Experiences of and attitudes towards pornography among a group of Swedish high school students.
To investigate consumption of and attitudes toward pornography in relation to demographic factors and relationships to parents among third-year high school students. A random sample of 718 students with a mean age 18 years (range 17-21) completed a classroom questionnaire consisting of 89 questions. More students in practical than in theoretical study programmes had parents with a practical profession (p < 0.001). More parents to students attending theoretical programmes owned their housing (p < 0.001). More men than women had ever consumed pornography (98% vs. 72%; p < 0.001). More practical than theoretical students were influenced by watching pornographic films, fantasizing about (p < 0.05) or having performed acts inspired by pornography (p < 0.05). Both theoretical and practical male students had more favourable attitudes toward pornography than either group of female students (p < 0.001; p = 0.037). More female, than male students, were of the opinion that pornography could create uncertainty and demands. Students' high school programme choices partly reflect their social background. Pornography was consumed mainly by male students, who also had the most favourable attitudes, while females mainly had negative attitudes. To promote sexual health these differences between genders and study programmes should be taken into consideration in counselling, and in sex- and relationships education.


L-Arginine, the substrate for NO synthesis: an alternative treatment for premature atherosclerosis?
L-Arginine is the substrate of endothelial nitric oxide synthase (eNOS) and the main precursor of nitric oxide (NO) in the vascular endothelium. L-Arginine improves endothelial function in patients with hypercholesterolemia, hypertension and smokers, while its role in diabetes remains unclear. Oral supplementation of L-arginine leads to a significant improvement of endothelium-dependent forearm vasodilation in hypercholesterolemic patients, while intravenous infusion of L-arginine improves endothelial function in healthy smokers. L-Arginine has anti-hypertensive properties, although its effects on endothelial function in hypertensive patients needs further evaluation. In conclusion, L-arginine administration may be useful in patients with premature atherosclerosis.


Nucleic acid amplification-based diagnosis of respiratory virus infections.
The appearance of eight new respiratory viruses in the human population in the past 9 years, including two new pandemics (SARS coronavirus in 2003 and swine-origin influenza A/H1N1 in 2009), has tested the ability of virology laboratories to develop diagnostic tests to identify these viruses. Nucleic acid amplification tests (NATs) that first appeared two decades ago have been developed for both conventional and emerging viruses and now form the backbone of the clinical laboratory. NATs provide fast, accurate and sensitive detection of respiratory viruses and have significantly increased our understanding of the epidemiology of these viruses. Multiplex PCR assays have been introduced recently and several commercial tests are now available. The final chapter in the evolution of respiratory virus diagnostics will be the addition of allelic discrimination and detection of single nucleotide polymorphisms associated with antiviral resistance to multiplex assays. These resistance assays together with new viral load tests will enable clinical laboratories to provide physicians with important information for optimal treatment of patients.


Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and management.
Multiple myeloma accounts for approximately 10% of hematologic malignancies. The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end-organ damage. If end-organ damage is not present, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma. In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) translocation are considered intermediate-risk. All others are considered as standard-risk. Risk-adapted initial therapy: Standard-risk patients can be treated with lenalidomide plus low-dose dexamethasone (Rd), or a bortezomib-containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate-risk and high-risk patients require a bortezomib-based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients who are not candidates for transplant, initial therapy is given for approximately 12 to 18 months. Maintenance therapy: After initial therapy, lenalidomide maintenance is considered for standard risk patients who are not in very good partial response or better, while maintenance with a bortezomib-based regimen should be considered in patients with intermediate or high risk myeloma. Management of refractory disease: Patients with indolent relapse can be treated first with 2-drug or 3-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents.


Arabidopsis DGD1 SUPPRESSOR1 Is a Subunit of the Mitochondrial Contact Site and Cristae Organizing System and Affects Mitochondrial Biogenesis.
Mitochondrial and plastid biogenesis requires the biosynthesis and assembly of proteins, nucleic acids, and lipids. In Arabidopsis (Arabidopsis thaliana), the mitochondrial outer membrane protein DGD1 SUPPRESSOR1 (DGS1) is part of a large multi-subunit protein complex that contains the mitochondrial contact site and cristae organizing system 60-kD subunit, the translocase of outer mitochondrial membrane 40-kD subunit (TOM40), the TOM20s, and the Rieske FeS protein. A point mutation in DGS1, dgs1-1, altered the stability and protease accessibility of this complex. This altered mitochondrial biogenesis, mitochondrial size, lipid content and composition, protein import, and respiratory capacity. Whole plant physiology was affected in the dgs1-1 mutant as evidenced by tolerance to imposed drought stress and altered transcriptional responses of markers of mitochondrial retrograde signaling. Putative orthologs of Arabidopsis DGS1 are conserved in eukaryotes, including the Nuclear Control of ATP Synthase2 (NCA2) protein in yeast (Saccharomyces cerevisiae), but lost in Metazoa. The genes encoding DGS1 and NCA2 are part of a similar coexpression network including genes encoding proteins involved in mitochondrial fission, morphology, and lipid homeostasis. Thus, DGS1 links mitochondrial protein and lipid import with cellular lipid homeostasis and whole plant stress responses.


Occurrence of trace organic contaminants in wastewater sludge and their removals by anaerobic digestion.
This study aims to evaluate the occurrence of trace organic contaminants (TrOCs) in wastewater sludge and their removal during anaerobic digestion. The significant occurrence of 18 TrOCs in primary sludge was observed. These TrOCs occurred predominantly in the solid phase. Some of these TrOCs (e.g. paracetamol, caffeine, ibuprofen and triclosan) were also found at high concentrations (>10,000ng/L) in the aqueous phase. The overall removal of TrOCs (from both the aqueous and solid phase) by anaerobic digestion was governed by their molecular structure (e.g. the presence/absence of electron withdrawing/donating functional groups). While an increase in sludge retention time (SRT) of the digester resulted in a small but clearly discernible increase in basic biological performance (e.g. volatile solids removal and biogas production), the impact of SRT on TrOC removal was negligible. The lack of SRT influence on TrOC removal suggests that TrOCs were not the main substrate for anaerobic digestion.


Use of postpheresis plasma to improve granulocyte yields for transfusion.
Humoral factors which stimulate release of mature granulocytes from body reserves are presumed to be the mechanism through which high yields of granulocytes are obtained from donors by filtration leukopheresis. Postpheresis plasma (PPP) obtained 2 hr after leukopheresis, when infused into normal rats, induced a peak granulocytosis at 3 hr of 22,000/cu mm above controls. A substance in the nylon filters, which caused a peak granulocytosis at 4 hr of 7600/cu mm above controls, was eliminated by washing the filter with 30 volumes of saline. Injection of PPP obtained following leukopheresis with washed filters resulted in an 8000/cu mm increase in granulocytes. One milliliter of PPP given 1 hr before pheresis increased the granulocyte yield from 4.3 to 8.7 times 10-7 granulocytes in a 2-hr run. We conclude that (1) a humoral substance elaborated by the host during filtration leukopheresis induces a granulocytosis in the donor, (2) a substance in commercial leukopaks, which can be eliminated by vigorous washing of the filters, may be responsible in part for granulocytosis observed during leukopheresis, (3) PPP may be used to increase granulocyte yields in donors undergoing leukopheresis.


Exploring critical pathways for urban water management to identify robust strategies under deep uncertainties.
Long-term projections for key drivers needed in urban water infrastructure planning such as climate change, population growth, and socio-economic changes are deeply uncertain. Traditional planning approaches heavily rely on these projections, which, if a projection stays unfulfilled, can lead to problematic infrastructure decisions causing high operational costs and/or lock-in effects. New approaches based on exploratory modelling take a fundamentally different view. Aim of these is, to identify an adaptation strategy that performs well under many future scenarios, instead of optimising a strategy for a handful. However, a modelling tool to support strategic planning to test the implication of adaptation strategies under deeply uncertain conditions for urban water management does not exist yet. This paper presents a first step towards a new generation of such strategic planning tools, by combing innovative modelling tools, which coevolve the urban environment and urban water infrastructure under many different future scenarios, with robust decision making. The developed approach is applied to the city of Innsbruck, Austria, which is spatially explicitly evolved 20 years into the future under 1000 scenarios to test the robustness of different adaptation strategies. Key findings of this paper show that: (1) Such an approach can be used to successfully identify parameter ranges of key drivers in which a desired performance criterion is not fulfilled, which is an important indicator for the robustness of an adaptation strategy; and (2) Analysis of the rich dataset gives new insights into the adaptive responses of agents to key drivers in the urban system by modifying a strategy.


Pathogenesis of Listeria monocytogenes for gnotobiotic rats.
Listeria monocytogenes colonized the gastrointestinal tract of adult germfree rats (10(10) to 10(11)/g, dry weight) within 24 h after oral exposure. Between 3 and 14 days after monoassociation, L. monocytogenes caused a self-limiting pseudomembranous colitis, bacteremia, and infection of the spleen and liver. Monoassociation of rats with Listeria for 8 weeks stimulated 32- and 4-fold increases in serum immunoglobulin A (IgA) and IgG, respectively, whereas serum IgM decreased 2-fold. The normal microbial flora was inhibitory to Listeria colonization, since L. monocytogenes was cleared from the gastrointestinal tract of formerly monoassociated rats within 20 days after conventionalization and did not colonize the gastrointestinal tract of conventional rats after intragastric instillation of 10(8) viable L. monocytogenes. Listeria-monoassociated rats delivered large litters of healthy pups whose gastrointestinal tracts were slowly colonized with L. monocytogenes. between 3 and 60 days of age, Listeria-monoassociated rat pups exhibited eight- and fourfold increases in serum IgG and IgM, respectively; however, serum IgA was elevated (16-fold) only at 9 to 15 days of age. Adult Listeria-monoassociated rats had acquired cellular resistance to intravenous challenge with L. monocytogenes. Prolonged monoassociation of L. monocytogenes in rats attenuated its virulence for conventional rats.


Prediction of malignant sinonasal inverted papilloma transformation by preoperative computed tomography and magnetic resonance imaging.
Accurate preoperative prediction of the malignant transformation of sinonasal inverted papilloma (SNIP) is essential for radical resection of tumours and prevention of recurrence. We here explored the predictive value of preoperative computed tomography (CT) and magnetic resonance imaging (MRI). The study was performed on 268 patients with SNIP with (n = 78) or without (n = 190) coexistent malignant transformation. We used univariate and multivariate logistic regression analysis method to screen for independent risk factors, and established a nomogram model. Finally, using receiver operating characteristic curves, we assessed the diagnostic value of the independent risk factors for malignant transformation of SNIP. We identified bone erosion on CT, change in convoluted cerebriform pattern (CCP) on MRI, and washout-type time intensity curve (TIC) of dynamic contrast-enhanced (DCE)-MRI were independent predictors of malignant transformation of SNIP. The scores of these three independent risk factors from the nomogram model were 10, 7 and 8, respectively. The area under the receiver operating characteristic curve for predicting SNIP malignancy was 0.954 for the nomogram model, 0.826 for bone erosion, 0.776 for washout-type TIC, and 0.810 for CCP mutation. Of the independent risk factors and related combination identified, the nomogram model based on bone destruction on CT, CCP mutation on MRI, and washout-type TIC of DCE-MRI had the best predictive value for malignant transformation of SNIP.


Pharmacophore-guided fragment-based design of novel mammalian target of rapamycin inhibitors: extra precision docking, fingerprint-based 2D and atom-based 3D-QSAR modelling.
Rapamycin and their derivatives known as rapalogs were the first-generation mTOR inhibitors which interacted with mTORC1 but not with the mTORC2 protein. Second-generation inhibitors could bind with both and showed excellent anti-proliferative activity. Our aim was to design novel mTOR inhibitors which could bind at both the allosteric and the kinase site. The FRB domain is present in both the mTORC1 and mTORC2 protein complexes. We have employed e-pharmacophore-guided fragment-based design to develop novel mTOR inhibitors. The affinity of designed molecules at both the sites was analysed using molecular docking in extra precision mode. The atom-based 3D-QSAR model was developed to predict the activity while the fingerprint-based 2D-QSAR model was employed to refine an identified hit as potent dual mTOR inhibitor. Ligand ASK23 showed a docking score of -15.452 kcal/mol at the allosteric site (PDB ID 5GPG) while ASK38 showed a docking score of -11.535 kcal/mol at the kinase site (PDB ID 4JT6). Ligand ASK12 showed binding energy of -106.23 kcal/mol at the allosteric site. Refined molecule ASK12a from ASK12 showed the highest predicted activity (pIC50: 6.512). The stability of the best hits and receptor complex was analysed using molecular dynamics simulation studies. Herein we report five potential mTOR dual inhibitors based on the predicted activity, drug-likeness analysis and off-target effects. To the best of our knowledge, this is the first report on pharmacophore-guided fragment-based drug design for mTOR inhibitors. This design strategy can be used for the rational drug design against other proteins for which only apo-structures are available. Communicated by Ramaswamy H. Sarma.


A Period 2 genetic variant interacts with plasma SFA to modify plasma lipid concentrations in adults with metabolic syndrome.
Genetic variants of Period 2 (PER2), a circadian clock gene, have been linked to metabolic syndrome (MetS). However, it is still unknown whether these genetic variants interact with the various types of plasma fatty acids. This study investigated whether common single nucleotide polymorphisms (SNPs) in the PER2 locus (rs934945 and rs2304672) interact with various classes of plasma fatty acids to modulate plasma lipid metabolism in 381 participants with MetS in the European LIPGENE study. Interestingly, the rs2304672 SNP interacted with plasma total SFA concentrations to affect fasting plasma TG, TG-rich lipoprotein (TRL-TG), total cholesterol, apoC-II, apoB, and apoB-48 concentrations (P-interaction < 0.001-0.046). Carriers of the minor allele (GC+GG) with the highest SFA concentration (>median) had a higher plasma TG concentration (P = 0.001) and higher TRL-TG (P < 0.001) than the CC genotype. In addition, participants carrying the minor G allele for rs2304672 SNP and with a higher SFA concentration (>median) had higher plasma concentrations of apo C-II (P < 0.001), apo C-III (P = 0.009), and apoB-48 (P = 0.028) compared with the homozygotes for the major allele (CC). In summary, the rs2304672 polymorphism in the PER2 gene locus may influence lipid metabolism by interacting with the plasma total SFA concentration in participants with MetS. The understanding of these gene-nutrient interactions could help to provide a better knowledge of the pathogenesis in MetS.


Effects of Chronic Caffeine Administration on Behavioral and Molecular Adaptations to Sensory Contact Model Induced Stress in Adolescent Male Mice.
Previous studies have shown that caffeine attenuates stress-induced mood dysfunction and memory deterioration through neuronal adenosine A2A receptors antagonism. However, whether caffeine exerts this effect through modulating other molecular targets, which interfere with the resilience to social defeat stress in adolescent male mice is unknown. This study was conducted to investigate the role of caffeine in the behavioral responses to social stress induced by the sensory contact model (SCM) and the possible alteration of the gene expression level of Na/K ATPase pump. Adolescent male mice were exposed to SCM for 12 days. Caffeine was administered intraperitoneal daily for 14 days after SCM. The time spent in interaction zone, social interaction ratio, preference index to novel objects, time spent in the open arms and immobility time in forced swimming test were used to measure the locomotor activity, social avoidance, short-term memory, anxiety and depression in mice. The results showed that chronic treatment with caffeine for 14 days improved locomotor activity, reversed the avoidance of social behavior, improved preference to novel objects, and reversed depression induced by social defeat stress in adolescent male mice, suggesting the enhancement of the resilience to social defeat stress induced by caffeine. Moreover, caffeine treatment did alter gene expression levels of Na/K ATPase isoforms in both prefrontal cortex and hippocampus. Altered gene expression was significant in most cases and correlates with the observed behavioral changes. Taken together, our findings provide new insight into the effects of chronic caffeine administration on locomotor activity, social avoidance, short-term memory and depression in adolescent male mice exposed to SCM.


Gender differences in the evolution of illness understanding among patients with advanced cancer.
Patient understanding of advanced metastatic disease is central to decisions about care near death. Prior studies have focused on gender differences in communication style rather than on illness understanding. : To evaluate gender differences in terminal illness acknowledgement (TIA), understanding that the disease is incurable and the advanced stage of the disease. To evaluate gender differences in patients' reports of discussions of life expectancy with oncology providers and its effect on differences in illness understanding. Coping with Cancer 2 patients (N = 68) were interviewed before and after a visit with their oncology providers to discuss scan results. At the prescan interview, there were no statistically significant gender differences in patient measures of illness understanding. At the postscan interview, women were more likely than men to recognize that their illness was incurable (Adjusted Odds Ratio, [AOR] = 5.29; P = .038), know that their cancer was at an advanced stage (AOR = 6.38; P = .013), and report having had discussions of life expectancy with their oncologist (AOR = 4.77; P = .021). Controlling discussions of life expectancy, women were more likely than men to report that their cancer was at an advanced stage (AOR = 9.53; P = .050). Controlling for gender, discussions of life expectancy were associated with higher rates of TIA (AOR = 4.65; P = .036) and higher rates of understanding that the cancer was incurable (AOR = 4.09; P = .085). Due largely to gender differences in communication, women over time have a better understanding of their illness than men. More frequent discussions of life expectancy should enhance illness understanding and reduce gender differences.


Phylogenetic detection of conserved gene clusters in microbial genomes.
Microbial genomes contain an abundance of genes with conserved proximity forming clusters on the chromosome. However, the conservation can be a result of many factors such as vertical inheritance, or functional selection. Thus, identification of conserved gene clusters that are under functional selection provides an effective channel for gene annotation, microarray screening, and pathway reconstruction. The problem of devising a robust method to identify these conserved gene clusters and to evaluate the significance of the conservation in multiple genomes has a number of implications for comparative, evolutionary and functional genomics as well as synthetic biology. In this paper we describe a new method for detecting conserved gene clusters that incorporates the information captured by a genome phylogenetic tree. We show that our method can overcome the common problem of overestimation of significance due to the bias in the genome database and thereby achieve better accuracy when detecting functionally connected gene clusters. Our results can be accessed at database GeneChords http://genomics10.bu.edu/GeneChords. The methodology described in this paper gives a scalable framework for discovering conserved gene clusters in microbial genomes. It serves as a platform for many other functional genomic analyses in microorganisms, such as operon prediction, regulatory site prediction, functional annotation of genes, evolutionary origin and development of gene clusters.


Screening of excitons in single, suspended carbon nanotubes.
Resonant Raman spectroscopy of single carbon nanotubes suspended across trenches displays red-shifts of up to 30 meV of the electronic transition energies as a function of the surrounding dielectric environment. We develop a simple scaling relationship between the exciton binding energy and the external dielectric function and thus quantify the effect of screening. Our results imply that the underlying particle interaction energies change by hundreds of meV.


Phylogenetic evidence for deleterious mutation load in RNA viruses and its contribution to viral evolution.
Populations of RNA viruses are often characterized by abundant genetic variation. However, the relative fitness of these mutations is largely unknown, although this information is central to our understanding of viral emergence, immune evasion, and drug resistance. Here we develop a phylogenetic method, based on the distribution of nonsynonymous and synonymous changes, to assess the relative fitness of polymorphisms in the structural genes of 143 RNA viruses. This reveals that a substantial proportion of the amino acid variation observed in natural populations of RNA viruses comprises transient deleterious mutations that are later purged by purifying selection, potentially limiting virus adaptability. We also demonstrate, for the first time, the existence of a relationship between amino acid variability and the phylogenetic distribution of polymorphisms. From this relationship, we propose an empirical threshold for the maximum viable deleterious mutation load in RNA viruses.


Extrinsic cues suppress the encoding of intrinsic cues.
Remembering where objects are in space is fundamental to adaptive behavior. Little is known about how intact humans combine information from intrinsic (egocentric) and extrinsic (exocentric, allocentric, or landmark-based) coordinate systems to locate objects. Using a simple location estimation paradigm, this study finds that we mostly remember position in extrinsic coordinates. Intrinsic-coordinate-based mapping of space is less precise in the presence of landmarks or extrinsic cues than in their absence. Thus, not only do extrinsic frames of reference dominate internal representations of space, they suppress intrinsic-based representations as well. We speculate that this dominance-suppression hierarchy undercuts intersystem conflicts and underlies a single, undissociated spatial map in intact humans.


Landscape genetics: the correlation of spatial and genetic distances of Oncomelania hupensis, the intermediate host snail of Schistosoma japonicum in mainland China.
Two internal transcribed spacer (ITS1 and ITS2) sequences of the non-coding region of the rDNA and a 16S RNA gene fragment of the mtDNA of Oncomelania hupensis, the intermediate host snail of Schistosoma japonicum in mainland China, have been investigated with a view to illustrate the influence of the environment on genetic differentiation. Thirteen populations of O. hupensis snails, representing four types of ecological settings, were collected to compare genetic and spatial distances. The length of the ITS1-5.8S-ITS2 gene sequence showed a range from 752 to 796 bp with a guanine-cytosine (GC) content of 49.1-50.3%, while that of the 16S sequence ranged from 505 to 508 bp with a GC content of 33.5-35.1%. The 5.8S fragment was shown to be highly conserved and it was therefore removed in the subsequent analysis. In contrast, the ITS flanking sequences and the 16S fragment were found useful for further study as their degree of polymorphism amounted to 13.2% and 8.6%, respectively. The genetic relationship was investigated using tools based on maximum parsimony, minimum evolution and neighbour-joining algorithms. Four branches of O. hupensis were found to be clearly represented on the 16S phylogenetic tree, namely (i) the mountainous region population (from Sichuan and Yunnan provinces); (ii) the Karst region population (from Guangxi autonomous region); (iii) the population representing the region of swamps and lakes along the Yangtze River basin which stretches through the Anhui, Hunan, Hubei, Jiangxi, Jiangsu and Zhejiang provinces; and (iv) the littoral, hilly region population (from Fujian province). These four population branches were found to be correlated to environmental features based on the concept of landscape ecology attributing genetic differentiation to differences in ecological features. However, only three main branches could be found on the ITS1-ITS2 phylogenetic tree. The swamps and lakes population (from the Yangtze River basin) and the littoral, hilly population (from Fujian province) were clustered on the third branch in spite of these two populations not being spatially related, i.e. no firm genetic demarcation between their snail populations was found. Thus, it seems that the Fujian population does not constitute a separate branch but belongs to the third branch. This fact, together with the strong genetic evidence that the subspecies O. hupensis guangxiensis represents a discrete branch, support the hypothesis that genetic differentiation of O. hupensis in mainland China is ultimately structured by landscape ecology.


A highly efficient in situ N-acetylation approach for solid phase synthesis.
We describe a new general N-acetylation method for solid phase synthesis. Malonic acid is used as a precursor and the reaction proceeds by in situ formation of a reactive ketene intermediate at room temperature. We have successfully applied this methodology to peptides and non-peptidic molecules containing a variety of functional groups. The reaction gave high yields compared to known acetylation methods, irrespective of the structure, conformation and sequence of the acetylated molecule. Computational studies revealed that the concerted mechanism via the ketene intermediate is kinetically favorable and leads to a thermodynamically stable acetylated product. In conclusion, our method can be easily applied to acetylation in a wide variety of chemical reactions performed on the solid phase.


IL-1ra serum levels in disease stages of MS--a marker for progression?
Interleukin-1 (IL-1) is one of the major proinflammatory cytokines expressed consistently in multiple sclerosis (MS) lesions. Interleukin-1 receptor antagonist (IL-1ra) is the only known naturally occurring specific antagonistic cytokine counteracting IL-1. Thus IL-1ra may have a downregulating potential in the disease course of MS. We analysed if circulating IL-1ra could be associated with different disease stages of MS in sera of 84 MS patients and 18 controls. IL-1ra showed considerable variations in MS patients and controls. Nevertheless we found significantly elevated serum levels in active as well as in stable disease stages compared to controls. IL-1ra levels were higher in progressive disease courses compared to relapsing-remitting MS, but not statistically significant (median: 516 versus 434 pg/ml). Further analysis with larger groups of patients and longitudinal studies will clarify if IL-1ra is useful as a prognostic serum marker in MS.


Fast Click Rate Electrocochleography and Auditory Brainstem Response in Normal-Hearing Adults Using Continuous Loop Averaging Deconvolution.
Using the continuous loop averaging deconvolution (CLAD) technique for conventional electrocochleography (ECochG) and auditory brainstem response (ABR) recordings, the effects of testing at high stimulus rates may have the potential to diagnose disorders of the inner ear and auditory nerve. First, a body of normative data using the CLAD technique must be established. Extratympanic click ECochG and ABR to seven stimulus rates using CLAD were measured simultaneously from a tympanic membrane electrode and surface electrodes on the forehead and mastoid of 42 healthy individuals. Results showed that the compound action potential (AP) of the ECochG and waves I, III, and V of the ABR decreased in amplitude and increased in latency as stimulus rate was increased from standard 7.1 clicks/s up to 507.81 clicks/s, with sharp reduction in AP amplitude at 97.66 clicks/s and reaching asymptote at 292.97 clicks/s. The summating potential (SP) of the ECochG, however, stayed relatively stable, resulting in increased SP/AP ratios with increasing rate. The SP/AP amplitude ratio showed more stability than AP amplitude findings, thus it is recommended for use in evaluation of cochlear and neural response. Results of both amplitude and latency data from this normative neural adaptation function of the auditory pathway serves as guide for improving diagnostic utility of both ECochG and ABR using CLAD as a reliable technique in distinguishing inner ear and auditory nerve disorders.


A "no-hybrids" screen for functional antagonizers of human p53 transactivator function: dominant negativity in fission yeast.
We have developed a functional "no-hybrids" screen in the fission yeast Schizosaccharomyces pombe based on the transcription transactivator activity of human p53. The screen can be used to identify antagonizers and modulators of p53 activity. Expression of functional full-length human p53 is conditionally lethal to the screen reporter strains. Co-expression of specific inhibitory proteins promotes cell survival and growth. We have validated the "no-hybrids" system by (a) successful modeling of human wild-type p53 interaction with SV40 large T antigen, Mdm2 and a panel of tumor-derived human p53 mutants, (b) demonstrating the screening system's efficiency through identification of a dominant negative fragment of p53 itself in a library screen context and (c) using Drosophila p53 to demonstrate that the system can detect evolutionarily distant p53 homologues based on their transactivator activity. The "no-hybrids" screen will be of utility in searches for p53 function-modulators of both cellular and viral origin.


My Home is my Castle? The Role of Living Arrangements on Experiencing the COVID-19 Pandemic: Evidence From Germany.
During the early months of the COVID-19 pandemic in Germany, social restrictions and social distancing policies forced large parts of social life to take place within the household. However, comparatively little is known about how private living situations shaped individuals experiences of this crisis. To investigate this issue, we analyze how experiences and concerns vary across living arrangements along two dimensions that may be associated with social disadvantage: loneliness and care. In doing so, we employ quantitative text analysis on open-ended questions from survey data on a sample of 1,073 individuals living in Germany. We focus our analyses on four different household structures: living alone, shared living without children, living with a partner and children, and single parents. We find that single parents (who are primarily single mothers) are at high risk of experiencing care-related worries, particularly regarding their financial situation, while individuals living alone are most likely to report feelings of loneliness. Those individuals living in shared houses, with or without children, had the lowest risk of experiencing both loneliness and care-related worries. These findings illustrate that the living situation at home substantially impacts how individuals experienced and coped with the pandemic situation during the first wave of the pandemic.


Defensin-like peptide-2 from platypus venom: member of a class of peptides with a distinct structural fold.
The venom of the male Australian duck-billed platypus contains a family of four polypeptides of appox. 5 kDa, which are referred to as defensin-like peptides (DLPs). They are unique in that their amino acid sequences have no significant similarities to those of any known peptides; however, the tertiary structure of one of them, DLP-1, has recently been shown to be similar to beta-defensin-12 and to the sodium neurotoxin peptide ShI (Stichodactyla helianthus neurotoxin I). Although DLPs are the major peptides in the platypus venom, little is known about their biological roles. In this study, we determined the three-dimensional structure of DLP-2 by NMR spectroscopy, with the aim of gaining insights into the natural function of the DLPs in platypus venom. The DLP-2 structure was found to incorporate a short helix that spans residues 9-12, and an antiparallel beta-sheet defined by residues 15-18 and 37-40. The overall fold and cysteine-pairing pattern of DLP-2 were found to be similar to those of DLP-1, and hence beta-defensin-12; however, the sequence similarities between the three molecules are relatively small. The distinct structural fold of the DLP-1, DLP-2, and beta-defensin-12 is based upon several key residues that include six cysteines. DLP-3 and DLP-4 are also likely to be folded similarly since they have high sequence similarity with DLP-2. The DLPs, and beta-defensin-12 may thus be grouped together into a class of polypeptide molecules which have a common or very similar global fold. The fact that the DLPs did not display antimicrobial, myotoxic, or cell-growth-promoting activities implies that the nature of the side chains in this group of peptides is likely to play an important role in defining the biological function(s).


Risk assessment in the face of a changing environment: gypsy moth and climate change in Utah.
The importance of efficaciously assessing the risk for introduction and establishment of pest species is an increasingly important ecological and economic issue. Evaluation of climate is fundamental to determining the potential success of an introduced or invasive insect pest. However, evaluating climatic suitability poses substantial difficulties; climate can be measured and assessed in a bewildering array of ways. Some physiological filter, in essence a lens that focuses climate through the requirements and constraints of a potential pest introduction, is required. Difficulties in assessing climate suitability are further exacerbated by the effects of climate change. Gypsy moth (Lymantria dispar L.) is an exotic, tree-defoliating insect that is frequently introduced into the western United States. In spite of an abundance of potential host species, these introductions have yet to result in established populations. The success of eradication efforts and the unsuccessful establishment of many detected and undetected introductions may be related to an inhospitable climate. Climatic suitability for gypsy moth in the western United States, however, is potentially improving, perhaps rapidly, due to a general warming trend that began in the mid 1970s and continues today. In this work, we describe the application of a physiologically based climate suitability model for evaluating risk of gypsy moth establishment on a landscape level. Development of this risk assessment system first required amassing databases that integrated the gypsy moth climatic assessment model, with host species distributions, and climate (historical, present, and future). This integrated system was then used to evaluate climate change scenarios for native host species in Utah, with the result that risk of establishment will dramatically increase during the remainder of the 21st century under reasonable climate change scenarios. We then applied the risk assessment system to several case histories of detected gypsy moth introductions in Utah. These applications demonstrated the general utility of the system for predicting risk of establishment and for designing improved risk detection strategies.


Terahertz in-line digital holography of human hepatocellular carcinoma tissue.
Terahertz waves provide a better contrast in imaging soft biomedical tissues than X-rays, and unlike X-rays, they cause no ionisation damage, making them a good option for biomedical imaging. Terahertz absorption imaging has conventionally been used for cancer diagnosis. However, the absorption properties of a cancerous sample are influenced by two opposing factors: an increase in absorption due to a higher degree of hydration and a decrease in absorption due to structural changes. It is therefore difficult to diagnose cancer from an absorption image. Phase imaging can thus be critical for diagnostics. We demonstrate imaging of the absorption and phase-shift distributions of 3.2 mm × 2.3 mm × 30-μm-thick human hepatocellular carcinoma tissue by continuous-wave terahertz digital in-line holography. The acquisition time of a few seconds for a single in-line hologram is much shorter than that of other terahertz diagnostic techniques, and future detectors will allow acquisition of meaningful holograms without sample dehydration. The resolution of the reconstructions was enhanced by sub-pixel shifting and extrapolation. Another advantage of this technique is its relaxed minimal sample size limitation. The fibrosis indicated in the phase distribution demonstrates the potential of terahertz holographic imaging to obtain a more objective, early diagnosis of cancer.


Transcriptional silencing of the Dickkopfs-3 (Dkk-3) gene by CpG hypermethylation in acute lymphoblastic leukaemia.
DKK-3: is a newly characterised mortalisation-related gene and an antagonist of the Wnt oncogenic signalling pathway whose expression is decreased in a variety of cancer cell lines, suggesting that the Dkk-3 gene, located at chromosome 11p15.1, functions as a tumour suppressor gene. Although 11p15 is a 'hot spot' for methylation in acute lymphoblastic leukaemia (ALL), the role of Dkk-3 abnormalities has never been evaluated in this disease. We analysed CpG island methylation of the Dkk-3 promoter in six ALL cell lines and 183 ALL patients. We observed Dkk-3 hypermethylation in all cell lines and in cells from 33% (60/183) of ALL patients. Moreover, Dkk-3 methylation was associated with decreased Dkk-3 mRNA expression and this expression was restored after exposure to the demethylating agent 5-AzaC. Clinical features did not differ between hypermethylated and unmethylated patients. Estimated disease-free survival (DFS) and overall survival at 10 and 11 years, respectively, were 49.8 and 45.6% for normal patients and 10.5 and 15.1% for hypermethylated patients (P=0.001 and 0.09). Multivariate analysis demonstrated that Dkk-3 methylation was an independent prognostic factor predicting DFS (P=0.0009). Our data suggest that Dkk-3 methylation occurs at an early stage in ALL pathogenesis and probably influences the clinical behaviour of the disease.


Improving drug use in rheumatic disorders.
A recent study concluded that approximately 50 elderly people are admitted to the major teaching hospital in Tasmania, Australia each year suffering from gastrointestinal bleeding related to the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to examine whether academic detailing, designed to encourage a rational approach to the prescribing of NSAIDs and performed by a pharmacist; could modify prescribing practices in the community. The intervention was conducted in Southern Tasmania, using the north of the state as a control area. The target group of all general practitioners (approximately 250) working in Southern Tasmania was sent educational material designed to assist in the appropriate prescribing of NSAIDs. A pharmacist then visited each general practitioner and discussed the rational use of NSAIDs directly with them. The outcome of the programme was measured using evaluation feedback from the general practitioners and pharmacoepidemiological data provided by (i) a state-wide pharmacoepidemiology database derived from community pharmacy records, and (ii) dispensing under the Pharmaceutical Benefits and Repatriation Pharmaceutical Benefits Schemes. The key variable examined was the defined daily dose (DDD) dispensed for the NSAIDs compared with paracetamol. The educational programme was very well received by the general practitioners. Changes in the prescribing of NSAIDs were evident in both study regions, but were more marked in the intervention area. For instance, the state-wide pharmacoepidemiological database indicated that the ratio of dispensed DDDs of NSAIDs: paracetamol declined from 3.00 to 2.59 in the intervention region and remained steadier (3.16 to 2.92) in the north of the state. The improvement was significantly greater in the intervention region. This study has revealed that an educational programme utilizing academic detailing by pharmacists can modify prescribing practices within the community setting.


Clinical trials of interactive computerized patient education: implications for family practice.
A systematic review of randomized clinical trials was conducted to evaluate the acceptability and usefulness of computerized patient education interventions. The Columbia Registry, MEDLINE, Health, BIOSIS, and CINAHL bibliographic databases were searched. Selection was based on the following criteria: (1) randomized controlled clinical trials, (2) educational patient-computer interaction, and (3) effect measured on the process or outcome of care. Twenty-two studies met the selection criteria. Of these, 13 (59%) used instructional programs for educational intervention. Five studies (22.7%) tested information support networks, and four (18%) evaluated systems for health assessment and history-taking. The most frequently targeted clinical application area was diabetes mellitus (n = 7). All studies, except one on the treatment of alcoholism, reported positive results for interactive educational intervention. All diabetes education studies, in particular, reported decreased blood glucose levels among patients exposed to this intervention. Computerized educational interventions can lead to improved health status in several major areas of care, and appear not to be a substitute for, but a valuable supplement to, face-to-face time with physicians.


Exploring a neuroplasticity model of music therapy.
Given that music therapists work across a wide range of disabilities, it is important that therapists have at least a fundamental understanding of the neurophysiology associated with the client/patient populations that they serve. Yet, there is a large gap of evidence regarding the neurophysiological changes associated with applying music as therapy. The purpose of this article is to provide music therapists with a general background in neuroplasticity principles that can be applied to the use of music therapy with multiple populations. This article will review literature on neuroplasticity and literature supporting the specific attributes of music therapy that apply to neuroplasticity. Finally, examples of how to use neuroplasticity principles to explain and support clinical music therapy will be provided. Using the material presented in this review, music therapists will be equipped with information to effectively communicate why music therapy works using three neuroplasticity principles; increase in dopamine, neural synchrony, and a clear signal. Music therapy is a powerful tool to enhance neuroplasticity in the brain.


A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.
Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).


Decreased platelet APP isoform ratios in autosomal dominant Alzheimer's disease: baseline data from a DIAN cohort subset.
This study examines platelet amyloid precursor protein (APP) isoform ratios of 120KDa to 110KDa (APPr) between mutation carriers (MC) carrying a mutation for autosomal dominant Alzheimer's disease (ADAD) and non-carriers (NC). Two previous studies reported no significant difference in APPr between ADAD MC and NC, which may have been due to the small sample size in both studies. The current study examines APPr in MC versus NC in a larger sample. In addition, it investigated whether APPr correlate with neuroimaging data, neuropsychological data and cerebrospinal fluid biomarkers in a cohort subset derived from the Dominantly Inherited Alzheimer Network (DIAN) study. APPr were quantified by western blotting. Fifteen MC (symptomatic and asymptomatic) were compared against twelve NC using univariate general linear model. All participants underwent neuroimaging and neuropsychological testing which were correlated with APPr using Pearson's correlation coefficient (r). APPr were lower in MC compared to NC (p=0.003) while Mini-Mental State Examination (MMSE) scores were not significantly different (p>0.1). Furthermore, APPr inversely correlated with amyloid imaging in the Caudate Nucleus (r=-0.505; p<0.05) and Precuneus (r=-0.510; p<0.05). APPr are lower in ADAD MC compared to NC, and inversely correlated with brain amyloid load prior to significant differences in cognitive health. However, the use of APPr as a biomarker needs to be explored further.


Neonicotinoid-contaminated pollinator strips adjacent to cropland reduce honey bee nutritional status.
Worldwide pollinator declines are attributed to a number of factors, including pesticide exposures. Neonicotinoid insecticides specifically have been detected in surface waters, non-target vegetation, and bee products, but the risks posed by environmental exposures are still not well understood. Pollinator strips were tested for clothianidin contamination in plant tissues, and the risks to honey bees assessed. An enzyme-linked immunosorbent assay (ELISA) quantified clothianidin in leaf, nectar, honey, and bee bread at organic and seed-treated farms. Total glycogen, lipids, and protein from honey bee workers were quantified. The proportion of plants testing positive for clothianidin were the same between treatments. Leaf tissue and honey had similar concentrations of clothianidin between organic and seed-treated farms. Honey (mean±SE: 6.61 ± 0.88 ppb clothianidin per hive) had seven times greater concentrations than nectar collected by bees (0.94 ± 0.09 ppb). Bee bread collected from organic sites (25.8 ± 3.0 ppb) had significantly less clothianidin than those at seed treated locations (41.6 ± 2.9 ppb). Increasing concentrations of clothianidin in bee bread were correlated with decreased glycogen, lipid, and protein in workers. This study shows that small, isolated areas set aside for conservation do not provide spatial or temporal relief from neonicotinoid exposures in agricultural regions where their use is largely prophylactic.


MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.
Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.


Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich's ataxia patients.
MicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich's ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich's ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated. We found seven differentially expressed miRNAs, and we propose that these miRNAs represent key mechanisms in the modulation of several signalling pathways that regulate the physiopathology of FRDA. If this is the case, miRNAs can be used to characterize phenotypic variation in FRDA and stratify patients' risk of cardiomyopathy. In this study, we identify miR-323-3p as a candidate marker for phenotypic differentiation in FRDA patients suffering from cardiomyopathy. We propose the use of dynamic miRNAs as biomarkers for phenotypic characterization and prognosis of FRDA.


Single-cell Raman spectral profiles of Pseudomonas fluorescens SBW25 reflects in vitro and in planta metabolic history.
Single-cell Raman microspectroscopy has the potential to report on the whole-cell chemical composition of bacteria, reflecting metabolic status as well as growth history. This potential has been demonstrated through the discriminant functional analysis of Raman spectral profiles (RSP) obtained from the soil and plant-associated bacterium Pseudomonas fluorescens SBW25, grown in vitro using defined media, and in planta using 3-month-old sugar beets (Beta vulgaris var. Roberta). SBW25 in vitro RSP data showed significant variation between those cells grown on different amino acids, sugars, TCA cycle intermediates, rich King's B, and culture media derived from the sugar beet phytosphere. Raman analysis was also able to follow the transition of SBW25 starved of carbon over a period of days, and SBW25 in planta RSP data also showed variation with significant differences between bacteria recovered from soil and the rhizosphere. SBW25 whole-cell chemical composition, and therefore growth and metabolic history, could be interpreted by coanalyzing in vitro and in planta RSP data. SBW25 recovered from the phytosphere was found to be more similar to SBW25 grown in vitro on Fru or Asp, rather than on Glc or Arg, and quite dissimilar to that resulting from carbon starvation. This suggests that SBW25 growth in the phytosphere is generally neither carbon-catabolite-repressed nor carbon-limited. These findings demonstrate that the analysis of single-cell RSP can differentiate between isogenic populations of bacteria with different metabolic histories or after recovery from different parts of their natural environment. In addition, Raman analysis is also capable of providing biologically relevant biochemical inferences, which might then be tested to uncover the mechanistic basis (biochemical-metabolic-genetic) differentiating bacteria growing in complex environments and exposed to different conditions.


Radiation dose reduction in chest CT--review of available options.
Computed tomography currently accounts for the majority of radiation exposure related to medical imaging. Although technological improvement of CT scanners has reduced the radiation dose of individual examinations, the benefit was overshadowed by the rapid increase in the number of CT examinations. Radiation exposure from CT examination should be kept as low as reasonably possible for patient safety. Measures to avoid inappropriate CT examinations are needed. Principles and information on radiation dose reduction in chest CT are reviewed in this article. The reduction of tube current and tube potential are the mainstays of dose reduction methods. Study results indicate that routine protocols with reduced tube current are feasible with diagnostic results comparable to conventional standard dose protocols. Tube current adjustment is facilitated by the advent of automatic tube current modulation systems by setting the appropriate image quality level for the purpose of the examination. Tube potential reduction is an effective method for CT pulmonary angiography. Tube potential reduction often requires higher tube current for satisfactory image quality, but may still contribute to significant radiation dose reduction. Use of lower tube potential also has considerable advantage for smaller patients. Improvement in image production, especially the introduction of iterative reconstruction methods, is expected to lower radiation dose significantly. Radiation dose reduction in CT is a multifaceted issue. Understanding these aspects leads to an optimal solution for various indications of chest CT.


The p68 and p72 DEAD box RNA helicases interact with HDAC1 and repress transcription in a promoter-specific manner.
p68 (Ddx5) and p72 (Ddx17) are highly related members of the DEAD box family and are established RNA helicases. They have been implicated in growth regulation and have been shown to be involved in both pre-mRNA and pre-rRNA processing. More recently, however, these proteins have been reported to act as transcriptional co-activators for estrogen-receptor alpha (ER alpha). Furthermore these proteins were shown to interact with co-activators p300/CBP and the RNA polymerase II holoenzyme. Taken together these reports suggest a role for p68 and p72 in transcriptional activation. In this report we show that p68 and p72 can, in some contexts, act as transcriptional repressors. Targeting of p68 or p72 to constitutive promoters leads to repression of transcription; this repression is promoter-specific. Moreover both p68 and p72 associate with histone deacetylase 1 (HDAC1), a well-established transcriptional repression protein. It is therefore clear that p68 and p72 are important transcriptional regulators, functioning as co-activators and/or co-repressors depending on the context of the promoter and the transcriptional complex in which they exist.


Sepsis-associated encephalopathy and its differential diagnosis.
Sepsis is often complicated by an acute and reversible deterioration of mental status, which is associated with increased mortality and is consistent with delirium but can also be revealed by a focal neurologic sign. Sepsis-associated encephalopathy is accompanied by abnormalities of electroencephalogram and somatosensory-evoked potentials, increased in biomarkers of brain injury (i.e., neuron-specific enolase, S-100 beta-protein) and, frequently, by neuroradiological abnormalities, notably leukoencephalopathy. Its mechanism is highly complex, resulting from both inflammatory and noninflammatory processes that affect all brain cells and induce blood-brain barrier breakdown, dysfunction of intracellular metabolism, brain cell death, and brain injuries. Its diagnosis relies essentially on neurologic examination that can lead one to perform specific neurologic tests. Electroencephalography is required in the presence of seizure; neuroimaging in the presence of seizure, focal neurologic signs or suspicion of cerebral infection; and both when encephalopathy remains unexplained. In practice, cerebrospinal fluid analysis should be performed if there is any doubt of meningitis. Hepatic, uremic, or respiratory encephalopathy, metabolic disturbances, drug overdose, withdrawal of sedatives or opioids, alcohol withdrawal delirium, and Wernicke's encephalopathy are the main differential diagnoses of sepsis-associated encephalopathy. Patient management is based mainly on controlling infection, organ system failure, and metabolic homeostasis, at the same time avoiding neurotoxic drugs.


The Placenta: Applications in Orthopaedic Sports Medicine.
Placenta has a long history of use for treating burns and wounds. It is a rich source of collagen and other extracellular matrix proteins, tissue reparative growth factors, and stem cells, including mesenchymal stem cells (MSCs). Recent data show its therapeutic potential for orthopaedic sports medicine indications. To provide orthopaedic surgeons with an anatomic description of the placenta, to characterize its cellular composition, and to review the literature reporting the use of placenta-derived cells and placental tissue allografts for orthopaedic sports medicine indications in animal models and in humans. Systematic review. Using a total of 63 keyword combinations, the PubMed and MEDLINE databases were searched for published articles describing the use of placental cells and/or tissue for orthopaedic sports medicine indications. Information was collected on placental tissue type, indications, animal model, study design, treatment regimen, safety, and efficacy outcomes. Results were categorized by indication and subcategorized by animal model. Outcomes for 29 animal studies and 6 human studies reporting the use of placenta-derived therapeutics were generally positive; however, the placental tissue source, clinical indication, and administration route were highly variable across these studies. Fourteen animal studies described the use of placental tissue for tendon injuries, 13 studies for osteoarthritis or articular cartilage injuries, 3 for ligament injuries, and 1 for synovitis. Both placenta-derived culture-expanded cells (epithelial cells or MSCs) and placental tissue allografts were used in animal studies. In all human studies, commercial placental allografts were used. Five of 6 human studies examined the treatment of foot and ankle pathological conditions, and 1 studied the treatment of knee osteoarthritis. A review of the small number of reported studies revealed a high degree of variability in placental cell types, placental tissue preparation, routes of administration, and treatment regimens, which prohibits making any definitive conclusions. Currently, the clinical use of placenta is limited to only commercial placental tissue allografts, as there are no placenta-derived biological drugs approved for the treatment of orthopaedic sports medicine conditions in the United States. However, this review shows that the application of placental cells or tissue allografts appears to be safe and has potential to improve outcomes for orthopaedic sports medicine indications.


Paroxysmal autonomic alterations mimicking epilepsy: a case report.
A 22-year-old male patient presented with paroxysmal hyperhidrosis, mydriasis, hypertension, and tachycardia. Cranial and cervical MRI revealed focal atrophy in the high order zone of the central autonomic network and syringomyelia. His physical and neurological examinations were unremarkable. Physiological testing included EEG, SPECT, serum/urine tests and autonomic testing. A poor response was achieved with the medical and interventional procedures employed. As the central autonomic network is an integral component of the internal regulation system of the brain, any lesion, no matter where in the network, may lead to paroxysmal autonomic alterations mimicking epilepsy (Published with videosequences).


Assembly of Complete Genome Sequences of Negative-Control and Experimental Strain Variants of Staphylococcus aureus ATCC BAA-39 Selected under the Effect of the Drug FS-1, Which Induces Antibiotic Resistance Reversion.
Staphylococcus aureus ATCC BAA-39 is the reference organism for a multidrug-resistant Staphylococcus aureus (MRSA) strain that was used to study drug-induced resistance reversion by an iodine-containing nanomolecular complex, FS-1. PacBio sequencing was performed on both the experimental and control strains, followed by genome assembly, variant calling, and DNA modification profiling.


Ancestral Hybridization Facilitated Species Diversification in the Lake Malawi Cichlid Fish Adaptive Radiation.
The adaptive radiation of cichlid fishes in East African Lake Malawi encompasses over 500 species that are believed to have evolved within the last 800,000 years from a common founder population. It has been proposed that hybridization between ancestral lineages can provide the genetic raw material to fuel such exceptionally high diversification rates, and evidence for this has recently been presented for the Lake Victoria region cichlid superflock. Here, we report that Lake Malawi cichlid genomes also show evidence of hybridization between two lineages that split 3-4 Ma, today represented by Lake Victoria cichlids and the riverine Astatotilapia sp. "ruaha blue." The two ancestries in Malawi cichlid genomes are present in large blocks of several kilobases, but there is little variation in this pattern between Malawi cichlid species, suggesting that the large-scale mosaic structure of the genomes was largely established prior to the radiation. Nevertheless, tens of thousands of polymorphic variants apparently derived from the hybridization are interspersed in the genomes. These loci show a striking excess of differentiation across ecological subgroups in the Lake Malawi cichlid assemblage, and parental alleles sort differentially into benthic and pelagic Malawi cichlid lineages, consistent with strong differential selection on these loci during species divergence. Furthermore, these loci are enriched for genes involved in immune response and vision, including opsin genes previously identified as important for speciation. Our results reinforce the role of ancestral hybridization in explosive diversification by demonstrating its significance in one of the largest recent vertebrate adaptive radiations.


Virtual Screening Against Carbohydrate-Binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin.
Bacterial adhesion to human epithelia via lectins constitutes a therapeutic opportunity to prevent infection. Specifically, BambL (the lectin from Burkholderia ambifaria) is implicated in cystic fibrosis, where lectin-mediated bacterial adhesion to fucosylated lung epithelia is suspected to play an important role. We employed structure-based virtual screening to identify inhibitors of BambL-saccharide interaction with potential therapeutic value. To enable such discovery, a virtual screening protocol was iteratively developed via 194 retrospective screening protocols against 4 bacterial lectins (BambL, BC2L-A, FimH, and LecA) with known ligands. Specific attention was given to the rigorous evaluation of retrospective screening, including calculation of analytical errors for enrichment metrics. The developed virtual screening workflow used crystallographic constraints, pharmacophore filters, and a final manual selection step. The protocol was applied to BambL, predicting 15 active compounds from virtual libraries of approximately 7 million compounds. Experimental validation using fluorescence polarization confirmed micromolar inhibitory activity for two compounds, which were further characterized by isothermal titration calorimetry and surface plasmon resonance. Subsequent testing against LecB from Pseudomonas aeruginosa demonstrated binding specificity of one of the hit compounds. This report demonstrates the utility of virtual screening protocols, integrating ligand-based pharmacophore filtering and structure-based constraints, in the search for bacterial lectin inhibitors.


Mannose-binding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus.
Cardiovascular disease is an important complication in patients with systemic lupus erythematosus (SLE). Variant alleles of the mannose-binding lectin gene are associated with SLE as well as with severe atherosclerosis. We determined whether mannose-binding lectin variant alleles were associated with an increased risk of arterial thrombosis among patients with SLE. Mannose-binding lectin alleles were genotyped by means of a polymerase-chain-reaction assay in 91 Danish patients with SLE. Arterial and venous thromboses occurring after the diagnosis of SLE were assessed in a prospective study. Arterial and venous thromboses were confirmed by appropriate diagnostic methods. Fifty-four patients had no mannose-binding lectin variant alleles (A/A genotype), 30 were heterozygous (A/O genotype), and 7 were homozygous (O/O genotype). During a median follow-up of 9.1 years, arterial thromboses (cerebral or myocardial infarction or leg embolus) developed in 6 of the 7 patients with the O/O genotype, as compared with 18 of the 84 patients with the other two genotypes (hazard ratio, 5.8; 95 percent confidence interval, 2.2 to 15.2; overall incidence, 26 percent). After correction for other known risk factors, the hazard ratio was 7.0 (95 percent confidence interval, 1.9 to 25.4). Venous thromboses, which occurred in 14 patients, were statistically unrelated to the mannose-binding lectin genotype. Among patients with SLE, homozygosity for mannose-binding lectin variant alleles is associated with an increased risk of arterial thrombosis. The risk of venous thrombosis is not increased, indicating that mannose-binding lectin has a specific role in providing protection against arterial thrombosis.


Randomized Trials of Systemic Medically-treated Malignant Mesothelioma: A Systematic Review.
Malignant pleural mesothelioma (MPM) is a rare but aggressive malignancy mainly localized to the pleura. Malignant mesothelioma grows highly invasive into surrounding tissue and has a low tendency to metastasize. The median overall survival (OS) of locally advanced or metastatic disease without treatment is 4-13 months but, during recent years, improvement in survival has been achieved since treatment for patients with mesothelioma has improved with better palliative care, systemic medical treatment, surgery and improved diagnostics methods. The present review aims at describing available data from randomized trials considering systemic medical treatment for this patient category.


Fatty Liver Among Adolescent Offspring of Women With Type 1 Diabetes (the EPICOM Study).
Intrauterine exposure to maternal type 1 diabetes is associated with a less favorable metabolic profile later in life. Nonalcoholic fatty liver disease is the hepatic manifestation of a cluster of metabolic abnormalities linked to insulin resistance. This study aimed to evaluate the effect of maternal pregestational type 1 diabetes on the presence of fatty liver in offspring and the association between maternal BMI, glycemic control during pregnancy, offspring metabolic risk factors, and offspring level of soluble CD163 (sCD163) (a marker of macrophage activation) and risk of fatty liver. This study was a prospective nationwide follow-up study of offspring (n = 278) of mothers with pregestational type 1 diabetes between 1993 and 1999 and matched control subjects (n = 303). Mean age at the time of follow-up was 16.7 years (range 13.0-20.4 years). We used the fatty liver index (FLI) and waist-to-height ratio (WHtR) to evaluate the presence of fatty liver among the offspring. An FLI ≥60 or WHtR >0.469 were used as cutoff points for fatty liver. More type 1 diabetes-exposed offspring had high FLI and WHtR indices compared with unexposed control subjects. We found significant associations between increasing maternal prepregnancy BMI, being born large for gestational age, offspring level of sCD163, as well as offspring metabolic risk factors (decreasing adiponectin and HDL cholesterol and increasing leptin, HOMA of insulin resistance, and HOMA of insulin secretion) and degree of fatty liver. Intrauterine exposure to maternal type 1 diabetes and higher maternal prepregnancy BMI may predispose to fatty liver in the offspring. Offspring metabolic risk factors, including sCD163 levels, are associated with indices of fatty liver.


Efficient Dynamic Nuclear Polarization at 800 MHz/527 GHz with Trityl-Nitroxide Biradicals.
Cross-effect (CE) dynamic nuclear polarization (DNP) is a rapidly developing technique that enhances the signal intensities in magic-angle spinning (MAS) NMR spectra. We report CE DNP experiments at 211, 600, and 800 MHz using a new series of biradical polarizing agents referred to as TEMTriPols, in which a nitroxide (TEMPO) and a trityl radical are chemically tethered. The TEMTriPol molecule with the optimal performance yields a record (1) H NMR signal enhancement of 65 at 800 MHz at a concentration of 10 mM in a glycerol/water solvent matrix. The CE DNP enhancement for the TEMTriPol biradicals does not decrease as the magnetic field is increased in the manner usually observed for bis-nitroxides. Instead, the relatively strong exchange interaction between the trityl and nitroxide moieties determines the magnetic field at which the optimum enhancement is observed.


Reflections on the 1976 swine flu vaccination program.
In 1976, 2 recruits at Fort Dix, New Jersey, had an influenza like illness. Isolates of virus taken from them included A/New Jersey/76 (Hsw1n1), a strain similar to the virus believed at the time to be the cause of the 1918 pandemic, commonly known as swine flu. Serologic studies at Fort Dix suggested that >200 soldiers had been infected and that person-to-person transmission had occurred. We review the process by which these events led to the public health decision to mass-vaccinate the American public against the virus and the subsequent events that led to the program's cancellation. Observations of policy and implementation success and failures are presented that could help guide decisions regarding avian influenza.


Mediation of PACAP-like neuropeptide transmission by coactivation of Ras/Raf and cAMP signal transduction pathways in Drosophila.
Much work on the signal transduction mechanisms underlying neurotransmission has been directed towards studying the roles of the cyclic AMP and phosphoinositide pathways. Upon ligand binding, the transmitter receptors interact with heterotrimeric G proteins, allowing G alpha and G beta gamma subunits to disengage. The free G alpha then modulates the activity of adenylyl cyclase and phospholipase C. It has been suggested that the G beta gamma complex which is activated through muscarinic or neuropeptide receptors can stimulate mitogen-activated protein kinase (MAPK) via activation of the small guanine-nucleotide-binding protein Ras. Sequential activation of the intermediates in the Ras/Raf serine-threonine protein kinase/MAPK kinase/MAPK/transcription factor pathway has emerged as a central mechanism for controlling cell proliferation and differentiation in yeast, worms, fruitflies and mammals. Here we show, by analysis of Drosophila mutants, that synaptic current and modulation of K+ current, triggered by a pituitary adenylyl cyclase-activating polypeptide-like neuropeptide, are mediated by coactivation of the Ras/Raf and Rutabaga-adenylyl cyclase pathways. Thus the Ras/Raf pathway also appears to be essential for G-protein-coupled neurotransmission.


Exploring reservoir dynamics: a case study of rabies in the Serengeti ecosystem.
Knowledge of infection reservoir dynamics is critical for effective disease control, but identifying reservoirs of multi-host pathogens is challenging. Here, we synthesize several lines of evidence to investigate rabies reservoirs in complex carnivore communities of the Serengeti ecological region in northwest Tanzania, where the disease has been confirmed in 12 carnivore species.Long-term monitoring data suggest that rabies persists in high-density domestic dog Canis familiaris populations (> 11 dogs km(-2)) and occurs less frequently in lower-density (< 5 dogs km(-2)) populations and only sporadically in wild carnivores.Genetic data show that a single rabies virus variant belonging to the group of southern Africa canid-associated viruses (Africa 1b) circulates among a range of species, with no evidence of species-specific virus-host associations.Within-species transmission was more frequently inferred from high-resolution epidemiological data than between-species transmission. Incidence patterns indicate that spill-over of rabies from domestic dog populations sometimes initiates short-lived chains of transmission in other carnivores.Synthesis and applications. The balance of evidence suggests that the reservoir of rabies in the Serengeti ecosystem is a complex multi-host community where domestic dogs are the only population essential for persistence, although other carnivores contribute to the reservoir as non-maintenance populations. Control programmes that target domestic dog populations should therefore have the greatest impact on reducing the risk of infection in all other species including humans, livestock and endangered wildlife populations, but transmission in other species may increase the level of vaccination coverage in domestic dog populations necessary to eliminate rabies.


Absolute lymphocyte count at day 29 of treatment is a powerful predictor of outcome in multiple myeloma.
Survival outcomes for patients who receive treatment for newly diagnosed multiple myeloma (MM) are highly variable. We conducted a retrospective analysis of 38 unselected MM patients who received treatment with cyclophosphamide, thalidomide, and dexamethasone to evaluate the prognostic value of the absolute lymphocyte count at diagnosis and at the end of the initial cycle of treatment defined as day 29, termed ALC-29. The median follow-up was 54 months (range, 2-83 months). We found that ALC-29, as a continuous variable, was a predictor of overall survival (OS) in MM patients (hazard ratio, 0.208; 95% confidence interval, 0.093-0.689; P = .007). Patients with an ALC-29 ≥ 0.8 × 10(9)/L (n = 16) experienced a superior median OS compared with patients with an ALC-29 < 0.8 × 10(9)/L (n = 22) with a median OS of 58.3 months versus 42.5 months respectively (P = .006). Multivariate analysis confirmed that ALC-29 ≥ 0.8 × 10(9)/L was an independent prognostic indicator of OS in our cohort of MM patients. We concluded that the ALC-29 is a useful and simple predictor of outcome in newly diagnosed MM patients who receive standard chemotherapy. Our results support the hypothesis that host immunity plays an important role in tumor control in MM.


Information thermodynamics of near-equilibrium computation.
In studying fundamental physical limits and properties of computational processes, one is faced with the challenges of interpreting primitive information-processing functions through well-defined information-theoretic as well as thermodynamic quantities. In particular, transfer entropy, characterizing the function of computational transmission and its predictability, is known to peak near critical regimes. We focus on a thermodynamic interpretation of transfer entropy aiming to explain the underlying critical behavior by associating information flows intrinsic to computational transmission with particular physical fluxes. Specifically, in isothermal systems near thermodynamic equilibrium, the gradient of the average transfer entropy is shown to be dynamically related to Fisher information and the curvature of system's entropy. This relationship explicitly connects the predictability, sensitivity, and uncertainty of computational processes intrinsic to complex systems and allows us to consider thermodynamic interpretations of several important extreme cases and trade-offs.


Memory T cells protect against Plasmodium vivax infection.
Immunity induced by Plasmodium vivax infection leads to memory T cell recruitment activated during "relapse" or "re-infection". This study aims to characterise memory T cells in patients with acute or convalescent P. vivax infection. Lymphocytes were collected from patients infected by P. vivax, immune controls and naive controls. The proportion of immature memory T cells, expressing CD45RO(+)CD27(+), and mature cells lacking CD27 was assessed. A statistically significant increase in the median percentage of memory T cell subsets expressing CD4(+) was observed in material from patients with an acute infection compared with that from either naive or immune controls. The high percentage of memory T cells in infected patients was maintained until 60 days post treatment. The immune controls living in a malaria endemic area had a somewhat increased proportion of memory T cell subsets expressing CD8(+). An approximately three-fold increase of these cell types was shown in patients with an acute infection and the level persisted until 60 days post treatment. Phenotypic characterisation of the peripheral lymphocytes during acute infection revealed that a large fraction of the lymphocytes carried the gammadelta phenotypes suggesting a role for these cells in the early response against P. vivax. Very low levels of P. vivax specific antibody were found. This might suggest that cell-mediated immunity may play a greater role in the development of naturally acquired protection against P. vivax infection than humoral immunity. Our results provide further insight into the mechanism of cell-mediated immunity to P. vivax infection that could be important for the future development of a successful vaccine and anti-malarial drug designation.


Does Vascular Calcification Accelerate Inflammation?: A Substudy of the dal-PLAQUE Trial.
Atherosclerosis is an inflammatory condition with calcification apparent late in the disease process. The extent and progression of coronary calcification predict cardiovascular events. Relatively little is known about noncoronary vascular calcification. This study investigated noncoronary vascular calcification and its influence on changes in vascular inflammation. A total of 130 participants in the dal-PLAQUE (Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) study underwent fluorodeoxyglucose positron emission tomography/computed tomography at entry and at 6 months. Calcification of the ascending aorta, arch, carotid, and coronary arteries was quantified. Cardiovascular risk factors were related to arterial calcification. The influences of baseline calcification and drug therapy (dalcetrapib vs. placebo) on progression of calcification were determined. Finally, baseline calcification was related to changes in vascular inflammation. Age >65 years old was consistently associated with higher baseline calcium scores. Arch calcification trended to progress more in those with calcification at baseline (p = 0.055). There were no significant differences between progression of vascular calcification with dalcetrapib compared to that with placebo. Average carotid target-to-background ratio indexes declined over 6 months if carotid calcium was absent (single hottest slice [p = 0.037], mean of maximum target-to-background ratio [p = 0.010], and mean most diseased segment [p < 0.001]), but did not significantly change if calcification was present at baseline. Across multiple arterial regions, higher age is consistently associated with higher calcium scores. The presence of vascular calcification at baseline is associated with progressive calcification; in the carotid arteries, calcification appears to influence vascular inflammation. Dalcetrapib therapy did not affect vascular calcification.


Drift Barriers to Quality Control When Genes Are Expressed at Different Levels.
Gene expression is imperfect, sometimes leading to toxic products. Solutions take two forms: globally reducing error rates, or ensuring that the consequences of erroneous expression are relatively harmless. The latter is optimal, but because it must evolve independently at so many loci, it is subject to a stringent "drift barrier"-a limit to how weak the effects of a deleterious mutation s can be, while still being effectively purged by selection, expressed in terms of the population size N of an idealized population such that purging requires s < -1/N In previous work, only large populations evolved the optimal local solution, small populations instead evolved globally low error rates, and intermediate populations were bistable, with either solution possible. Here, we take into consideration the fact that the effectiveness of purging varies among loci, because of variation in gene expression level, and variation in the intrinsic vulnerabilities of different gene products to error. The previously found dichotomy between the two kinds of solution breaks down, replaced by a gradual transition as a function of population size. In the extreme case of a small enough population, selection fails to maintain even the global solution against deleterious mutations, explaining the nonmonotonic relationship between effective population size and transcriptional error rate that was recently observed in experiments on Escherichia coli, Caenorhabditis elegans, and Buchnera aphidicola.


Do clinicians understand the size of treatment effects? A randomized survey across 8 countries.
Meta-analyses of continuous outcomes typically provide enough information for decision-makers to evaluate the extent to which chance can explain apparent differences between interventions. The interpretation of the magnitude of these differences - from trivial to large - can, however, be challenging. We investigated clinicians' understanding and perceptions of usefulness of 6 statistical formats for presenting continuous outcomes from meta-analyses (standardized mean difference, minimal important difference units, mean difference in natural units, ratio of means, relative risk and risk difference). We invited 610 staff and trainees in internal medicine and family medicine programs in 8 countries to participate. Paper-based, self-administered questionnaires presented summary estimates of hypothetical interventions versus placebo for chronic pain. The estimates showed either a small or a large effect for each of the 6 statistical formats for presenting continuous outcomes. Questions addressed participants' understanding of the magnitude of treatment effects and their perception of the usefulness of the presentation format. We randomly assigned participants 1 of 4 versions of the questionnaire, each with a different effect size (large or small) and presentation order for the 6 formats (1 to 6, or 6 to 1). Overall, 531 (87.0%) of the clinicians responded. Respondents best understood risk difference, followed by relative risk and ratio of means. Similarly, they perceived the dichotomous presentation of continuous outcomes (relative risk and risk difference) to be most useful. Presenting results as a standardized mean difference, the longest standing and most widely used approach, was poorly understood and perceived as least useful. None of the presentation formats were well understood or perceived as extremely useful. Clinicians best understood the dichotomous presentations of continuous outcomes and perceived them to be the most useful. Further initiatives to help clinicians better grasp the magnitude of the treatment effect are needed.


Lymphokine gene expression in vivo is inhibited by cyclosporin A.
Murine T cells were stimulated in vivo by administering allogeneic cells or mitogens into the foot pads and then examining the draining popliteal lymph nodes. Allogeneic spleen cells induced the expression of IL2 and IFN-gamma mRNAs in a time- and dose-dependent manner. Induction of these transcripts also was detected after administration of Con A and anti-CD3 mAb. An increase in DNA-synthesizing cells was observed by 48 h, and these were shown to be T cells because of their sensitivity to anti-Thy-1 but not anti-B220 mAb and complement, and because of their localization to the T-dependent areas of the lymph node. The in vivo administration of cyclosporin A (CSA) reduced several of these T cell responses. The level of DNA synthesis and the frequency of cells synthesizing DNA were decreased by approximately 75%, while the induction of IL-2 responsiveness was not substantially diminished. IL-2 and IFN-gamma transcripts were inhibited at least 70-90%, as determined by Northern blot and in situ hybridization. Although the inhibition by CSA was not as complete in animals as observed previously in tissue culture, our findings indicate that in both systems, a major site of action of CSA is to inhibit T cell growth by inhibiting lymphokine production.


Passenger rail security, planning, and resilience: application of network, plume, and economic simulation models as decision support tools.
We built three simulation models that can assist rail transit planners and operators to evaluate high and low probability rail-centered hazard events that could lead to serious consequences for rail-centered networks and their surrounding regions. Our key objective is to provide these models to users who, through planning with these models, can prevent events or more effectively react to them. The first of the three models is an industrial systems simulation tool that closely replicates rail passenger traffic flows between New York Penn Station and Trenton, New Jersey. Second, we built and used a line source plume model to trace chemical plumes released by a slow-moving freight train that could impact rail passengers, as well as people in surrounding areas. Third, we crafted an economic simulation model that estimates the regional economic consequences of a variety of rail-related hazard events through the year 2020. Each model can work independently of the others. However, used together they help provide a coherent story about what could happen and set the stage for planning that should make rail-centered transport systems more resistant and resilient to hazard events. We highlight the limitations and opportunities presented by using these models individually or in sequence.


Physical activity of urban community-dwelling older Latino adults.
To date, little is known about the physical activity (PA) levels and commonly reported modes of PA of older Latinos, and this information is critical to developing interventions for this population. The purpose of the current study was to examine PA assessed by self-report and accelerometer and to assess the influence of acculturation, gender, and age on the PA of urban community-dwelling older Latino adults. Participants were self-identified Latinos, primarily women (73%), and individuals aged 50 to 59 (31%), 60 to 69 (30%), and 70+ (39%). PA was measured with an accelerometer and the Community Healthy Activity Model Program for Seniors (CHAMPS) PA questionnaire. Men reported engaging in, and objectively participated in, significantly more minutes of moderate/vigorous PA than women, but women reported greater light intensity household PA. Latinos aged 50 to 59 engaged in significantly more accelerometer-assessed PA than Latinos aged 60 to 69 and 70+, respectively. The majority of participants did not meet the PA Guidelines for Americans. No differences in PA were demonstrated by acculturation level. Older Latino men and women reported walking and dancing as modes of leisure PA. These findings suggest PA interventions should be targeted toward older Latinos, taking into account gender and age.


Central vein sign: comparison of multiple sclerosis and leukoaraiosis.
Leukoaraiosis produces white matter lesions (WML) similar to multiple sclerosis (MS) on brain magnetic resonance imaging (MRI), and the distinction between these two conditions is difficult radiologically. This study aimed to investigate the role of the central vein sign (CVS) in susceptibility-weighted imaging (SWI) sequence in distinguishing MS lesions from leukoaraiosis lesions in Turkish population. In this prospective study, axial SWI and sagittal three-dimensional fluid-attenuated inversion recovery (3DFLAIR) were obtained in 374 consecutive patients. The study consisted of 169 (89 MS patients, 80 patients with leukoaraiosis) patients according to the inclusion and exclusion criteria. Two observers evaluated MR images by consensus, and observers were unaware of the patient's clinical findings. Locations (periventricular, juxtacortical, and deep white matter) and the presence of CVS were investigated for each of the lesions. Differences between patients in the leukoaraiosis and MS groups were investigated using the Mann-Whitney U test or chi-square analysis. In addition, receiver operating characteristic (ROC) analysis was used to analyze the diagnostic performance of CVS. A total of 1908 WMLs (1265 MS lesions, 643 leukoaraiosis) were detected in 169 patients. The CVS was significantly higher in the MS lesions (p < 0.001). The CVS positivity rate in periventricular WMLs was higher than in juxtacortical WMLs or deep WMLs, both for all patients and for patients with MS (p < 0.001). The area under the curve (AUC) of the ROC analysis was 0.88 (95% confidence interval 0.83-0.93) for CVS in the distinction of MS lesions and leukoaraiosis. The presence of CVS in the SWI sequence can be used as an auxiliary finding for the diagnosis of MS in the differentiation of MS and leukoaraiosis lesions.


PET segmentation of bulky tumors: Strategies and workflows to improve inter-observer variability.
PET-based tumor delineation is an error prone and labor intensive part of image analysis. Especially for patients with advanced disease showing bulky tumor FDG load, segmentations are challenging. Reducing the amount of user-interaction in the segmentation might help to facilitate segmentation tasks especially when labeling bulky and complex tumors. Therefore, this study reports on segmentation workflows/strategies that may reduce the inter-observer variability for large tumors with complex shapes with different levels of user-interaction. Twenty PET images of bulky tumors were delineated independently by six observers using four strategies: (I) manual, (II) interactive threshold-based, (III) interactive threshold-based segmentation with the additional presentation of the PET-gradient image and (IV) the selection of the most reasonable result out of four established semi-automatic segmentation algorithms (Select-the-best approach). The segmentations were compared using Jaccard coefficients (JC) and percentage volume differences. To obtain a reference standard, a majority vote (MV) segmentation was calculated including all segmentations of experienced observers. Performed and MV segmentations were compared regarding positive predictive value (PPV), sensitivity (SE), and percentage volume differences. The results show that with decreasing user-interaction the inter-observer variability decreases. JC values and percentage volume differences of Select-the-best and a workflow including gradient information were significantly better than the measurements of the other segmentation strategies (p-value<0.01). Interactive threshold-based and manual segmentations also result in significant lower and more variable PPV/SE values when compared with the MV segmentation. FDG PET segmentations of bulky tumors using strategies with lower user-interaction showed less inter-observer variability. None of the methods led to good results in all cases, but use of either the gradient or the Select-the-best workflow did outperform the other strategies tested and may be a good candidate for fast and reliable labeling of bulky and heterogeneous tumors.


Low-level lead exposure, intelligence and academic achievement: a long-term follow-up study.
The implications of low-level lead exposure for children's intellectual and academic performance at school age are uncertain. This issue was investigated in a prospective study of middle-class and upper-middle-class children with low lifetime exposures to lead. A battery of neuropsychological tests was administered at age 10 years to 148 children whose lead exposure and cognitive function had been previously assessed at ages 6, 12, 18, 24, and 57 months. Primary endpoints were Wechsler Intelligence Scale for Children-Revised (WISC-R) and the Kaufman Test of Educational Achievement (K-TEA). Higher levels of blood lead at age 24 months, but not at other ages, were significantly associated with lower global scores on both the WISC-R and the K-TEA after adjustment for potential confounders. Over the range of approximately 0 to 25 micrograms/dL, a 0.48-mumol/L (10 micrograms/dL) increase in blood lead at 24 months was associated with a 5.8-point decline in WISC-R Full-Scale IQ (95% confidence interval: 1.7 to 9.9, P = .007) and an 8.9-point decline in K-TEA Battery Composite score (95% confidence interval: 4.2 to 13.6, P = .0003). Mean blood lead level at age 24 months was 0.31 mumol/L (6.5 micrograms/dL; SD: 4.9, 90% percentile: 12.5). Slightly elevated blood lead levels around the age of 24 months are associated with intellectual and academic performance deficits at age 10 years.


Predictors of Acute Kidney Injury and Mortality in Intensive Care Unit at a Teaching Tertiary Hospital_ID.
Despite the increased rates of acute kidney injury (AKI) in intensive care units (ICU) and associated mortality, information on the epidemiology of AKI is sparse in sub-Saharan Africa (SSA). We investigated the rates and predictors of AKI and associated mortality in a tertiary ICU. This retrospective study analyzed 280 hospital records of patients admitted to the ICU at a tertiary teaching hospital who were aged ≥15 years from January 2017 to May 31, 2018. The outcome parameters of the study were rates of AKI in the ICU, associated risk factors, and mortalities. Acute kidney injury and ICU mortality were established by the multivariate logistic analysis. The median age was 36 years (IQR 28, 52). The rate of AKI was 52.9%, and the presence of human immunodeficiency virus (HIV) and oliguria was 2.3-fold (0.004) and 4-fold (0.016) positive predictors of ICU-AKI, respectively. Male gender (0.003), diabetes mellitus (DM) (0.010), respiratory disease (0.001), inotropes (0.004), and ventilator support (0.017) were predictors for ICU mortality after controlling for confounders. The rate of AKI is significantly higher in a referral tertiary hospital in Zambia compared to developed countries and the presence of HIV and noncommunicable diseases such as DM impacts severely on outcomes. Banda J, Chenga N, Nambaya S, Bulaya T, Siziya S. Predictors of Acute Kidney Injury and Mortality in Intensive Care Unit at a Teaching Tertiary Hospital_ID. Indian J Crit Care Med 2020;24(2):116-121.