A new high-throughput method for simultaneous detection of drug resistance associated mutations in Plasmodium vivax dhfr, dhps and mdr1 genes

<p>Abstract</p> <p>Background</p> <p>Reports of severe cases and increasing levels of drug resistance highlight the importance of improved <it>Plasmodium vivax </it>case management. Whereas monitoring <it>P. vivax </it>resistance to anti-malarial drug by <it>in vivo </it>and <it>in vitro </it>tests remain challenging, molecular markers of resistance represent a valuable tool for high-scale analysis and surveillance studies. A new high-throughput assay for detecting the most relevant markers related to <it>P. vivax </it>drug resistance was developed and assessed on Papua New Guinea (PNG) patient isolates.</p> <p>Methods</p> <p><it>Pvdhfr, pvdhps </it>and <it>pvmdr1 </it>fragments were amplified by multiplex nested PCR. Then, PCR products were processed through an LDR-FMA (ligase detection reaction - fluorescent microsphere assay). 23 SNPs, including <it>pvdhfr </it>57-58-61 and 173, <it>pvdhps </it>382-383, 553, 647 and <it>pvmdr1 </it>976, were simultaneously screened in 366 PNG <it>P. vivax </it>samples.</p> <p>Results</p> <p>Genotyping was successful in 95.4% of the samples for at least one gene. The coexistence of multiple distinct haplotypes in the parasite population necessitated the introduction of a computer-assisted approach to data analysis. Whereas 73.1% of patients were infected with at least one wild-type genotype at codons 57, 58 and 61 of <it>pvdhfr</it>, a triple mutant genotype was detected in 65.6% of the patients, often associated with the 117T mutation. Only one patient carried the 173L mutation. The mutant 647P <it>pvdhps </it>genotype allele was approaching genetic fixation (99.3%), whereas 35.1% of patients were infected with parasites carrying the <it>pvmdr1 </it>976F mutant allele.</p> <p>Conclusions</p> <p>The LDR-FMA described here allows a discriminant genotyping of resistance alleles in the <it>pvdhfr</it>, <it>pvdhps</it>, and <it>pvmdr1 </it>genes and can be used in large-scale surveillance studies.</p

Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity

BACKGROUND: Inflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-alpha induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines. OBJECTIVES: To determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Mood questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed an implicit emotional face perception task during functional magnetic resonance imaging. Analyses focused on neurobiological correlates of inflammation-associated mood change and affective processing within regions responsive to emotional expressions and implicated in the etiology of depression. RESULTS: Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6. CONCLUSIONS: Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokine

Neural origins of human sickness in interoceptive responses to inflammation

BACKGROUND: Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning. RESULTS: Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions. CONCLUSIONS: These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states. PMID:19409533[PubMed - indexed for MEDLINE] PMCID: PMC2885492Free PMC Articl

The Sloan Digital Sky Survey Quasar Catalog IV. Fifth Data Release

We present the fourth edition of the Sloan Digital Sky Survey (SDSS) Quasar Catalog. The catalog contains 77,429 objects; this is an increase of over 30,000 entries since the previous edition. The catalog consists of the objects in the SDSS Fifth Data Release that have luminosities larger than M_i = -22.0 (in a cosmology with H_0 = 70 km/s/Mpc, Omega_M = 0.3, and Omega_Lambda = 0.7) have at least one emission line with FWHM larger than 1000 km/s, or have interesting/complex absorption features, are fainter than i=15.0, and have highly reliable redshifts. The area covered by the catalog is 5740 sq. deg. The quasar redshifts range from 0.08 to 5.41, with a median value of 1.48; the catalog includes 891 quasars at redshifts greater than four, of which 36 are at redshifts greater than five. Approximately half of the catalog quasars have i < 19; nearly all have i < 21. For each object the catalog presents positions accurate to better than 0.2 arcsec. rms per coordinate, five-band (ugriz) CCD-based photometry with typical accuracy of 0.03 mag, and information on the morphology and selection method. The catalog also contains basic radio, near-infrared, and X-ray emission properties of the quasars, when available, from other large-area surveys. The calibrated digital spectra cover the wavelength region 3800--9200A at a spectral resolution of ~2000. The spectra can be retrieved from the public database using the information provided in the catalog. The average SDSS colors of quasars as a function of redshift, derived from the catalog entries, are presented in tabular form. Approximately 96% of the objects in the catalog were discovered by the SDSS.Comment: 37 pages, Accepted for publication in A

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

The roles and values of wild foods in agricultural systems

Almost every ecosystem has been amended so that plants and animals can be used as food, fibre, fodder, medicines, traps and weapons. Historically, wild plants and animals were sole dietary components for hunter–gatherer and forager cultures. Today, they remain key to many agricultural communities. The mean use of wild foods by agricultural and forager communities in 22 countries of Asia and Africa (36 studies) is 90–100 species per location. Aggregate country estimates can reach 300–800 species (e.g. India, Ethiopia, Kenya). The mean use of wild species is 120 per community for indigenous communities in both industrialized and developing countries. Many of these wild foods are actively managed, suggesting there is a false dichotomy around ideas of the agricultural and the wild: hunter–gatherers and foragers farm and manage their environments, and cultivators use many wild plants and animals. Yet, provision of and access to these sources of food may be declining as natural habitats come under increasing pressure from development, conservation-exclusions and agricultural expansion. Despite their value, wild foods are excluded from official statistics on economic values of natural resources. It is clear that wild plants and animals continue to form a significant proportion of the global food basket, and while a variety of social and ecological drivers are acting to reduce wild food use, their importance may be set to grow as pressures on agricultural productivity increase.</jats:p

The Sloan Digital Sky Survey Quasar Catalog V. Seventh Data Release

We present the fifth edition of the Sloan Digital Sky Survey (SDSS) Quasar Catalog, which is based upon the SDSS Seventh Data Release. The catalog, which contains 105,783 spectroscopically confirmed quasars, represents the conclusion of the SDSS-I and SDSS-II quasar survey. The catalog consists of the SDSS objects that have luminosities larger than M_i = -22.0 (in a cosmology with H_0 = 70 km/s/Mpc Omega_M = 0.3, and Omega_Lambda = 0.7) have at least one emission line with FWHM larger than 1000 km/s or have interesting/complex absorption features, are fainter than i > 15.0 and have highly reliable redshifts. The catalog covers an area of 9380 deg^2. The quasar redshifts range from 0.065 to 5.46, with a median value of 1.49; the catalog includes 1248 quasars at redshifts greater than four, of which 56 are at redshifts greater than five. The catalog contains 9210 quasars with i < 18; slightly over half of the entries have i< 19. For each object the catalog presents positions accurate to better than 0.1" rms per coordinate, five-band (ugriz) CCD-based photometry with typical accuracy of 0.03 mag, and information on the morphology and selection method. The catalog also contains radio, near-infrared, and X-ray emission properties of the quasars, when available, from other large-area surveys. The calibrated digital spectra cover the wavelength region 3800-9200 Ang. at a spectral resolution R = 2000 the spectra can be retrieved from the SDSS public database using the information provided in the catalog. Over 96% of the objects in the catalog were discovered by the SDSS. We also include a supplemental list of an additional 207 quasars with SDSS spectra whose archive photometric information is incomplete.Comment: Accepted, to appear in AJ, 7 figures, electronic version of Table 2 is available, see http://www.sdss.org/dr7/products/value_added/qsocat_dr7.htm

Evaluation of RTS,S/AS02A and RTS,S/AS01B in Adults in a High Malaria Transmission Area

This study advances the clinical development of the RTS,S/AS01B candidate malaria vaccine to malaria endemic populations. As a primary objective it compares the safety and reactogenicity of RTS,S/AS01B to the more extensively evaluated RTS,S/AS02A vaccine.A Phase IIb, single centre, double-blind, controlled trial of 6 months duration with a subsequent 6 month single-blind follow-up conducted in Kisumu West District, Kenya between August 2005 and August 2006. 255 healthy adults aged 18 to 35 years were randomized (1ratio1ratio1) to receive 3 doses of RTS,S/AS02A, RTS,S/AS01B or rabies vaccine (Rabipur; Chiron Behring GmbH) at months 0, 1, 2. The primary objective was the occurrence of severe (grade 3) solicited or unsolicited general (i.e. systemic) adverse events (AEs) during 7 days follow up after each vaccination.Both candidate vaccines had a good safety profile and were well tolerated. One grade 3 systemic AE occurred within 7 days of vaccination (RTS,S/AS01B group). No unsolicited AEs or SAEs were related to vaccine. A marked increase in anti-CS antibody GMTs was observed post Dose 2 of both RTS,S/AS01B (31.6 EU/mL [95% CI: 23.9 to 41.6]) and RTS,S/AS02A (16.7 EU/mL [95% CI: 12.9 to 21.7]). A further increase was observed post Dose 3 in both the RTS,S/AS01B (41.4 EU/mL [95% CI: 31.7 to 54.2]) and RTS,S/AS02A (21.4 EU/mL [95% CI: 16.0 to 28.7]) groups. Anti-CS antibody GMTs were significantly greater with RTS,S/AS01B compared to RTS,S/AS02A at all time points post Dose 2 and Dose 3. Both candidate vaccines produced strong anti-HBs responses. Vaccine efficacy in the RTS,S/AS01B group was 29.5% (95% CI: -15.4 to 56.9, p = 0.164) and in the RTS,S/AS02A group 31.7% (95% CI: -11.6 to 58.2, p = 0.128).Both candidate malaria vaccines were well tolerated over a 12 month surveillance period. A more favorable immunogenicity profile was observed with RTS,S/AS01B than with RTS,S/AS02A.Clinicaltrials.gov NCT00197054