Design and synthesis of novel organometallic complexes using boronated phenylalanine derivatives as potential anticancer agents.
Drug design and discovery studies are important because of the prevalence of diseases without available medical cures. New anticancer agents are particularly urgent because of the high mortality rate associated with cancer. A series of mononuclear gold (III) and platinum (II) complexes based on boronated phenylalanine (BPA) were designed and synthesized using 4,4'-dimethyl-2,2'-dipyridyl (L1) or 1,10-phenanthroline-5,6-dion (L2) ligands to obtain promising anticancer drug candidates. Proton nuclear magnetic resonance, infrared, mass spectrometry, and elemental analyses were utilized for chemical characterizations. Cell viability, cancer cell colony formation, endothelial tube formation, and cytoskeleton staining assays were performed using A549 lung adenocarcinoma and human umbilical vein endothelial cells (HUVECs) to investigate preliminary pharmacological activities. L1-based platinum (II) complex (BPA-L1-Pt) was the most promising complex, and has similar activity with the approved chemotherapy drug cis-platinum. Half maximal inhibitory concentration values for BPA-L1-Pt were 9.15 µM on A549s and 16.61 µM on HUVECs; the values for cis-platinum were 5.24 µM on A549s and 23.14 µM on HUVECs. Consequently, further synthesis studies should be performed to boost the cancer cell selectivity feature of BPA by varying metal and ligand types.


Pancreatic alpha-cell differentiation by mesenchyme-to-epithelial transition: implications for cell-based therapies in children.
Stem cell-derived tissue may provide a curative treatment for children with type 1 diabetes. Using an avian model, we have previously shown that foregut mesenchyme is able to differentiate into insulin-positive beta-cell islets (B islets). Successful clinical islet transplantation, however, is reliant on graft tissue containing both insulin- and glucagon-secreting cells. Therefore, in this study, we assessed the ability of foregut mesenchyme to differentiate into glucagon-positive alpha-cell islets (A islets). Chimeric recombinants (n = 14) were constructed using chick pancreatic epithelium combined with quail stomach mesenchyme from day 4 avian embryos and then cultured in 3 dimensions for 7 days. Cryosectioned recombinants were analyzed using immunocytochemistry against glucagon, insulin, and the quail-specific nucleolar antigen. The A islets and B islets were determined to be of solely epithelial, solely mesenchymal, or mixed origin according to the coexpression of the quail-specific nucleolar antigen. Forty-eight A islets and 34 B islets were analyzed. Eighty-five percent of the A islets were solely derived from the epithelium, but, notably, 5% were solely derived from the mesenchyme and 10% were of mixed origin. A-islet differentiation from foregut mesenchyme was reduced as compared with B islets (P = .03). We demonstrate that foregut mesenchyme is able to differentiate into both alpha and beta cells, albeit with quantitative differences. These findings may have important implications for the derivation of islet tissue from mesenchymal stem cells to cure juvenile-onset diabetes.


Analysis of CO2 emissions and energy consumption by sources in MENA countries: evidence from quantile regressions.
The development of economies and energy usage can significantly impact the carbon dioxide (CO2) emissions in the Middle East and North Africa (MENA) countries. Therefore, this study aims to analyze the factors that determine CO2 emissions in MENA under the environmental Kuznets curve (EKC) framework by applying novel quantile techniques on data for CO2 emissions, real income, renewable and non-renewable energy consumption, and urbanization over the period from 1990 to 2015. The results from the estimations suggest that renewable energy consumption significantly reduces the level of emissions; furthermore, its impact increases with higher quantiles. In addition, non-renewable energy consumption increases CO2 emissions, while its magnitude decreases with higher quantiles. The empirical results also confirm the validity of EKC hypothesis for the panel of MENA economies. Policymakers in the region should implement policies and regulations to promote the adoption and use of renewable energy to mitigate carbon emissions.


Mimicry in butterflies: co-option and a bag of magnificent developmental genetic tricks.
Butterfly wing patterns are key adaptations that are controlled by remarkable developmental and genetic mechanisms that facilitate rapid evolutionary change. With swift advancements in the fields of genomics and genetic manipulations, identifying the regulators of wing development and mimetic wing patterns has become feasible even in nonmodel organisms such as butterflies. Recent mapping and gene expression studies have identified single switch loci of major effects such as transcription factors and supergenes as the main drivers of adaptive evolution of mimetic and polymorphic butterfly wing patterns. We highlight several of these examples, with emphasis on doublesex, optix, WntA and other dynamic, yet essential, master regulators that control critical color variation and sex-specific traits. Co-option emerges as a predominant theme, where typically embryonic and other early-stage developmental genes and networks have been rewired to regulate polymorphic and sex-limited mimetic wing patterns in iconic butterfly adaptations. Drawing comparisons from our knowledge of wing development in Drosophila, we illustrate the functional space of genes that have been recruited to regulate butterfly wing patterns. We also propose a developmental pathway that potentially results in dorsoventral mismatch in butterfly wing patterns. Such dorsoventrally mismatched color patterns modulate signal components of butterfly wings that are used in intra- and inter-specific communication. Recent advances-fuelled by RNAi-mediated knockdowns and CRISPR/Cas9-based genomic edits-in the developmental genetics of butterfly wing patterns, and the underlying biological diversity and complexity of wing coloration, are pushing butterflies as an emerging model system in ecological genetics and evolutionary developmental biology. WIREs Dev Biol 2018, 7:e291. doi: 10.1002/wdev.291 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Comparative Development and Evolution > Regulation of Organ Diversity Comparative Development and Evolution > Evolutionary Novelties.


Urine liver-type fatty acid-binding protein predicts graft outcome up to 2 years after kidney transplantation.
Several new biomarkers for the detection of early tubular injury have been investigated in kidney transplant recipients. We recently identified day 2 urinary neutrophil gelatinase-associated lipocalin (NGAL) as a predictor of slow graft function and adverse 1-year outcome. In the present study, we further investigated the value of urinary NGAL and liver-type fatty acid binding protein (L-FABP) for predicting long-term graft outcomes up to 2 years. This study was a single-center, prospective observational study. Serial urinary NGAL and L-FABP levels at 0 hours, 2 days, and 6 days after kidney transplantation (KT) were measured, and the clinical data were assessed during the 2-year period after KT. During the 2-year follow-up period, 13 (18.8%), 5 (7.2%), and 4 (5.8%) patients were diagnosed with acute T-cell-mediated rejection, acute antibody-mediated rejection (AMR) and chronic AMR, respectively. In addition, 10 patients (14.3%) developed calcineurin inhibitor toxicity and 6 (8.7%) developed BK viremia. The mean estimated glomerular filtration rates (eGFR) at 1 and 2 years after KT were 65.1 ± 19.1 and 58.5 ± 22.6 mL/min/1.73 m(2), respectively, When poor long-term graft function was defined as eGFR of less than 50 mL/min/1.73 m(2) at 2 years, elderly donors, acute rejection, and high 0-hour urinary L-FABP levels were significant risk factors. Furthermore, in rejection-free patients, L-FABP was strongly associated with poor long-term graft function (P = .006). Multivariate logistic regression analysis showed that high 0-hour L-FABP (P = .015) and acute rejection (P = .006) were independent factors predicting poor long-term graft function. Receiver operating characteristic analysis showed that the area under the curve for urinary L-FABP was 0.692 (P = .036). Our results suggest that urinary L-FABP may be a useful predictor of adverse long-term outcomes in KT patients.


Implanting totally implantable venous access port via the internal jugular vein guided by ultrasonography is feasible and safe in patients with breast cancer.
Because of long-term use for chemotherapy and fluid administration in cancer patients, a totally implantable venous access port (TIVAP) has been advised as a feasible catheter. The purpose of this study was to evaluate the effectiveness and safety of ultrasound (US)-guided internal jugular vein (IJV) puncture for TIVAP implantation in patients with breast cancer. We reviewed the medical records of 492 patients who underwent US-guided IJV puncture for TIVAP implantation at our oncology department between 2010 and 2013. Indications, surgical complications, and early and long-term complications were analyzed. All TIVAPs were implanted successfully. Indications for TIVAP were chemotherapy alone (88 patients), chemoradiotherapy (387 patients), surgery (12 patients), and parenteral nutrition (5 patients). Complications were observed in 65 (13.21%) patients. The median duration of the TIVAP was 359 days (range, 28 to 712 days) without damage to the port or catheter, or leakage of drugs outside of the port system. A TIVAP can be employed for chemotherapy and parenteral nutrition on the implantation day. Using a US-guided IJV puncture to completely implant a TIVAP is feasible and safe in patients with breast cancer.


Countries with Higher Levels of Gender Equality Show Larger National Sex Differences in Mathematics Anxiety and Relatively Lower Parental Mathematics Valuation for Girls.
Despite international advancements in gender equality across a variety of societal domains, the underrepresentation of girls and women in Science, Technology, Engineering, and Mathematics (STEM) related fields persists. In this study, we explored the possibility that the sex difference in mathematics anxiety contributes to this disparity. More specifically, we tested a number of predictions from the prominent gender stratification model, which is the leading psychological theory of cross-national patterns of sex differences in mathematics anxiety and performance. To this end, we analyzed data from 761,655 15-year old students across 68 nations who participated in the Programme for International Student Assessment (PISA). Most importantly and contra predictions, we showed that economically developed and more gender equal countries have a lower overall level of mathematics anxiety, and yet a larger national sex difference in mathematics anxiety relative to less developed countries. Further, although relatively more mothers work in STEM fields in more developed countries, these parents valued, on average, mathematical competence more in their sons than their daughters. The proportion of mothers working in STEM was unrelated to sex differences in mathematics anxiety or performance. We propose that the gender stratification model fails to account for these national patterns and that an alternative model is needed. In the discussion, we suggest how an interaction between socio-cultural values and sex-specific psychological traits can better explain these patterns. We also discuss implications for policies aiming to increase girls' STEM participation.


Cervical ripening: a randomized study comparing prostaglandin E2 gel to prostaglandin E2 suppositories.
Prostaglandin (PG) E2 has proven effective in many studies as a pre-induction agent for cervical ripening. The purpose of this study was to compare the efficacy of a 5-mg dose of PGE2 prepared gel with that of a quartered PGE2 20-mg suppository. Previous studies have documented uniform distribution of PGE2 in the suppository. After 90 patients entered the study, there appeared to be an unacceptable rate of hyperstimulation following the induction dose using the suppository. The study was discontinued, and data analysis revealed a 24% hyperstimulation rate with the quartered suppository versus 0% with the gel. The successful vaginal delivery rates were equivalent, at 75% for the gel and 66% for the suppository. The 5-mg quartered suppository appeared to initiate an unacceptable amount of uterine activity, much greater than with the 5-mg gel dose.


Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template.
Deregulated origin licensing and rereplication promote genome instability and tumorigenesis by largely elusive mechanisms. Investigating the consequences of Early mitotic inhibitor 1 (Emi1) depletion in human cells, previously associated with rereplication, we show by DNA fiber labeling that origin reactivation occurs rapidly, well before accumulation of cells with >4N DNA, and is associated with checkpoint-blind ssDNA gaps and replication fork reversal. Massive RPA chromatin loading, formation of small chromosomal fragments, and checkpoint activation occur only later, once cells complete bulk DNA replication. We propose that deregulated origin firing leads to undetected discontinuities on newly replicated DNA, which ultimately cause breakage of rereplicating forks.


Interfacial microfluidic transport on micropatterned superhydrophobic textile.
Textile-enabled interfacial microfluidics, utilizing fibrous hydrophilic yarns (e.g., cotton) to guide biological reagent flows, has been extended to various biochemical analyses recently. The restricted capillary-driving mechanism, however, persists as a major challenge for continuous and facilitated biofluidic transport. In this paper, we have first introduced a novel interfacial microfluidic transport principle to drive three-dimensional liquid flows on a micropatterned superhydrophobic textile (MST) platform in a more autonomous and controllable manner. Specifically, the MST system utilizes the surface tension-induced Laplace pressure to facilitate the liquid motion along the hydrophilic yarn, in addition to the capillarity present in the fibrous structure. The fabrication of MST is simply accomplished by stitching hydrophilic cotton yarn into a superhydrophobic fabric substrate (contact angle 140 ± 3°), from which well-controlled wetting patterns are established for interfacial microfluidic operations. The geometric configurations of the stitched micropatterns, e.g., the lengths and diameters of the yarn and bundled arrangement, can all influence the transport process, which is investigated both experimentally and theoretically. Two operation modes, discrete and continuous transport, are also presented in detail. In addition, the gravitational effect as well as the droplet removal process have been also considered and quantitatively analysed during the transport process. As a demonstration, an MST design has been implemented on an artificial skin surface to collect and remove sweat in a highly efficient and facilitated means. The results have illustrated that the novel interfacial transport on the textile platform can be potentially extended to a variety of biofluidic collection and removal applications.


The interaction of serum folate and estradiol levels in Alzheimer's disease.
In vitro and in vivo animal studies suggest that sex steroids, such as estrogens and testosterone, could protect the brain. However, estrogen replacement therapy (ERT) for Alzheimer's disease (AD) in women has not been successful. We hypothesised that the lack of effect of ERT might be related to an interaction between estrogens and some other factor(s) associated with AD. We analysed total estrogen (TE) and testosterone (TT) levels in women diagnosed with AD and controls of the Oxford Project To Investigate Memory and Ageing. Because estradiol (TE2) after the menopause is largely derived from estrone (TE1), we computed the ratio TE2/(TE1+TE2) and a total steroid index (TT+TE2+TE1). Women with AD (n=66) had significantly higher levels of TE2 (27+/-13 vs. 21+/-13) and a higher TE2/(TE1+TE2) ratio. Stepwise logistic regression analyses showed that the TE2/(TE1+TE2) ratio was the main sex steroid predictor for AD (O.R.=1.06, 95% C.I.=1.01-1.11, p<0.01). Multiple regression analyses revealed that dementia severity was associated with an interaction between the TE2/(TE1+TE2) ratio and serum folate (B=4.59 (SE=1.48), beta=1.22, 95% C.I.=1.62-7.56, p<0.005). None of the other potential mediators of this association (body mass index, sex hormone binding globulin, homocysteine levels, ApoE genotype, smoking, diabetes, blood pressure) was significant. A high ratio of estradiol to total estrogens is associated with AD but, in subjects with a high ratio, the dementia severity was lower in those with high serum folate levels. If this association is causal, then supplementation with folic acid might be considered in future studies on ERT in AD.


Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI.
Genetic variability has been shown to affect statin responsiveness. Participants from the Utrecht Cardiovascular Pharmacogenetics (UCP) studies were enrolled from a population-based registry of pharmacy records linked to hospital discharge records (PHARMO) to investigate tagging SNPs within candidate genes involved in the cholesterol lowering pathway for modification of the effectiveness of statins in reducing the risk of myocardial infarction (MI). Patients who received a prescription for an antihypertensive drug and/or had hypercholesterolemia were selected from the PHARMO database. We designed a nested case-control study in which cases were hospitalized for MI and controls were not. Patients were contacted through their community pharmacies. For this study, only hypercholesterolemic participants were selected. Logistic regression analysis was used to investigate pharmacogenetic interactions. The Heart and Vascular Health Study (HVH) was used to replicate findings from UCP. The study population included 668 cases and 1217 controls. We selected 231 SNPs of which 209 SNPs in 27 genes passed quality control. Ten SNPs in eight genes were found to influence the effectiveness of statins in UCP, of which the most significant interaction was found with SCARB1 rs4765615. Other genes that reached statistical significance (p<0.05) included two SNPs in PCSK9 (rs10888896 and rs505151 (E670G)), two SNPs in ABCG5 (rs4245786 and rs1864815), LIPC rs16940379, ABCA1 rs4149264, PPARG rs2972164, LRP1 rs715948, and SOAT1 rs2493121. None of the total of 5 SNPs that were available for replication in HVH reached statistical significance. In conclusion, ten SNPs were found to modify the effectiveness of statins in reducing the risk of MI in the UCP study. Five were also tested in the HVH study, but no interactions reached statistical significance.


Path analysis of the energy density of wood in eucalyptus clones.
Path analysis has been used for establishing selection criteria in genetic breeding programs for several crops. However, it has not been used in eucalyptus breeding programs yet. In the present study, we aimed to identify the wood technology traits that could be used as the criteria for direct and indirect selection of eucalyptus genotypes with high energy density of wood. Twenty-four eucalyptus clones were evaluated in a completely randomized design with five replications. The following traits were assessed: basic wood density, total extractives, lignin content, ash content, nitrogen content, carbon content, hydrogen content, sulfur content, oxygen content, higher calorific power, holocellulose, and energy density. After verifying the variability of all evaluated traits among the clones, a two-dimensional correlation network was used to determine the phenotypic patterns among them. The obtained coefficient of determination (0.94) presented a higher magnitude in relation to the effect of the residual variable, and it served as an excellent model for explaining the genetic effects related to the variations observed in the energy density of wood in all eucalyptus clones. However, for future studies, we recommend evaluating other traits, especially the morphological traits, because of the greater ease in their measurement. Selecting clones with high basic density is the most promising strategy for eucalyptus breeding programs that aim to increase the energy density of wood because of its high heritability and magnitude of the cause-and-effect relationship with this trait.


The Toxins of Nemertean Worms.
Most ribbon worms (phylum: Nemertea) are found in marine environments, where they act as predators and scavengers. They are characterized by an eversible proboscis that isused to hunt for prey and thick mucus covering their skin. Both proboscis and epidermal mucus mediate toxicity to predators and preys. Research into the chemical nature of the substances that render toxicity has not been extensive, but it has nevertheless led to the identification of several compounds of potential medicinal use or for application in biotechnology. This review provides a complete account of the current status of research into nemertean toxins.


Quality-of-life impact of primary treatments for localized prostate cancer in patients without hormonal treatment.
Earlier studies evaluating the effect on quality of life (QoL) of localized prostate cancer interventions included patients receiving adjuvant hormone therapy, which could have affected their outcomes. Our objective was to compare the QoL impact of the three most common primary treatments on patients who were not receiving adjuvant hormonal treatment. This was a prospective study of 435 patients treated with radical prostatectomy, external-beam radiotherapy, or brachytherapy. QoL was assessed before and after treatment with the Short Form-36 and the Expanded Prostate Cancer Index Composite. Differences between groups were tested by analysis of variance. Distribution of outcome at 3 years was examined by stratifying according to baseline status. Generalized estimating equation models were constructed to assess the effect of treatment over time. Compared with the brachytherapy group, the prostatectomy group showed greater deterioration on urinary incontinence and sexual scores but better urinary irritative-obstructive results (-18.22, -13.19, and +6.38, respectively, at 3 years; P < .001). In patients with urinary irritative-obstructive symptoms at baseline, improvement was observed in 64% of those treated with nerve-sparing radical prostatectomy. Higher bowel worsening (-2.87, P = .04) was observed in the external radiotherapy group, with 20% of patients reporting bowel symptoms. Radical prostatectomy caused urinary incontinence and sexual dysfunction but improved pre-existing urinary irritative-obstructive symptoms. External radiotherapy and brachytherapy caused urinary irritative-obstructive adverse effects and some sexual dysfunction. External radiotherapy also caused bowel adverse effects. Relevant differences between treatment groups persisted for up to 3 years of follow-up, although the difference in sexual adverse effects between brachytherapy and prostatectomy tended to decline over long-term follow-up. These results provide valuable information for clinical decision making.


Parent/Adolescent Weight Status Concordance and Parent Feeding Practices.
Previous studies have examined the independent influence of mother's weight status or child's weight status on parents' use of specific feeding practices (ie, food restriction, pressure-to-eat). However, studies have not examined the mutual influence of parents' and adolescents' weight status on parents' feeding practices. This study examines the relationship between parent and adolescent weight status concordance and discordance and parent feeding practices. Data from 2 linked population-based studies, Eating and Activity in Teens (EAT) 2010 and Families and Eating and Activity in Teens (F-EAT), were used for cross-sectional analysis. Parents (n = 3252; 63% female; mean age 42.6 years) and adolescents (n = 2153; 54% female; mean age 14.4 years) were socioeconomically and racially/ethnically diverse. Anthropometric assessments and surveys were completed at school by adolescents, and surveys were completed at home by parents. Parents used the highest levels of pressure-to-eat feeding practices when parents and adolescents were both nonoverweight compared with all other combinations of concordant and discordant parent/adolescent weight status categories. Additionally, parents used the highest levels of food restriction when parents and adolescents were both overweight/obese compared with all other combinations of concordant and discordant parent/adolescent weight status categories. Sensitivity analyses with 2-parent households revealed similar patterns. Results suggest that parents use feeding practices in response to both their adolescents' and their own weight status. Results may inform health care providers and public health interventionists about which parent/adolescent dyads are at highest risk for experiencing food restriction or pressure-to-eat parent feeding practices in the home environment and whom to target in interventions.


Quantifying the role of PSA screening in the US prostate cancer mortality decline.
To quantify the plausible contribution of prostate-specific antigen (PSA) screening to the nearly 30% decline in the US prostate cancer mortality rate observed during the 1990s. Two mathematical modeling teams of the US National Cancer Institute's Cancer Intervention and Surveillance Modeling Network independently projected disease mortality in the absence and presence of PSA screening. Both teams relied on Surveillance, Epidemiology, and End Results (SEER) registry data for disease incidence, used common estimates of PSA screening rates, and assumed that screening, by shifting disease from distant to local-regional clinical stage, confers a corresponding improvement in disease-specific survival. The teams projected similar mortality increases in the absence of screening and decreases in the presence of screening after 1985. By 2000, the models projected that 45% (Fred Hutchinson Cancer Research Center) to 70% (University of Michigan) of the observed decline in prostate cancer mortality could be plausibly attributed to the stage shift induced by screening. PSA screening may account for much, but not all, of the observed drop in prostate cancer mortality. Other factors, such as changing treatment practices, may also have played a role in improving prostate cancer outcomes.


Phenotypic and Molecular Diversity of Cochliobolus sativus Populations from Wheat.
Spot blotch, caused by Cochliobolus sativus, is a devastating foliar disease of wheat in Nepal and in the Northern Great Plains of the United States. However, limited information on variation in virulence and genetic structure of C. sativus from wheat is available. In this study, pathogenic variation of 96 isolates of C. sativus from the Hill and Plain areas in Nepal (n = 48) and in the Central and Northern areas in North Dakota (n = 48) were evaluated on 12 differential wheat lines. DNA polymorphisms in all isolates were analyzed using eight selected amplified fragment length polymorphism primer combinations. Phenotypic data analysis showed the isolates varied greatly and were classified into 47 pathotypes. Cluster analysis indicated the isolates fell into three distinct groups with low, intermediate, and high virulence. Population genetic analysis revealed significant linkage disequilibrium ( = 0.066 to 0.292), indicating that sexual reproduction plays little or no role in evolution and disease epidemiology in wheat fields. Furthermore, the corrected standardized fixation index (G″ST = 0.05 and 0.02) showed no evidence of genetic differentiation in C. sativus populations. Collectively, these results confirmed high pathogenic and molecular diversity in the C. sativus populations collected from wheat foliar infections and will be useful to assist in developing resistant cultivars to manage this disease.


High affinity binding of hydrophobic and autoantigenic regions of proinsulin to the 70 kDa chaperone DnaK.
Chaperones facilitate proper folding of peptides and bind to misfolded proteins as occurring during periods of cell stress. Complexes of peptides with chaperones induce peptide-directed immunity. Here we analyzed the interaction of (pre)proinsulin with the best characterized chaperone of the hsp70 family, bacterial DnaK. Of a set of overlapping 13-mer peptides of human preproinsulin high affinity binding to DnaK was found for the signal peptide and one further region in each proinsulin domain (A- and B-chain, C-peptide). Among the latter, peptides covering most of the B-chain region B11-23 exhibited strongest binding, which was in the range of known high-affinity DnaK ligands, dissociation equilibrium constant (K'd) of 2.2 ± 0.4 μM. The B-chain region B11-23 is located at the interface between two insulin molecules and not accessible in insulin oligomers. Indeed, native insulin oligomers showed very low DnaK affinity (K'd 67.8 ± 20.8 μM) whereas a proinsulin molecule modified to prevent oligomerization showed good binding affinity (K'd 11.3 ± 7.8 μM). Intact insulin only weakly interacts with the hsp70 chaperone DnaK whereas monomeric proinsulin and peptides from 3 distinct proinsulin regions show substantial chaperone binding. Strongest binding was seen for the B-chain peptide B 11-23. Interestingly, peptide B11-23 represents a dominant autoantigen in type 1 diabetes.


A process for controlling intracellular bacterial infections induced by membrane injury.
Strategies for inhibiting phagolysosome fusion are essential for the intracellular survival and replication of many pathogens. We found that the lysosomal synaptotagmin Syt VII is required for a mechanism that promotes phagolysosomal fusion and limits the intracellular growth of pathogenic bacteria. Syt VII was required for a form of Ca2+-dependent phagolysosome fusion that is analogous to Ca2+-regulated exocytosis of lysosomes, which can be triggered by membrane injury. Bacterial type III secretion systems, which permeabilize membranes and cause Ca2+ influx in mammalian cells, promote lysosomal exocytosis and inhibit intracellular survival in Syt VII +/+ but not -/- cells. Thus, the lysosomal repair response can also protect cells against pathogens that trigger membrane permeabilization.


Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1.
A human cytochrome P-450 (P450) 1B1 cDNA was expressed in Saccharomyces cerevisiae and the microsomes containing P450 1B1 were used to examine the selectivity of this enzyme in the activation of a variety of environmental carcinogens and mutagens in Salmonella typhimurium TA1535/pSK1002 or NM2009 tester strains, using the SOS response as an end point of DNA damage. We also determined and compared these activities of P450 1B1 with those catalyzed by recombinant human P450s 1A1 and 1A2, which were purified from membranes of Escherichia coli. The carcinogenic chemicals tested included 27 polycyclic aromatic hydrocarbons and their dihydrodiol derivatives, 17 heterocyclic and aryl amines and aminoazo dyes, three mycotoxins, two nitroaromatic hydrocarbons, N-nitrosodimethylamine, vinyl carbamate, and acrylonitrile. Among the three P450 enzymes examined here, P450 lB1 was found to have the highest catalytic activities for the activation of 11,12-dihydroxy-11,12-dihydrodibenzo[a,l]pyrene, 1,2-dihydroxy-1,2-dihydro-5-methylchrysene, (+)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, 11,12-dihydroxy-11,12-dihydrobenzo[g]chrysene, 3,4-dihydroxy-3,4-dihydrobenzo[c]phenanthrene, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-aminoanthracene, 3-methoxy-4-aminoazobenzene, and 2-nitropyrene. P450 1B1 also catalyzed the activation of 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3-methylimidazo[4,5-f]quinoline, 2-aminofluorene, 6-aminochrysene and its 1,2-dihydrodiol, (-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, 1,2-dihydroxy-1,2-dihydrochrysene, 1,2-dihydroxy-1,2-dihydro-5,6-dimethylchrysene, 2,3-dihydroxy-2,3-dihydrofluoranthene, 3,4-dihydroxy-3,4-dihydro-7,12-dimethylbenz[a]anthracene, and 6-nitrochrysene to appreciable extents. However, P450 1B1 did not produce genotoxic products from benzo[a]pyrene, trans- 3,4-dihydroxy-3,4-dihydrobenzo[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenzo[a]anthracene, 7,12-dimethylbenz[a]anthracene and its cis-5,6-dihydrodiol, 5-methylchrysene, 11,12-dihydroxy-11,12-dihydro-3-methylcholanthrene, 1,2-dihydroxy-1,2-dihydro-6-methylchrysene, benzo[c]phenanthrene, 2-amino-6-methyldipyridol[1,2-a:3',2'-d]imidazole, 2-acetylaminofluorene, benzidine, 2-naphthylamine, aflatoxin B1, aflatoxin G1, sterigmatocystin, N-nitrosodimethylamine, vinyl carbamate, or acrylonitrile in this assay system. P450 1B1 is expressed constitutively in extrahepatic organs, including fetal tissue samples, and is highly inducible in various organs by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds in experimental animal models. Thus, activation of procarcinogens by P450 lB1 may contribute to human tumors of extrahepatic origin.


Effects of abomasal infusion of long-chain fatty acids on intake, feeding behavior and milk production in dairy cows.
Fat is often fed to dairy cows to increase the energy concentration of their diet; however, feeding fat often reduces dry matter intake (DMI), which limits its impact on metabolizable energy (ME) intake. To investigate the effects of postruminal fat infusion on intake, feeding behavior, and milk production of dairy cows at two stages of lactation (55 and 111 d postpartum), six Holstein x British Friesian cows were infused into the abomasum, with a mixture of rapeseed and sunflower oils supplying predominantly unsaturated long-chain fatty acids (LCFA). Dry matter intake was significantly depressed by oil infusion, but estimated ME intake was unchanged, and thus there was no effect of oil infusion on milk yield. There was no effect of stage of lactation on the DM or ME intake response to oil infusion. Milk fat concentration was increased by oil infusion in mid-lactation but not in early lactation, suggesting that the infused LCFA were utilized differently in early compared with midlactation. Cows spent an average of 654 min idling, 462 min ruminating, and 248 min eating during the last 22.8 h of each infusion. There were no significant effects of oil infusion or stage of lactation on the total time spent engaged in these activities. An assessment of the circadian pattern of feeding behavior suggested that the depression in DMI in response to oil infusion occurred after the 1630 and 2230 h feeding times. This may reflect differences in mechanisms regulating feed intake behavior and appetite during the day. Comparison of the results of the present study with the results of other trials involving postruminal fat infusion suggests that polyunsaturated nonesterified fatty acids have the most potent effect on DMI intake.


Resolution Enhancement in PET Reconstruction Using Collimation.
Collimation can improve both the spatial resolution and sampling properties compared to the same scanner without collimation. Spatial resolution improves because each original crystal can be conceptually split into two (i.e., doubling the number of in-plane crystals) by masking half the crystal with a high-density attenuator (e.g., tungsten); this reduces coincidence efficiency by 4× since both crystals comprising the line of response (LOR) are masked, but yields 4× as many resolution-enhanced (RE) LORs. All the new RE LORs can be measured by scanning with the collimator in different configurations. In this simulation study, the collimator was assumed to be ideal, neither allowing gamma penetration nor truncating the field of view. Comparisons were made in 2D between an uncollimated small-animal system with 2-mm crystals that were assumed to be perfectly absorbing and the same system with collimation that narrowed the effective crystal size to 1 mm. Digital phantoms included a hot-rod and a single-hot-spot, both in a uniform background with activity ratio of 4:1. In addition to the collimated and uncollimated configurations, angular and spatial wobbling acquisitions of the 2-mm case were also simulated. Similarly, configurations with different combinations of the RE LORs were considered including (i) all LORs, (ii) only those parallel to the 2-mm LORs; and (iii) only cross pairs that are not parallel to the 2-mm LORs. Lastly, quantitative studies were conducted for collimated and uncollimated data using contrast recovery coefficient and mean-squared error (MSE) as metrics. The reconstructions show that for most noise levels there is a substantial improvement in image quality (i.e., visual quality, resolution, and a reduction in artifacts) by using collimation even when there are 4× fewer counts or - in some cases - comparing with the noiseless uncollimated reconstruction. By comparing various configurations of sampling, the results show that it is the matched combination of both improved spatial resolution of each LOR and the increase in the number of LORs that yields improved reconstructions. Further, the quantitative studies show that for low-count scans, the collimated data give better MSE for small lesions and the uncollimated data give better MSE for larger lesions; for high-count studies, the collimated data yield better quantitative values for the entire range of lesion sizes that were evaluated.


Temperature- and strain-independent torsion sensor using a fiber loop mirror based on suspended twin-core fiber.
In this Letter, we present a fiber loop mirror configuration based on a suspended twin-core fiber for sensing applications. Using the suspended twin-core fiber, the fringe pattern is due to the differential optical patch of the light in the two cores associated with a refractive index difference of approximately 10(-3), which indicates an advantage of this approach compared with those based on high-birefringent fibers, namely, the possibility of using a small length of fiber. The sensing configuration was characterized for torsion, temperature, and strain. Using the fast Fourier transform technique, it is possible to obtain measurand-induced amplitude variations of the fringe pattern. The results obtained indicate the viability of a temperature- and strain-independent torsion sensor.


Reverse transcription polymerase chain reaction and electrospray ionization mass spectrometry for identifying acute viral upper respiratory tract infections.
Diagnosis of respiratory viruses traditionally relies on culture or antigen detection. We aimed to demonstrate capacity of the reverse transcription polymerase chain reaction/electrospray ionization mass spectrometry (RT-PCR/ESI-MS) platform to identify clinical relevant respiratory viruses in nasopharyngeal aspirate (NPA) samples and compare the diagnostic performance characteristics relative to conventional culture- and antigen-based methods. An RT-PCR/ESI-MS respiratory virus surveillance kit designed to detect respiratory syncytial virus, influenza A and B, parainfluenza types 1-4, Adenoviridae types A-F, Coronaviridae, human bocavirus, and human metapneumovirus was evaluated using both mock-ups and frozen archived NPA (N = 280), 95 of which were positive by clinical virology methods. RT-PCR/ESI-MS detected 74/95 (77.9%) known positive samples and identified an additional 13/185 (7%) from culture-negative samples. Viruses that are nondetectable with conventional methods were also identified. Viral load was semiquantifiable and ranged from 2400 to >320 000 copies/mL. Time to results was 8 h. RT-PCR/ESI-MS showed promise in rapid detection of respiratory viruses and merits further evaluation for use in clinical settings.


Human immunodeficiency virus infection and pulmonary hypertension: two new cases and a review of 86 reported cases.
In this article, we describe pulmonary hypertension in two men (31 and 43 years of age) with human immunodeficiency virus (HIV) infection who were examined at Mayo Clinic Rochester. Among 88 reported cases (including the two current ones) of HIV- or acquired immunodeficiency syndrome (AIDS)-associated pulmonary hypertension, 61% were male; the age range was 2 to 56 years (mean, 32). Dyspnea was the usual initial symptom. Of the 74 patients in whom pulmonary artery pressure was recorded or calculated by echocardiography, systolic pressures ranged from 49 to 118 mm Hg (mean, 68). Of the 33 cases in which lung tissue was evaluated microscopically, 28 (85%) were of the plexogenic variant of pulmonary arterial hypertension. Of the other five cases examined histologically, three consisted of thrombotic pulmonary arteriopathy (one was due to recurrent thromboembolism, and the other two were due to in situ thrombosis), and two were of pulmonary venoocclusive disease. No correlation existed between either CD4 counts or a history of pulmonary infections and the development of pulmonary hypertension. In 15 of the 88 patients (17%), confounding factors for hypertensive pulmonary vascular disease were present, including coexisting liver disease in 13 and coagulation abnormalities in 2. In 83% of the patients, the development of pulmonary hypertension seems to have been related primarily to the chronic HIV infection. Pulmonary hypertension was more rapidly progressive in patients with HIV or AIDS than in those with primary pulmonary hypertension; the reported time intervals between onset of symptoms and diagnosis were 6 months and 30 months, respectively. The 1-year survival rate for patients with HIV and pulmonary hypertension was 51%, based on the follow-up data compiled from the 63 patients in whom it was described; this compares with a 1-year survival rate of 68% for patients with primary pulmonary hypertension. Death was considered a direct consequence of pulmonary hypertension in 29 (76%) of the 38 fatal cases.


Why healthcare workers are sick of TB.
Dr Thato Mosidi never expected to be diagnosed with tuberculosis (TB), despite widely prevalent exposure and very limited infection control measures. The life-threatening diagnosis of primary extensively drug-resistant TB (XDR-TB) came as an even greater shock. The inconvenient truth is that, rather than being protected, Dr Mosidi and thousands of her healthcare colleagues are at an increased risk of TB and especially drug-resistant TB. In this viewpoint paper we debunk the widely held false belief that healthcare workers are somehow immune to TB disease (TB-proof) and explore some of the key factors contributing to the pervasive stigmatization and subsequent non-disclosure of occupational TB. Our front-line workers are some of the first to suffer the consequences of a progressively more resistant and fatal TB epidemic, and urgent interventions are needed to ensure the safety and continued availability of these precious healthcare resources. These include the rapid development and scale-up of improved diagnostic and treatment options, strengthened infection control measures, and focused interventions to tackle stigma and discrimination in all its forms. We call our colleagues to action to protect themselves and those they care for.


Clozapine treatment in Russia: a review of clinical research.
This paper is intended to help American clinicians and investigators further their understanding of the clinical use of clozapine by reviewing experience with the drug in Russia, where it was introduced 17 years before it became available in the United States. Key articles on clozapine from the Russian clinical research literature were reviewed by the first two authors, former Russian clinical investigators. The third author comments briefly about the implications of this work from a contemporary American perspective. The review found that although clozapine was not widely distributed in Russia, it was investigated at several large psychiatric research institutions and hospitals. It was not reserved for neuroleptic-resistant disorders but instead was used with some success as a first-line treatment in acute disorders. Although no controlled clinical trials were conducted, results of long-term outcome studies of treatment-resistant schizophrenia were largely in agreement with those of controlled trials and clinical follow-up studies in the U.S. The studies found short-term gains for previously refractory patients as well as improvements in social functioning that continued for extended periods in some cases. Russian investigators described clozapine as an effective antipsychotic agent that lacked the extrapyramidal side effects of other neuroleptics.


Identification of infants with significant refractive error and strabismus in a population screening program using noncycloplegic videorefraction and orthoptic examination.
The second Cambridge Infant Vision Screening Program examined whether screening for accommodative errors by using videorefraction without cycloplegia could effectively serve as a first stage of screening for refractive errors, measured by standard cycloplegic retinoscopy. The screening also included an orthoptic examination for detection of strabismus. All infants born in the Cambridge (UK) Health District, over a 2-year period, were invited for screening. Of those 5142 (76%) with mean age 8.1 +/- 0.8 months (SD) attended and received noncycloplegic videorefraction and an orthoptic examination. All those with a focusing error or orthoptic problem, as well as a randomly selected sample of visually normal control subjects, were invited to follow-up a month later for cycloplegic retinoscopy, repeat noncycloplegic videorefraction and orthoptic examination. Of the 5142 screened, 514 had a focusing error or orthoptic problem (positives). Four hundred thirty-nine of these and 284 visually normal control subjects (negatives) attended follow-up. A refractive or orthoptic condition was confirmed in 59.0% of the positive cases, whereas infants in 96.8% of the negative cases were confirmed normal. Adjusting for the proportions of the population represented by those infants seen at follow-up, sensitivity for the screening procedure was calculated at 0.67 and specificity at 0.96. Detailed results are presented in terms of the different conditions detected at screening (far, near, and anisometropic focus and orthoptic error), distribution of greatest axes at screening, and a comparison of initial videorefraction with repeat videorefraction and cycloplegic retinoscopy. A noncycloplegic screening procedure, simpler to perform than cycloplegic screening, succeeded in detecting a large proportion of infants with significant ametropia, particularly those with significant hyperopia, which is considered to be a strabismogenic and amblyogenic risk factor.


Repeated dose and reproductive/developmental toxicity of perfluoroundecanoic acid in rats.
Perfluoroalkyl acids (PFAAs) are environmental contaminants that have received attention because of their possible effects on wildlife and human health. In order to obtain initial risk information on the toxicity of perfluoroundecanoic acid (PFUA), we conducted a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD test guideline 422). PFUA was administered by gavage to rats at 0 (vehicle: corn oil), 0.1, 0.3 or 1.0 mg/kg/day. At 1.0 mg/kg/day, body weight gain was inhibited in both sexes, and there was a decrease in fibrinogen in both sexes and shortening of the activated partial thromboplastin time in males. An increase in blood urea nitrogen and a decrease in total protein in both sexes and increases in alkaline phosphatase and alanine transaminase and a decrease in albumin in males were observed at 1.0 mg/kg/day. Liver weight was increased in males at 0.3 mg/kg/day and above and in females at 1.0 mg/kg/day, and this change was observed after a recovery period. In both sexes, centrilobular hypertrophy of hepatocytes was observed at 0.3 mg/kg/day and above and focal necrosis was observed at 1.0 mg/kg/day. In reproductive/developmental toxicity, body weight of pups at birth was lowered and body weight gain at 4 days after birth was inhibited at 1.0 mg/kg/day, while no dose-related changes were found in the other parameters. Based on these findings, the no observed adverse effect levels (NOAELs) for the repeated dose and reproductive/developmental toxicity were considered to be 0.1 mg/kg/day and 0.3 mg/kg/day, respectively.


Glucose deprivation-induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma.
Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.


Revisiting the Regenerative Therapeutic Advances Towards Erectile Dysfunction.
Erectile dysfunction (ED) is an inability to attain or maintain adequate penile erection for successful vaginal intercourse, leading to sexual and relationship dissatisfaction. To combat ED, various surgical and non-surgical approaches have been developed in the past to restore erectile functions. These therapeutic interventions exhibit significant impact in providing relief to patients; however, due to their associated adverse effects and lack of long-term efficacy, newer modalities such as regenerative therapeutics have gained attention due to their safe and prolonged efficacy. Stem cells and platelet-derived biomaterials contained in platelet-rich plasma (PRP) are thriving as some of the major therapeutic regenerative agents. In recent years, various preclinical and clinical studies have evaluated the individual, as well as combined of stem cells and PRP to restore erectile function. Being rich in growth factors, chemokines, and angiogenic factors, both stem cells and PRP play a crucial role in regenerating nerve cells, myelination of axons, homing and migration of progenitor cells, and anti-fibrosis and anti-apoptosis of damaged cavernous nerve in corporal tissues. Further, platelet-derived biomaterials have been proven to be a biological supplement for enhancing the proliferative and differentiation potential of stem cells towards neurogenic fate. Therefore, this article comprehensively analyzes the progresses of these regenerative therapies for ED.


Effect of the melt granulation technique on the dissolution characteristics of griseofulvin.
This work describes a melt granulation technique to improve the dissolution characteristics of a poorly water-soluble drug, griseofulvin. Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. Granules were prepared in a lab scale high shear mixer, using a jacket temperature of 60 degrees C and an impeller speed of approximately 20,000 rpm. The effect of drug loading (2.5/5%), binder (PEG 3350/Gelucire 44/14), filler (starch/lactose), and HPMC on the dissolution of griseofulvin was investigated using a half two level-four factor factorial design. The granules were characterized using powder XRD, DSC and SEM techniques. A significant enhancement in the in vitro dissolution profiles of the granules was observed compared to the pure drug and drug excipient physical mixtures. The factorial design results indicated that higher drug loading and the presence of HPMC reduced the extent of dissolution of the drug, whereas, the presence of starch enhanced the dissolution rate. XRD data confirmed crystalline drug in formulation matrices. DSC results indicated monotectic mixtures of griseofulvin with PEG in the granulated formulations. In conclusion, the results of this work suggest that melt granulation is a useful technique to enhance the dissolution rate of poorly water-soluble drugs, such as, griseofulvin.


Broadband control of plate radiation using a piezoelectric, double-amplifier active-skin and structural acoustic sensing
The potential of a piezoelectric, double-amplifier active-skin with structural acoustic sensing (SAS) is demonstrated for the reduction of broadband acoustic radiation from a clamped, aluminum plate. The active-skin is a continuous covering of the vibrating portions of the plate with active, independently controllable piezoelectric, double-amplifier elements and is designed to affect control by altering the continuous structural radiation impedance rather than structural vibration. In simulation, acoustic models are sought for the primary and secondary sources that incorporate finite element methods. Simulation indicates that a total radiated power attenuation in excess of 10 dB may be achieved between 250 and 750 Hz with microphone error sensing, while under SAS the radiated power is reduced by nearly 8 dB in the same frequency range. In experiment, the adaptive feed forward filtered-x LMS (least mean square) algorithm, implemented on a Texas Instruments C40 DSP, was used in conjunction with the 6I6O control system. With microphone error sensing, 11.8-dB attenuation was achieved in the overall radiated power between 175 and 600 Hz, while inclusion of SAS resulted in a 7.3-dB overall power reduction in this frequency band.


Cross-cultural comparison of patients undergoing ACL reconstruction in the United States and Norway.
Data from large prospectively collected anterior cruciate ligament (ACL) cohorts are being utilized to address clinical questions regarding ACL injury demographics and outcomes of ACL reconstruction. These data are affected by patient and injury factors as well as surgical factors associated with the site of data collection. The aim of this article is to compare primary ACL reconstruction data from patient cohorts in the United States and Norway, demonstrating the similarities and differences between two large cohorts. Primary ACL reconstruction data from the Multicenter Orthopaedic Outcomes Network (MOON) in the United States and the Norwegian National Knee Ligament Registry (NKLR) were compared to identify similarities and differences in patient demographics, activity at injury, preoperative Knee injury and Osteoarthritis Outcome Score (KOOS), time to reconstruction, intraarticular pathology, and graft choice. Seven hundred and thirteen patients from the MOON cohort were compared with 4,928 patients from the NKLR. A higher percentage of males (NKLR 57%, MOON 52%; P < 0.01) and increased patient age (NKLR 27 years, MOON 23 years; P\0.001) were noted in the NKLR population. The most common sports associated with injury in the MOON cohort were basketball (20%), soccer (17%), and American football (14%); while soccer (42%), handball (26%), and downhill skiing (10%) were most common in the NKLR. Median time to reconstruction was 2.4 (Interquartile range [IQR] 1.2-7.2) months in the MOON cohort and 7.9 (IQR 4.2-17.8) months in the NKLR cohort (P < 0.001). Both meniscal tears (MOON 65%, NKLR 48%; P < 0.001) and articular cartilage defects (MOON 46%, NKLR 26%; P < 0.001) were more common in the MOON cohort. Hamstring autografts (MOON 44%, NKLR 63%) and patellar tendon autografts (MOON 42%, NKLR 37%) were commonly utilized in both cohorts. Allografts were much more frequently utilized in the MOON cohort (MOON 13%, NKLR 0.04%; P < 0.001). Significant diversity in patient, injury, and surgical factors exist among large prospective cohorts collected in different locations. Surgeons should investigate and consider the characteristics of these cohorts when applying knowledge gleaned from these groups to their own patient populations.


Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial.
To determine the safety and efficacy of etanercept in a multicenter, randomized, placebo-controlled, double-blind trial of adults with moderate to severe active ankylosing spondylitis (AS). Patients (n = 277) were treated with either etanercept 25 mg (n = 138) or placebo (n = 139) subcutaneously twice weekly for 24 weeks. The primary outcome measures were the percentages of patients achieving the Assessments in Ankylosing Spondylitis 20% response (ASAS20) at weeks 12 and 24. Other outcome measures included the percentage of patients achieving higher ASAS responses, and the safety of etanercept in patients with AS. All outcome measures were assessed at 2, 4, 8, 12, and 24 weeks. Treatment with etanercept resulted in dramatic improvement. The ASAS20 was achieved by 59% of patients in the etanercept group and by 28% of patients in the placebo group (P < 0.0001) at week 12, and by 57% and 22% of patients, respectively, at week 24 (P < 0.0001). All individual ASAS components, acute-phase reactant levels, and spinal mobility measures were also significantly improved. The safety profile of etanercept was similar to that reported in studies of patients with rheumatoid arthritis or psoriatic arthritis. The only adverse events that occurred significantly more often in the etanercept group were injection-site reactions, accidental injuries, and upper respiratory tract infections. Etanercept is a highly effective and well tolerated treatment in patients with active AS.


Cardiopulmonary Resuscitation during COVID-19 Pandemic: Outcomes, Risks, and Protective Strategies for the Healthcare Workers and Ethical Considerations.
The crisis caused by Coronavirus disease-2019 (COVID-19) pandemic has led us to safeguard ourselves and our colleagues against transmission of this highly contagious infection, while aiming for the same goals of care. In spite of the stringent measures adopted by affected countries, rising number of healthcare workers (HCWs) are getting infected, dwindling the scarce manpower at our disposal. In the pre-COVID-19 times, cardiopulmonary resuscitation (CPR) was offered unhesitantly to all patients, who had even a slim chance of achieving return of spontaneous circulation. In COVID-19 era, CPR, due to some components being high aerosol-generating procedures (AGPs), has become high-risk procedure for the HCWs. Instead of "Primum non nocere" (first do no harm), we are forced to change to "Primum non nocere ad te" (first do no harm to yourself). The challenge is therefore to provide best possible chance of survival to deserving patients, whose COVID-19 status might be unknown, without causing harm to the HCWs. In this review, we discuss the current data regarding infected HCWs, outcomes of inhospital and out-of-hospital cardiac arrests, components of CPR which are high-risk AGPs, how to safeguard the HCWs while offering CPR, and the ethical considerations when CPR is considered, in this COVID-19 era. We wish to emphasize here that there is NO EMERGENCY in a pandemic, and time must be made for donning appropriate PPE. We feel that clear policies need to be developed by the institutions to deliver CPR to correct population, in this challenging period. How to cite this article: Kulkarni AP, Singh Y, Garg H, Jha S. Cardiopulmonary Resuscitation during COVID-19 Pandemic: Outcomes, Risks, and Protective Strategies for the Healthcare Workers and Ethical Considerations. Indian J Crit Care Med 2020;24(9):868-872.


Inhibition of human immunodeficiency virus type 1 and type 2 Tat function by transdominant Tat protein localized to both the nucleus and cytoplasm.
We introduced various mutations into the activation and RNA binding domains of human immunodeficiency virus type 1 (HIV-1) Tat in order to develop a novel and potent transdominant Tat protein and to characterize its mechanism of action. The different mutant Tat proteins were characterized for their abilities to activate the HIV LTR and inhibit the function of wild-type Tat in trans. A Tat protein containing a deletion of the basic domain (Tat(delta)49-57) localized exclusively to the cytoplasm of transfected human cells was nonfunctional and inhibited both HIV-1 and HIV-2 Tat function in a transdominant manner. Tat proteins containing mutations in the cysteine-rich and core domains were nonfunctional but failed to inhibit Tat function in trans. When Tat nuclear or nucleolar localization signals were fused to the carboxy terminus of Tat(delta)49-57, the chimeric proteins localized to the nucleus or nucleolus, respectively, and remained capable of acting in a transdominant manner. Introduction of secondary mutations in the cysteine-rich and core domains of the various transdominant Tat proteins completely eliminated their abilities to act in a transdominant fashion. Our data best support a mechanism in which these transdominant Tat proteins squelch a cellular factor or factors that interact with the Tat activation domain and are required for Tat to function.


The aromatase enzyme: from cloning to cancer.
Estrogen production by adipose tissue has been implicated in the etiology of such human cancers as endometrial and breast cancer. Estrogen production by adipose cells is subject to complex multifactorial regulation by a number of growth factors and cytokines, including those produced by breast cancer cells. In order to understand the mechanisms responsible for aromatase regulation, the structural gene encoding aromatase cytochrome P-450 (P-450AROM) was isolated from human genomic DNA. The gene spans at least 70 kb and is comprised of 10 exons, the first of which is untranslated. DNA sequence analysis indicates that the gene has a putative TATA (ATAAAA) sequence at -23 bp and putative CAAT binding sequences beginning at -41, -67, and -83 bp, that constitute a promoter region responsible for expression in placenta. However, this promoter does not appear to be responsible for expression in adipose, which may therefore be under the control of another, tissue-specific, promoter. Use of Polymerase Chain Reaction (PCR) technology has allowed for determination of expression of P-450AROM in samples of breast adipose. Preliminary results indicate that expression is highest in the upper lateral region, similar to the site of most frequent localization of tumors.


Women as agents of change: Female income and mobility in India.
Economic globalization will give many women in developing countries access to steady and relatively remunerative employment for the first time, potentially shifting bargaining power within their households and changing the choices that are made for their children. This paper exploits a unique setting - a group of tea plantations in South India where women are employed in permanent wage labor and where incomes do not vary by caste - to anticipate the impact of globalization on mobility across social groups in the future. The main result of the paper is that a relative increase in female income weakens the family's ties to the ancestral community and the traditional economy, but these mobility enhancing effects are obtained for certain historically disadvantaged castes alone. Although the paper provides a context-specific explanation for why the women from these castes emerge as agents of change, the first general implication of the analysis is that the incentive and the ability of women to use their earnings to influence household decisions depends importantly on their social background. The second implication is that historically disadvantaged groups may, in fact, be especially responsive to new opportunities precisely because they have fewer ties to the traditional economy to hold them back.


Characterization of the gastric immune response in cheetahs (Acinonyx jubatus) with Helicobacter-associated gastritis.
Captive cheetahs have an unusually severe progressive gastritis that is not present in wild cheetahs infected with the same strains of Helicobacter. This gastritis, when severe, has florid lymphocyte and plasma cell infiltrates in the epithelium and lamina propria with gland destruction, parietal cell loss, and, in some cases, lymphoid follicles. The local gastric immune response was characterized by immunohistochemistry in 21 cheetahs with varying degrees of gastritis. The character of the response was similar among types of gastritis except that cheetahs with severe gastritis had increased numbers (up to 70%) of lamina proprial CD79a+CD21- B cells. CD3+CD4+ T cells were present in the lamina propria, and CD3+CD8α+ T cells were within the glandular epithelium. Lymphoid aggregates had follicular differentiation with a central core of CD79a+/CD45R+ B cells and with an outer zone of CD3+ T cells that expressed both CD4 and CD8 antigens. MHC II antigens were diffusely expressed throughout the glandular and superficial epithelium. No cheetah had evidence of autoantibodies against the gastric mucosa when gastric samples from 30 cheetahs with different degrees of gastritis were incubated with autologous and heterologous serum. These findings indicate that T-cell distribution in cheetahs is qualitatively similar to that in other species infected with Helicobacter but that large numbers of lamina propria activated B cells and plasma cells did distinguish cheetahs with severe gastritis. Further research is needed to determine whether alterations in the Th1:Th2 balance are the cause of this more plasmacytic response in some cheetahs.


Developmental differences in sensitivity to semantic relations among good and poor comprehenders: evidence from semantic priming.
Semantic priming for category coordinates (e.g. CAT-DOG; AEROPLANE-TRAIN) and for pairs of words related through function (e.g. BROOM-FLOOR; SHAMPOO-HAIR) was assessed in children with good and poor reading comprehension, matched for decoding skill. Lexical association strength was also manipulated by comparing pairs of words that were highly associated with pairs that shared low association strength. Both groups of children showed priming for function-related words, but for the category co-ordinates, poor comprehenders only showed priming if the category pairs also shared high association strength. Good comprehenders showed priming for category-related targets, irrespective of the degree of prime-target association. These findings are related to models of language development in which category knowledge is gradually abstracted and refined from children's event-based knowledge and it is concluded that in the absence of explicit co-occurrence, poor comprehenders are less sensitive to abstract semantic relations than normal readers.


Establishment of a 7-ethyl-10-hydroxy-camptothecin-resistant small cell lung cancer cell line.
Irinotecan is one of the most active drugs used in the treatment of small cell lung cancer (SCLC). 7-Ethyl-10-hydroxy-camptothecin (SN-38) is an active metabolite of irinotecan. We established an SN-38-resistant subline (SBC-3/SN-38) by continuous exposure of SN-38 to a human SCLC cell line, SBC-3. Using the 3-[4, 5-dimethyl-thiazol-2-yl] 2, 5-diphenyltetrazolium bromide assay, we evaluated the cytotoxicity of 17 anticancer agents. The SBC-3/SN-38 cells were 73-fold more resistant than the parental SBC-3 cells to SN-38 and showed cross-resistance not only to topoisomerase (topo) I inhibitors (irinotecan and topotecan), but also to topo II inhibitors (adriamycin and etoposide), antimicrotubule agents (vincristine, vindesine, vinorelbine and docetaxel), alkylating agents (cyclophosphamide and ifosfamide), platinum (cisplatin and carboplatin) and antifolate (methotrexate). Interestingly, the resistant subline reserved the sensitivity to bleomycin and 5-fluorouracil. The SBC-3/SN-38 cells had decreased topo I and II activity compared to the parent cells. The SN-38-resistant cell line, SBC-3/SN-38, will be useful to elucidate the mechanism of action of the topo I inhibitors.


Intra- and Intersexual swim bladder dimorphisms in the plainfin midshipman fish (Porichthys notatus): Implications of swim bladder proximity to the inner ear for sound pressure detection.
The plainfin midshipman fish, Porichthys notatus, is a nocturnal marine teleost that uses social acoustic signals for communication during the breeding season. Nesting type I males produce multiharmonic advertisement calls by contracting their swim bladder sonic muscles to attract females for courtship and spawning while subsequently attracting cuckholding type II males. Here, we report intra- and intersexual dimorphisms of the swim bladder in a vocal teleost fish and detail the swim bladder dimorphisms in the three sexual phenotypes (females, type I and II males) of plainfin midshipman fish. Micro-computerized tomography revealed that females and type II males have prominent, horn-like rostral swim bladder extensions that project toward the inner ear end organs (saccule, lagena, and utricle). The rostral swim bladder extensions were longer, and the distance between these swim bladder extensions and each inner-ear end organ type was significantly shorter in both females and type II males compared to that in type I males. Our results revealed that the normalized swim bladder length of females and type II males was longer than that in type I males while there was no difference in normalized swim bladder width among the three sexual phenotypes. We predict that these intrasexual and intersexual differences in swim bladder morphology among midshipman sexual phenotypes will afford greater sound pressure sensitivity and higher frequency detection in females and type II males and facilitate the detection and localization of conspecifics in shallow water environments, like those in which midshipman breed and nest.


Synthesis and characterisation of luminescent rhenium tricarbonyl complexes with axially coordinated 1,2,3-triazole ligands.
A series of 1-alkyl-4-aryl-1,2,3-triazoles (1-methyl-4-phenyl-1,2,3-triazole (1a); 1-propyl-4-phenyl-1,2,3-triazole (1b); 1-benzyl-4-phenyl-1,2,3-triazole (1c); 1-propyl-4-p-tolyl-1,2,3-triazole (1d)) have been prepared through a one-pot procedure involving in situ generation of the alkyl azide from a halide precursor followed by copper catalysed alkyne/azide cycloaddition (CuAAC) with the appropriate aryl alkyne. Cationic Re(I) complexes [Re(bpy)(CO)(3)(1a-d)]PF(6) (2a-d) were then prepared by stirring [Re(bpy)(CO)(3)Cl] with AgPF(6) in dichloromethane in the presence of ligands 1a-d. X-ray crystal structures were obtained for 2a and 2b. In the solid state, 2a adopts a highly distorted geometry, which is not seen for 2b, in which the plane of the triazole ligand tilts by 13° with respect to the Re-N bond as a result of a π-stacking interaction between the Ph substituent and one of the rings of the bpy ligand. This π-stacking interaction also results in severe twisting of the bpy ligand. Infrared spectra of 2a-d exhibit ν(CO) bands at ∼2035 and ∼1926 cm(-1) suggesting that these ligands are marginally better donors than pyridine (ν(CO) = 2037, 1932 cm(-1)). The complexes are luminescent in aerated dichloromethane at room temperature with emission maxima at 542 to 552 nm comparable to that of the pyridine analogue (549 nm) and blue shifted relative to the parent chloride complex. Long luminescent lifetimes are observed for the triazole complexes (475 to 513 ns) in aerated dichloromethane solutions at room temperature.


Protective Effects of Enriched Environment Against Transient Cerebral Ischemia-Induced Impairment of Passive Avoidance Memory and Long-Term Potentiation in Rats.
Enriched Environment (EE), a complex novel environment, has been demonstrated to improve synaptic plasticity in both injured and intact animals. The present study investigated the capacity of an early environmental intervention to normalize the impairment of passive avoidance memory and Long-Term Potentiation (LTP) induced by transient bilateral common carotid artery occlusion (2-vessel occlusion, 2VO) in rats. After weaning, young Wistar rats (22 days old) were housed in EE or Standard Environment (SE) for 40 days. Transient (30-min) incomplete forebrain ischemia was induced 4 days before the passive avoidance memory test and LTP induction. The transient forebrain ischemia led to impairment of passive avoidance memory and LTP induction in the Perforant Path-Dentate Gyrus (PP-DG) synapses. Interestingly, housing and growing in EE prior to 2VO was found to significantly reverse 2VO-induced cognitive and LTP impairments. Our results suggest that early housing and growing in EE exhibits therapeutic potential to normalize cognitive and LTP abnormalities induced by 2VO ischemic model in rats.


Expression of beta 1 integrin complexes on the surface of unfertilized mouse oocyte.
Integrins are a family of cell surface receptors that mediate cell-cell and cell-matrix interactions in a variety of different cellular systems. Here we show that unfertilized mouse oocytes express beta 1 class integrins both at mRNA and protein levels. Using the reverse transcription polymerase chain reaction and oligonucleotide primers based on the DNA sequence of mouse integrins, the RNA transcripts for the beta 1, alpha 5 and alpha 6 subunits were detected in unfertilized oocytes. The expression of the mRNAs is paralleled by the expression of the corresponding proteins, in fact, the alpha 5/beta 1 and the alpha 6/beta 1 complexes can be immunoprecipitated with specific antibodies form 125I-surface-labeled oocytes. Using subunit-specific antibodies we also demonstrate the presence of the alpha 3/beta 1 at the oocyte surface but alpha 1, alpha 2, alpha 4 or alpha V subunits were not detectable. Since the mouse alpha 3 DNA sequence is not available, we have not tested for the corresponding transcript. Integrin subunits alpha 6 and beta 1 were differently distributed on the oocyte surface, as visualized by immunofluorescence staining and by immunoelectron microscopy. alpha 6 antigen was mainly confined to the microvillous area of the oocyte surface, while beta 1 was more homogeneously distributed over the whole oolemma. These data demonstrate for the first time the expression of three beta 1 integrin complexes in unfertilized mouse oocytes. Such proteins may have a role in sperm-egg interaction or during very early steps of embryogenesis.


Respiratory infections in acute stroke: nasogastric tubes and immobility are stronger predictors than dysphagia.
Swallowing problems occur in 37-78 % of stroke patients. Evidence points to multiple factors contributing to the development of pneumonia in the first week post stroke, of which the presence of dysphagia is one. A heightened understanding of the very acute phase (first 7 days post stroke) is required to improve management of this population. We conducted a retrospective review of 536 stroke patients admitted to Australian hospitals in 2010. Data were collected on 37 clinical and demographic parameters. Descriptive statistics and univariate and multivariate logistic regression analyses were performed. Dysphagia was present in 58.5 % of admissions. For those patients remaining in the study for the full week there was a recovery rate from dysphagia of 30.5 %. Overall incidence of respiratory infection was 11 %. Respiratory infections developed in 17 % of patients with dysphagia. Impaired Glasgow Coma Scale, ischemic stroke, and significantly impaired mobility were associated with swallowing difficulties. Being nil by mouth and insertion of a nasogastric tube were significant predictors for respiratory infections. This study of a large cohort of acute stroke patients supports research indicating that aspiration pneumonia is multifactorial in nature and the incidence of respiratory infection is significant in the very acute stroke period.


Defective sialic acid egress from isolated fibroblast lysosomes of patients with Salla disease.
Normal fibroblasts exposed to N-acetylmannosamine yielded lysosome-rich granular fractions loaded with free (unbound) sialic acid, whose velocity of egress increased with increasing initial loading. Fibroblast granular fractions of patients with Salla disease exhibited negligible egress of sialic acid, whether endogenous or derived from N-acetylmannosamine exposure. Salla disease represents the first disorder demonstrated to be caused by defective transport of a monosaccharide out of cellular lysosomes.


Cholesterol and egg intakes and the risk of type 2 diabetes: the Japan Public Health Center-based Prospective Study.
Limited and inconsistent associations between cholesterol and egg consumption and type 2 diabetes risk have been observed in Western countries. In the present study, the association of dietary cholesterol and egg intakes with type 2 diabetes risk was examined prospectively. The study subjects comprised 27, 248 men and 36,218 women aged 45-75 years who participated in the second survey of the Japan Public Health Center-based Prospective Study and had no histories of type 2 diabetes or other serious diseases. Dietary cholesterol and egg intakes were estimated using a validated 147-item FFQ. The OR of self-reported, physician-diagnosed type 2 diabetes over 5 years were estimated using multiple logistic regression. A total of 1165 newly diagnosed cases of type 2 diabetes were self-reported. Although dietary cholesterol intake was not associated with type 2 diabetes risk in men, it was found to be associated with a 23 % lower odds of type 2 diabetes risk in women in the highest quartile of intake, albeit not statistically significant, compared with those in the lowest quartile (P trend= 0·08). Such risk reduction was somewhat greater among postmenopausal women; the multivariable-adjusted OR for the highest quartile of cholesterol intake compared with the lowest quartile was 0·68 (95 % CI 0·49, 0·94; P trend= 0·04). No association between egg intake and type 2 diabetes risk was found in either men or women. In conclusion, higher intake of cholesterol or eggs may not be associated with an increased risk of type 2 diabetes in Japanese populations. The observed association between decreased type 2 diabetes risk and higher dietary cholesterol intake in postmenopausal women warrants further investigation.


ChronicOnline: Implementing a mHealth solution for monitoring and early alerting in chronic obstructive pulmonary disease.
Lack of time or economic difficulties prevent chronic obstructive pulmonary disease patients from communicating regularly with their physicians, thus inducing exacerbation of their chronic condition and possible hospitalization. Enhancing Chronic patients' Health Online proposes a new, sustainable and innovative business model that provides at low cost and at significant savings to the national health system, a preventive health service for chronic obstructive pulmonary disease patients, by combining human medical expertise with state-of-the-art online service delivery based on cloud computing, service-oriented architecture, data analytics, and mobile applications. In this article, we implement the frontend applications of the Enhancing Chronic patients' Health Online system and describe their functionality and the interfaces available to the users.


Tailoring material properties of a nanofibrous extracellular matrix derived hydrogel.
In the native tissue, the interaction between cells and the extracellular matrix (ECM) is essential for cell migration, proliferation, differentiation, mechanical stability, and signaling. It has been shown that decellularized ECMs can be processed into injectable formulations, thereby allowing for minimally invasive delivery. Upon injection and increase in temperature, these materials self-assemble into porous gels forming a complex network of fibers with nanoscale structure. In this study we aimed to examine and tailor the material properties of a self-assembling ECM hydrogel derived from porcine myocardial tissue, which was developed as a tissue specific injectable scaffold for cardiac tissue engineering. The impact of gelation parameters on ECM hydrogels has not previously been explored. We examined how modulating pH, temperature, ionic strength, and concentration affected the nanoscale architecture, mechanical properties, and gelation kinetics. These material characteristics were assessed using scanning electron microscopy, rheometry, and spectrophotometry, respectively. Since the main component of the myocardial matrix is collagen, many similarities between the ECM hydrogel and collagen gels were observed in terms of the nanofibrous structure and modulation of properties by altering ionic strength. However, variation from collagen gels was noted for the gelation temperature along with varied times and rates of gelation. These discrepancies when compared to collagen are likely due to the presence of other ECM components in the decellularized ECM based hydrogel. These results demonstrate how the material properties of ECM hydrogels could be tailored for future in vitro and in vivo applications.


Current Insights into the Potential Misuse of Platelet-based Applications for Doping in Sports.
Platelet-based applications are currently used for the delivery of growth factors and other biomolecules as autologous biomaterials in regenerative medicine and cosmetic therapies. Many studies have revealed that platelet-based applications such as platelet-rich plasma and platelet releasate exhibit beneficial biological effects after a sports injury or trauma when administered locally by intramuscular injections. At present, treatment of the public, patients and athletes with platelet-based applications is permitted and regulated by the Food and Drug Administration and the World Anti-Doping Agency. Since 2011 the use of autologous platelet-rich plasma is permitted in competitive sports by the World Anti-Doping Agency, due to the lack of evidence in performance enhancement and anabolic effects. However, accumulating research has recently shed light on the role of platelet-derived growth factors in wound healing, skeletal myogenesis, muscle stem cell function and tissue regeneration. Although any ergogenic potential of platelet-rich plasma and platelet releasate on intact skeletal muscle and human sports performance remain to be established, novel evidence suggests that platelet-derived growth factors can modulate muscle, tendon, ligament, protein synthesis/degradation, vascularization, energy utilization and regenerative capacity in various experimental settings. Since platelet-based applications are currently not prohibited, they constitute a tool for potential abuse and doping in sports. The aim of this review is to critically discuss and assimilate current insights and biological evidence that set the ground for exploitation and misuse in competitive sports, and develop strategies to combat these activities.


A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy.
Dravet syndrome (DS) is a catastrophic epileptic encephalopathy characterised by childhood-onset polymorphic seizures, multiple neuropsychiatric comorbidities, and increased risk of sudden death. Heterozygous loss-of-function mutations in one allele of SCN1A, the gene encoding the voltage-gated sodium channel 1.1 (NaV1.1), lead to DS. NaV1.1 is primarily found in the axon initial segment of fast-spiking GABAergic inhibitory interneurons in the brain, and the principle mechanism proposed to underlie seizure genesis in DS is loss of inhibitory input due to dysfunctional firing of GABAergic interneurons. We hypothesised that DS symptoms could be ameliorated by a drug that activates the reduced population of functional NaV1.1 channels in DS interneurons. We recently identified two homologous disulfide-rich spider-venom peptides (Hm1a and Hm1b) that selectively potentiate NaV1.1, and showed that selective activation of NaV1.1 by Hm1a restores the function of inhibitory interneurons in a mouse model of DS. Here we produced recombinant Hm1b (rHm1b) using an E. coli periplasmic expression system, and examined its selectivity against a panel of human NaV subtypes using whole-cell patch-clamp recordings. rHm1b is a potent and highly selective agonist of NaV1.1 and NaV1.3 (EC50 ~12 nM for both). rHm1b is a gating modifier that shifts the voltage dependence of channel activation and inactivation to hyperpolarised and depolarised potentials respectively, presumably by interacting with the channel's voltage-sensor domains. Like Hm1a, the structure of rHm1b determined by using NMR revealed a classical inhibitor cystine knot (ICK) motif. However, we show that rHm1b is an order of magnitude more stable than Hm1a in human cerebrospinal fluid. Overall, our data suggest that rHm1b is an exciting lead for a precision therapeutic targeted against DS.


Value-based purchasing, efficiency, and hospital performance.
The Medicare hospital value-based purchasing (HVBP) program that links Medicare payments to quality of care became effective in 2013 in the United States. Hospital efficiency will be added to the HVBP in 2015. It is unclear whether hospital efficiency-specific hospital characteristics are associated with HVBP performance scores and the subsequent incentive payments. Using data from the American Hospital Association Annual Survey the Medicare Hospital Compare, this article examines the association of hospital efficiency hospital characteristics with the HVBP performance scores. The results indicate that less efficient hospitals are more likely to have lower patient satisfaction scores and total performance scores compared with more efficient hospitals. Hospital size, ownership, and payer mix also have significant impact on HVBP performance scores. The findings of this study provide significant policy practice implications. On the one hand, hospitals should consider investing their limited resources into identifying implementing the most cost-effective procedures to improve their patient experience total performance scores. On the other hand, policymakers should consider the unintended negative impact that these new payment incentives will likely have on hospitals that serve a higher proportion of low-income racial ethnic minority populations.


The person-based approach to intervention development: application to digital health-related behavior change interventions.
This paper describes an approach that we have evolved for developing successful digital interventions to help people manage their health or illness. We refer to this as the "person-based" approach to highlight the focus on understanding and accommodating the perspectives of the people who will use the intervention. While all intervention designers seek to elicit and incorporate the views of target users in a variety of ways, the person-based approach offers a distinctive and systematic means of addressing the user experience of intended behavior change techniques in particular and can enhance the use of theory-based and evidence-based approaches to intervention development. There are two key elements to the person-based approach. The first is a developmental process involving qualitative research with a wide range of people from the target user populations, carried out at every stage of intervention development, from planning to feasibility testing and implementation. This process goes beyond assessing acceptability, usability, and satisfaction, allowing the intervention designers to build a deep understanding of the psychosocial context of users and their views of the behavioral elements of the intervention. Insights from this process can be used to anticipate and interpret intervention usage and outcomes, and most importantly to modify the intervention to make it more persuasive, feasible, and relevant to users. The second element of the person-based approach is to identify "guiding principles" that can inspire and inform the intervention development by highlighting the distinctive ways that the intervention will address key context-specific behavioral issues. This paper describes how to implement the person-based approach, illustrating the process with examples of the insights gained from our experience of carrying out over a thousand interviews with users, while developing public health and illness management interventions that have proven effective in trials involving tens of thousands of users.


The effect of intrauterine infusion of dextrose on clinical endometritis cure rate and reproductive performance of dairy cows.
The main objective of this study was to evaluate the intrauterine administration use of 200 mL of 50% dextrose solution as a treatment against clinical endometritis (CE); CE cure rate and reproductive performance were evaluated. Additionally, the association of several relevant risk factors, such as retained placenta (RP), metritis, CE, anovulation, hyperketonemia, and body condition score with reproductive performance, early embryonic mortality, and CE were evaluated. A total of 1,313 Holstein cows housed on 4 commercial dairy farms were enrolled in the study. At 7±3 DIM cows were examined for metritis and had blood collected to determine serum β-hydroxybutyrate concentration. To determine if cows had ovulated at least once before 44±3 DIM, the presence of a corpus luteum was evaluated by ovarian ultrasonography at 30±3 DIM and at 44±3 DIM. At 30±3 DIM, CE was diagnosed using the Metricheck device (SimcroTech, Hamilton, New Zealand); cows with purulent or mucopurulent vaginal discharge were diagnosed as having CE. Cows diagnosed with CE (n=175) were randomly allocated into 2 treatment groups: treatment (intrauterine infusion of 200 mL of 50% dextrose) or control (no infusion). Clinical endometritis cows were re-evaluated as described above at 44±3 DIM, and cows that were free of purulent or mucopurulent vaginal discharge were considered cured. Intrauterine infusion of dextrose tended to have a detrimental effect on CE cure rate, and treatment did not have an effect on first-service conception rate and early embryonic mortality. A multivariable Cox's proportional hazard model was performed to evaluate the effect of several variables on reproductive performance; the variables RP, CE, parity, anovulation, and the interaction term between parity and anovulation were associated with hazard of pregnancy. Cows that did not have RP or CE were more likely to conceive than cows that were diagnosed with RP or CE. Cows that had RP were at 3.36 times higher odds of losing their pregnancy than cows that did not have RP. In addition, cows diagnosed with CE were at 2.16 higher odds of losing their pregnancy than cows without CE. In conclusion, intrauterine infusion of 200 mL of 50% dextrose solution as a treatment for CE had a strong statistical tendency to decrease CE cure rate, did not improve first-service conception rate and early embryonic mortality, and did not decrease calving-to-conception interval.


Visual light effects on mitochondria: The potential implications in relation to glaucoma.
Light of different wave-lengths have the potential to interact with four major mitochondrial protein complexes that are involved in the generation of ATP. Neurones of the central nervous system have an absolute dependence on mitochondrial generated ATP. Laboratory studies show that short-wave or blue light (400-480nm) that impinges on the retina affect flavin and cytochrome constituents associated with mitochondria to decrease the rate of ATP formation, stimulate ROS and results in cell death. This suggests that blue light could potentially have a negative influence on retinal ganglion cell (RGC) mitochondria that are abundant and not shielded by macular pigments as occurs for photoreceptor mitochondria. This might be of significance in glaucoma where it is likely that RGC mitochondria are already affected and therefore be more susceptible to blue light. Thus simply filtering out some natural blue light from entering the eye might be beneficial for the treatment of glaucoma. Long-wave or red light (650-800nm) affects mitochondrial complex IV or cytochrome oxidase to increase the rate of formation of ATP and ROS causing the generation of a number of beneficial factors. Significantly, laboratory studies show that increasing the normal amount of natural red light reaching rat RGC mitochondria in situ, subjected to ischemia, proved to be beneficial. A challenge now is to test whether extra red light delivered to the human retina can slow-down RGC loss in glaucoma. Such a methodology has also the advantage of being non-invasive. One very exciting possibility might be in the production of a lens where solar UV light is convertes to add to the amount of natural red light entering the eye.


A psychometric evaluation of the four-item version of the Control Attitudes Scale for patients with cardiac disease and their partners.
The four-item Control Attitudes Scale (CAS) was developed to measure control perceived by patients with cardiac disease and their family members, but extensive psychometric evaluation has not been performed. The aim was to translate, culturally adapt and psychometrically evaluate the CAS in a Swedish sample of implantable cardioverter defibrillator (ICD) recipients, heart failure (HF) patients and their partners. A sample (n=391) of ICD recipients, HF patients and partners were used. Descriptive statistics, item-total and inter-item correlations, exploratory factor analysis, ordinal regression modelling and Cronbach's alpha were used to validate the CAS. The findings from the factor analyses revealed that the CAS is a multidimensional scale including two factors, Control and Helplessness. The internal consistency was satisfactory for all scales (α=0.74-0.85), except the family version total scale (α=0.62). No differential item functioning was detected which implies that the CAS can be used to make invariant comparisons between groups of different age and sex. The psychometric properties, together with the simple and short format of the CAS, make it to a useful tool for measuring perceived control among patients with cardiac diseases and their family members. When using the CAS, subscale scores should be preferred.


The case of an arctic wild ass highlights the utility of ancient DNA for validating problematic identifications in museum collections.
Museum collections are essential for reconstructing and understanding past biodiversity. Many museum specimens are, however, challenging to identify. Museum samples may be incomplete, have an unusual morphology, or represent juvenile individuals, all of which complicate accurate identification. In some cases, inaccurate identification can lead to false biogeographic reconstructions with cascading impacts on paleontological and paleoecological research. Here, we analyzed an unusual Equid mandible found in the Far North of the Taymyr peninsula that was identified morphologically as Equus hemionus, an ancestor of present-day Asiatic wild asses. If correct, this identification represents the only finding of a putative Late Pleistocene hemione in the Arctic region, and is therefore critical to understanding wild ass evolution and paleoecology. To confirm the accuracy of this specimen's taxonomic assignment, we used ancient DNA and mitochondrial hybridization capture to identify and place this specimen in the larger equid phylogeny. We find that the specimen is actually a member of E. caballus, the ancestor of domestic horses. Our study demonstrates the utility of ancient DNA to validate morphological identification, in particular of incomplete, otherwise problematic, or taxonomically unusual museum specimens.