (a bradyzoite-specific lectin) and a monoclonal antibody against P36 (a bradyzoite-specific surface antigen). After differentiation, all gene-trapped clones had Dolichos immunofluorescence and all but one expressed P36. The sequences flanking the insertion site of this P36-negative strain were homologous to the Toxoplasma family of surface antigens, strongly suggesting that P36 is encoded by the disruptive gene. Genetic mapping and complementation of the P36-negative strain further indicated that the disrupted gene is P36. Reverse transcriptase PCR and S1 nuclease digestion were used to compare mRNA levels during the tachyzoite and bradyzoite stages. The presumptive P36 gene does not appear to regulate its mRNA levels between the two stages, indicating a posttranscriptional mechanism of regulation for early bradyzoite-specific genes.


Lived Experience of Dementia in the New Zealand Indian Community: A Qualitative Study with Family Care Givers and People Living with Dementia.
Currently, there are estimated to be 70,000 people living with dementia in Aotearoa, New Zealand (NZ). This figure is projected to more than double by 2040, but due to the more rapid growth of older age groups in non-European populations, prevalence will at least triple amongst the NZ Indian population. The impact of dementia in the NZ Indian community is currently unknown. The aim of this study was to explore the lived experiences of NZ Indians living with dementia and their caregivers. Ten caregivers (age range: 41-81) and five people living with mild dementia (age range: 65-77) were recruited from a hospital memory service and two not-for-profit community organisations in Auckland, Aotearoa, NZ. Semi-structured interviews were conducted by bilingual/bicultural researchers and transcribed for thematic analysis in the original languages. Dementia was predominantly thought of as being part of normal ageing. Getting a timely diagnosis was reported as difficult, with long waiting times. Cultural practices and religion played a large part in how both the diagnosis and ongoing care were managed. Caregivers expressed concerns about societal stigma and about managing their own health issues, but the majority also expressed a sense of duty in caring for their loved ones. Services were generally well-received, but gaps were identified in the provision of culturally appropriate services. Future health services should prioritise a timely diagnosis, and dementia care services should consider specific cultural needs to maximise uptake and benefit for Indian families living with dementia.


Education and Training in End-of-Life Care for Certified Nursing Assistants in Long-Term Care.
The growth in the number of older adults in the United States requires appropriately prepared health care providers at all levels who will be able to effectively care for this population. First-line caregivers such as certified nursing assistants (CNAs) need education and training in end-of-life care so they can provide high-quality care for residents and families in the long-term-care (LTC) setting. CNAs were recruited from an LTC facility in western New York to attend an educational intervention consisting of six 45-minute sessions on various topics selected by the researchers using the curriculum from the Core Curriculum for the Hospice and Palliative Nursing Assistant. Pretests and posttests were administered to assess changes in knowledge, and a satisfaction survey was used for the CNAs to identify additional learning needs. Nineteen CNAs completed the six education and training sessions. Data analysis revealed a significant increase in knowledge for the participants. CNAs were also able to identify additional learning needs. Significant improvement in knowledge was seen after the CNAs attended the educational intervention. CNAs working in LTC facilities need education and training in end-of-life care so they can provide appropriate and effective care to residents and their families. Education and training for CNAs led to increased knowledge of end-of-life care and desire for more educational opportunities. J Contin Educ Nurs. 2017;48(2):81-85.


Crystalline complex of syndiotactic polystyrene with poly(ethylene glycol) dimethyl ethers.
It has been clarified that syndiotactic polystyrene (sPS) forms co-crystalline structures with polyethylene glycol dimethyl ethers (PEGDMEs) with molecular weights ranging from 178 to 1,000 g·mol(-1) through a guest exchange procedure assisted by a plasticizing agent. The PEGDME molecules are incorporated into the spaces between sPS polymer sheets consisting of (T(2)G(2))(2) helices. The results of X-ray diffraction and gravimetric measurements suggest that one or less molecules are included per unit cell for PEGDME with average molecular weight of 1,000 g·mol(-1), which indicates the possibility that longer polymeric molecules can be introduced into sPS lattices with multiple site occupation.


Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients.
The concentration of albumin in serum is maintained by its rates of synthesis, catabolism, and distribution between vascular and extravascular compartments. Albumin synthesis is suppressed when there is inflammation or inadequate protein intake. This study was conducted to establish whether a decline in serum albumin of >0.3 g/dL was accompanied by a change in albumin synthesis and if so whether these changes were associated with increased levels of acute phase proteins and/or with a decrease in equilibrated normalized protein catabolic rate (enPCR). Seventy-nine patients in the National Institutes of Health (NIH)-sponsored HEMO Study had baseline measurements of albumin synthesis (measured kinetically as the disappearance of [125]I human serum albumin), the serum concentrations of albumin, transferrin, C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1AG), ceruloplasmin, interleukin-6 (IL-6), plus monthly measurements of enPCR. The plasma levels of all proteins and enPCR were measured regularly over 2 years or until serum albumin decreased by >0.3 g/dL on two sequential measurements. Albumin synthesis was measured a second time when serum albumin declined by >0.3 g/dL or after 2 years. Fifty-nine patients [21 with a significant decrease in serum albumin (decliners) and 38 with stable values of serum albumin] had albumin synthesis measured twice. A decline in albumin concentration and synthesis was associated with an increase in alpha1AG when data from all patients were analyzed as a group. In decliners, albumin synthesis decreased significantly but was unchanged in stable. Likewise, in decliners, IL-6, CRP, alpha1AG, and ceruloplasmin increased significantly but were unchanged in stable. enPCR was unchanged in both groups and was not associated with either changes in albumin level or synthesis in the whole group. A decrease in serum albumin of >0.3 g/dL that persists for a period of 6 weeks is associated a decrease in albumin synthesis. This response is associated with evidence of activation of the acute phase response (inflammation) but not with changes in enPCR. In well-dialyzed patients, inflammation is the principal cause of a decrease in serum albumin while protein intake plays an insignificant role.


Systematic review of the association between chronic social stress and telomere length: A life course perspective.
Our aim was to examine whether chronic social stress is associated with telomere length throughout the life course, following our protocol published in 2014. Structured searches were conducted in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and grey from their start date onwards. Reference lists of retrieved citations were hand searched for relevant studies. Eighteen studies published until May 1, 2015 investigating the association between chronic social stress (as defined by poverty, exposure to violence, or family caregiving) and telomere length in healthy or diseased adults and children were independently selected by 2 reviewers. Sixteen of those studies were cross-sectional and two had a longitudinal design. Studies differed in type of stress exposure, method to measure telomere length and cell type. As meta-analysis could not be conducted, the data were synthesized as a narrative review. Based on this comprehensive review, chronic social stress accompanies telomere shortening in both early and adult exposures, with most eligible studies showing a significant relationship. We discuss the significance of chronic stress of social origin and the potential for social interventions through public policies and we recommend methodological improvements that would allow for future meta-analysis.


Role of calcium in effects of atrial natriuretic peptide on aldosterone production in adrenal glomerulosa cells.
Atrial natriuretic peptide (ANP) inhibits the stimulation of aldosterone secretion by isolated adrenal glomerulosa cells produced by angiotensin II (ANG II), ACTH, and potassium. The effect of ANP on the dose-response curve of aldosterone stimulated by ANG II, ACTH, and potassium on isolated rat adrenal glomerulosa cells was studied. In the presence of ANP the maximal response of aldosterone output stimulated by ANG II or potassium decreased and the half-maximum (EC50) of the response to ACTH was displaced to the right. Because these effects resemble those of calcium-channel blockers, we investigated the effect of different concentrations of nifedipine, a dihydropyridine calcium-channel blocker, on the dose-response curve of aldosterone stimulated by ANG II, ACTH, and potassium. Nifedipine produced effects similar to ANP. The maximal response of aldosterone stimulated by ANG II and potassium was decreased and the dose-response curve to ACTH was displaced to the right. ANP decreased the maximal response of aldosterone to the dihydropyridine derivative BAY K8644, a calcium-channel "activator," without change in its EC50. In contrast, nifedipine displaced the dose-response curve to BAY K8644 to the right as expected of a competitive inhibitor. The effect of ANP and nifedipine on basal and stimulated 45Ca influx into isolated rat adrenal glomerulosa cells was studied. Basal calcium influx was not significantly affected by ANP or nifedipine. Angiotensin II-, ACTH-, potassium-, and BAY K8644-stimulated calcium influx were significantly decreased by 1 nM ANP or 30 microM nifedipine. ANP may act on the rat adrenal glomerulosa cells at least in part by interference with calcium entry.


Solving Dynamic Traveling Salesman Problems With Deep Reinforcement Learning.
A traveling salesman problem (TSP) is a well-known NP-complete problem. Traditional TSP presumes that the locations of customers and the traveling time among customers are fixed and constant. In real-life cases, however, the traffic conditions and customer requests may change over time. To find the most economic route, the decisions can be made constantly upon the time-point when the salesman completes his service of each customer. This brings in a dynamic version of the traveling salesman problem (DTSP), which takes into account the information of real-time traffic and customer requests. DTSP can be extended to a dynamic pickup and delivery problem (DPDP). In this article, we ameliorate the attention model to make it possible to perceive environmental changes. A deep reinforcement learning algorithm is proposed to solve DTSP and DPDP instances with a size of up to 40 customers in 100 locations. Experiments show that our method can capture the dynamic changes and produce a highly satisfactory solution within a very short time. Compared with other baseline approaches, more than 5% improvements can be observed in many cases.


Production and identification of natural monocyte chemotactic protein from virally infected murine fibroblasts. Relationship with the product of the mouse competence (JE) gene.
Primary cultures of mouse embryonic fibroblasts and confluent monolayers of mouse fibroblastoid cells (L929) were found to secrete a chemotactic factor specific for monocytes. It biological activity was deduced from both the migration distance under agarose and the number of migrated monocytes in the micropore filter method. The monocyte chemotactic protein (MCP) was inducible in these cells by double-stranded RNA and by infection with virus. In embryonic fibroblasts MCP was also produced in response to the cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF). Under all conditions for induction of MCP tested no production of chemotactic activity for granulocytes could be detected. MCP activity from virally infected L929 cells was concentrated and purified by sequential adsorption to controlled pore glass, heparin-Sepharose chromatography, ion-exchange FPLC and reversed-phase HPLC. Pure MCP was found to occur mainly as a 7-8-kDa protein. Although the mature protein possessed a blocked NH2-terminus, it was identified by enzymatic cleavage and sequence analysis of an internal fragment. The sequence obtained corresponded to a part of the cDNA-derived protein sequence of the murine 'competence' (JE) gene, inducible in fibroblasts by cytokines and virus. In all probability the 7-8-kDa MCP form represents the natural product of the mouse gene JE. Murine MCP can thus be classified in the novel family of small inducible inflammatory proteins.


Characterization and AAV-mediated CRB gene augmentation in human-derived CRB1KO and CRB1KOCRB2+/- retinal organoids.
The majority of patients with mutations in CRB1 develop either early-onset retinitis pigmentosa as young children or Leber congenital amaurosis as newborns. The cause for the phenotypic variability in CRB1-associated retinopathies is unknown, but might be linked to differences in CRB1 and CRB2 protein levels in Müller glial cells and photoreceptor cells. Here, CRB1KO and CRB1KOCRB2+/- differentiation day 210 retinal organoids showed a significant decrease in the number of photoreceptor nuclei in a row and a significant increase in the number of photoreceptor cell nuclei above the outer limiting membrane. This phenotype with outer retinal abnormalities is similar to CRB1 patient-derived retinal organoids and Crb1 or Crb2 mutant mouse retinal disease models. The CRB1KO and CRB1KOCRB2+/- retinal organoids develop an additional inner retinal phenotype due to the complete loss of CRB1 from Müller glial cells, suggesting an essential role for CRB1 in proper localization of neuronal cell types. Adeno-associated viral (AAV) transduction was explored at early and late stages of organoid development. Moreover, AAV-mediated gene augmentation therapy with AAV.hCRB2 improved the outer retinal phenotype in CRB1KO retinal organoids. Altogether, these data provide essential information for future gene therapy approaches for patients with CRB1-associated retinal dystrophies.


Induction of subcutaneous tissue fibrosis in newborn mice by transforming growth factor beta-simultaneous application with basic fibroblast growth factor causes persistent fibrosis.
To establish an appropriate animal model of skin fibrosis by exogenous application of growth factors, we investigated the in vivo effects of transforming growth factor-beta by injection into subcutaneous tissue of newborn mice. Histological examination revealed that TGF-beta1, beta2, and beta3 induced granulation tissue formation after 3 days of injection, while these changes had disappeared after 7 days. The changes after 3 days of injection were more pronounced in the tissue injected with TGF-beta2 or beta3 than that with TGF-beta1. In situ hybridization analysis indicated that connective tissue growth factor mRNA was strongly expressed in the fibroblasts at the site of TGF-beta injection, which suggested that fibroblasts were activated by TGF-beta. Next, we investigated the cooperative effects of TGF-beta and other growth factors including basic fibroblast growth factor (bFGF). The simultaneous application of TGF-beta and bFGF caused apparent tissue fibrosis which persisted for at least 2 weeks, while bFGF alone caused slight fibrotic changes after 7 days of injection. Thus, we succeeded in establishing an animal model of skin fibrotic disorders by the exogenous addition of growth factors, and this animal model will be useful for future studies in this area.


Prolonged stability of antimicrobial activity in peritoneal dialysis solutions.
To evaluate the stability of the antimicrobial chemical and bioactivity of gentamicin, vancomycin, and gentamicin and vancomycin in combination, and the stability of the bioactivity of ceftazidime, admixed in standard peritoneal dialysis solutions and then maintained over a 14-day period at room temperature or under refrigeration. Peritoneal dialysis center and microbiology laboratory at a military, teaching medical center. Standard peritoneal dialysate bags admixed with gentamicin, vancomycin, gentamicin and vancomycin in combination, or ceftazidime were stored at either 4 degrees C or 20 degrees C for 14 days. Sequential aliquots were withdrawn and assayed for antibiotic activity by bioassay and, except for ceftazidime, immunoassay for chemical activity. The bioassay was performed using a standardized Kirby-Bauer disc method. Significance was determined by ANOVA and, where the effect size was significant at the p < 0.05 level, the application of the paired t-test or the Wilcoxon signed rank test to the difference in activity between the first and last samples. Antibiotic concentration by immunoassay did not significantly deteriorate over 14 days for vancomycin or gentamicin when either room temperature or refrigerated samples were studied. By bioassay, gentamicin and ceftazidime, but not vancomycin, lost moderate but significant activity over 14 days when refrigerated bags were assayed (except for an insignificant decrement in gentamicin in the combined vancomycin and gentamicin bags). Bags stored at room temperature, in general, lost significant bioactivity over 14 days, but to levels where clinical efficacy would still be expected. The vancomycin bioassay performed on the combination bags demonstrated a remarkably enhanced bioactivity, presumably reflecting synergy with gentamicin. These data indicate that the study antibiotics admixed with peritoneal dialysis fluids retain stable chemical activity, whether refrigerated or kept at room temperature, for at least 14 days. A moderate decrement in bioactivity occurred for study antibiotics when stored either refrigerated or at room temperature over 14 days, although clinically significant levels were maintained. The clinical significance of a possible synergy between vancomycin and gentamicin is yet to be determined.


"It is not possible for me to have diabetes"-community perceptions on diabetes and its risk factors in Rural Purworejo District, Central Java, Indonesia.
Accumulating evidence suggests that negative perceptions towards diabetes can limit the management and prevention of the disease. The negative perceptions towards diabetes are prevalent in many different settings, especially among rural communities. Few qualitative studies have been performed to understand how the community views diabetes and its associated risk factors. This study aimed to explore general community perceptions of diabetes and its risk factors in rural Indonesia. A total of 68 participants were recruited to 12 focus group discussions (FGDs) comprised of different age groups and sexes. The FGDs were conducted in six villages in rural Purworejo District, Central Java, Indonesia, from 2011 to 2012. All FGDs were recorded and transcribed. Qualitative content analysis was performed to describe and analyse how the rural community perceived diabetes and its risk factors. Diabetes was perceived as a visible and scary sugar disease, and the affected individuals themselves were blamed for getting the disease. Recognised as 'sugar' or 'sweet-pee' disease with terrifying effects, diabetes was believed to be a disease with no cure. The participants seemed to have an unrealistic optimism with regards to the diabetes risk factors. They believed that diabetes would not affect them, only others, and that having family members with diabetes was necessary for one to develop diabetes. Our findings demonstrate that rural communities have negative perceptions about diabetes and at the same time individuals have unrealistic optimism about their own risk factors. Understanding how such communities perceive diabetes and its risk factors is important for planning prevention strategies. Health messages need to be tailored to health-related behaviours and the local culture's concepts of diseases and risk factors.


Lipid content influences division of labour in a clonal ant.
The fat body, a major metabolic hub in insects, is involved in many functions, e.g. energy storage, nutrient sensing and immune response. In social insects, fat appears to play an additional role in division of labour between egg layers and workers, which specialize in non-reproductive tasks inside and outside their nest. For instance, reproductives are more resistant to starvation, and changes in fat content have been associated with the transition from inside to outside work or reproductive activities. However, most studies have been correlative and we still need to unravel the causal interrelationships between fat content and division of both reproductive and non-reproductive labour. Clonal ants, e.g. Platythyrea punctata, are ideal models for studying task partitioning without confounding variation in genotype and morphology. In this study, we examined the range of variation and flexibility of fat content throughout the lifespan of workers, the threshold of corpulence associated with foraging or reproduction and whether low fat content is a cause rather than a consequence of the transition to foraging. We found that lipid stores change with division of labour from corpulent to lean and, in reverted nurses, back to corpulent. In addition, our data show the presence of fat content thresholds that trigger the onset of foraging or egg-laying behaviour. Our study supports the view that mechanisms that regulate reproduction and foraging in solitary insects, in particular the nutritional status of individuals, have been co-opted to regulate division of labour in colonies of social insects.


Small Flocks Show Higher Levels of Welfare in Mexican Semi-Intensive Sheep Farming Systems.
In order to assess the level of sheep welfare in small traditional farms as compared with farms of increased size we evaluated several animal-based parameters and applied a modified Animal Needs Index (ANI) protocol in farms located in the North-East of the country. We selected ten sheep farms: 5 farms had less than 20 ewes per flock (Group L20), whereas 5 farms had more than 20 ewes per flock (Group M20). Based on the recordings performed using the ANI scheme Group L20 constantly showed higher scores as compared with Group M20. In Group M20 a higher proportion of animals was affected by skin and wool damages, low body condition, tail mutilation, ocular discharge, nasal discharge, diarrhoea (P < 0.05) and lameness (P < 0.01). We observed a higher percentage of non-anaemic animals in group L20 and a higher percentage of anaemic animals in Group M20 (P < 0.01). Although based on a small sample, our results showed that several animal-based measures were able to discriminate the two groups of farms with higher levels of animal welfare detected in small flocks.


Stable cyclic (alkyl)(amino)carbene (cAAC) radicals with main group substituents.
Isolation and characterization of stable radicals has been a long-pursued quest. While there has been some progress in this field particularly with respect to carbon, radicals involving heavier p-block elements are still considerably sparse. In this review we describe our recent successful efforts on the isolation of stable p-block element radicals particularly those involving aluminum, silicon, and phosphorus.


Expansion of T follicular helper-T helper 1 like cells through epigenetic regulation by signal transducer and activator of transcription factors.
T follicular helper (Tfh) cells are critical in the development and progression of systemic lupus erythematosus (SLE). To assess the characteristics and mechanisms of differentiation of Tfh cells, we investigated the phenotype of T helper cells in patients with SLE and underlying epigenetic modifications by cytokine-induced signal transducer and activators of transcription (STAT) family factors. Peripheral blood mononuclear cells from patients and healthy donors were analysed by flow cytometry. CD4+ T cells were isolated and cultured under various stimulations. Expression of characteristic markers and phosphorylation of STATs were analysed by flow cytometry and quantitative PCR. Histone modifications were analysed by chromatin immunoprecipitation (ChIP)-PCR. Differentiation of CD4+CXCR5+CXCR3+Bcl-6+T-bet+IL-21+IFN-γ+Tfh-Th1-like cells was induced by interleukin (IL)-12-induced activation of STAT1 and STAT4 simultaneously. The loci of Bcl-6 and T-bet at STAT binding sites were marked by bivalent histone modifications. After IL-12 stimulation, both STAT1 and STAT4 directly bound on BCL6 and TBX21 gene loci accompanied by suppression of repressive histone mark trimethylated histone 3 lysine 27. Levels of serum IL-12 and interferon (IFN)-γ, expression of IL-12 receptors and proportion of CXCR5+CXCR3+ activated Tfh-Th1-like cells were increased in patients with SLE. Furthermore, the level of pSTAT1, pSTAT4 and T-bet were higher in activated Tfh-Th1-like cells than non-Tfh-Th1 cells. Our findings suggest that IL-12-mediated co-activation of STAT1 and STAT4 alters histone modification, resulting in differentiation of Tfh-Th1-like cells that are characteristically expanded in patients with SLE. This could be one of the underlying mechanisms responsible for expansion of Tfh-Th1-like cells and potentially helpful towards development of cell-specific treatment for SLE.


Antiviral effect of Hornstedtia bella Škorničk essential oil from the whole plant against vaccinia virus (VV).
In the prevention of epidemic and pandemic emerging and neglected viral infections, natural products are an important source of lead compounds. Hornstedtia bella Škorničkis is a rhizomatous herb growing in the forest of central Vietnam. Hornstedtia bella essential oil (Hb EO) was recently characterised by our group as endowed of antimicrobial activity against Staphylococcus aureus Methicillin-Resistant strains. Here, we describe for the first time the evaluation of Hb EO against a spectrum of viruses responsible for important human diseases. Hb EO resulted active against Vaccinia virus (VV) (EC50 values 80 μg/mL), closely related to variola virus, causative agent of smallpox. Hb EO was able to strongly reduce the viral VV titer in cell-based assay at not cytotoxic concentration and its potential mode of action was characterised by virucidal activity evaluation followed by time-of-addition assay. Furthermore, Hb EO antiviral activity was implemented in a combination study with the mycophenolic acid.


The Wnt antagonist sFRP1 in colorectal tumorigenesis.
Regions of the short arm of chromosome 8 are deleted frequently in a range of solid tumors, indicating that tumor suppressor genes reside at these loci. In this study, we have examined the properties of the Wnt signaling antagonist secreted frizzled-related protein (sFRP) 1 as a candidate for this role at c8p11.2. An initial survey of 10 colorectal tumors, selected by the presence of isolated short deletions of the 8p11.2 region, identified three chain-terminating mutations, all within the first exon, which encodes the cysteine-rich domain. None of these tumors exhibited microsatellite instability, indicating intact mismatch repair gene function. The preserved sFRP1 alleles in the remaining seven tumors each contained a polymorphic three-base insertion in the signal sequence, but in a broader study, no association was found between this and the development of colorectal cancer. Epigenetic inhibition of sFRP1 transcription was investigated, and increased methylation of the promotor region was demonstrated in an additional cohort of 51 locally advanced colorectal cancers. Hypermethylation was identified in 40 of 49 (82%) cancers and in only 11 of 36 (30%) matched normal mucosal samples (P < 0.001). Semiquantitative analysis, by real-time PCR, of mRNA expression in 37 of the same cohort of 51 cancers revealed that sFRP1 mRNA expression was down-regulated in 28 (76%) cases compared with matched normal large bowel mucosa. The 3' end of the sFRP1 mRNA also was found to be alternatively spliced, compared with the prototype liver and lung forms, in the colon and a number of other tissues, yielding an extended COOH terminus, which may influence its activity in a tissue-specific manner. The inactivation and down-regulation of sFRP1 observed are consistent with it acting as a tumor suppressor gene in colorectal carcinogenesis. Because beta-catenin is constitutively active in the majority of colorectal tumors, it is unlikely that sFRP1 can act in the canonical Wnt response pathway. Therefore, we propose that the reduced activity or absence of sFRP1 allows the transduction of noncanonical Wnt signals, which contribute to tumor progression.


Development of a cost-effectiveness analysis of leafy green marketing agreement irrigation water provisions.
An analysis of the effectiveness of meeting the irrigation water provisions of the Leafy Green Marketing Agreement (LGMA) relative to its costs provides an approach to evaluating the cost-effectiveness of good agricultural practices that uses available data. A case example for lettuce is used to evaluate data requirements and provide a methodological example to determine the cost-effectiveness of the LGMA water quality provision. Both cost and field data on pathogen or indicator bacterial levels are difficult and expensive to obtain prospectively. Therefore, methods to use existing field and experimental data are required. Based on data from current literature and experimental studies, we calculate a cost-efficiency ratio that expresses the reduction in E. coli concentration per dollar expenditure on testing of irrigation water. With appropriate data, the same type of analysis can be extended to soil amendments and other practices and to evaluation of public benefits of practices used in production. Careful use of existing and experimental data can lead to evaluation of an expanded set of practices.


Psychometric properties of the Arab Heritage Activity Card Sort.
The Activity Card Sort is a valid and reliable assessment tool that was created to assess Participation. It has been translated to several languages and adapted to different international cultures. The most recent version of this tool is the Arabic Heritage Activity Card Sort (A-ACS). The purpose of this study was to establish the psychometric properties of the new Arabic version in Jordanian adults. Forty three Jordanian patients with multiple sclerosis (MS) and 62 healthy adults were recruited to test the psychometric properties of the tool. The A-ACS correlated moderately with the participation index of the Mayo-Portland Adaptability Inventory (r = -0.458, p < 0.00) (concurrent validity), was able to discriminate between patients and healthy participants on the current and retained levels of participation (F = 5.09, p < 0.03; F = 6.01, p < 0.02, respectively) (discriminative validity), and correlated moderately with the total scores of the Mayo-Portland Adaptability Inventory (r = -0.458, p < 0.00) and the total score on the Arabic version of the self-report Performance Assessment of Self-care Skills (r = 0.581, p < 0.00) (convergent validity). The tool also showed good test-retest reliability (r = 0.80, p < 0.00) and excellent internal consistency (α = 0.90). The Arabic Heritage of the Activity Card Sort is a valid and reliable tool for Arabic-speaking occupational therapists to use when assessing participation in Jordanian patients with MS or healthy adults. Limitations of this study include using only one diagnostic group from Jordan and examining only the Recovery and Community Versions of the tool. Future studies are needed to examine further psychometric properties for patients with different diagnoses and from different countries in the Arabic region for all three versions of the A-ACS.


Northern Hemisphere hydroclimate variability over the past twelve centuries.
Accurate modelling and prediction of the local to continental-scale hydroclimate response to global warming is essential given the strong impact of hydroclimate on ecosystem functioning, crop yields, water resources, and economic security. However, uncertainty in hydroclimate projections remains large, in part due to the short length of instrumental measurements available with which to assess climate models. Here we present a spatial reconstruction of hydroclimate variability over the past twelve centuries across the Northern Hemisphere derived from a network of 196 at least millennium-long proxy records. We use this reconstruction to place recent hydrological changes and future precipitation scenarios in a long-term context of spatially resolved and temporally persistent hydroclimate patterns. We find a larger percentage of land area with relatively wetter conditions in the ninth to eleventh and the twentieth centuries, whereas drier conditions are more widespread between the twelfth and nineteenth centuries. Our reconstruction reveals that prominent seesaw patterns of alternating moisture regimes observed in instrumental data across the Mediterranean, western USA, and China have operated consistently over the past twelve centuries. Using an updated compilation of 128 temperature proxy records, we assess the relationship between the reconstructed centennial-scale Northern Hemisphere hydroclimate and temperature variability. Even though dry and wet conditions occurred over extensive areas under both warm and cold climate regimes, a statistically significant co-variability of hydroclimate and temperature is evident for particular regions. We compare the reconstructed hydroclimate anomalies with coupled atmosphere-ocean general circulation model simulations and find reasonable agreement during pre-industrial times. However, the intensification of the twentieth-century-mean hydroclimate anomalies in the simulations, as compared to previous centuries, is not supported by our new multi-proxy reconstruction. This finding suggests that much work remains before we can model hydroclimate variability accurately, and highlights the importance of using palaeoclimate data to place recent and predicted hydroclimate changes in a millennium-long context.


Economic consequences of failure of initial antibiotic therapy in hospitalized adults with complicated intra-abdominal infections.
Initial antibiotic therapy in hospitalized adults with complicated intra-abdominal infection (cIAI) usually is empiric. We explored the economic consequences of failure of such therapy in this patient population. Using a large U.S. multi-institutional database, we identified all hospitalized adults admitted between April 1, 2003, and March 31, 2004; who had any cIAI; underwent laparotomy, laparoscopy, or percutaneous drainage of an intra-abdominal abscess ("surgery"); and received intravenous (IV) antibiotics. Initial therapy was characterized in terms of all IV antibiotics received, on the day of or one day before initial surgery. Antibiotic failure was designated on the basis of the need for reoperation or receipt of other IV antibiotics postoperatively. Switches to narrower spectrum agents and changes in regimen prior to discharge with no other evidence of clinical failure were not counted as antibiotic failures. Using multivariable linear regression, duration of IV antibiotic therapy, hospital length of stay, and total inpatient charges were compared between patients who did and did not fail initial therapy. Mortality was compared using multivariable logistic regression. Among 6,056 patients who met the study entrance criteria, 22.4% failed initial antibiotic therapy. Patients who failed received an additional 5.6 days of IV antibiotic therapy (10.4 total days [95% confidence interval 10.1, 10.8] days vs. 4.8 total days [4.8, 4.9] for those not failing), were hospitalized an additional 4.6 days (11.6 total days [11.3, 11.9] vs. 6.9 total days [6.8, 7.0], respectively), and incurred $6,368 in additional inpatient charges ($16,520 [$16,131, $16,919] vs. $10,152 [$10,027, $10,280]) (all, p < 0.01). They also were more likely to die in the hospital (9.5% vs. 1.3%; multivariable odds ratio 3.58 [95% confidence interval 2.53, 5.06]). Failure of initial IV antibiotic therapy in hospitalized adults with cIAIs is associated with longer hospitalization, higher hospital charges, and a higher mortality rate.


Brain-computer interface controlled robotic gait orthosis.
Excessive reliance on wheelchairs in individuals with tetraplegia or paraplegia due to spinal cord injury (SCI) leads to many medical co-morbidities, such as cardiovascular disease, metabolic derangements, osteoporosis, and pressure ulcers. Treatment of these conditions contributes to the majority of SCI health care costs. Restoring able-body-like ambulation in this patient population can potentially reduce the incidence of these medical co-morbidities, in addition to increasing independence and quality of life. However, no biomedical solution exists that can reverse this loss of neurological function, and hence novel methods are needed. Brain-computer interface (BCI) controlled lower extremity prostheses may constitute one such novel approach. One able-bodied subject and one subject with paraplegia due to SCI underwent electroencephalogram (EEG) recordings while engaged in alternating epochs of idling and walking kinesthetic motor imagery (KMI). These data were analyzed to generate an EEG prediction model for online BCI operation. A commercial robotic gait orthosis (RoGO) system (suspended over a treadmill) was interfaced with the BCI computer to allow for computerized control. The subjects were then tasked to perform five, 5-min-long online sessions where they ambulated using the BCI-RoGO system as prompted by computerized cues. The performance of this system was assessed with cross-correlation analysis, and omission and false alarm rates. The offline accuracy of the EEG prediction model averaged 86.30% across both subjects (chance: 50%). The cross-correlation between instructional cues and the BCI-RoGO walking epochs averaged across all subjects and all sessions was 0.812 ± 0.048 (p-value <10(-4)). Also, there were on average 0.8 false alarms per session and no omissions. These results provide preliminary evidence that restoring brain-controlled ambulation after SCI is feasible. Future work will test the function of this system in a population of subjects with SCI. If successful, this may justify the future development of BCI-controlled lower extremity prostheses for free overground walking for those with complete motor SCI. Finally, this system can also be applied to incomplete motor SCI, where it could lead to improved neurological outcomes beyond those of standard physiotherapy.


Binding of a radiolabeled triazolopyridazine to a subtype of benzodiazepine receptor in the rat cerebellum.
The triazolopyridazine (TPZ) drugs, typified by CL218,872 (CL), have a relatively higher affinity for a subpopulation of benzodiazepine (BZ) receptors. The binding of radiolabeled CL to membranes from rat cerebellum, a region enriched in the TPZ-preferring ("Type 1") BZ receptor, was characterized and compared with that of [3H]flunitrazepam ([3H]FLU) in the same preparation. [3H]CL had clonazepam displaceable binding which was saturable. The Kd was approximately 21 nM and the Bmax was approximately 600 fmol/mg of protein. [3H]CL binding was similar to that for [3H]FLU in that exogenous gamma-aminobutyric acid (GABA) enhanced the binding; however, [3H]CL binding differed from that for [3H]FLU in that anions, cartazolate and pentobarbital did not enhance [3H]CL binding. These data suggest that [3H]CL binds to the Type 1 BZ receptor in a manner different from that of a BZ drug such as FLU. Inasmuch as GABA enhances [3H]CL binding, but anions, cartazolate and pentobarbital do not, [3H]CL may bind to the Type 1 BZ receptor in such a way that it interacts with the GABA site, but perhaps not directly with the ionophore or the postulated pyrazolopyridine-barbiturate site. Thus, TPZ drugs may affect the GABA receptor complex in a different or perhaps less extensive way than the BZs. This, in addition to the regional localization of the Type 1 receptor, may be an important part of the mechanism of action of the TPZs.


Alcohol consumption and mortality rates from traffic accidents, accidental falls, and other accidents in 14 European countries.
To evaluate the effects of changes in aggregate alcohol consumption on fatal motor vehicle traffic accidents, accidental falls, and other accidents in 14 western European countries after 1950, and to compare traditional beer, wine and spirits countries. The countries were sorted into three groups. Gender-specific, age-adjusted annual mortality rates (15-69 years) were analysed in relation to per capita alcohol consumption, utilizing the Box-Jenkins technique for time series analysis. All series were different to remove long-term trends. The results of the analyses of individual countries were pooled within each group of countries to increase the statistical power. Overall accident mortality data for 5-year age groups were converted to age-adjusted mortality rates for the age group 15-69 years, using a European standard population. Data on per capita alcohol consumption were converted to consumption per inhabitant 15 years and older. For male accidental falls, the analyses uncovered a statistically significant association with alcohol consumption in northern and central Europe, but not in southern Europe. Among females the association was insignificant in all regions. For male traffic accidents, significant relationships were uncovered in central and southern Europe, but not in northern Europe. Among females the effect was significant only in central Europe. For the remaining fatal accidents a significant relationship was found for north European males only. The association between aggregate alcohol consumption and rates of fatal accidents is mainly due to traffic accidents in central and southern Europe, and to falls and other accidents in northern Europe.


Superresolved digital in-line holographic microscopy for high-resolution lensless biological imaging.
Digital in-line holographic microscopy (DIHM) is a modern approach capable of achieving micron-range lateral and depth resolutions in three-dimensional imaging. DIHM in combination with numerical imaging reconstruction uses an extremely simplified setup while retaining the advantages provided by holography with enhanced capabilities derived from algorithmic digital processing. We introduce superresolved DIHM incoming from time and angular multiplexing of the sample spatial frequency information and yielding in the generation of a synthetic aperture (SA). The SA expands the cutoff frequency of the imaging system, allowing submicron resolutions in both transversal and axial directions. The proposed approach can be applied when imaging essentially transparent (low-concentration dilutions) and static (slow dynamics) samples. Validation of the method for both a synthetic object (U.S. Air Force resolution test) to quantify the resolution improvement and a biological specimen (sperm cells biosample) are reported showing the generation of high synthetic numerical aperture values working without lenses.


Failed induction of labor: strategies to improve the success rates.
The rates of induction of labor (IOL) are rising all over the world. In developed countries, one of every 4 babies is born after IOL at term. The recent World Health Organization guidelines on IOL recommend that failure of induction does not necessitate cesarean delivery [WHO recommendations for induction of labor. World Health Organization, 2011]. These guidelines come when there are concerns that failed primary inductions in nulliparous women, which have led to escalation of the cesarean delivery rates. Obstetricians must recognize the risks associated with IOL (including failure and need for cesarean delivery) and avoid inductions for borderline indications, which are not evidence based. The issue of "failed induction of labor" is topical, and there is a need to define this entity and offer alternatives to cesarean delivery in the management of this group of women. Research is required to develop a test to accurately identify those fetuses most at risk of morbidity or stillbirth who would truly benefit from an early IOL and assess the cost-effectiveness of policies of routine IOL. In this review, we summarized the current recommendations for best practice in the area of IOL, defined "failed induction," and described options to improve the success rate after "failed primary induction of labor." Obstetricians & Gynecologists and Family Physicians. After the completing the CME activity, physicians should be better able to classify the factors determining success or failure of induction of labor, counsel women about risks and benefits of various methods of induction of labor, and compare the options of management available after failed primary induction of labor.


Fetal loss in threatened abortion after demonstration of fetal cardiac activity in a low socioeconomic population.
This study was conducted to determine the incidence and risk factors of fetal loss in threatened abortion after ultrasonographic detection of fetal cardiac activity in a low socioeconomic population. A total of 202 women with singleton pregnancies who presented with vaginal bleeding in which fetal heart activity was ultrasonographically demonstrated between 5 and 14 weeks' gestation were included. Pregnancies with fetal abnormalities were excluded from the study. All cases were followed-up with respect to pregnancy outcomes. A total of 54 of 202 pregnancies (26.7%) resulted in fetal loss before 20 weeks' gestation. The mean fetal heart rate (FHR) and cervical length values were lower in spontaneous abortions than in viable pregnancies (121.2 +/- 13.3 vs 143.5 +/- 12.4 and 41 +/- 6.0 vs. 34.8 +/- 6.1, respectively; p < 0.001). A receiver operating characteristic (ROC) curve analysis revealed an area under the curve of 0.88 for FHR and 0.77 for cervical length. A FHR value <130 b.p.m. was 81.4% sensitive, 85.1% specific and a cervical length value <40 mm was 80.8% sensitive, 54.7% specific for determination of fetal loss before 20 weeks' gestation. Fetal loss was observed in about one-quarter of pregnancies admitted with threatened abortion in a low socioeconomic population. Bradycardia and short cervix were found to be significant risk factors affecting the pregnancy outcome in women presenting with vaginal bleeding, in whom fetal cardiac activity was documented.


Cardiac arrhythmias during the combined use of beta-adrenergic agonist drugs and theophylline.
We studied 15 nonsmoking, clinically stable asthmatic subjects aged 27 to 39 years to evaluate the potential cardiotoxic effects of combined use of a beta-adrenergic agonist drug and theophylline in the treatment of asthma. Subjects underwent a one-week washout period followed by two one-week periods of study receiving either oral terbutaline or sustained-release theophylline during week 1 and both drugs during week 2. Thirty-six-hour Holter monitoring was performed at the end of each period of study. No significant increase in the total number of ventricular premature beats was noted, although the average heart rate increased significantly between each period of study. Although not statistically significant, the number of individuals with multiform or complete and repetitive ventricular premature beats increased from one at baseline to three during each period of study, including one subject with ventricular tachycardia on combined therapy. These data suggest that combined therapy with theophylline and a beta-adrenergic agonist in young, otherwise healthy asthmatic subjects does not lead to an increase in the total number of ectopic beats but may increase the degree of complexity of ventricular premature beats.


Facial, cervical, and mediastinal emphysema of the clarinet player: case report.
Cervicofacial emphysema may arise due to the leakage of air from a defect in the aerodigestive tract to the fascial layers of neck and face. Rarely, it may be caused by insufflation of air through the Stensen's duct. We present a case with diffuse facial, cervical and mediastinal emphysema due to playing a wind instrument immediately after a facial trauma. There was no mucosal defect or laceration noticed by examination which could explain the origin of the emphysema. Despite the widespread cervicofacial emphysema with mediastinal involvement, the patient significantly improved within 48 hours without any intervention. Even though cervicofacial emphysema ameliorates spontaneously, increased care must be taken, especially when there is pneumomediastinum and/or pneumothorax.


The effect of acute urinary retention on serum prostate-specific antigen level.
Our aim was to evaluate the effect of acute urinary retention on serum prostate-specific antigen (PSA) level. Men aged 50 years and older who presented with acute urinary retention were studied. Patients with urethral stricture, neurogenic bladder, prostate cancer, and those with a history of recent instrumentation or prostate biopsy were excluded. Blood samples for serum PSA measurement were obtained (PSA1), and an indwelling urethral catheter was inserted for 2 weeks. Before catheter removal, a second blood sample for measurement of serum PSA level (PSA2) was obtained. In patients who were able to void, a third sample was obtained 3 weeks later (PSA3). In the first and second visits, digital rectal examinations (DRE1, DRE2) were performed to assess prostate volume. Mean PSA levels (PSA1, PSA2, and PSA3) and prostate volumes (DRE1, DRE2) were compared. Forty-five patients with a mean age of 70.18 years (range 56 to 85 years) participated in this study. Mean PSA1 and PSA2 levels were 9.8 ng/mL and 5.05 ng/mL, respectively (P < 0.001; medians, 6.2 and 4.2 ng/mL). Mean prostate volumes at the time of retention and 2 weeks later were 43.4 mL and 37.8 mL, respectively (P < 0.001; medians, 45 and 40 mL). PSA3 was measured in 31 patients 2 weeks after catheter removal. In this group of patients, mean PSA2 and PSA3 levels were 5.03 ng/mL and 4.97 ng/mL, respectively (P = 0.49; medians, 4.3 and 4.1 ng/mL). Acute urinary retention can increase serum PSA levels by approximately 2 fold. In this series, we found that this effect may continue up to 2 weeks.


Positive evolutionary selection on the RIG-I-like receptor genes in mammals.
The mammalian RIG-I-like receptors, RIG-I, MDA5 and LGP2, are a family of DExD/H box RNA helicases responsible for the cytoplasmic detection of viral RNA. These receptors detect a variety of RNA viruses, or DNA viruses that express unusual RNA species, many of which are responsible for a great number of severe and lethal diseases. Host innate sentinel proteins involved in pathogen recognition must rapidly evolve in a dynamic arms race with pathogens, and thus are subjected to long-term positive selection pressures to avoid potential infections. Using six codon-based Maximum Likelihood methods, we were able to identify specific codons under positive selection in each of these three genes. The highest number of positively selected codons was detected in MDA5, but a great percentage of these codons were located outside of the currently defined protein domains for MDA5, which likely reflects the imposition of both functional and structural constraints. Additionally, our results support LGP2 as being the least prone to evolutionary change, since the lowest number of codons under selection was observed for this gene. On the other hand, the preponderance of positively selected codons for RIG-I were detected in known protein functional domains, suggesting that pressure has been imposed by the vast number of viruses that are recognized by this RNA helicase. Furthermore, the RIG-I repressor domain, the region responsible for recognizing and binding to its RNA substrates, exhibited the strongest evidence of selective pressures. Branch-site analyses were performed and several species branches on the three receptor gene trees showed evidence of episodic positive selection. In conclusion, by looking for evidence of positive evolutionary selection on mammalian RIG-I-like receptor genes, we propose that a multitude of viruses have crafted the receptors biological function in host defense, specifically for the RIG-I gene, contributing to the innate species-specific resistance/susceptibility to diverse viral pathogens.


Risk of Toxicity from Topical 5-Fluorouracil Treatment in Patients Carrying DPYD Variant Alleles.
Patients carrying DPYD variant alleles have increased risk of severe toxicity from systemic fluoropyrimidine chemotherapy. There is a paucity of data regarding risk of toxicity from topical 5-fluorouracil (5-FU) treatment in these patients, leading to inconsistent guideline recommendations for pre-treatment testing and topical 5-FU dosing. The objective of this retrospective cohort study was to investigate whether DPYD variant allele carriers have increased risk of toxicity from topical 5-FU. Treatment and toxicity data were retrospectively abstracted from the electronic medical records. Genotypes for the five DPYD variants that are associated with increased toxicity from systemic fluoropyrimidine chemotherapy (DPYD*2A, DPYD*13, DPYD p.D949V, DPYD HapB3, and DPYD p.Y186C) were collected from a genetic data repository. Incidence of grade 3+ (primary endpoint) and 1+ (secondary endpoint) toxicity was compared between DPYD variant carriers vs. wild-type patients using Fisher's exact tests. The analysis included 201 patients, 7% (14/201) of whom carried a single DPYD variant allele. No patients carried two variant alleles or experienced grade 3+ toxicity. DPYD variant allele carriers did not have a significantly higher risk of grade 1+ toxicity (21.4% vs. 10.2%, odds ratio=2.40 [95% Confidence Interval: 0.10-2.53], p=0.19). Given the low toxicity risk in patients carrying a single DPYD variant allele, there is limited potential clinical benefit of DPYD genetic testing prior to topical 5-FU. However, the risk of severe toxicity in patients with complete DPD deficiency remains unknown and topical 5-FU treatment should be avoided in these patients.


Novel 'Candidatus Liberibacter' species identified in the Australian eggplant psyllid, Acizzia solanicola.
A novel candidate species of the liberibacter genus, 'Candidatus Liberibacter brunswickensis' (CLbr), was identified in the Australian eggplant psyllid, Acizzia solanicola. This is the first discovery of a species belonging to the liberibacter genus in Australia and the first report of a liberibacter species in the psyllid genus Acizzia. This new candidate liberibacter species has not been associated with plant disease, unlike other psyllid-vectored species in the genus including 'Candidatus Liberibacter asiaticus' (CLas), 'Candidatus Liberibacter africanus' (CLaf) and 'Ca. Liberibacter solanacearum' (CLso). This study describes novel generic liberibacter genus primers, used to screen Australian psyllids for the presence of microflora that may confound diagnosis of exotic pathogens. CLbr forms a unique clade in the liberibacter genus based on phylogenetic analysis of the 16S ribosomal ribonucleic acid (rRNA) region and multilocus sequence analysis (MLSA) of seven highly conserved genes, dnaG, gyrB, mutS, nusG, rplA, rpoB and tufB. The MLSA mapping approach described in this article was able to discriminate between two 'Ca. Liberibacter' species within a metagenomic data set and represents a novel approach to detecting and differentiating unculturable species of liberibacter. Further, CLbr can confound the Li et al. (2006) quantitative PCR (qPCR) diagnostic tests for CLas and CLaf.


Preadolescent Peer Sexual Abuse: A Systematic Literature Review.
Child sexual abuse (CSA) is a worldwide social problem which has received much attention from policy makers, researchers, and practitioners. A considerable portion of CSA research has focused on adult offenders, the result of which is that most of our existing knowledge regarding prevention and intervention has been based on abuse perpetrated by this population. The current literature review, by contrast, was designed to spotlight the phenomenon of preadolescent peer sexual abuse (PAPSA), focusing on children ages 12 and under, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The results revealed scant empirical data, with only nine studies focusing on this phenomenon. As the basis of their investigations, most of the reviewed studies used definitions of sexual harassment among peers, rather than definitions of more severe forms of sexual abuse, and showed conflicting results depending on the ages and genders of the peers involved. In addition, prevention programs for peer sexual abuse/harassment were not targeted toward preadolescents. Additional findings indicated a lack of empirical knowledge with respect to core aspects such as victims' personal characteristics and subjective experience, the dynamic of the abuse, and the disclosure process. This systematic literature review emphasizes the need for an in-depth and thorough conceptualization and empirical examination of the PAPSA phenomenon and its unique characteristics.


Overexpression of CD300A inhibits progression of NSCLC through downregulating Wnt/β-catenin pathway.
CD300A, a type I transmembrane glycoprotein receptor, plays an important role in immune response. Recent studies have reported that CD300A is involved in the development of hematological malignancies. The objective of this study was to investigate the role of CD300A in the progression of non-small-cell lung cancer (NSCLC) and explore the associated mechanism. Gene Expression Profiling Interactive Analysis (GEPIA) was used to analyze the expression of CD300A in NSCLC and its prognostic value. NSCLC cell lines A549 and H1650 were transfected with siRNA-CD300A or pcDNA3.1-CD300A vector to down- or up-regulate the expression of CD300A. Cell Counting Kit 8, colony formation and Transwell assays were used to assess the effects of CD300A on cell proliferation and migration capacities. Flow cytometry was performed to examine rate of apoptosis, and the protein levels of associated proteins was detected using Western blot assay. From GEPIA analysis, we observed that expression of CD300A mRNA was downregulated in NSCLC and positively correlated with the overall survival of NSCLC patients. Overexpression of CD300A significantly suppressed cell growth and migration capacities of A549 and H1650 cells and induced cell apoptosis via regulating apoptosis-related proteins. Moreover, decreasing level of CD300A promoted cell growth and migration and blocked apoptosis of NSCLC cells. Furthermore, upregulation of CD300A led to significant decrease in expression level of Wnt3 and β-catenin, the pivotal components in Wnt/β-catenin signaling pathway, and an increase in expression of E-cad, a key protein in tumor metastasis, in A549 and H1650 cells; while depletion of CD300A up-regulated the Wnt/β-catenin signaling pathway. In conclusion, the present study highlighted an anti-oncogenic role of CD300A in the progression of NSCLC via inhibiting Wnt/β-catenin pathway, suggesting that CD300A might be a potential target for the treatment of NSCLC. CD300A plays an anti-oncogenic role in the progression of NSCLC through inhibiting the Wnt/β-catenin pathway, suggesting that CD300A might be a potential target for the treatment of NSCLC.


A supramolecular host for phosphatidylglycerol (PG) lipids with antibacterial activity.
Lipids fulfill a variety of important physiological functions, such as energy storage, providing a hydrophobic barrier, and signal transduction. Despite this plethora of biological roles, lipids are rarely considered a potential target for medical applications. Here, we report a set of neutral small molecules that contain boronic acid and urea functionalities to selectively recognize the bacterial lipid phosphatidylglycerol (PG). The affinity and selectivity was determined using 1H NMR titrations and a liposome-based Alizarin Red S assay. Minimum inhibitory concentrations (MIC) were determined to assess antibacterial activity. The most potent compounds display an association constant with PG in liposomes of at least 5 × 103 M-1, function as antibacterial agents against Gram-positive bacteria (MIC = 12.5-25 μM), and show little hemolytic activity. Mode of action studies suggest that the boronic acids bind to the headgroup of the PG lipids, which leads to a change in membrane fluidity and ultimately causes membrane depolarization and cell death.


A periodontist's view on the assessment of periodontal disease in the community.
Periodontal treatment differs from other forms of dental treatment in that it demands long term cooperation from the patient without which the dentists' efforts are largely without value. The earliest stage of periodontal disease is gingivitis which is characterized by bleeding on gentle probing. It is a reversible condition which, depending on many poorly understood factors, may or may not progress to periodontal disease. This stage is characterized by the apical migration of junctional epithelium, pocket formation and loss of alveolar bone. Pocket depth, though not indicating the presence of active disease, is the best available measure of periodontal disease. In school children the majority of disease is gingivitis which can be largely eliminated by plaque control which they should be taught to practise from themselves. In adults a screening procedure has been developed which will rapidly identify those in need of treatment. Patients with gingivitis can be referred to hygienists. Those with moderately advanced disease are scheduled for non-surgical periodontal therapy which should be followed by re-evaluation and redefinition of the treatment plan. Those with advanced periodontal disease are usually referred for specialist treatment. It has been shown that pockets of up to 5 mm in depth can be maintained without further destruction by plaque control combined with scaling and root planing. The most important aspect of periodontal health remains the quality of long term maintenance care and the motivation of the patient to accept responsibility for it.


Thioredoxin reductase as a novel molecular target for cancer therapy.
Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential targets for therapeutic intervention. Redox-sensitive signaling factors also regulate multiple cellular processes including proliferation, cell cycle, and pro-survival signaling cascades, suggesting their potential as molecular targets for anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular markers. We hypothesized that thioredoxin reductase-1 (TR), a component of several redox-regulated pathways, may represent a potential molecular target candidate in response to agents that induce oxidative stress. There have been numerous biological studies over the last decade investigating the cell biological, biochemical, and genetic properties of TR both in culture and in in vivo models. In addition, using a series of permanent cell lines that express either a wild-type TR or a dominant mutant TR gene or a chemical agent that inhibits TR we demonstrated that TR meets most criteria that would identify a molecular target. Based on these results we believe TR is a potential molecular target and discuss potential clinical possibilities.


Using sEMG Signal Frequency to Evaluate Post-Stroke Elbow Spasticity.
Spasticity is a motor disorder with high prevalence and critical consequences following a stroke. Reliable and sensitive measurements are important to guide the selection and evaluation of treatment strategies. Technology-assisted methods, such as the surface electromyography (sEMG) technique, have been developed to measure spasticity as sensitive and accurate alternatives to commonly used clinical scales. However, sEMG amplitude based measures may confound spasticity-induced muscle activities with other types of muscle contractions. This study thus introduces the idea of using sEMG frequency information to detect spasticity as a potential solution to overcome the limitations of existing sEMG based measures. The preliminary results of three patients demonstrate the possibility and future research directions for this approach.


Comparison of helium dilution and plethysmographic lung volumes in pregnant women.
The multibreath helium equilibration method is the technique recommended for routine measurement of static lung volumes in normal subjects. However, pregnancy could be an exception to this general rule, due to airway closure during the second half of gestation. The aim of this study was to compare the measurements of lung volumes by plethysmography and helium dilution during pregnancy. Twenty three healthy women were studied at 12, 24 and 36 weeks of pregnancy, and 4 months postpartum. Total lung capacity (TLC), functional residual capacity (FRC) and residual volume (RV) were measured by multibreath helium equilibration (TLCHe, FRCHe and RVHe) and by plethysmography (TLCbox, FRCbox and RVbox). Only at 36 weeks were there differences between the two methods. RVbox was significantly larger than RVHe (1.01+/-0.18 vs 0.77+/-0.21 L; p<0.001). FRCbox was larger than FRCHe (1.95+/-0.32 vs 1.60+/-0.32 L; p<0.001) and TLCbox was larger than TLCHe (4.83+/-0.52 vs 4.45+/-0.51 L; p<0.05). The 95% limits of agreement for differences between lung volumes measured by the two techniques (helium dilution - plethysmography) at 36 weeks were: -0.42 to -0.06 L for RV; -0.54 to -0.17 L for FRC; and -0.66 to -0.11 L for TLC. We conclude that using the multibreath helium equilibration method to measure lung volumes in at-term pregnant women results in underestimation of functional residual capacity and total lung capacity.


Long-Term Survival Rates of Inflatable Penile Prostheses: Systematic Review and Meta-Analysis.
The purpose of this study was to determine long-term survival of inflatable penile prosthesis (PP) and identify potential factors that may influence device survival. We performed a systematic review of Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies of men treated with inflatable PP with at least 5 years of device survival data. We performed a random effects meta-analysis to estimate device survival at 1, 3, 5, 10, 15, and 20 years of follow-up. The robustness of the meta-analysis results was evaluated in a 1-study removed sensitivity analysis and sources of heterogeneity among studies were investigated with subgroup analysis. In 12 studies (20,161 patients; median age 57 years), PP device survival was 93.3% at 1 year, 91.0% at 3 years, 87.2% at 5 years, 76.8% at 10 years, 63.7% at 15 years, and 52.9% at 20 years. The results of the meta-analysis were not significantly influenced by single study effects in a 1-study removed sensitivity analysis. In a subgroup analysis, 5-year device survival rates were 90.6% vs 82.1% (P = .01) comparing newer vs older studies; no other patient or study design characteristic was statistically associated with device survival rates. In conclusion, the median device survival time of an inflatable PP is approximately 20 years. The factors responsible for improved device survival in newer studies remain unclear and warrant further study.


ZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer.
Reduced BRCA1 expression causes homologous recombination (HR) repair defects in high-grade serous ovarian cancers (HGSOCs). Here, we demonstrate that BRCA1 is transcriptionally activated by a previously unknown function of ZC3H18. We show that ZC3H18 is a DNA-binding protein that interacts with an E2F site in the BRCA1 promoter where it facilitates recruitment of E2F4 to an adjacent E2F site to promote BRCA1 transcription. Consistent with ZC3H18 role in activating BRCA1 expression, ZC3H18 depletion induces BRCA1 promoter methylation, reduces BRCA1 expression, disrupts HR, and sensitizes cells to DNA crosslinkers and poly(ADP-ribose) polymerase inhibitors. Moreover, in patient-derived xenografts and primary HGSOC tumors, ZC3H18 and E2F4 mRNA levels are positively correlated with BRCA1 mRNA levels, further supporting ZC3H18 role in regulating BRCA1. Given that ZC3H18 lies within 16q24.2, a region with frequent copy number loss in HGSOC, these findings suggest that ZC3H18 copy number losses could contribute to HR defects in HGSOC.


[Thyroid cancers in Madagascar].
This is a retrospective study, conducted on thyroid cancer observed for 13 months (from June 1(st) 2004 to June 30(th) 2005). Data were collected from four main surgical pathology laboratories in Antananarivo, Madagascar. Among 6,036 surgical samples, 179 were of thyroid gland, a rate that is near 3% of the total. Among them were found 40 cases of thyroid cancer, which is 0.66% of all screened samples, and 22.32% of all examined thyroid samples. In the studied population was observed a female preponderance (82%) with a mean age of 43.9 years when diagnosis was confirmed. It was evidenced a 50 % of papillary carcinoma and 45% of follicular carcinoma, with a rate of 2.5% respectively for the medullar and anaplastic carcinoma. Metastases were seen in 20%, originated from papillary type for the lymph node involvement and from the follicular type for the bone involvement. In Antananarivo, thyroid cancer is seen mainly in people from the surrounding Highlands, supposed to be sites of endemic goiter related to iodine deficiency. Despite its limits, this study may be used as reference about thyroid cancer in Madagascar. Further studies are required to find out other factors involved in the development of this disease.


[Radiation doses in children of the Tomsk region during inhalation of radon-222].
The paper presents the results of the studies of the levels of radon in the premises of 30 kindergartens and 36 schools of Tomsk and its region, which were conducted in 1989 to 2000. The volume activity of radon in the air of the premises was measured by using passive track detectors of gamma-radiation upon a long-term exposure of 1-3 months. In parallel with these measurements, statistical data required for a more accurate assessment of effective doses were collected. Analysis of the statistical processing of the data on the levels of radon has indicated that the arithmetic mean, geometric mean, and standard deviation are 60, 51, and 33 Bq/m3, respectively, for kindergartens and 50, 38, and 56 Bq/m3 for schools. The mean annual radiation doses obtained on inhalation exposure to radon-222 and its degradation products are 1.06 and 1.08 mZv for preschool and school children, respectively.


Acute reorganization of the forepaw representation in the rat SI cortex after focal cortical injury: neuroprotective effects of piracetam treatment.
Immediate postlesion reorganization of the somatosensory cortical representation was examined in adult rats. Response properties of small clusters of neurons were recorded in the area of the primary somatosensory cortex (SI) devoted to the contralateral forepaw representation. Electrophysiological maps were elaborated on the basis of the sensory 'submodality' (cutaneous or noncutaneous) and the location of the peripheral receptive fields (RFs) of layer IV neurons. Recordings were made prior to, and from 1 to 12 h after, induction of a focal neurovascular lesion to the SI cortex that initially destroyed a part (8.5%) of the cutaneous representation. Moreover, the influence of an anti-ischaemic substance (piracetam) on lesion-induced changes was analysed. The main observations were: (i) a gradual outward expansion of the area of the functional lesion, which was smaller in the piracetam-treated (PT) rats than in the control, placebo-treated (PL) rats; (ii) a substantial remodelling of the spared representational zones, both in cortical sectors adjoining the site of injury and those remote from the site; (iii) a significant postlesion increase in the size of cutaneous RFs in the PT rats, but not in the PL rats; (iv) a better preservation of RF submodality and topographic organization in the PT maps than in the PL maps; and (v) a decrease in neuronal responsiveness to cutaneous stimulation which was less pronounced in the PT than in the PL rats. Our results can be ascribed to a rapid change in the balance of excitatory and inhibitory connections which leads to unmasking of subthreshold inputs converging onto cortical neurons. Our findings also indicate that acute piracetam treatment exerts a protective function on the physiological response properties of cortical neurons after focal injury.


Pediatric Hospital Acquired Venous Thromboembolism.
Pediatric hospital acquired venous thromboembolism (HA-VTE) is an increasing problem with an estimated increase from 5.3 events per 10,000 pediatric hospital admissions in the early 1990s to a current estimate of 30-58 events per 10,000 pediatric hospital admissions. Pediatric HA-VTE is associated with significant morbidity and mortality. The etiology is multifactorial but central venous catheters remain the predominant risk factor. Additional HA-VTE risk factors include both acquired (recent surgery, immobility, inflammation, and critical illness) and inherited risk factors. Questions remain regarding the most effective method to assess for HA-VTE risk in hospitalized pediatric patients and what preventative strategies should be implemented. While several risk-assessment models have been published in pediatric patients, these studies have limited power due to small sample size and require prospective validation. Potential thromboprophylactic measures include mechanical and pharmacologic methods both of which have associated harms, the most significant of which is bleeding from anticoagulation. Standard anticoagulation options in pediatric patients currently include unfractionated heparin, low molecular weight heparin, or warfarin all of which pose a monitoring burden. Ongoing pediatric studies with direct oral anticoagulants could potentially revolutionize the prevention and treatment of pediatric thrombosis with the possibility of a convenient route of administration and no requirement for monitoring. Further studies assessing clinical outcomes of venous thromboembolism (VTE) prevention strategies are critical to evaluate the effectiveness and harm of prophylactic interventions in children. Despite HA-VTE prevention efforts, thrombotic events can still occur, and it is important that clinicians have a high clinical suspicion to ensure prompt diagnosis and treatment to prevent further associated harms.


The surgical management of pediatric fractures of the upper extremity.
The vast majority of pediatric fractures of the upper extremity can and should be treated with closed reduction, immobilization, and close follow-up. However, there is an ongoing debate in the orthopaedic community regarding the exact role of surgical management in the treatment of pediatric fractures. In the past 2 decades, surgical management of certain fractures (e.g., percutaneous pinning of displaced supracondylar fractures) has provided better results than closed management. Surgical management is clearly indicated for certain injuries, such as those requiring anatomic realignment of the physis or articular surface. Increasingly, however, surgical management is being used to maintain optimal alignment or to allow early motion. In many such cases, both nonsurgical and surgical methods have yielded good results and have vocal advocates. Certain technical advances, such as flexible intramedullary fixation and bioreabsorbable implants, have further increased enthusiasm for surgical management of pediatric fractures.


Darker eumelanic barn owls better withstand food depletion through resistance to food deprivation and lower appetite.
The intensity of selection exerted on ornaments typically varies between environments. Reaction norms may help to identify the conditions under which ornamented individuals have a selective advantage over drab conspecifics. It has been recently hypothesized that in vertebrates eumelanin-based coloration reflects the ability to regulate the balance between energy intake and expenditure. We tested two predictions of this hypothesis in barn owl nestlings, namely that darker eumelanic individuals have a lower appetite and lose less weight when food-deprived. We found that individuals fed ad libitum during 24 h consumed less food when their plumage was marked with larger black spots. When food-deprived for 24 h nestlings displaying larger black spots lost less weight. Thus, in the barn owl the degree of eumelanin-based coloration reflects the ability to withstand periods of food depletion through lower appetite and resistance to food restriction. Eumelanic coloration may therefore be associated with adaptations to environments where the risk of food depletion is high.


The enhancement of ozone-liquid mass transfer performance in a PTFE hollow fiber membrane contactor using ultrasound as a catalyzer.
A comprehensive assessment of a polytetrafluoroethylene (PTFE) hollow fiber membrane contactor and ultrasound for intensifying ozone-liquid mass transfer was conducted simultaneously. The initial part of the study concentrates on the systematic analysis of the previous literature related to the reinforcement on the ozone-liquid mass transfer. In this paper, the introduction of a membrane contactor and ultrasound as a catalyzer that increased the mass transfer coefficient (K L a) may be partially attributed to the increase of the net surface area and the decrease of the mass transfer resistance, thus leading to the enhancement of the ozone mass transfer rate and acceleration of the ozone decomposition in solution. Results revealed that the maximum value of the K L a value was 0.7858 min-1 in the PTFE hollow fiber membrane contactor in the presence of the ultrasound, while only 0.5154 min-1 in a single ozone aeration at an intake flow of 300 L h-1, ozone dosage of 32.38 mg L-1 and operating temperature of 293.15 K. A 52.46% improvement of the K L a value was obtained in the presence of the ultrasound. In addition, the dosage of sodium chloride appeared to have a positive correlation with K L a, but a negative correlation with the concentration of dissolved ozone. The sulfolane destruction by ozonation, ultrasound and the combination between the ozonation and ultrasound were performed to further verify the enhancement of the ozone mass transfer performance. It has been established that the O3/US combined process was a promising method, giving the maximum degradation of sulfolane (96.5%) with the synergistic index as 2.41.


Soccer heading frequency predicts neuropsychological deficits.
This study investigated the presence of neuropsychological deficits associated with hitting the ball with one's head (heading) during soccer play. A neuro-cognitive test battery was administered to 60 male soccer players, high school, amateur and professional level, and 12 nonplaying control participants. The effects of currently reported heading behavior as well as that of estimated lifetime heading experience on neuropsychological test performance were examined. Players with the highest lifetime estimates of heading had poorer scores on scales measuring attention, concentration, cognitive flexibility and general intellectual functioning. Players' current level of heading was less predictive of neuro-cognitive level. Comparison of individual scores to age-appropriate norms revealed higher probabilities of clinical levels of impairment in players who reported greater lifetime frequencies of heading. Because of the worldwide popularity of the game, continued research is needed to assess the interaction between heading and soccer experience in the development of neuropsychological deficits associated with soccer play.


Personal protective equipment use by healthcare workers in intensive care unit during the early phase of COVID-19 pandemic in Italy: a secondary analysis of the PPE-SAFE survey.
Italy was the first Western country to be heavily affected by COVID-19. Healthcare workers (HCWs) were exposed to a high risk of occupational infection, partially due to insufficient personal protective equipment (PPE) supplies. This study aimed to describe the practices, availability, training, confidence in PPE use and the adverse effects due to extended PPE use, as reported by HCWs in Italy. We also aimed to provide a comparison between Italian data and those from other countries. This study was a secondary analysis of a previously published international study, the PPE-SAFE Survey, conducted in April 2020. Data were analysed from the original study database. We analysed the responses from 380 healthcare workers based in Italy, out of the 2711 respondents to the international survey. Among the Italian respondents, FFP2 and FFP3 respirators or equivalent were the most used masks for routine tasks (respectively 188/380, 50%; and 163/380, 43%). The median time of wearing PPE without taking a break was 5 h [interquartile range (IQR) 4-6], with statistically significant difference from other countries [median 4 h (IQR 2-5) p < 0.0001]. In Italy, 249 out of 380 (65%) HCWs had never performed a formal fit test for a N95 mask or equivalent and 91/380 (24%) never had a partner for donning and doffing procedures. Most of the respondents (299/380, 79%) had received formal training in PPE use at any time. Most of the surveyed Italian HCWs reported working at above usual capacity, long shifts with PPE without breaks and routine use in intensive care unit of aerosol protection (e.g. FFP2/FFP3), hazmat suits and face shields/visors. The correct adherence to safety procedures (e.g. donning/doffing in pairs, performing fit test) has substantial scope for improvement in the future.


Spanish-language tobacco-related posts on Twitter: content analysis.
Twitter data has been used to surveil public sentiment about tobacco products, however, most tobacco-related Twitter research has been conducted with English-language posts. There is a gap in the literature on tobacco-related discussions on Twitter in languages other than English. This study summarized tobacco-related discussions in Spanish on Twitter. A set of Spanish terms reflecting electronic cigarettes (e.g., cigarillos electrónicos), cigarettes (e.g., "pitillo"), and cigars (e.g., "cigaro") were identified. A content analysis of tweets (n=1,352) drawn from 2021 was performed to examine themes and sentiment. An initial codebook was developed in English then translated to Spanish and then translated back to English by a bilingual (Spanish and English) member of the research team. Two bilingual members of the research team coded the tweets into themes and sentiment. Themes in the tweets included 1) product promotion (n=168, 12.4%), 2) health warnings (n=161, 11.9%), 3) tobacco use (n=136, 10.1%), 4) health benefits of vaping (n=58, 4.3%), 5) cannabis use (n=50, 3.7%), 6) cessation (n=47, 3.5%), 7) addiction (n=33, 2.4%), 8) policy (n=27, 2.0%), and 9) polysubstance use (n=12, 0.9%). Neutral (n=955, 70.6%) was the most common category of sentiment observed in the data. Tobacco products are discussed in multiple languages on Twitter and can be summarized by bilingual research teams. Future research should determine if Spanish-speaking individuals are frequently exposed to pro-tobacco content on social media and if such exposure increases susceptibility to use tobacco among never users or sustained use among current users. Spanish-language pro-tobacco content exists on Twitter, which has implications for Spanish-speaking individuals who may be exposed to this content. Spanish-language pro-tobacco-related posts may help normalize tobacco use among Spanish-speaking populations. As a result, anti-tobacco tweets in Spanish may be necessary to counter areas of the online environment that can be considered pro-tobacco.


Ultrasound for measurement of skeletal muscle mass quantity and muscle composition/architecture in critically ill patients: A scoping review on studies' aims, methods, and findings.
This scoping review aimed to identify, explore, and map the objectives, methodological aspects, and results of studies that used ultrasound (US) to assess skeletal muscle (SM) in critically ill patients. A scoping review was conducted according to the Joanna Briggs Institute's methodology. All studies that evaluated SM parameters from the US in patients admitted to the intensive care unit (ICU) were considered eligible. We categorized muscle thickness and cross-sectional area as parameters for assessing SM quantity, while echogenicity, fascicle length, and pennation angle analysis were used to evaluate muscle "quality" (composition/architecture). A literature search was conducted using four databases for articles published until December 2022. Independent reviewers selected the studies and extracted data. Descriptive statistics were calculated to present the results. A total of 107 studies were included, the majority of which were prospective cohort studies (59.8 %) conducted in general ICUs (49.5 %). The most frequent objective of the studies was to evaluate SM quantity depletion during the ICU stay (25.2 %), followed by determining whether a specific intervention would modify SM (21.5 %). Most studies performed serial SM evaluations (76.1 %). The rectus femoris muscle thickness was evaluated in most studies (67.9 %), followed by the rectus femoris cross-sectional area (54.3 %) and the vastus intermedius muscle thickness (40.2 %). The studies demonstrated the feasibility and reproducibility of US for SM evaluation, especially related to quantitative parameters. Most studies (70.3 %) reported significant SM quantity depletion during hospitalization. However, the accuracy of the US in measuring SM varied across the studies. The lack of detailed description and standardization in the protocols adopted by the studies included in this scoping review precludes the translation of the evidence related to US for SM assessment into clinical practice.


A vascular perspective on neuronal migration.
During CNS development and adult neurogenesis, immature neurons travel from the germinal zones towards their final destination using cellular substrates for their migration. Classically, radial glia and neuronal axons have been shown to act as physical scaffolds to support neuroblast locomotion in processes known as gliophilic and neurophilic migration, respectively (Hatten, 1999; Marin and Rubenstein, 2003; Rakic, 2003). In adulthood, long distance neuronal migration occurs in a glial-independent manner since radial glia cells differentiate into astrocytes after birth. A series of studies highlight a novel mode of neuronal migration that uses blood vessels as scaffolds, the so-called vasophilic migration. This migration mode allows neuroblast navigation in physiological and also pathological conditions, such as neuronal precursor migration after ischemic stroke or cerebral invasion of glioma tumor cells. Here we review the current knowledge about how vessels pave the path for migrating neurons and how trophic factors derived by glio-vascular structures guide neuronal migration both during physiological as well as pathological processes.


A connection between pre-mRNA splicing and the cell cycle in fission yeast: cdc28+ is allelic with prp8+ and encodes an RNA-dependent ATPase/helicase.
The fission-yeast gene cdc28+ was originally identified in a screen for temperature-sensitive mutants that exhibit a cell-division cycle arrest and was found to be required for mitosis. We undertook a study of this gene to understand more fully the general requirements for entry into mitosis. Cells carrying the conditional lethal cdc28-P8 mutation divide once and arrest in G2 after being shifted to the restrictive temperature. We cloned the cdc28+ gene by complementation of the temperature-sensitive growth arrest in cdc28-P8. DNA sequence analysis indicated that cdc28+ encodes a member of the DEAH-box family of putative RNA-dependent ATPases or helicases. The Cdc28 protein is most similar to the Prp2, Prp16, and Prp22 proteins from budding yeast, which are required for the splicing of mRNA precursors. Consistent with this similarity, the cdc28-P8 mutant accumulates unspliced precursors at the restrictive temperature. Independently, we isolated a temperature-sensitive pre-mRNA splicing mutant prp8-1 that exhibits a cell-cycle phenotype identical to that of cdc28-P8. We have shown that cdc28 and prp8 are allelic. These results suggest a connection between pre-mRNA splicing and progression through the cell cycle.


Spontaneous mutation in the AgrRS two-component regulatory system of Cupriavidus metallidurans results in enhanced silver resistance.
The uncontrolled and widespread use of (nano)silver compounds has led to the increased release of these compounds into the environment, raising concerns about their negative impact on ecosystems. Concomitantly, silver resistance determinants are widely spread among environmental and clinically relevant bacteria although the underlying mechanisms are not yet fully understood. We show that Cupriavidus metallidurans is able to adapt to toxic silver concentrations. However, none of the known silver resistance determinants present in C. metallidurans are involved in the adaptative response. Instead, increased silver resistance is achieved by the concerted action of a two-component system AgrR-AgrS, previously not associated with metal resistance, and two periplasmic proteins PrsQ1 and PrsQ2. Both proteins belong to an unique group of small, uncharacterized, secreted proteins restricted to the genera Cupriavidus and Ralstonia. This system gives C. metallidurans the ability to withstand much higher silver concentrations. The latter could be facilitated by the accumulation of silver ions and the formation of silver nanoparticles.


Human IgG3 with extended half-life does not improve Fc-gamma receptor-mediated cancer antibody therapies in mice.
Current anti-cancer therapeutic antibodies that are used in the clinic are predominantly humanized or fully human immunoglobulin G1 (IgG1). These antibodies bind with high affinity to the target antigen and are efficient in activating the immune system via IgG Fc receptors and/or complement. In addition to IgG1, three more isotypes are present in humans, of which IgG3 has been found to be superior compared to human IgG1 in inducing antibody dependent cell cytotoxicity (ADCC), phagocytosis or activation of complement in some models. Nonetheless, no therapeutic human IgG3 mAbs have been developed due to the short in vivo half-life of most known IgG3 allotypes. In this manuscript, we compared the efficacy of V-gene matched IgG1 and IgG3 anti-tumour mAb (TA99) in mice, using natural variants of human IgG3 with short- or long half-life, differing only at position 435 with an arginine or histidine, respectively. In vitro human IgG1 and IgG3 did not show any differences in opsonisation ability of B16F10-gp75 mouse melanoma cells. IgG1, however, was superior in inducing phagocytosis of tumour cells by mouse macrophages. Similarly, in a mouse peritoneal metastasis model we did not detect an improved effect of IgG3 in preventing tumour outgrowth. Moreover, replacing the arginine at position 435 for a histidine in IgG3 to enhance half-life did not result in better suppression of tumour outgrowth compared to wild type IgG3 when injected prior to tumour cell injection. In conclusion, human IgG3 does not have improved therapeutic efficacy compared to human IgG1 in a mouse tumour model.


Preparation of lipid emulsions by pressure extrusion.
Lipid emulsions consisting of a surface monolayer of phospholipid enclosing a core of neutral lipids have been prepared by repeated extrusion through polycarbonate filters of defined pore size. Particle size, as measured by photon correlation spectroscopy, decreases on successive passes through a 100 nm filter, reaching a near constant value (130-150 nm) after 4 passes. A corresponding decrease in the standard deviation of the particle size distribution occurs during this process. The recovery of lipids, especially of cholesterol and cholesterol ester, is improved if the emulsion is sonicated before extrusion through filters. [31P]-NMR and fluorescence techniques are used to confirm that the resulting structures are emulsions rather than lipid bilayers.