Breaking the Spell: Combating Multidrug Resistant 'Superbugs'.
Multidrug-resistant (MDR) bacteria have become a severe threat to community wellbeing. Conventional antibiotics are getting progressively more ineffective as a consequence of resistance, making it imperative to realize improved antimicrobial options. In this review we emphasized the microorganisms primarily reported of being resistance, referred as ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacteriaceae) accentuating their capacity to "escape" from routine antimicrobial regimes. The upcoming antimicrobial agents showing great potential and can serve as alternative therapeutic options are discussed. We also provided succinct overview of two evolving technologies; specifically network pharmacology and functional genomics profiling. Furthermore, In vivo imaging techniques can provide novel targets and a real time tool for potential lead molecule assessment. The employment of such approaches at prelude of a drug development process, will enables more informed decisions on candidate drug selection and will maximize or predict therapeutic potential before clinical testing.


Permafrost conditions in peatlands regulate magnitude, timing, and chemical composition of catchment dissolved organic carbon export.
Permafrost thaw in peatlands has the potential to alter catchment export of dissolved organic carbon (DOC) and thus influence downstream aquatic C cycling. Subarctic peatlands are often mosaics of different peatland types, where permafrost conditions regulate the hydrological setting of each type. We show that hydrological setting is key to observed differences in magnitude, timing, and chemical composition of DOC export between permafrost and nonpermafrost peatland types, and that these differences influence the export of DOC of larger catchments even when peatlands are minor catchment components. In many aspects, DOC export from a studied peatland permafrost plateau was similar to that of a forested upland catchment. Similarities included low annual export (2-3 g C m(-2) ) dominated by the snow melt period (~70%), and how substantial DOC export following storms required wet antecedent conditions. Conversely, nonpermafrost fens had higher DOC export (7 g C m(-2) ), resulting from sustained hydrological connectivity during summer. Chemical composition of catchment DOC export arose from the mixing of highly aromatic DOC from organic soils from permafrost plateau soil water and upland forest surface horizons with nonaromatic DOC from mineral soil groundwater, but was further modulated by fens. Increasing aromaticity from fen inflow to outlet was substantial and depended on both water residence time and water temperature. The role of fens as catchment biogeochemical hotspots was further emphasized by their capacity for sulfate retention. As a result of fen characteristics, a 4% fen cover in a mixed catchment was responsible for 34% higher DOC export, 50% higher DOC concentrations and ~10% higher DOC aromaticity at the catchment outlet during summer compared to a nonpeatland upland catchment. Expansion of fens due to thaw thus has potential to influence landscape C cycling by increasing fen capacity to act as biogeochemical hotspots, amplifying aquatic C cycling, and increasing catchment DOC export.


Collagen type I and hyaluronic acid based hybrid scaffolds for heart valve tissue engineering.
Tissue engineers have achieved limited success so far in designing an ideal scaffold for aortic valve; scaffolds lack in mechanical compatibility, appropriate degradation rate, and microstructural similarity. This paper, therefore, has demonstrated a carbodiimide-based sequential crosslinking technique to prepare aortic valve extracellular matrix mimicking (ECM) hybrid scaffolds from collagen type I and hyaluronic acid (HA), the building blocks of heart valve ECM, with tailorable crosslinking densities. Swelling studies revealed that crosslinking densities of parent networks increased with increasing the concentration of the crosslinking agents whereas crosslinking densities of hybrid scaffolds averaged from those of parent collagen and HA networks. Hybrid scaffolds also offered a wide range of pore size (66-126 μm) which fulfilled the criteria for valvular tissue regeneration. Scanning electron microscopy and images of Alcian blue-Periodic acid Schiff stained samples suggested that our crosslinking technique yielded an ECM mimicking microstructure with interlaced bands of collagen and HA in the hybrid scaffolds. The mutually reinforcing networks of collagen and HA also resulted in increased bending moduli up to 1660 kPa which spanned the range of natural aortic valves. Cardio sphere-derived cells (CDCs) from rat hearts showed that crosslinking density affected the available cell attachment sites on the surface of the scaffold. Increased bending moduli of CDCs seeded scaffolds up to two folds (2-6 kPa) as compared to the non-seeded scaffolds (1 kPa) suggested that an increase in crosslinking density of the scaffolds could not only increase the in vitro bending modulus but also prevented its disintegration in the cell culture medium.


ID1 expression associates with other molecular markers and is not an independent prognostic factor in cytogenetically normal acute myeloid leukaemia.
In acute myeloid leukaemia with normal karyotype (CN-AML), gene mutations (e.g. NPM1, FLT3, CEBPA) as well as deregulated gene expression affect outcome. High expression of ID1 was described as a negative prognostic factor. We have shown that CEBPA regulates ID1 expression. Therefore, we analysed the prognostic impact of ID1 expression in 269 patients (aged 16-60 years) with CN-AML in the context of other molecular markers, particularly CEBPA mutations. ID1(high) status was an independent negative prognostic factor for overall survival (OS) in multivariate analysis when analysed together with age, extramedullary disease, platelets, expression of BAALC and WT1, FLT3-internal tandem duplication, NPM1, WT1 single nucleotide polymorphism rs16754 and IDH1. ID1 expression was higher in CEBPA wildtype patients than in patients with monoallelic CEBPA mutations and these patients showed higher ID1 expression compared to patients with biallelic CEBPA mutations. Thus, when CEBPA mutations were considered, ID1 expression lost its prognostic impact. Likewise, the negative impact of ID1(high) status on relapse-free survival (RFS) was lost when CEBPA mutations were included in the analysis. In CEBPA wildtype patients, ID1 expression had no impact on complete remission-rate, OS or RFS. In conclusion, CEBPA mutations seem to deregulate ID1 expression. Therefore, ID1 expression is not an independent prognostic factor in CN-AML.


The impact of hunting on tropical mammal and bird populations.
Hunting is a major driver of biodiversity loss, but a systematic large-scale estimate of hunting-induced defaunation is lacking. We synthesized 176 studies to quantify hunting-induced declines of mammal and bird populations across the tropics. Bird and mammal abundances declined by 58% (25 to 76%) and by 83% (72 to 90%) in hunted compared with unhunted areas. Bird and mammal populations were depleted within 7 and 40 kilometers from hunters' access points (roads and settlements). Additionally, hunting pressure was higher in areas with better accessibility to major towns where wild meat could be traded. Mammal population densities were lower outside protected areas, particularly because of commercial hunting. Strategies to sustainably manage wild meat hunting in both protected and unprotected tropical ecosystems are urgently needed to avoid further defaunation.


Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers.
An essential protein of the SARS-CoV-2 virus, the envelope protein E, forms a homopentameric cation channel that is important for virus pathogenicity. Here we report a 2.1-Å structure and the drug-binding site of E's transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal α-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs.


Comparative analysis of targeted next-generation sequencing for Plasmodium falciparum drug resistance markers.
Well-defined molecular resistance markers are available for a range of antimalarial drugs, and molecular surveillance is increasingly important for monitoring antimalarial drug resistance. Different genotyping platforms are available, but these have not been compared in detail. We compared Targeted Amplicon Deep sequencing (TADs) using Ion Torrent PGM with Illumina MiSeq for the typing of antimalarial drug resistance genes. We developed and validated protocols to type the molecular resistance markers pfcrt, pfdhfr, pfdhps, pfmdr1, pfkelch, and pfcytochrome b, in Plasmodium falciparum for the Ion Torrent PGM and Illumina MiSeq sequencing platforms. With P. falciparum 3D7 and K1 as reference strains, whole blood samples (N = 20) and blood spots from Rapid Diagnostic Test (RDT) samples (N = 5) from patients with uncomplicated falciparum malaria from Ubon Ratchathani were assessed on both platforms and compared for coverage (average reads per amplicon), sequencing accuracy, variant accuracy, false positive rate, false negative rate, and alternative allele detection, with conventional Sanger sequencing as the reference method for SNP calling. Both whole blood and RDT samples could be successfully sequenced using the Ion Torrent PGM and Illumina MiSeq platforms. Coverage of reads per amplicon was higher with Illumina MiSeq (28,886 reads) than with Ion Torrent PGM (1754 reads). In laboratory generated artificial mixed infections, the two platforms could detect the minor allele down to 1% density at 500X coverage. SNPs calls from both platforms were in complete agreement with conventional Sanger sequencing. The methods can be multiplexed with up to 96 samples per run, which reduces cost by 86% compared to conventional Sanger sequencing. Both platforms, using the developed TAD protocols, provide an accurate method for molecular surveillance of drug resistance markers in P. falciparum, but Illumina MiSeq provides higher coverage than Ion Torrent PGM.


Quality of care in contraceptive services provided to young people in two Ugandan districts: a simulated client study.
Low and inconsistent use of contraceptives by young people contributes to unintended pregnancies. This study assessed quality of contraceptive services for young people aged 15-24 in two rural districts in Uganda. Five female and two male simulated clients (SCs) interacted with 128 providers at public, private not-for-profit (PNFP), and private for profit (PFP) health facilities. After consultations, SCs were interviewed using a structured questionnaire. Six aspects of quality of care (client's needs, choice of contraceptive methods, information given to users, client-provider interpersonal relations, constellation of services, and continuity mechanisms) were assessed. Descriptive statistics and factor analysis were performed. Means and categorized quality scores for all aspects of quality were low in both public and private facilities. The lowest quality scores were observed in PFP, and medium scores in PNFP facilities. The choice of contraceptive methods and interpersonal relations quality scores were slightly higher in public facilities. Needs assessment scores were highest in PNFP facilities. All facilities were classified as having low scores for appropriate constellation of services. Information given to users was suboptimal and providers promoted specific contraceptive methods. Minority of providers offered preferred method of choice and showed respect for privacy. The quality of contraceptive services provided to young people was low. Concurrent quality improvements and strengthening of health systems are needed.


The protective effect of aloe vera juice on lindane induced hepatotoxicity and genotoxicity.
The protective effect of fresh aloe vera (AV) leaves extract on lindane (LD) - induced hepatoxicity and genotoxicity was studied. Serum levels of hepatic enzyme markers: glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP) were determined after oral administration of aloe vera leaves extract and lindane. The level of polychromatic erythrocytes was also observed. Pretreatment with aloe vera leaves extract at concentration of 1.0 ml/kg body weight significantly decreased (P<0.05) the serum levels of GPT (by 41.8%), GOT (by 36.5%), GGT (by 14.3%) and ALP (by 10.7%) induced by 100mg/kg body weight of lindane. The level of polychromatic erythrocytes observed was not statistically significant when compared to control.


Asthma and its relationship to mitochondrial copy number: Results from the Asthma Translational Genomics Collaborative (ATGC) of the Trans-Omics for Precision Medicine (TOPMed) program.
Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis. Given the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma. Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing. Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes. We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.


Metformin in patients with type 2 diabetes and kidney disease: a systematic review.
Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person-years to 10 per 100,000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus--use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.


Multiple effects of trehalose on protein folding in vitro and in vivo.
The disaccharide trehalose is produced in large quantities by diverse organisms during a variety of stresses. Trehalose prevents proteins from denaturing at high temperatures in vitro, but its function in stress tolerance in vivo is controversial. We report that trehalose stabilizes proteins in yeast cells during heat shock. Surprisingly, trehalose also suppresses the aggregation of denatured proteins, maintaining them in a partially-folded state from which they can be activated by molecular chaperones. The continued presence of trehalose, however, interferes with refolding, suggesting why it is rapidly hydrolyzed following heat shock. These findings reconcile conflicting reports on the role of trehalose in stress tolerance, provide a novel tool for accessing protein folding intermediates, and define new parameters for modulating stress tolerance and protein aggregation.


High frequencies of exposure to the novel human parvovirus PARV4 in hemophiliacs and injection drug users, as detected by a serological assay for PARV4 antibodies.
PARV4 is a human parvovirus that was first detected in and cloned from an individual with a human immunodeficiency virus (HIV) seroconversion-like illness and that subsequently persisted in the lymphoid tissue and bone marrow. In contrast to human parvovirus B19 infections, PARV4 infections are most frequently detected in injection drug users (IDUs), particularly those who are coinfected with HIV type 1 (HIV-1). To investigate the routes of transmission of PARV4 and to ascertain whether infections are acquired through plasma-derived blood products, we developed a novel anti-PARV4 enzyme-linked immunosorbent assay (ELISA) to determine its seroprevalence in subjects with parenteral exposure. PARV4 viral protein 2 (VP2) was expressed and used as antigen in an indirect ELISA, to detect anti-PARV4 immunoglobulin G. All 50 adult control subjects who were nonparenterally exposed to PARV4 were anti-PARV4 negative, in contrast to HIV-infected and HIV-uninfected IDUs, who had antibody frequencies of 67% and 33%, respectively. Predominantly parenteral transmission was confirmed by the finding of similar frequencies of infection among HIV-coinfected and HIV-uninfected hemophiliacs (11 of 20 individuals and 4 of 15 individuals, respectively) who were treated with nonvirally inactivated factor VIII/factor IX, whereas all but 1 of the 35 nonhemophiliac siblings of these siblings were found to be seronegative (despite having close household contact). The present study provides convincing evidence that PARV4 is primarily transmitted parenterally. Evidence for widespread infection of hemophiliacs treated with nonvirally inactivated clotting factor creates fresh safety concerns for plasma-derived blood products, particularly because parvoviruses are relatively resistant to virus inactivation.


[Telemetric intraoperative diagnosis among hospitals in Trentino: first evaluations and optimization of the procedure].
Telemetric, intraoperative frozen section diagnosis may be a useful tool for rural hospitals lacking an in-house pathology service. As a part of a Health Ministry Project on Telemedicine in Trentino (northern Italy), we developed a static telemicroscopy system (STeMiSy). This system connects the rural hospital of Cles with the main hospital of Trento. The two hospitals are 40 kilometers apart, and the road connecting the two towns runs across the mountains and has a heavy traffic. Before putting STeMiSy into practice, we tested the software and hardware on the LAN of the regional hospital system, by connecting the pathology services of Trento and Rovereto (20 kilometers apart). This test phase lasted three months and has not revealed major problems in the LAN nor in the robotic microscope, which was always precise and reliable. The quality of the images and the speed of transmission were largely sufficient for intraoperative frozen section diagnosis. Minor details of the histological slides were not always appreciated on the panoramic view. This loss of some details may be due to the quality of the panoramic view, which represents the 'surfing map' to read the cases. Nevertheless, the recognition of these small details was not so relevant as to change the surgical approaches. An audioconference system, utilizing the same transmission channel, not only slightly slowed the transmission but also caused some instability to the system. The audioconference system has therefore been abandoned, and when necessary we used the normal telephone. Macroscopic images of the whole surgical specimen, the surgeon's responsibility for the sampling, good technical quality of the slide, and good training will allow us to perform remote frozen section diagnosis in the absence of the pathologist. We believe that the main, and probably only, difficulty for this approach is not of a technical nature, but reflects the pathologist's resistance to making a remote video diagnosis.


Dendritic cells in tissues: in situ stimulation of immunity and immunopathology.
Dendritic cells (DCs) prime and orchestrate naïve T cell immunity in lymphoid organs, but recent data also highlight the importance of DC-effector T cell interactions in tissues. These studies suggest that effector T cells require a second activating step in situ from tissue DCs to become fully competent for effector functions and/or proliferation and survival. DC stimulation of effector T cells within tissues has evolved as a mechanism to ensure that T cells are activated to their full potential only at the site of ongoing infection. Here, we propose that under conditions of uncontrolled inflammation and release of tissue antigens, the same DC-dependent checkpoint perpetuates a destructive response and immunopathology.


Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment.
Multiple studies demonstrate that the brain in Alzheimer's disease (AD) contains extensive oxidative damage. Most of these studies used advanced-stage AD patients raising the question of whether oxidative damage is a late effect of neurodegeneration or precedes and contributes to the pathogenesis of AD. Here we describe F(2)-isoprostane (F(2)-IsoP) and F(4)-neuroprostane (F(4)-NP) levels in longitudinally followed, well documented autopsied normal control subjects and patients with amnestic mild cognitive impairment (MCI), and late-stage AD. Gas chromatography/negative ion chemical ionization/mass spectrometry was used to determine F(2)-IsoP and F(4)-NP levels. Significant increases in F(2)-IsoP levels were found in frontal, parietal and occipital lobes in MCI and late AD compared to controls but no significant differences were present between MCI and late AD. A significant increase in F(4)-NPs was present in parietal and occipital lobes in MCI compared to controls and a significant increase was present in these regions and hippocampus in late AD compared to controls. The only difference between MCI and late AD was significantly increased F(4)-NP in hippocampus in late AD. Our data indicate that lipid peroxidation is present in the brain of MCI patients and suggest that oxidative damage may play a role in the pathogenesis of AD.


Culture filtrate proteins of Dermatophilus congolensis.
In previous studies on the antigens of Dermatophilus congolensis very little attention has been given to the hyphae and to excreted-secreted products (ESP) of actively growing bacteria. In this study we have grown four isolates of D. congolensis in a serum free synthetic liquid culture medium based on RPMI 1640. Diafiltration and ultrafiltration were used to prepare ESP from infected culture fluid. These methods produced sufficient quantities of ESP that the polypeptide profiles of the four isolates could be examined by SDS-PAGE and Western immunoblotting. The four isolates produced a large number of polypeptides in culture, most of which were produced by all four isolates. However each isolate produced polypeptides that were unique to it. Western immunoblotting studies using pooled sera from chronically affected animals from Ghana showed that a number of polypeptides in ESP of a Ghanaian isolate were antigenic. When the same sera was tested against ESP from a Scottish isolate a number of polypeptides of the same molecular weight as those in the Ghanaian isolate and some at different molecular weights were recognized. This indicates that isolates of D. congolensis from different geographical areas produce ESP with shared antigenic determinants.


The U.S. Army Person-Event Data Environment: A Military-Civilian Big Data Enterprise.
This report describes a groundbreaking military-civilian collaboration that benefits from an Army and Department of Defense (DoD) big data business intelligence platform called the Person-Event Data Environment (PDE). The PDE is a consolidated data repository that contains unclassified but sensitive manpower, training, financial, health, and medical records covering U.S. Army personnel (Active Duty, Reserve, and National Guard), civilian contractors, and military dependents. These unique data assets provide a veridical timeline capturing each soldier's military experience from entry to separation from the armed forces. The PDE was designed to afford unprecedented cost-efficiencies by bringing researchers and military scientists to a single computerized repository rather than porting vast data resources to individual laboratories. With funding from the Robert Wood Johnson Foundation, researchers from the University of Pennsylvania Positive Psychology Center joined forces with the U.S. Army Research Facilitation Laboratory, forming the scientific backbone of the military-civilian collaboration. This unparalleled opportunity was necessitated by a growing need to learn more about relations between psychological and health assets and health outcomes, including healthcare utilization and costs-issues of major importance for both military and civilian population health. The PDE represents more than 100 times the population size and many times the number of linked variables covered by the nation's leading sources of population health data (e.g., the National Health and Nutrition Examination Survey). Following extensive Army vetting procedures, civilian researchers can mine the PDE's trove of information using a suite of statistical packages made available in a Citrix Virtual Desktop. A SharePoint collaboration and governance management environment ensures user compliance with federal and DoD regulations concerning human subjects' protections and also provides a secure portal for multisite collaborations. Taking similarities and differences between military and civilian populations into account, PDE studies can provide much more detailed insight into health-related questions of broad societal concern. Finding ways to make the rich repository of digitized information in the PDE available through military-civilian collaboration can help solve critical medical and behavioral issues affecting the health and well-being of our nations' military and civilian populations.


Attention as foraging for information and value.
What is the purpose of attention? One avenue of research has led to the proposal that attention might be crucial for gathering information about the environment, while other lines of study have demonstrated how attention may play a role in guiding behavior to rewarded options. Many experiments that study attention require participants to make a decision based on information acquired discretely at one point in time. In real-world situations, however, we are usually not presented with information about which option to select in such a manner. Rather we must initially search for information, weighing up reward values of options before we commit to a decision. Here, we propose that attention plays a role in both foraging for information and foraging for value. When foraging for information, attention is guided toward the unknown. When foraging for reward, attention is guided toward high reward values, allowing decision-making to proceed by accept-or-reject decisions on the currently attended option. According to this account, attention can be regarded as a low-cost alternative to moving around and physically interacting with the environment-"teleforaging"-before a decision is made to interact physically with the world. To track the timecourse of attention, we asked participants to seek out and acquire information about two gambles by directing their gaze, before choosing one of them. Participants often made multiple refixations on items before making a decision. Their eye movements revealed that early in the trial, attention was guided toward information, i.e., toward locations that reduced uncertainty about value. In contrast, late in the trial, attention was guided by expected value of the options. At the end of the decision period, participants were generally attending to the item they eventually chose. We suggest that attentional foraging shifts from an uncertainty-driven to a reward-driven mode during the evolution of a decision, permitting decisions to be made by an engage-or-search strategy.


The effect of low childhood income on self-harm in young adulthood: Mediation by adolescent mental health, behavioural factors and school performance.
Low childhood income is an established risk factor of self-harm in adolescence and young adulthood, and childhood income is additionally associated with various correlates of self-harm. How these correlates, such as psychiatric disorders, substance abuse, violent behaviour and school problems, mediate the effect of childhood income on self-harm, is less understood. The purpose of the current paper is to examine this mediation. The study is based on administrative register data on all Finnish children born in 1990-1995. An analytical sample of 384,121 children is followed from age 8 to 22. We apply the parametric g-formula to study the effect of childhood income on the risk of self-harm in young adulthood. Adolescent psychiatric disorders, substance abuse, prior self-harm, violent criminality and victimization, out-of-home placements, not being in education, employment or training and school performance are considered as potential mediators. We control for confounding factors related to childhood family characteristics. As a hypothetical intervention, we moved those in the lowest childhood income quintile to the second-lowest quintile, which resulted in a 7% reduction in hospital-presenting self-harm in young adulthood among those targeted by the intervention (2% reduction in the total population). 67% of the effect was mediated through the chosen mediators. The results indicate that increases in childhood material resources could protect from self-harm in young adulthood. Moreover, the large proportion of mediation suggests that targeted interventions for high-risk adolescents may be beneficial. To our knowledge, this is the first paper to use the parametric g-formula to study youth self-harm. Future applications are encouraged as the method offers several further opportunities for analysing the complex life course pathways to self-harm.


Efficiency of organised and opportunistic cytological screening for cancer in situ of the cervix.
Cervical cancer incidence and mortality can be reduced by removal of precursor lesions detected at cytological screening. Organised screening, i.e. regular invitation of defined target groups, is generally considered more effective than opportunistic screening. The latter method however, is predominant in most settings. There is no scientific basis for advocating one type of screening or the other. Our aim was to compare the two types and to analyse their efficiency. We analysed 466,275 smears taken in an open cohort of 118,890 women during 1969-88. A computerised database permitted standardised classification of all smears and complete ascertainment of cancer in situ through record linkage. The number of in situ cancers detected per 1000 smears, the detection ratio, was used as an outcome measure both in univariate analyses and in multivariate logistic regression models. Cancer in situ was detected in 1076 women in the study cohort, with a detection ratio of 3.0 at organised and 2.1 at opportunistic screening, yielding an unadjusted odds ratio of 0.69 (95% CI 0.61-0.79). After adjustment for age and time period, the probability of detecting cancer in situ was around 25% higher with opportunistic than with organised screening (OR = 1.26; 95% CI 1.09-1.46). This difference in favour of opportunistic screening was most pronounced in the first 10 year period and disappeared during the last decade. The difference in efficiency between organised and opportunistic screening in the detection of cancer in situ was slight, if any. The dogma that organised screening is significantly more efficient than the opportunistic type needs reconsideration.


An Essential Regulatory System Originating from Polygenic Transcriptional Rewiring of PhoP-PhoQ of Xanthomonas campestris.
How essential, regulatory genes originate and evolve is intriguing because mutations of these genes not only lead to lethality in organisms, but also have pleiotropic effects since they control the expression of multiple downstream genes. Therefore, the evolution of essential, regulatory genes is not only determined by genetic variations of their own sequences, but also by the biological function of downstream genes and molecular mechanisms of regulation. To understand the origin of essential, regulatory genes, experimental dissection of the complete regulatory cascade is needed. Here, we provide genetic evidences to reveal that PhoP-PhoQ is an essential two-component signal transduction system in the gram-negative bacterium Xanthomonas campestris, but that its orthologs in other bacteria belonging to Proteobacteria are nonessential. Mutational, biochemical, and chromatin immunoprecipitation together with high-throughput sequencing analyses revealed that phoP and phoQ of X. campestris and its close relative Pseudomonas aeruginosa are replaceable, and that the consensus binding motifs of the transcription factor PhoP are also highly conserved. PhoP Xcc in X. campestris regulates the transcription of a number of essential, structural genes by directly binding to cis-regulatory elements (CREs); however, these CREs are lacking in the orthologous essential, structural genes in P. aeruginosa, and thus the regulatory relationships between PhoP Pae and these downstream essential genes are disassociated. Our findings suggested that the recruitment of regulatory proteins by critical structural genes via transcription factor-CRE rewiring is a driving force in the origin and functional divergence of essential, regulatory genes.


The simultaneous mass and energy evaporation (SM2E) model.
In this article, the Simultaneous Mass and Energy Evaporation (SM2E) model is presented. The SM2E model is based on theoretical models for mass and energy transfer. The theoretical models systematically under or over predicted at various flow conditions: laminar, transition, and turbulent. These models were harmonized with experimental measurements to eliminate systematic under or over predictions; a total of 113 measured evaporation rates were used. The SM2E model can be used to estimate evaporation rates for pure liquids as well as liquid mixtures at laminar, transition, and turbulent flow conditions. However, due to limited availability of evaporation data, the model has so far only been tested against data for pure liquids and binary mixtures. The model can take evaporative cooling into account and when the temperature of the evaporating liquid or liquid mixture is known (e.g., isothermal evaporation), the SM2E model reduces to a mass transfer-only model.


Expression of microRNA-497 and its prognostic significance in human breast cancer.
Dysregulation of microRNAs (miRNAs) plays critical roles in tumor progression. The aim of this study was to investigate the clinicopathologic and prognostic significance of miR-497 expression in human breast cancer (BC). Taqman qRT-PCR assay was performed to detect the expression of microRNA (miR)-497 in 30 pairs of BC tissues and corresponding noncancerous breast tissues. Additionally, the expression of this miRNA was detected in another 128 BC tissues and its correlations with clinicopathologic features of patients were analyzed. Kaplan-Meier analyses were used to assess survival of patients. Univariate and multivariate analyses were performed using the Cox proportional hazards model to analyze the prognostic significance of miR-497 expression. Our data indicated that the relative level of miR-497 expression in BC tissues was significantly lower than that in corresponding noncancerous breast tissues (P = 0.0046). Of 128 BC patients, 74 (57.8%) were placed in the high-miR-497 group and 54 (42.2%) were placed in the low-miR-497 group. By statistical analyses, low miR-497 expression was observed to be closely correlated with higher differentiation grade, positive HER-2 expression, higher incidence of lymph node metastasis and advanced clinical stage. Moreover, patients with high miR-497 expression had better 5-year disease-free and overall survival compared with the low miR-497 group (P = 0.0124 and 0.0018, respectively). Univariate and multivariate analyses indicated that low miR-497 expression was an independent poor prognostic factor for BC patients. Our data provided the first evidence that downregulation of miR-497 was correlated with BC progression, and miR-497 might be a potential molecular biomarker for predicting the prognosis of patients. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2025828761093488.


Lattice model of oligonucleotide hybridization in solution. I. Model and thermodynamics.
A coarse-grained lattice model of DNA oligonucleotides is proposed to investigate the general mechanisms by which single-stranded oligonucleotides hybridize to their complementary strands in solution. The model, based on a high-coordination cubic lattice, is simple enough to allow the direct simulation of DNA solutions, yet capturing how the fundamental thermodynamic processes are microscopically encoded in the nucleobase sequences. Physically relevant interactions are considered explicitly, such as interchain excluded volume, anisotropic base-pairing and base-stacking, and single-stranded bending rigidity. The model is studied in detail by a specially adapted Monte Carlo simulation method, based on parallel tempering and biased trials, which is designed to overcome the entropic and enthalpic barriers associated with the sampling of hybridization events of multiple single-stranded chains in solution. This methodology addresses both the configurational complexity of bringing together two complementary strands in a favorable orientation (entropic barrier) and the energetic penalty of breaking apart multiple associated bases in a double-stranded state (enthalpic barrier). For strands with sequences restricted to nonstaggering association and homogeneous pairing and stacking energies, base-pairing is found to dominate the hybridization over the translational and conformational entropy. For strands with sequence-dependent pairing corresponding to that of DNA, the complex dependence of the model's thermal stability on concentration, sequence, and degree of complementarity is shown to be qualitatively and quantitatively consistent both with experiment and with the predictions of statistical mechanical models.


Protective immunity against HIV infection: lessons from HIV-2 infection.
Despite two decades of intensive research, the correlates of protective immunity to HIV-1 infection remain elusive. Much less attention has been paid to the related human virus strain, HIV-2, which can cause AIDS, but does not usually do so in the majority of infected people. What can be learned from HIV-2 infection about how the human host can peacefully coexist with a pathogenic retrovirus?


Prostanoids in cortical subarachnoid cerebrospinal fluid and pial arterial diameter in newborn pigs.
These studies were designed to investigate the relationship between cerebral prostanoid synthesis and pial arterial caliber in chloralose-anesthetized newborn pigs with normal blood gases and pH and during combined arterial hypoxia and hypercapnia. Piglets less than 5 days old were equipped with closed cranial windows to allow direct observation of pial vessels, application of prostaglandin E2, and sampling of cortical subarachnoid cerebrospinal fluid. We found that prostanoids accumulate in cerebrospinal fluid on the cortical surface. The only prostanoid detected in arterial blood was 6-keto-prostaglandin F1 alpha [442 +/- 74 pg/ml (radioimmunoassay)]. Only small quantities of 6-keto-prostaglandin F1 alpha (214 +/- 53 pg/ml) and thromboxane B2 (122 +/- 18 pg/ml) were found in cerebrospinal fluid from the cisterna magna. Higher concentrations of 6-keto-prostaglandin F1 alpha (1056 +/- 159 pg/ml), thromboxane B2 (229 +/- 64 pg/ml), and prostaglandin E2 (4235 +/- 269 pg/ml) were found in cortical subarachnoid fluid. In contrast to arterial and cisternal concentrations, the concentrations of 6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2 in cortical subarachnoid fluid were increased reversibly by ventilation with 9% carbon dioxide, 10% oxygen, (6-keto-prostaglandin F1 alpha, 5436 +/- 1576 pg/ml; thromboxane B2, 694 +/- 122 pg/ml; and, prostaglandin E2, 12,455 +/- 3688 pg/ml). Further, pial arteries dilated in response to topical application of prostaglandin E2 at the concentration that was found in cortical subarachnoid fluid during combined hypoxia and hypercapnia. Systemic administration of indomethacin trihydrate (5 mg/kg) markedly reduced cortical subarachnoid fluid prostanoid concentrations and attenuated the pial artery vasodilation induced by combined hypoxia and hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)


A Distribution-Free Convolution Model for background correction of oligonucleotide microarray data.
Affymetrix GeneChip high-density oligonucleotide arrays are widely used in biological and medical research because of production reproducibility, which facilitates the comparison of results between experiment runs. In order to obtain high-level classification and cluster analysis that can be trusted, it is important to perform various pre-processing steps on the probe-level data to control for variability in sample processing and array hybridization. Many proposed preprocessing methods are parametric, in that they assume that the background noise generated by microarray data is a random sample from a statistical distribution, typically a normal distribution. The quality of the final results depends on the validity of such assumptions. We propose a Distribution Free Convolution Model (DFCM) to circumvent observed deficiencies in meeting and validating distribution assumptions of parametric methods. Knowledge of array structure and the biological function of the probes indicate that the intensities of mismatched (MM) probes that correspond to the smallest perfect match (PM) intensities can be used to estimate the background noise. Specifically, we obtain the smallest q2 percent of the MM intensities that are associated with the lowest q1 percent PM intensities, and use these intensities to estimate background. Using the Affymetrix Latin Square spike-in experiments, we show that the background noise generated by microarray experiments typically is not well modeled by a single overall normal distribution. We further show that the signal is not exponentially distributed, as is also commonly assumed. Therefore, DFCM has better sensitivity and specificity, as measured by ROC curves and area under the curve (AUC) than MAS 5.0, RMA, RMA with no background correction (RMA-noBG), GCRMA, PLIER, and dChip (MBEI) for preprocessing of Affymetrix microarray data. These results hold for two spike-in data sets and one real data set that were analyzed. Comparisons with other methods on two spike-in data sets and one real data set show that our nonparametric methods are a superior alternative for background correction of Affymetrix data.


Comparative analysis of viral RNA signatures on different RIG-I-like receptors.
The RIG-I-like receptors (RLRs) play a major role in sensing RNA virus infection to initiate and modulate antiviral immunity. They interact with particular viral RNAs, most of them being still unknown. To decipher the viral RNA signature on RLRs during viral infection, we tagged RLRs (RIG-I, MDA5, LGP2) and applied tagged protein affinity purification followed by next-generation sequencing (NGS) of associated RNA molecules. Two viruses with negative- and positive-sense RNA genome were used: measles (MV) and chikungunya (CHIKV). NGS analysis revealed that distinct regions of MV genome were specifically recognized by distinct RLRs: RIG-I recognized defective interfering genomes, whereas MDA5 and LGP2 specifically bound MV nucleoprotein-coding region. During CHIKV infection, RIG-I associated specifically to the 3' untranslated region of viral genome. This study provides the first comparative view of the viral RNA ligands for RIG-I, MDA5 and LGP2 in the presence of infection.


Higher rates of coronary angiography and revascularization following myocardial infarction may be associated with greater survival in the United States than in Canada. The CARS Investigators (Coumadin/Aspirin Reinfarction Study).
Significant differences are known to exist between the United States and Canada with respect to coronary catheterization and intervention. In a post hoc analysis, it was hypothesized that these differences may have the greatest impact on outcome in patients at risk for recurrent events such as those following myocardial infarction (MI). The hypothesis was tested in a nonrandomized comparison of the catheterization and revascularization patterns for patients following acute MI in 7029 patients in the United States and 1774 patients in Canada who participated in the Coumadin/Aspirin Reinfarction Study (CARS). CARS tested the effectiveness of low dose warfarin in combination with acetylsalicylic acid (ASA) versus ASA alone in reducing cardiovascular morbidity and mortality. Before study enrollment (median day 7 to 8), 84.5% of the American patients underwent coronary angiography compared with only 7.7% in Canada (P<0.01). CARS patients in the United States underwent significantly more frequent angioplasty during their hospital admission before study enrollment than their Canadian counterparts (55.8% versus 3.0%, respectively, P<0.01), and there was a more frequent use of intravenous heparin among American CARS patients (96% versus 88%, respectively, P<0.01) but less frequent administration of thrombolytic therapy (44% versus 49%, respectively, P<0.01). For follow-up of up to 32 months, American CARS patients had significantly fewer primary events (cardiovascular deaths, nonfatal MI, nonfatal ischemic stroke) than Canadian patients. Cumulative estimate of a primary end point comparing American with Canadian patients was, respectively, 2.0% versus 3.1% at one month, 8.0% versus 11.3% at one year and 11.6% versus 15.0% at two years. Thus, time to the primary event was significantly longer in American patients (P=0.0001). All-cause mortality estimates at 12 months were 2.2% and 4.0%, respectively, for the American and Canadian CARS subgroups. When management for the index MI (ie, angiography and angioplasty) is included in the model, the risk of death for Canadian versus American subgroups of CARS is not statistically different (0.9, 95% CI 0.6 to 1.2, P=0.40). Among study participants, American patients experienced a better outcome than Canadian patients, which may be attributable to more aggressive management based on early coronary angiography and angioplasty. However, angioplasty before study enrollment in American patients may have resulted in enrollment of lower risk patients. This selection bias limits the scope of the comparison.


Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates.
Immunoconjugates (BR96-DOX) were prepared between chimeric monoclonal antibody BR96 and the anticancer drug doxorubicin. The monoclonal antibody binds an antigen related to Lewis Y that is abundantly expressed at the surface of cells from many human carcinomas; it has a high degree of tumor selectivity and is internalized after binding. BR96-DOX induced complete regressions and cures of xenografted human lung, breast, and colon carcinomas growing subcutaneously in athymic mice and cured 70 percent of mice bearing extensive metastases of a human lung carcinoma. Also, BR96-DOX cured 94 percent of athymic rats with subcutaneous human lung carcinoma, even though the rats, like humans and in contrast to mice, expressed the BR96 target antigen in normal tissues.


Evaluation of recombinant sporozoite antigen SPAG-1 as a vaccine candidate against Theileria annulata by the use of different delivery systems.
The major sporozoite surface antigen of Theileria annulata (SPAG-1) is a candidate for inclusion in a subunit vaccine. In this paper we summarize the results of 4 vaccination experiments using recombinant SPAG-1 expressed in different systems and presented in different adjuvants. The antigen has been presented as either a C terminal 108 amino acid peptide (called SR1) expressed as both beta-galactosidase and hepatitis B core antigen fusions or as a full-length form expressed as a GST fusion with an N terminal His6 tag. We used different adjuvants, namely Freund's, saponin, ISCOMs and a proprietary adjuvant supplied by SmithKline Beecham, which we call SKBA. The data point to the conclusion that SPAG-1 can elicit partial protection and is therefore suitable for inclusion in an eventual multicomponent subunit vaccine.


Effects of pre-treatment with magnetic ion exchange resins on coagulation/flocculation process.
A new Magnetic Ion EXchange resin for DOC (Dissolved Organic Carbon) removal (MIEX DOC Resin) has been evaluated as water pre-treatment at the Drinking Water Treatment Plant (DWTP) of Florence in order to reduce the oxidant demand and disinfection by-products (DBPs) formation potential. This pre-treatment leads to several effects on downstream treatment processes. In this experimental study the effects of MIEX pre-treatment on clariflocculation process were evaluated with respect to coagulant demand reduction and characteristics of flocs formed. The analysis was conducted using traditional jar test procedures and a Photometric Dispersion Analyser (PDA2000) which provided continuous information about the aggregation state of particles during the jar tests. For a fixed turbidity goal in clarified water, ion exchange pre-treatment led to coagulant dosage reduction up to 60% and PDA results shown that flocs formed in pre-treated water were bigger and more resistant to shearing effects than those formed by conventional clariflocculation.


Search for heavy resonances that decay into a vector boson and a Higgs boson in hadronic final states at s = 13 TeV.
A search for heavy resonances with masses above 1 TeV , decaying to final states containing a vector boson and a Higgs boson, is presented. The search considers hadronic decays of the vector boson, and Higgs boson decays to b quarks. The decay products are highly boosted, and each collimated pair of quarks is reconstructed as a single, massive jet. The analysis is performed using a data sample collected in 2016 by the CMS experiment at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV , corresponding to an integrated luminosity of 35.9 fb - 1 . The data are consistent with the background expectation and are used to place limits on the parameters of a theoretical model with a heavy vector triplet. In the benchmark scenario with mass-degenerate W ' and Z ' bosons decaying predominantly to pairs of standard model bosons, for the first time heavy resonances for masses as high as 3.3 TeV are excluded at 95% confidence level, setting the most stringent constraints to date on such states decaying into a vector boson and a Higgs boson.


Hurricane risk assessment in a multi-hazard context for Dominica in the Caribbean.
Hurricanes can trigger widespread landslides and flooding creating compound hazards and multiple risks for vulnerable populations. An example is the island of Dominica in the Caribbean, where the population lives predominantly along the coast close to sea level and is subject to storm surge, with steep topography rising behind, with a propensity for landslides and flash river flooding. The simultaneous occurrence of the multiple hazards amplifies their impacts and couples with physical and social vulnerabilities to threaten lives, livelihoods, and the environment. Neglecting compound hazards underestimates overall risk. Using a whole island macroscale, (level-I) analysis, susceptibility scenarios for hurricanes, triggered landslides, and floods were developed by incorporating physical process parameters. The susceptibilities were combined with vulnerability indicators to map spatial patterns of hurricane multi-risks in Dominica. The analysis adopted a coupled approach involving the frequency ratio (FR), analytic hierarchy process (AHP), and geographic information system (GIS). Detailed hazard modelling was done at selected sites (level-II), incorporating storm surge estimates, landslide runout simulations, and steady flow analysis for floods. High-resolution terrain data and simulation models, the Rapid Mass Movement Simulation (RAMMS) and the hydrologic engineering center's river analysis system (HEC-RAS), were employed. Ground validation confirmed reasonable agreement between projected and observed scenarios across different spatial scales. Following the United Nations Office for disaster risk reduction (UNDRR) call for the inclusion of local, traditional, and indigenous knowledge, feedback, and expert opinion to improve understanding of disaster risk, 17 interviews with local experts and 4 participatory workshops with residents were conducted, and findings were incorporated into the analysis, so as to gain insights into risk perceptions. The study's outcomes encompass projections and quantification of hurricane compound hazards, vulnerabilities, accumulated risks, and an understanding of local priorities. These findings will inform decision-making processes for risk mitigation choices and community actions by providing a new framework for multi-hazard risk assessment that is easy to implement in combining different data forms.


CTGF is a therapeutic target for metastatic melanoma.
Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.


Anatomic study of cranial nerve emergence and associated skull foramina in cats using CT and MRI.
Magnetic resonance (MR) images of the brain of four normal cats were reviewed retrospectively to assess the emergence and course of the cranial nerves (CNs). Two-millimeter-thick images were obtained in transverse, sagittal, and dorsal planes using a 1.5 T unit. CN skull foramina, as anatomic landmarks for MR imaging, were identified by computed tomography performed on an isolated cat skull using thin wire within each skull foramen. Thin slice (1 mm slice thickness) images were obtained with a high-resolution bone filter scan protocol. The origins of CNs II, V, VII, and VIII and the group of IX, X, XI, and XII could be identified. The pathway and proximal divisions of CNs V were described. CNs III, IV, and VI were not distinguished from each other but could be seen together in the orbital fissure. CN V was characterized by slight contrast enhancement.


Corticosteroids inhibit complement-induced granulocyte aggregation. A possible mechanism for their efficacy in shock states.
Granulocyte (PMN) aggregation and embolization may underlie complement (C)-mediated organ dysfunction in such syndromes as hemodialysis neutropenia and Purtscher's ischem;c retinopathy. Because of clinical and pathologic parallels, we have further suggested a role for this phenomenon in the genesis of the adult respiratory distress syndrome (ARDS). Because corticosteroids are commonly used in immune diseases, and have particularly been claimed efficacious in shock and ARDS, we tested the capability of methylprednisolone (MP), hydrocortisone (HC), and dexamethasone (DEX) to inhibit PMN aggregation. Aggregation engendered in vitro by zymosan-activated plasma (ZAP) was inhibited by MP and HC at concentrations approximating plasma levels achieved with the large bolus (30 mg/kg i.v) therapy advocated in shock states; DEX was almost without effect. Using intravital fluorescence microscopy, we observed PMN aggregation and embolization in the mesenteric vessels of rats given intra-arterial infusions of ZAP; this was also prevented by pretreatment with 30 mg/kg MP. Steroid inhibition of aggregation seemed not to involve disruption of receptor function, because aggregation induced by alternative agents, n-formyl-Met-Leu-Phe and the ionophore A23187, was also inhibited by MP. Moreover, corticosteroid inhibition of PMN prostaglandin synthesis is also an unlikely explanation for our results, since aspirin and ibuprofen failed to block aggregation and arachidonic acid neither effected aggregation itself nor ameliorated the steroid effect. Our studies provide a plausible rationale for the empiric observation that high-dose corticosteroids may benefit patients with syndromes associated with microvascular leukostasis.


Probiotics in 14-day triple therapy for Asian pediatric patients with Helicobacter pylori infection: a network meta-analysis.
Although 14-day triple therapy has been widely administrated for eradicating Helicobacter pylori (H. pylori) in Asia, its antibiotic-associated side effects restrict the effectivity of eradication therapy in pediatric patients. Therefore, a network meta-analysis (NMA) was conducted to compare the efficacy and safety of probiotics supplemented in 14-day triple therapy in Asian pediatric patients. Randomized controlled trials (RCTs) were retrieved comprehensively in electronic databases (such as PubMed, Cochrane library, Embase, CNKI, Wan fang database, VIP database and CBM) until April 2017. Additional references were obtained from reviewed articles. NMA was performed using a random-effects model under a frequentist framework. Seventeen RCTs were included. NMA indicated that Bifidobacterium infantis+Clostridium butyricum was most beneficial for H. pylori eradication rates (P-score = 0.82) and Bacillus mesentericus+Clostridium butyricum+Streptococcus faecalis for total side effects (P-score = 0.77). Taken together, Bacillus mesentericus+Clostridium butyricum+Streptococcus faecalis was the best one to supplement in 14-day triple therapy due to its efficacy (P-score = 0.72) and safety (P-score = 0.77). Additionally, pairwise meta-analysis indicated that probiotics supplemented 14-day triple therapy significantly increased H. pylori eradication rates (RR: 1.16, 95%CI: 1.07-1.26) and reduced the incidence of total side effects (RR: 0.40, 95%CI: 0.34-0.48) compared with placebo. Bacillus mesentericus+Clostridium butyricum+Streptococcus faecalis is the optimal probiotic regime of reducing total side effects and improving eradication rates when supplemented 14-day triple therapy. Further direct evidence is needed to warrant it.


Divergent role for TNF-alpha in IFN-gamma-induced killing of Toxoplasma gondii and Salmonella typhimurium contributes to selective susceptibility of patients with partial IFN-gamma receptor 1 deficiency.
Patients with defects in IFN-gamma- or IL-12-mediated immunity are susceptible to infections with Salmonella and non-tuberculous mycobacteria, but rarely suffer from infections with other intracellular pathogens such as Toxoplasma gondii. Here we describe macrophage and T cell function in eight individuals with partial IFN-gamma receptor 1 (IFN-gammaR1) deficiency due to a mutation that results in elevated cell surface expression of a truncated IFN-gammaR1 receptor that lacks the intracellular domain. We show that various effector mechanisms dependent on IFN-gammaR signaling are affected to different extents. Whereas TNF-alpha production was normally up-regulated in response to IFN-gamma, IL-12 production and CD64 up-regulation were strongly reduced, and IFN-gamma-mediated killing of the intracellular pathogens Salmonella typhimurium and T. gondii was completely abrogated in patient's macrophages. Since these patients suffer selectively from infections with non-tuberculous mycobacteria and Salmonella, but not T. gondii, despite sero-immunity in six of eight patients, which indicates previous contact with this pathogen, we next studied the role of TNF-alpha as a possible immune compensatory mechanism. IFN-gamma-induced killing of T. gondii appeared to be partially mediated by TNF-alpha, and addition of TNF-alpha could compensate for the abrogated killing of T. gondii in the patient's macrophages. In contrast, IFN-gamma-mediated killing of S. typhimurium appeared to be independent of TNF-alpha. We propose that the divergent role of TNF-alpha in IFN-gamma-induced killing of T. gondii and S. typhimurium may at least partially explain the highly selective susceptibility of patients.


Predicting fibromyalgia, a narrative review: are we better than fools and children?
Fibromyalgia syndrome (FMS) is a common and intriguing condition, manifest by chronic pain and fatigue. Although the pathogenesis of FMS is not yet completely understood, predicting the future development of FMS and chronic pain is a major challenge with great potential advantages, both from an individual as well as an epidemiological standpoint. Current knowledge indicates a genetic underpinning for FMS, and as increasing data are accumulated regarding the genetics involved, the prospect of utilizing these data for prediction becomes ever more attractive. The co-existence of FMS with multiple other functional disorders indicates that the clinical identification of such symptom constellations in a patient can alert the physician to the future development of FMS. Hypermobility syndrome is another clinical (as well as genetic) phenotype that has emerged as a risk factor for the development of FMS. Stressful events, including early life trauma, are also harbingers of the future development of FMS. Functional neuroimaging may help to elucidate the neural processes involved in central sensitization, and may ultimately also evolve into markers of predictive value. Last but not least, obesity and disturbed sleep are clinical (inter-related) features relevant for this spectrum. Future efforts will aim at integrating genetic, clinical and physiological data in the prediction of FMS and chronic pain.


Atomoxetine reduces anticipatory responding in a 5-choice serial reaction time task for adult zebrafish.
Deficits in impulse control are related to a number of psychiatric diagnoses, including attention deficit hyperactivity disorder, addiction, and pathological gambling. Despite increases in our knowledge about the underlying neurochemical and neuroanatomical correlates, understanding of the molecular and cellular mechanisms is less well established. Understanding these mechanisms is essential in order to move towards individualized treatment programs and increase efficacy of interventions. Zebrafish are a very useful vertebrate model for exploring molecular processes underlying disease owing to their small size and genetic tractability. Their utility in terms of behavioral neuroscience, however, hinges on the validation and publication of reliable assays with adequate translational relevance. Here, we report an initial pharmacological validation of a fully automated zebrafish version of the commonly used five-choice serial reaction time task using a variable interval pre-stimulus interval. We found that atomoxetine reduced anticipatory responses (0.6 mg/kg), whereas a high-dose (4 mg/kg) methylphenidate increased anticipatory responses and the number of trials completed in a session. On the basis of these results, we argue that similar neurochemical processes in fish as in mammals may control impulsivity, as operationally defined by anticipatory responses on a continuous performance task such as this, making zebrafish potentially a good model for exploring the molecular basis of impulse control disorders and for first-round drug screening.


Population genomics of pneumococcal carriage in South Africa following the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) immunization.
Streptococcus pneumoniae is a major human pathogen responsible for over 317000 deaths in children <5 years of age with the burden of the disease being highest in low- and middle-income countries including South Africa. Following the introduction of the 7-valent and 13-valent pneumococcal conjugate vaccine (PCV) in South Africa in 2009 and 2011, respectively, a decrease in both invasive pneumococcal infections and asymptomatic carriage of vaccine-type pneumococci were reported. In this study, we described the changing epidemiology of the pneumococcal carriage population in South Africa, by sequencing the genomes of 1825 isolates collected between 2009 and 2013. Using these genomic data, we reported the changes in serotypes, Global Pneumococcal Sequence Clusters (GPSCs), and antibiotic resistance before and after the introduction of PCV13. The pneumococcal carriage population in South Africa has a high level of diversity, comprising of 126 GPSCs and 49 serotypes. Of the ten most prevalent GPSCs detected, six were predominantly found in Africa (GPSC22, GPSC21, GPSC17, GPSC33, GPSC34 and GPSC52). We found a significant decrease in PCV7 serotypes (19F, 6B, 23F and 14) and an increase in non-vaccine serotypes (NVT) (16F, 34, 35B and 11A) among children <2 years of age. The increase in NVTs was driven by pneumococcal lineages GPSC33, GPSC34, GPSC5 and GPSC22. Overall, a decrease in antibiotic resistance for 11 antimicrobials was detected in the PCV13 era. Further, we reported a higher resistance prevalence among vaccine types (VTs), as compared to NVTs; however, an increase in penicillin resistance among NVT was observed between the PCV7 and PCV13 eras. The carriage isolates from South Africa predominantly belonged to pneumococcal lineages, which are endemic to Africa. While the introduction of PCV resulted in an overall reduction of resistance in pneumococcal carriage isolates, an increase in penicillin resistance among NVTs was detected in children aged between 3 and 5 years, driven by the expansion of penicillin-resistant clones associated with NVTs in the PCV13 era.


Health Functionality and Quality Control of Laver (Porphyra, Pyropia): Current Issues and Future Perspectives as an Edible Seaweed.
The growing interest in laver as a food product and as a source of substances beneficial to health has led to global consumer demand for laver produced in a limited area of northeastern Asia. Here we review research into the benefits of laver consumption and discuss future perspectives on the improvement of laver product quality. Variation in nutritional/functional values among product types (raw and processed (dried, roasted, or seasoned) laver) makes product-specific nutritional analysis a prerequisite for accurate prediction of health benefits. The effects of drying, roasting, and seasoning on the contents of both beneficial and harmful substances highlight the importance of managing laver processing conditions. Most research into health benefits has focused on substances present at high concentrations in laver (porphyran, Vitamin B12, taurine), with assessment of the expected effects of laver consumption. Mitigation of chemical/microbiological risks and the adoption of novel technologies to exploit under-reported biochemical characteristics of lavers are suggested as key strategies for the further improvement of laver product quality. Comprehensive analysis of the literature regarding laver as a food product and as a source of biomedical compounds highlights the possibilities and challenges for application of laver products.


Does Patient Frailty Status Influence Recovery Following Spinal Fusion for Adult Spinal Deformity?: An Analysis of Patients With 3-Year Follow-up.
Retrospective review of a prospective database. The aim of this study was to evaluate postop clinical recovery among adult spinal deformity (ASD) patients between frailty states undergoing primary procedures SUMMARY OF BACKGROUND DATA.: Frailty severity may be an important determinant for impaired recovery after corrective surgery. It included ASD patients with health-related quality of life (HRQLs) at baseline (BL), 1 year (1Y), and 3 years (3Y). Patients stratified by frailty by ASD-frailty index scale 0-1(no frailty: <0.3 [NF], mild: 0.3-0.5 [MF], severe: >0.5 [SF]). Demographics, alignment, and SRS-Schwab modifiers were assessed with χ/paired t tests to compare HRQLs: Scoliosis Research Society 22-question Questionnaire (SRS-22), Numeric Rating Scale (NRS) Back/Leg Pain, Oswestry Disability Index (ODI). Area-under-the-curve (AUC) method generated normalized HRQL scores at baseline (BL) and f/u intervals (1Y, 3Y). AUC was calculated for each f/u, and total area was divided by cumulative f/u, generating one number describing recovery (Integrated Health State [IHS]). A total of 191 patients were included (59 years, 80% females). Breakdown of patients by frailty status: 43.6% NF, 40.8% MF, 15.6% SF. SF patients were older (P = 0.003), >body mass index (P = 0.002). MF and SF were significantly (P < 0.001) more malaligned at BL: pelvic tilt (NF: 21.6°; MF: 27.3°; SF: 22.1°), pelvic incidence and lumbar lordosis (7.4°, 21.2°, 19.7°), sagittal vertical axis (31 mm, 87 mm, 82 mm). By SRS-Schwab, NF were mostly minor (40%), and MF and SF markedly deformed (64%, 57%). Frailty groups exhibited BL to 3Y improvement in SRS-22, ODI, NRS Back/Leg (P < 0.001). After HRQL normalization, SF had improvement in SRS-22 at year 1 and year 3 (P < 0.001), and NRS Back at 1Y. 3Y IHS showed a significant difference in SRS-22 (NF: 1.2 vs. MF: 1.32 vs. SF: 1.69, P < 0.001) and NRS Back Pain (NF: 0.52, MF: 0.66, SF: 0.6, P = 0.025) between frailty groups. SF had more complications (79%). SF/marked deformity had larger invasiveness score (112) compared to MF/moderate deformity (86.2). Controlling for baseline deformity and invasiveness, SF showed more improvement in SRS-22 IHS (NF: 1.21, MF: 1.32, SF: 1.66, P < 0.001). Although all frailty groups exhibited improved postop disability/pain scores, SF patients recovered better in SRS-22 and NRS Back. Despite SF patients having more complications and larger invasiveness scores, they had overall better patient-reported outcomes, signifying that with frailty severity, patients have more room for improvement postop compared to BL quality of life. 3.


Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues.
Antigen-specific B cell responses to mucosally delivered proteins are dependent upon CD4-positive T helper (Th) cells, and the frequency of Th1 and Th2 cell responses after oral immunization may determine the level and isotype of mucosal antibody responses. We have used a protein-based vaccine, tetanus toxoid (TT), together with the mucosal adjuvant cholera toxin (CT), for oral immunization of mice to study the nature of antigen-specific Th cell subsets induced in Peyer's patches (PP) of the gastrointestinal (GI) tract and in the spleen (SP) during peak antibody responses. Mice orally immunized with TT and CT responded with antigen-specific secretory immunoglobulin A (S-IgA) antibodies in the GI tract, and with both IgG and IgA antibody responses in serum. PP and SP CD4+ T cells from mice orally immunized with TT plus CT were cultured with antigen-coated latex microspheres for induction of proliferative responses and for enumeration of cytokine producing CD4+ T cells. Interestingly, both PP and SP CD4+ T cell cultures showed increased numbers of IL-4- and IL-5 (Th2-type)-producing, spot-forming cells (SFCs) after 21 d of immunization, while essentially no interferon-gamma (IFN-gamma) or IL-2 (Th1-type) SFCs were noted. Cytokine-specific Northern blots and RT-PCR also revealed that significant IL-4 and IL-5 mRNA levels, but not IFN-gamma or IL-2 mRNA, were present in CD4+ T cells isolated from antigen-stimulated cultures. However, systemic immunization with TT and CT induced antigen-specific IgG and IgM but not IgA antibodies in serum. Further, both IL-2 and IFN-gamma-producing Th1-type cells as well as IL-4- and IL-5-secreting Th2-type cells were generated in SP. Our results show that oral immunization with TT and the mucosal adjuvant CT selectively induced antigen-specific Th2-type responses which may represent the major helper cell phenotype involved in mucosal IgA responses in the GI tract.


Maternal physical activity and insulin action in pregnancy and their relationships with infant body composition.
We sought to assess the association between maternal gestational physical activity and insulin action and body composition in early infancy. At 28-32 weeks' gestation, pregnant women participating in an observational study in Sweden underwent assessments of height, weight, and body composition, an oral glucose tolerance test, and 10 days of objective physical activity assessment. Thirty mothers and infants returned at 11-19 weeks postpartum. Infants underwent assessments of weight, length, and body composition. Early insulin response was correlated with total physical activity (r = -0.47; P = 0.007). Early insulin response (r = -0.36; P = 0.045) and total physical activity (r = 0.52; P = 0.037) were also correlated with infant fat-free mass. No maternal variable was significantly correlated with infant adiposity. The relationships between maternal physical activity, insulin response, and infant fat-free mass suggest that physical activity during pregnancy may affect metabolic outcomes in the mother and her offspring.


The Reflectance of Human Skin in the Millimeter-Wave Band.
The millimeter-wave band is an ideal part of the electromagnetic radiation to diagnose human skin conditions because this radiation interacts only with tissue down to a depth of a millimetre or less over the band range from 30 GHz to 300 GHz. In this paper, radiometry is used as a non-contact sensor for measuring the human skin reflectance under normal and wet skin conditions. The mean reflectance of the skin of a sample of 50 healthy participants over the (80-100) GHz band was found to be ~0.615 with a standard deviation of ~0.088, and an experimental measurement uncertainty of ±0.005. The thinner skin regions of the back of the hand, the volar forearms and the inner wrist had reflectances 0.068, 0.068 and 0.062 higher than the thicker skin regions of the palm of the hand, the dorsal forearm and the outer wrist skin. Experimental measurements of human skin reflectance in a normal and a wet state on the back of the hand and the palm of the hand regions indicated that the mean differences in the reflectance before and after the application of water were ~0.078 and ~0.152, respectively. These differences were found to be statistically significant as assessed using t-tests (34 paired t-tests and six independent t-tests were performed to assess the significance level of the mean differences in the reflectance of the skin). Radiometric measurements in this paper show the quantitative variations in the skin reflectance between locations, sexes, and individuals. The study reveals that these variations are related to the skin thickness and water content, a capability that has the potential to allow radiometry to be used as a non-contact sensor to detect and monitor skin conditions such as eczema, psoriasis, malignancy, and burn wounds.


Ambulatory care sensitive hospitalizations and emergency visits: experiences of Medicaid patients using federally qualified health centers.
Federally Qualified Health Centers (FQHCs) serve as regular sources of preventive and primary care for low-income families within their communities and are key parts of the health care safety net. Compare admissions and emergency room visits for ambulatory care sensitive conditions (ACSCs) among Medicaid beneficiaries relying on FQHCs to other Medicaid beneficiaries. Retrospective analysis of 1992 Medicaid claims data for 48,738 Medicaid beneficiaries in 24 service areas across five states. Medicaid beneficiaries receiving more than 50% of their preventive and primary care services from FQHCs are compared with Medicaid beneficiaries receiving outpatient care from other providers in the same areas. Exclusions-managed care enrollees, beneficiaries more than age 65, dual eligibles (Medicaid and Medicare), and institutionalized populations. Admissions and emergency room (ER) visits for a set of chronic and acute conditions, known in the literature as ambulatory care sensitive conditions (ACSCs). Medicaid beneficiaries receiving outpatient care from FQHCs were less likely to be hospitalized (1.5% vs. 1.9%, P < 0.007) or seek ER care (14.9% vs. 15.7%, P < 0.02) for ACSCs than the comparison group. Controlling for case mix and other demographic variables, the odds ratios were, for hospitalizations, OR, 0.80; 95% CI, 0.67 to 0.95; P < 0.01, and for ER visits, OR, 0.87; 95% CI, 0.82 to 0.92; P < 0.001. Having a regular source of care such as FQHCs can significantly reduce the likelihood of hospitalizations and ER visits for ACSCs. If the reported differentials in ACSC admissions and ER visits were consistently achieved for all Medicaid beneficiaries, substantial savings might be realized.


Heart transplantation in patients with dystrophinopathic cardiomyopathy: Review of the literature and personal series.
Cardiomyopathy associated with dystrophinopathies [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy (XL-dCM) and cardiomyopathy of Duchenne/Becker (DMD/BMD) carriers] is an increasing recognized manifestation of these neuromuscular disorders and notably contributes to their morbidity and mortality. Dystrophinopathic cardiomyopathy (DCM) is the result of the dystrophin protein deficiency at the myocardium level, parallel to the deficiency occurring at the skeletal muscle level. It begins as a "presymptomatic" stage in the first decade of life and evolves in a stepwise manner toward pictures of overt cardiomyopathy (hypertrophic stage, arrhythmogenic stage and dilated cardiomyopathy). The final stage caused by the extensive loss of cardiomyocytes results in an irreversible cardiac failure, characterized by frequent episodes of acute congestive heart failure (CHF), despite a correct pharmacological treatment. The picture of a severe dilated cardiomyopathy with intractable heart failure is typical of BMD, XL-dCM and cardiomyopathy of DMD/BMD carriers, while it is less frequently observed in patients with DMD. Heart transplantation (HT) is the only curative therapy for patients with dystrophinopathic end-stage heart failure who remain symptomatic despite an optimal medical therapy. However, no definitive figures exist in literature concerning the number of patients with DCM transplanted, and their outcome. This overview is to summarize the clinical outcomes so far published on the topic, to report the personal series of dystrophinopathic patients receiving heart transplantation and finally to provide evidence that heart transplantation is a safe and effective treatment for selected patients with end-stage DCM.


Low-cost Portable Raman Instrument, a Tool toward Counterfeit Medication Identification.
We have successfully built a low-cost (under 500 CHF) portable Raman spectrometer based on scavenged, consumer electronics. The instrument prototype is designed as a tool to help identify counterfeit medication in low-income countries. As a proof of concept, we confirmed the presence of acetaminophen, a type of analgesic, in over-the-counter drugs from around the world.


Need to Prioritize Education of the Public Regarding Stroke Symptoms and Faster Activation of the 9-1-1 System: Findings from the Florida-Puerto Rico CReSD Stroke Registry.
Objective: Demographic differences (race/ethnicity/sex) in 9-1-1 emergency medical services (EMS) access and utilization have been reported for various time-dependent critical illnesses along with associated outcome disparities. However, data are lacking with respect to measuring the various components of time taken to reach definitive care facilities following the onset of acute stroke symptoms (i.e., stroke onset to 9-1-1 call, EMS response, time on-scene, transport interval) and particularly with respect to any differences across ethnicities and sex. Therefore, the specific aim of this study was to measure the various time intervals elapsing following the first symptom onset (FSO) from an acute stroke until stroke hospital arrival (SHA) and to delineate any race/ethnic/sex-related differences among any of those measurements. Methods: The Florida-Puerto Rico Stroke Registry (FLPRSR) is an on-going, voluntary stroke registry of hospitals participating in the Get with the Guidelines-Stroke initiative. The study population included patients treated at Florida hospitals participating in the FLPRSR between 2010 and 2014 who had called 9-1-1 and were managed and transported by EMS. In total, 10,481 patients (16% black, 8% Hispanic, 74% white) had complete data-sets that included birthdate/year, sex, ethnic background, date/hour/minute of FSO and date/hour/minute of EMS response, scene arrival, and SHA. Results: Median time from FSO to SHA was 339 minutes (interquartile range [IQR] of 284-442), 301 of which constituted the time elapsed from FSO to the 9-1-1 call (IQR =249-392) versus only 10 from 9-1-1 call to EMS arrival (IQR =7-14), 14 on-scene (IQR =11-18) and 12 for transport to SHA (IQR =8-19). The FSO to 9-1-1 call interval, being by far the longest interval, was longest among whites and blacks (302 minutes for both) versus 291 for Hispanics (p = 0.01). However, this 11-minute difference was not deemed clinically-significant. There were neither significant sex-related differences nor any racial/ethnic/sex differences in the relatively short EMS-related intervals. Conclusions: Following acute stroke onset, time elapsed for EMS response and transport is relatively short compared to the lengthy intervals elapsing between symptom onset and 9-1-1 system activation, regardless of demographics. Exploration of innovative strategies to improve public education regarding stroke symptoms and immediate 9-1-1 system activation are strongly recommended.


Exercise-induced changes in the cortical bone of growing mice are bone- and gender-specific.
Fracture risk and mechanical competence of bone are functions of bone mass and tissue quality, which in turn are dependent on the bone's mechanical environment. Male mice have a greater response to non-weight-bearing exercise than females, resulting in larger, stronger bones compared with control animals. The aim of this study was to test the hypothesis that short-term weight-bearing running during growth (21 days starting at 8 weeks of age; 30 min/day; 12 m/min; 5 degrees incline; 7 days/week) would similarly have a greater impact on cross-sectional geometry and mechanical competence in the femora and tibiae of male mice versus females. Based on the orientation of the legs during running and the proximity of the tibia to the point of impact, this response was hypothesized to be greatest in the tibia. Exercise-related changes relative to controls were assayed by four-point bending tests, while volumetric bone mineral density and cross-sectional geometry were also assessed. The response to running was bone- and gender-specific, with male tibiae demonstrating the greatest effects. In male tibiae, periosteal perimeter, endocortical perimeter, cortical area, medial-lateral width and bending moment of inertia increased versus control mice suggesting that while growth is occurring in these mice between 8 and 11 weeks of age, exercise accelerated this growth resulting in a greater increase in bone tissue over the 3 weeks of the study. Exercise increased tissue-level strain-to-failure and structural post-yield deformation in the male tibiae, but these post-yield benefits came at the expense of decreased yield deformation, structural and tissue-level yield strength and tissue-level ultimate strength. These results suggest that exercise superimposed upon growth accelerated growth-related increases in tibial cross-sectional dimensions. Exercise also influenced the quality of this forming bone, significantly impacting structural and tissue-level mechanical properties.


Autofocusing system based on optical astigmatism analysis of single-molecule images.
Single-molecule fluorescence imaging has greatly contributed to our understanding of many bio-molecular systems. While reactions occurring in the range of several minutes can be readily studied using conventional single-molecule fluorescence microscopes, data acquisition for longer time scales is hindered by the focal drift of high numerical aperture objectives, which should be corrected in real time. Here, we developed a robust autofocusing system based on optical astigmatism analysis of single-molecule images. Compared to the previously developed methods, our approach has a merit of simplicity in that neither fiducial makers nor an additional laser-detector system is required. As a demonstration, we observed B-Z transition dynamics occurring for several hours.


Plasmodium vivax adherence to placental glycosaminoglycans.
Plasmodium vivax infections seldom kill directly but do cause indirect mortality by reducing birth weight and causing abortion. Cytoadherence and sequestration in the microvasculature are central to the pathogenesis of severe Plasmodium falciparum malaria, but the contribution of cytoadherence to pathology in other human malarias is less clear. The adherence properties of P. vivax infected red blood cells (PvIRBC) were evaluated under static and flow conditions. P. vivax isolates from 33 patients were studied. None adhered to immobilized CD36, ICAM-1, or thrombospondin, putative ligands for P. falciparum vascular cytoadherence, or umbilical vein endothelial cells, but all adhered to immobilized chondroitin sulphate A (CSA) and hyaluronic acid (HA), the receptors for adhesion of P. falciparum in the placenta. PvIRBC also adhered to fresh placental cells (N = 5). Pre-incubation with chondroitinase prevented PvIRBC adherence to CSA, and reduced binding to HA, whereas preincubation with hyaluronidase prevented adherence to HA, but did not reduce binding to CSA significantly. Pre-incubation of PvIRBC with soluble CSA and HA reduced binding to the immobilized receptors and prevented placental binding. PvIRBC adhesion was prevented by pre-incubation with trypsin, inhibited by heparin, and reduced by EGTA. Under laminar flow conditions the mean (SD) shear stress reducing maximum attachment by 50% was 0.06 (0.02) Pa but, having adhered, the PvIRBC could then resist detachment by stresses up to 5 Pa. At 37 °C adherence began approximately 16 hours after red cell invasion with maximal adherence at 30 hours. At 39 °C adherence began earlier and peaked at 24 hours. Adherence of P. vivax-infected erythrocytes to glycosaminoglycans may contribute to the pathogenesis of vivax malaria and lead to intrauterine growth retardation.


A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer.
Polymorphisms in the N-acetyltransferase 2 (NAT2) gene are determinants of the rate of metabolic activation of carcinogenic compounds such as aryl aromatic amines. Homozygosity for any combination of three variant alleles in Caucasians defines 'slow' acetylators; presence of one or two wild-type alleles characterizes 'rapid' acetylators. Although most previous studies have not observed an overall elevation in risk of breast cancer among slow acetylators, a recent study observed that cigarette smoking was associated with a large increase in risk of breast cancer among slow acetylators. We assessed the relation between NAT2 acetylation status and breast cancer risk, and its interaction with smoking, in a prospective study of mainly Caucasian US women. Four hundred and sixty-six incident cases who were diagnosed with breast cancer after giving a blood specimen in 1989-90 were matched to 466 controls in a nested case-control study. NAT2 genotype was determined using PCR-RFLP assays. The multivariate relative risk (RR) comparing slow with rapid acetylators was 0.9 (95% CI 0.7-1.2). Among slow acetylators, current smoking immediately prior to diagnosis was not associated with a significant elevation in risk compared with never smoking rapid acetylators (RR = 1.4, 95% CI 0.7-2.6). No significant association was seen between pack-years of smoking and risk of breast cancer among either slow or fast acetylators. A non-significant elevation in risk was observed among women who smoked for > or = 5 years prior to first pregnancy and were rapid acetylators, compared with never smoking rapid acetylators (RR = 1.5, 95% CI 0.9-2.6). In analyses limited to 706 post-menopausal women, the elevated risks for current smokers immediately prior to diagnosis who were slow acetylators compared with never smokers who were fast acetylators were slightly stronger but still not statistically significant. In summary, we observed little evidence of an association between NAT2 genotype and breast cancer. In this prospective study, cigarette smoking was not appreciably associated with breast cancer among either slow or fast NAT2 acetylators.


Microdistribution of immature African blackflies resulting from water velocity and turbulence preferences.
1. The velocity preferences of larval and pupal blackflies were studied experimentally by comparing the colonization of plastic strings placed in different velocity ranges; and also by investigating the simuliid microdistribution under natural conditions in the river. This required a novel method described for taking spot measurements of water velocity. 2. Simulium mcmahoni de Meillon, S. hirsutum Pomeroy and S. cervicornutum Pomeroy were most abundant in slow velocities (0.3-1.0 m s-1), S. colasbelcouri Grenier & Ovazza and S. hargreavesi Gibbins preferred 1.1-1.8 m s-1, S. squamosum Enderlein and S. vorax Pomeroy 1.9-2.2 m s-1. 3. The larvae of S. hargreavesi and S. cervicornutum preferred a higher velocity range compared with their pupae. 4. In moderate velocities (1.1-1.4 m s-1), the abundance of S. hargreavesi was greater under turbulent conditions than in smooth-flowing water, but this was reversed at very high velocities (2.3-2.6 m s-1). 5. Velocity had no apparent effect on substrate preference when substrates of different flexibilities were compared for three blackfly species. All avoided the most flexible substrates and preferred ones consisting of rigid articulating plates. Anisopteran predators were found to have a similar substrate choice.


Raman-induced interactions in a single-component Fermi gas near an s-wave Feshbach resonance.
Ultracold gases of interacting spin-orbit-coupled fermions are predicted to display exotic phenomena such as topological superfluidity and its associated Majorana fermions. Here, we experimentally demonstrate a route to strongly interacting single-component atomic Fermi gases by combining an s-wave Feshbach resonance (giving strong interactions) and spin-orbit coupling (creating an effective p-wave channel). We identify the Feshbach resonance by its associated atomic loss feature and show that, in agreement with our single-channel scattering model, this feature is preserved and shifted as a function of the spin-orbit-coupling parameters.


Lack of adequate appreciation of physical exercise's complexities can pre-empt appropriate design and interpretation in scientific discovery.
Two major issues are presented. First, a challenge is made by us that a misunderstanding of physiology has led to incomplete or wrong functional designations of genes in some cases. Normal physiological processes are dynamic, integrated and periodic, and, therefore, it is difficult to define normal physiological function by looking at a single time point or single process in a non-stressed subject. The ability of the organism to successfully respond to homeostatic disruptions defines normal physiology. Genes were selected for survival and to appropriately respond to stresses, such as physical activity. Omitting gene functions by restricting them to non-stressful conditions could lead to less than optimal primary preventions, treatments and cures for diseases. Physical exercise, as a stressor, should be used to better demonstrate the complete functional classifications of some genes. Second, the challenge from others of an 'exercise pill' as a mimetic of natural physical activity will be shown to be lacking a scientific basis. The concept of an 'exercise pill'/'exercise mimetic' demonstrates an inadequate appreciation of the complexities in integrating cell, tissue, organ and systems during both acute disruptions in homeostasis by a single bout of exercise, and longer-term chronic adaptations to different types of exercise such as resistance and endurance. It is our opinion that those promoting drugs targeting a single or few molecules should not redefine the term 'exercise' and exercise concepts in an attempt to sensationalize findings. Additionally, the scientific criteria that the authors demand to be met to legitimately use the terms 'exercise pill' and 'exercise mimetic' are presented.