Human genetics of diabetic vascular complications.
Diabetic vascular complications (DVC) affecting several important organ systems of human body such as the cardiovascular system constitute a major public health problem. There is evidence demonstrating that genetic factors contribute to the risk of DVC genetic variants, structural variants, and epigenetic changes play important roles in the development of DVC. Genetic linkage studies have uncovered a number of genetic loci that may shape the risk of DVC. Genetic association studies have identified many common genetic variants for susceptibility to DVC. Structural variants such as copy number variation and interactions of gene x environment have also been detected by association analysis. Apart from the nuclear genome, mitochondrial DNA plays a critical role in regulation of development of DVC. Epigenetic studies have indicated epigenetic changes in chromatin affecting gene transcription in response to environmental stimuli, which provided a large body of evidence of regulating development of diabetes mellitus. Recently, a new window has opened on identifying rare and common genetic loci through next generation sequencing technologies. This review focusses on the current knowledge of the genetic and epigenetic basis of DVC. Ultimately, identification of genes or genetic loci, structural variants and epigenetic changes contributing to risk of or protection from DVC will help uncover the complex mechanism(s) underlying DVC, with crucial implications for the development of personalized medicine for diabetes mellitus and its complications.


Arachidonic acid- and acetylcholine-induced relaxations of rabbit aorta.
The present study investigated the role of arachidonic acid and acetylcholine in mediating endothelium-dependent relaxations of rabbit aorta. Isolated thoracic aortic rings were precontracted with a submaximal concentration of norepinephrine, and the effect of various agents on arachidonic acid- and acetylcholine-induced relaxations was examined. Arachidonic acid elicited a concentration-related relaxation that was potentiated by the cyclooxygenase inhibitor indomethacin. Treatment with the lipoxygenase inhibitor nordihydroguaiaretic acid completely blocked but the cytochrome P450 inhibitor metyrapone had no effect on arachidonic acid-induced relaxation. NG-Monomethyl-L-arginine and nitro-L-arginine, compounds that inhibit the nitric oxide-like endothelium-derived relaxing factor, had little or no effect on arachidonic acid-induced relaxations. In contrast, nordihydroguaiaretic acid, metyrapone, NG-monomethyl-L-arginine, and nitro-L-arginine all attenuated the relaxation to acetylcholine; however, indomethacin had no effect on acetylcholine-induced relaxations. Arachidonic acid and acetylcholine had no effect on denuded rabbit aorta. Incubation of rabbit aorta with [14C]arachidonic acid resulted in the synthesis of major radioactive metabolites that comigrated with the prostaglandins and hydroxyeicosatetraenoic acids. Indomethacin selectively inhibited prostaglandin formation, nordihydroguaiaretic acid attenuated both prostaglandins and hydroxyeicosatetraenoic acids, and metyrapone blocked the epoxyeicosatrienoic acids. Additionally, acetylcholine elicited a twofold increase in tissue cyclic guanosine monophosphate content in contrast to a 59% reduction in cyclic guanosine monophosphate content observed with arachidonic acid. Therefore, these data suggest that in rabbit aorta, arachidonic acid-induced relaxations are mediated by an endothelium-dependent factor (or factors) that differs from the factor (or factors) released by acetylcholine. These results support the existence of multiple endothelium-derived relaxing factors.


Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity.
The effects of PD 176252 [3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(nitro-phenyl)ureido]propionamide], a nonpeptide bombesin (BB) BB1/BB2 receptor antagonist, were assessed in rats using several ethologically relevant tests of anxiety. Consistent with a role for the bombesin family of peptides in subserving anxiety behaviors, the antagonist increased social interaction (3.75 and 7.5 mg/kg, i.p.), dose-dependently attenuated the number of vocalizations emitted by guinea pig pups separated from their mother (1-30 mg/kg, i.p.), reduced latency to approach a palatable snack in an anxiogenic (unfamiliar) environment, and reduced the fear-potentiated startle response (5 and 10 mg/kg, i.p., and 100-200 ng per rat, i.c.v.). When administered directly to the dorsal raphé nucleus (DRN), PD 176252 (20-500 ng) increased social interaction under aversive conditions, as did the 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (50 ng). Furthermore, intra-DRN microinfusion of the peptide antagonist (PD 176252) suppressed, whereas its agonist [neuromedin B (NMB)-30] promoted, the in vivo release of 5-HT in the ventral hippocampus. In parallel, the suppressed social interaction elicited by intra-DRN administration of NMB was attenuated by a systemically administered 5-HT2C (but not 5-HT1A) receptor antagonist. Together, these findings suggest that endogenous BB-like peptides at the DRN evoke the release of 5-HT from the limbic nerve terminals originating from the raphé, specifically at the ventral hippocampus, resulting in anxiogenesis. The finding that this action was attenuated by BB receptor (BB1 and/or BB2) antagonists suggests that these compounds may represent a novel class of anxiolytic agents.


Vision of the Humboldt penguin (Spheniscus humboldti) in air and water.
Refractive states measured by retinoscopy and photorefraction indicate that the eyes of the Humboldt penguin, Spheniscus humboldti, are approximately emmetropic in air and water. Extensive myopia in air, as predicted by earlier authors and by a recent anatomical study, is non-existent. Photorefractive measurements of the refractive state, in water, of the Humboldt penguin indicate that it can accommodate sufficiently to make up the loss of the refractive power of the cornea. The cornea of the Humboldt penguin is flattened relative to the overall size of the eye. In all these respects (corneal flattening, and accommodation in air and water) the eyes of Humboldt penguins are like those of gentoo, (Pygoscelis papua), rockhopper (Eudyptes crestatus), Magellanic (Spheniscus magellanicus), and king penguins (Aptenodytes patagonica).


A novel reporter system for molecular imaging and high-throughput screening of anticancer drugs.
Apoptosis is irreversible programmed cell death, characterized by a cellular cascade activation of caspase 3, which subsequently degrades proteins and other components of cells with a motif sequence. Here we report a novel reporter system to detect apoptosis, growth arrest, and cell death based on controlled and self-amplified protein degradation. The key element of the reporter system is an apoptotic sensor chimerical protein which consists of three components: procaspase 3, ubiquitin (Ub), and a strong consensus sequence of N-degron. Between each of these units is a DEVD (Asp-Glu-Val-Asp) sequence, which acts as the cleavage target of caspase 3. This non-conventional signal loss approach is much more sensitive than other native methods that are based on signal gain. The superior sensitivity is demonstrated by its effective application in 386-well high-throughput screening (HTS) with low drug concentrations and a short incubation time. The HTS selection process using this reporter system is very simple and economic. The simplicity eliminates potential errors introduced by multiple steps; there is no need for any substrate. Furthermore, the cells in the assay need not be disrupted, and the morphology of the cells can provide additional information on mechanisms. After HTS, the intact cells can also be used for other analytic analysis. This system thus has a potentially important role in the discovery and development of new anticancer drugs. It also appears to be very versatile, can be used both in vitro and in vivo with different linked reporter genes, and can be used for a variety of imaging applications.


Optical fiber design and the trapping of Cerenkov radiation.
Cerenkov radiation is generated in optical fibers immersed in radiation fields and can interfere with signal transmission. We develop a theory for predicting the intensity of Cerenkov radiation generated within the core of a multimode optical fiber by using a ray optic approach and use it to make predictions of the intensity of radiation transmitted down the fiber in propagating modes. The intensity transmitted down the fiber is found to be dominated by bound rays with a contribution from tunneling rays. It is confirmed that for relativistic particles the intensity of the radiation that is transmitted along the fiber is a function of the angle between the particle beam and the fiber axis. The angle of peak intensity is found to be a function of the fiber refractive index difference as well as the core refractive index, with larger refractive index differences shifting the peak significantly toward lower angles. The angular range of the distribution is also significantly increased in both directions by increasing the fiber refractive index difference. The intensity of the radiation is found to be proportional to the cube of the fiber core radius in addition to its dependence on refractive index difference. As the particle energy is reduced into the nonrelativistic range the entire distribution is shifted toward lower angles. Recommendations on minimizing the quantity of Cerenkov light transmitted in the fiber optic system in a radiation field are given.


Experience-dependent modulation of feedback integration during singing: role of the right anterior insula.
Somatosensation plays an important role in the motor control of vocal functions, yet its neural correlate and relation to vocal learning is not well understood. We used fMRI in 17 trained singers and 12 nonsingers to study the effects of vocal-fold anesthesia on the vocal-motor singing network as a function of singing expertise. Tasks required participants to sing musical target intervals under normal conditions and after anesthesia. At the behavioral level, anesthesia altered pitch accuracy in both groups, but singers were less affected than nonsingers, indicating an experience-dependent effect of the intervention. At the neural level, this difference was accompanied by distinct patterns of decreased activation in singers (cortical and subcortical sensory and motor areas) and nonsingers (subcortical motor areas only) respectively, suggesting that anesthesia affected the higher-level voluntary (explicit) motor and sensorimotor integration network more in experienced singers, and the lower-level (implicit) subcortical motor loops in nonsingers. The right anterior insular cortex (AIC) was identified as the principal area dissociating the effect of expertise as a function of anesthesia by three separate sources of evidence. First, it responded differently to anesthesia in singers (decreased activation) and nonsingers (increased activation). Second, functional connectivity between AIC and bilateral A1, M1, and S1 was reduced in singers but augmented in nonsingers. Third, increased BOLD activity in right AIC in singers was correlated with larger pitch deviation under anesthesia. We conclude that the right AIC and sensory-motor areas play a role in experience-dependent modulation of feedback integration for vocal motor control during singing.


Genomic Description of 'Candidatus Abyssubacteria,' a Novel Subsurface Lineage Within the Candidate Phylum Hydrogenedentes.
The subsurface biosphere is a massive repository of fixed carbon, harboring approximately 90% of Earth's microbial biomass. These microbial communities drive transformations central to Earth's biogeochemical cycles. However, there is still much we do not understand about how complex subterranean microbial communities survive and how they interact with these cycles. Recent metagenomic investigation of deeply circulating terrestrial subsurface fluids revealed the presence of several novel lineages of bacteria. In one particular example, phylogenomic analyses do not converge on any one previously identified taxon; here we describe the first full genomic sequences of a new bacterial lineage within the candidate phylum Hydrogenedentes, 'Candidatus Abyssubacteria.' A global survey revealed that members of this proposed lineage are widely distributed in both marine and terrestrial subsurface environments, but their physiological and ecological roles have remained unexplored. Two high quality metagenome assembled genomes (SURF_5: 97%, 4%; SURF_17: 91% and 4% completeness and contamination, respectively) were reconstructed from fluids collected 1.5 kilometers below surface in the former Homestake gold mine-now the Sanford Underground Research Facility (SURF)-in Lead, South Dakota, United States. Metabolic reconstruction suggests versatile metabolic capability, including possible nitrogen reduction, sulfite oxidation, sulfate reduction and homoacetogenesis. This first glimpse into the metabolic capabilities of these cosmopolitan bacteria suggests that they are involved in key geochemical processes, including sulfur, nitrogen, and carbon cycling, and that they are adapted to survival in the dark, often anoxic, subsurface biosphere.


Depletion of white adipose tissue in cancer cachexia syndrome is associated with inflammatory signaling and disrupted circadian regulation.
Involuntary weight loss in patients with cancer is the hallmark of cancer cachexia. The etiology of cachexia is multifactorial involving loss of skeletal muscle and adipose tissue associated with high systemic levels of acute phase proteins and inflammatory cytokines. While muscle wasting overtly impacts on cancer patient quality of life, loss of lipid depots represents a sustained energy imbalance. In this study fat depletion was examined in Colon-26 model of cancer cachexia, which is a widely used rodent model of this syndrome. We investigated diurnal expression of circadian rhythm regulators as well as key mediators of energy metabolism and cytokine signaling. Mice bearing the C26 tumour exhibited reduced adipose mass, elevated adipose tissue lipolysis and a 5-fold increase in plasma levels of free fatty acids. These changes were associated with activated IL-6 signaling in WAT through a 3-fold increase in phosphorylated STAT3 and high SOCS3 gene expression levels. In addition perturbations in circadian regulation of lipid metabolism were also observed. Lipid catabolism did not appear to be influenced by the classical PKA pathway activating the lipase HSL. ATGL protein levels were elevated 2-fold in cachectic mice while 4-fold increase phosphorylated ACC and a 2-fold decrease in phosphorylated 4EBP1 was observed indicating that lipid metabolism is modulated by the ATGL & AMPK/mTOR pathways. This study provides evidence for activation of cytokine signaling and concomitant alterations in circadian rhythm and regulators of lipid metabolism in WAT of cachectic animals.


Killer Cell Immunoglobulin-Like Receptor Genotypes and Haplotypes Contribute to Susceptibility to Hepatitis B Virus and Hepatitis C Virus Infection in Cameroon.
Over 325 million people worldwide are living with hepatitis B and C viral infections and are at greater risk of developing hepatocellular carcinoma. The interactions between killer cell immunoglobulin-like receptors (KIRs) and their cognate ligands, human leukocyte antigens, modulate both infection processes and disease progression. We report here (1) genotype and haplotype variations in KIR genes in Cameroon and (2) their impact on susceptibility to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. In 98 unrelated individuals (33 HCV+, 31 HBV+, and 34 uninfected healthy controls), we determined the presence of 15 KIR genes by polymerase chain reaction-sequence-specific primer techniques. One pseudogene and all 14 KIR genes were present. We identified 36 KIR genotypes, 5 of which have not been previously reported in public databases. Two inhibitory (KIR2DL1 and KIR2DL3) and three activating (KIR2DS4, KIR2DS2, and KIR2DS3) genes were present in all HCV-infected individuals. Similarly, KIR3DL1, KIR2DL1, and KIR2DS4 were present at 100% in the HBV+ group. Compared with uninfected healthy controls, the frequencies of KIR2DL2 and KIR3DS1 were significantly lower in the HBV+ group (p = 0.003 and p < 0.001, respectively). Conversely, KIR3DS1 was significantly overrepresented in the HCV+ group compared with controls (97.0% vs. 64.7%, respectively, p < 0.001). These results may imply that KIR3DS1 carriers were less likely to be HBV infected, but may be predisposed to HCV infection compared with uninfected controls, indicating their important role in transmission of these viruses. However, phenotypic, functional, and genomic studies to elucidate the role of these KIR genotypes and haplotypes in infection with HBV and HCV are important.


Evolution of antibody responses up to 13 months after SARS-CoV-2 infection and risk of reinfection.
Assessment of the kinetics of SARS-CoV-2 antibodies is essential in predicting risk of reinfection and durability of vaccine protection. This is a prospective, monocentric, longitudinal, cohort clinical study. Healthcare workers (HCW) from Strasbourg University Hospital were enrolled between April 6th and May 7th, 2020 and followed up to 422 days. Serial serum samples were tested for antibodies against the Receptor Binding Domain (RBD) of the spike protein and nucleocapsid protein (N) to characterize the kinetics of SARS-CoV-2 antibodies and the incidence of reinfection. Live-neutralization assays were performed for a subset of samples before and after vaccination to analyze sensitivity to SARS-CoV-2 variants. A total of 4290 samples from 393 convalescent COVID-19 and 916 COVID-19 negative individuals were analyzed. In convalescent individuals, SARS-CoV-2 antibodies followed a triphasic kinetic model with half-lives at month (M) 11-13 of 283 days (95% CI 231-349) for anti-N and 725 days (95% CI 623-921) for anti-RBD IgG, which stabilized at a median of 1.54 log BAU/mL (95% CI 1.42-1.67). The incidence of SARS-CoV-2 infections was 12.22 and 0.40 per 100 person-years in COVID-19-negative and COVID-19-positive HCW, respectively, indicating a relative reduction in the incidence of SARS-CoV-2 reinfection of 96.7%. Live-virus neutralization assay revealed that after one year, variants D614G and B.1.1.7, but less so B.1.351, were sensitive to anti-RBD antibodies at 1.4 log BAU/mL, while IgG ≥ 2.0 log BAU/mL strongly neutralized all three variants. These latter anti-RBD IgG titers were reached by all vaccinated HCW regardless of pre-vaccination IgG levels and type of vaccine. Our study demonstrates a long-term persistence of anti-RBD antibodies that may reduce risk of reinfection. By significantly increasing cross-neutralizing antibody titers, a single-dose vaccination strengthens protection against variants. FUN1DING: None.


Aspirin and colorectal cancer: the promise of precision chemoprevention.
Aspirin (acetylsalicylic acid) has become one of the most commonly used drugs, given its role as an analgesic, antipyretic and agent for cardiovascular prophylaxis. Several decades of research have provided considerable evidence demonstrating its potential for the prevention of cancer, particularly colorectal cancer. Broader clinical recommendations for aspirin-based chemoprevention strategies have recently been established; however, given the known hazards of long-term aspirin use, larger-scale adoption of an aspirin chemoprevention strategy is likely to require improved identification of individuals for whom the protective benefits outweigh the harms. Such a precision medicine approach may emerge through further clarification of aspirin's mechanism of action.


Survival in HIV-positive transplant recipients compared with transplant candidates and with HIV-negative controls.
To evaluate the impact of liver and kidney transplantation on survival in HIV-positive transplant candidates and compare outcomes between HIV-positive and negative recipients. Observational cohort of HIV-positive transplant candidates and recipients and secondary analysis comparing study recipients to HIV-negative national registry controls. We fit proportional hazards models to assess transplantation impact on mortality among recipients and candidates. We compared time to graft failure and death with HIV-negative controls in unmatched, demographic-matched, and risk-adjusted models. There were 17 (11.3%) and 46 (36.8%) deaths among kidney and liver recipients during a median follow-up of 4.0 and 3.5 years, respectively. Transplantation was associated with survival benefit for HIV-infected liver recipients with model for end-stage liver disease (MELD) greater than or equal 15 [hazard ratio (HR) 0.1; 95% confidence interval (CI) 0.05, 0.01; P < 0.0001], but not for MELD less than 15 (HR 0.7; 95% CI 0.3, 1.8; P = 0.43) or for kidney recipients (HR 0.6; 95% CI 0.3, 1.4; P = 0.23). In HIV-positive kidney recipients, unmatched and risk-matched analyses indicated a marginally significant HR for graft loss [1.3 (P = 0.07) and HR 1.4 (P = 0.052)]; no significant increase in risk of death was observed. All models demonstrated a higher relative hazard of graft loss or death in HIV-positive liver recipients; the absolute difference in the proportion of deaths was 6.7% in the risk-matched analysis. Kidney transplantation should be standard of care for well managed HIV-positive patients. Liver transplant in candidates with high MELD confers survival benefit; transplant is a viable option in selected candidates. The increased mortality risk compared with HIV-negative recipients was modest. ClinicalTrials.Gov; NCT00074386; http://clinicaltrials.gov/.


Phylogenetics of Cucumis (Cucurbitaceae): cucumber (C. sativus) belongs in an Asian/Australian clade far from melon (C. melo).
Melon, Cucumis melo, and cucumber, C. sativus, are among the most widely cultivated crops worldwide. Cucumis, as traditionally conceived, is geographically centered in Africa, with C. sativus and C. hystrix thought to be the only Cucumis species in Asia. This taxonomy forms the basis for all ongoing Cucumis breeding and genomics efforts. We tested relationships among Cucumis and related genera based on DNA sequences from chloroplast gene, intron, and spacer regions (rbcL, matK, rpl20-rps12, trnL, and trnL-F), adding nuclear internal transcribed spacer sequences to resolve relationships within Cucumis. Analyses of combined chloroplast sequences (4,375 aligned nucleotides) for 123 of the 130 genera of Cucurbitaceae indicate that the genera Cucumella, Dicaelospermum, Mukia, Myrmecosicyos, and Oreosyce are embedded within Cucumis. Phylogenetic trees from nuclear sequences for these taxa are congruent, and the combined data yield a well-supported phylogeny. The nesting of the five genera in Cucumis greatly changes the natural geographic range of the genus, extending it throughout the Malesian region and into Australia. The closest relative of Cucumis is Muellerargia, with one species in Australia and Indonesia, the other in Madagascar. Cucumber and its sister species, C. hystrix, are nested among Australian, Malaysian, and Western Indian species placed in Mukia or Dicaelospermum and in one case not yet formally described. Cucumis melo is sister to this Australian/Asian clade, rather than being close to African species as previously thought. Molecular clocks indicate that the deepest divergences in Cucumis, including the split between C. melo and its Australian/Asian sister clade, go back to the mid-Eocene. Based on congruent nuclear and chloroplast phylogenies we conclude that Cucumis comprises an old Australian/Asian component that was heretofore unsuspected. Cucumis sativus evolved within this Australian/Asian clade and is phylogenetically far more distant from C. melo than implied by the current morphological classification.


Comparison of Nonblood-Based and Blood-Based Total CV Risk Scores in Global Populations.
Cost-effective primary prevention of cardiovascular disease (CVD) in low- and middle-income countries requires accurate risk assessment. Laboratory-based risk tools currently used in high-income countries are relatively expensive and impractical in many settings due to lack of facilities. This study sought to assess the correlation between a non-laboratory-based risk tool and 4 commonly used, laboratory-based risk scores in 7 countries representing nearly one-half of the world's population. We calculated 10-year CVD risk scores for 47,466 persons with cross-sectional data collected from 16 different cohorts in 9 countries. The performance of the non-laboratory-based risk score was compared with 4 laboratory-based risk scores: Pooled Cohort Risk Equations (ASCVD [Atherosclerotic Cardiovascular Disease]), Framingham, and SCORE (Systematic Coronary Risk Evaluation) for high- and low-risk countries. Rankings of each score were compared using Spearman rank correlations. Based on these correlations, we measured concordance between individual absolute CVD risk as measured by the Harvard NHANES (National Health and Nutrition Examination Survey) risk score, and the 4 laboratory-based risk scores, using both the conventional Framingham risk thresholds of >20% and the recent ASCVD guideline threshold of >7.5%. The aggregate Spearman rank correlations between the non-laboratory-based risk score and the laboratory-based scores ranged from 0.915 to 0.979 for women and from 0.923 to 0.970 for men. When applying the conventional Framingham risk threshold of >20% over 10 years, 92.7% to 96.0% of women and 88.3% to 92.8% of men were equivalently characterized as "high" or "low" risk. Applying the recent ASCVD guidelines risk threshold of >7.5% resulted in risk characterization agreement for women ranging from 88.1% to 94.4% and from 89.0% to 93.7% for men. The correlation between non-laboratory-based and laboratory-based risk scores is very high for both men and women. Potentially large numbers of high-risk individuals could be detected with relatively simple tools.


A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).
Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms. These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference.


TFIIS-Dependent Non-coding Transcription Regulates Developmental Genome Rearrangements.
Because of their nuclear dimorphism, ciliates provide a unique opportunity to study the role of non-coding RNAs (ncRNAs) in the communication between germline and somatic lineages. In these unicellular eukaryotes, a new somatic nucleus develops at each sexual cycle from a copy of the zygotic (germline) nucleus, while the old somatic nucleus degenerates. In the ciliate Paramecium tetraurelia, the genome is massively rearranged during this process through the reproducible elimination of repeated sequences and the precise excision of over 45,000 short, single-copy Internal Eliminated Sequences (IESs). Different types of ncRNAs resulting from genome-wide transcription were shown to be involved in the epigenetic regulation of genome rearrangements. To understand how ncRNAs are produced from the entire genome, we have focused on a homolog of the TFIIS elongation factor, which regulates RNA polymerase II transcriptional pausing. Six TFIIS-paralogs, representing four distinct families, can be found in P. tetraurelia genome. Using RNA interference, we showed that TFIIS4, which encodes a development-specific TFIIS protein, is essential for the formation of a functional somatic genome. Molecular analyses and high-throughput DNA sequencing upon TFIIS4 RNAi demonstrated that TFIIS4 is involved in all kinds of genome rearrangements, including excision of ~48% of IESs. Localization of a GFP-TFIIS4 fusion revealed that TFIIS4 appears specifically in the new somatic nucleus at an early developmental stage, before IES excision. RT-PCR experiments showed that TFIIS4 is necessary for the synthesis of IES-containing non-coding transcripts. We propose that these IES+ transcripts originate from the developing somatic nucleus and serve as pairing substrates for germline-specific short RNAs that target elimination of their homologous sequences. Our study, therefore, connects the onset of zygotic non coding transcription to the control of genome plasticity in Paramecium, and establishes for the first time a specific role of TFIIS in non-coding transcription in eukaryotes.


Longitudinal Changes in Familiarity, Free and Cued Odor Identification, and Edibility Judgments for Odors in Aging Individuals.
This longitudinal study investigated changes in olfaction as assessed by a set of tasks requiring different aspects of semantic information in normal aging individuals. Using 16 odorous items from a standardized olfactory test, the Scandinavian Odor Identification Test, 107 middle aged and older adults were assessed up to three times over a period of 6.5 years, requesting them to rate familiarity and edibility for each odorous item before identifying it with or without presenting verbal cues. Using linear mixed models, the longitudinal analyses revealed significant correlations between all olfactory measures. Furthermore, we found an almost parallel age-related decline in all olfactory tasks, although free identification performance indicated a trend toward faster decline with age. Women showed less decline compared with men, in particular for edibility judgments. The results corroborate earlier cross-sectional findings showing significant correlations between the olfactory tasks. In the present study of healthy middle-aged and older adults, we found a parallel longitudinal decline across different tests of olfaction.


Local chemical potential, local hardness, and dual descriptors in temperature dependent chemical reactivity theory.
In this work we establish a new temperature dependent procedure within the grand canonical ensemble, to avoid the Dirac delta function exhibited by some of the second order chemical reactivity descriptors based on density functional theory, at a temperature of 0 K. Through the definition of a local chemical potential designed to integrate to the global temperature dependent electronic chemical potential, the local chemical hardness is expressed in terms of the derivative of this local chemical potential with respect to the average number of electrons. For the three-ground-states ensemble model, this local hardness contains a term that is equal to the one intuitively proposed by Meneses, Tiznado, Contreras and Fuentealba, which integrates to the global hardness given by the difference in the first ionization potential, I, and the electron affinity, A, at any temperature. However, in the present approach one finds an additional temperature-dependent term that introduces changes at the local level and integrates to zero. Additionally, a τ-hard dual descriptor and a τ-soft dual descriptor given in terms of the product of the global hardness and the global softness multiplied by the dual descriptor, respectively, are derived. Since all these reactivity indices are given by expressions composed of terms that correspond to products of the global properties multiplied by the electrophilic or nucleophilic Fukui functions, they may be useful for studying and comparing equivalent sites in different chemical environments.


Correlates of relative lethality and suicidal intent among deliberate self-harm patients.
Conflicting findings have been reported regarding the relationship between the potential lethality of acts of deliberate self-harm (DSH) and suicidal intent, and how each relates to patient characteristics. This study examines the relationship of suicidal intent of DSH to lethality, the relationship of both to patient characteristics, and determines if intent or lethality are risk factors for repetition of DSH. Potential lethality and Suicide Intent Scale (SIS) scores for DSH episodes were examined in a representative sample of 150 patients presenting to a general hospital. Follow-up interviews were completed 12 to 20 months later. Lethality was strongly associated with high intent. Both lethality and intent were associated with male gender. Suicidal intent but not lethality was associated with the presence of psychiatric disorder and depression. Intent was significantly correlated with hopelessness scale score. Although intent was correlated with both depression and self-esteem scale scores, these correlations became nonsignificant when the effect of hopelessness was removed. Repetition of DSH during the follow-up period was related to neither lethality nor intent scores for the original episodes. Lethality and suicidal intent, although related, have somewhat different correlates. Both should be considered when assessing DSH patients, but their relationship to further suicidal behavior does not appear to be straightforward.


Alpha-adrenoceptors in dog mesenteric vessels--subcellular distribution and number of [3H]prazosin and [3H]rauwolscine binding sites.
Binding of the alpha-adrenergic antagonists [3H]prazosin and [3H]rauwolscine to well-characterized subcellular membrane fractions isolated from dog mesenteric arteries and veins was studied. Binding of both ligands was saturable with Kd values of 0.5 +/- 0.1 nM for [3H]prazosin and 5.85 +/- 0.85 nM for [3H]rauwolscine in arteries, and 0.87 +/- 0.4 nM for [3H]prazosin and 6.6 +/- 1.5 nM for [3H]rauwolscine in veins. In veins, the maximum number of binding sites for [3H]rauwolscine was higher than that for [3H]prazosin, whereas in arteries the maximum number of binding sites for each ligand was similar. In microsomes from dog aorta, the maximum number of bindings sites for [3H]prazosin was higher than that for [3H]rauwolscine. Neuronal membrane contamination in these studies was minimized by dissection procedures and evaluated by the comparison of [3H]saxitoxin binding in various preparations. Only mesenteric veins responded functionally to agonists acting on alpha 2 adrenoceptors. This study thus identified two distinct populations of [3H]prazosin and [3H]rauwolscine binding sites in the plasma membranes of dog mesenteric vessels and suggests that a much higher density of alpha 2-compared to alpha 1-adrenoceptor binding sites is required for a contractile response.


In the mind of the market: theory of mind biases value computation during financial bubbles.
The ability to infer intentions of other agents, called theory of mind (ToM), confers strong advantages for individuals in social situations. Here, we show that ToM can also be maladaptive when people interact with complex modern institutions like financial markets. We tested participants who were investing in an experimental bubble market, a situation in which the price of an asset is much higher than its underlying fundamental value. We describe a mechanism by which social signals computed in the dorsomedial prefrontal cortex affect value computations in ventromedial prefrontal cortex, thereby increasing an individual's propensity to 'ride' financial bubbles and lose money. These regions compute a financial metric that signals variations in order flow intensity, prompting inference about other traders' intentions. Our results suggest that incorporating inferences about the intentions of others when making value judgments in a complex financial market could lead to the formation of market bubbles.


Planomicrobium koreense gen. nov., sp. nov., a bacterium isolated from the Korean traditional fermented seafood jeotgal, and transfer of Planococcus okeanokoites (Nakagawa et al. 1996) and Planococcus mcmeekinii (Junge et al. 1998) to the genus Planomicrobium.
A bacterial strain, JG07T, isolated from the Korean traditional fermented seafood jeotgal, was subjected to a polyphasic taxonomic study. Cells of strain JG07T are cocci or short rods in the early growth phase but change to rods as the cultures age. The peptidoglycan type is A4alpha, based on L-Lys-D-Glu. The menaquinone profile is characterized by the predominance of MK-8 followed by MK-7 and MK-6. The cellular fatty acid profile contains major amounts of saturated, unsaturated and branched fatty acids. The cellular phospholipids are phosphatidylethanolamine, phosphatidylglycerol and bisphosphatidylglycerol. The G+C content of the DNA is 47 mol%. Phylogenetic analysis showed that strain JG07T forms a cluster with Planococcus okeanokoites and Planococcus mcmeekinii, and the relationship between this cluster and two other Planococcus species described previously is supported by bootstrap analysis at a confidence level of 100%. The 16S-23S internally transcribed spacer (ITS) sequence similarity and DNA-DNA relatedness values between strain JG07T and the type strains of other Planococcus species are in the range 74.6-83.2% and 10.4-20.5%, respectively. On the basis of the phenotypic and phylogenetic data and the genomic distinctiveness, strain JG07T is considered to represent a new genus and a new species, for which the name Planomicrobium koreense gen. nov., sp. nov. is proposed. It is also proposed that Planococcus okeanokoites and Planococcus mcmeekinii be transferred to the new genus Planomicrobium as Planomicrobium okeanokoites and Planomicrobium mcmeekinii, respectively.


The ionic mechanism of the slow outward current in Aplysia neurons.
A slow outward current associated with spike frequency adaptation has been studied in the giant Aplysia neurons R2 and LP1. The current was observed during 60-s voltage clamp commands to potentials just below spike threshold. The slow outward current shows a marked voltage dependence at membrane potential less negative than -40 mV. The slow outward current is associated with increased membrane conductance. The K+ sensitivity of the slow outward current was studied by varying the extracellular K+ concentration and also by measuring potassium efflux with a K+-sensitive electrode. Both procedures indicated that the slow outward current was K+ dependent. Tail currents following the activation of the slow outward current were examined. They were shown to have a similar potassium sensitivity as the slow outward current and had a reversal potential near the potassium equilibrium potential for these cells. The sensitivity of the slow outward current to known blockers of K+ currents, tetraethylammonium and 4-aminopyridine, was tested. The sensitivity was much less than that reported for other K+ currents. The sensitivity of the slow outward current to changes of the extracellular concentrations of Na+ and Cl- ions, as well as electrogenic pump inhibitors, was tested. The results indicate that the slow outward current is much less sensitive to these changes than to the manipulations of the extracellular K+ ion concentration. We tested the sensitivity of this current to manipulations of intracellular and extracellular Ca2+ ion concentrations. We found that the current persisted at a slightly reduced level in the absence of extracellular calcium or in the presence of calcium blocking agents, cobalt and lanthanum. Intracellular injection of the calcium chelator EGTA at a concentration sufficient to block the Ca2+-dependent K+ current, seen after a brief (1.4-s) burst of action potentials, had minimal effects on the slow outward current. Procedures thought to increase intracellular Ca2+ were tested. We found that exposure of the cell to solutions containing elevated Ca2+ concentrations for prolonged periods increased the slow outward current. Also, treatment with drugs thought to elevate intracellular Ca2+ increased the slow outward current. In conclusion, the slow outward current results from an increased K+ conductance.(ABSTRACT TRUNCATED AT 400 WORDS)


Contribution of Lumbar Spine BMD to Fracture Risk in Individuals With T-Score Discordance.
Fracture risk estimates are usually based on femoral neck (FN) BMD. It is unclear how to address T-score discordance, where lumbar spine (LS) T-score is lower than FN T-score. The objective of this work was to examine the impact of LS BMD on fracture risk, in individuals with lower LS T-score than FN T-score. Participants aged 60+ years from the Dubbo Osteoporosis Epidemiology Study with LS and FN BMD measured at first visit, and were followed from 1989 to 2014. Five-hundred and seventy-three (573) of 2270 women and 131 of 1373 men had lower LS than FN T-score by ≥ 0.6 standard deviation (SD) (low-LS group based on least significant change). In low-LS women, each 1 SD lower LS T-score than FN was associated with a 30% increase in fracture risk (hazard ratio [HR] 1.30; 95% CI, 1.11 to 1.45). For low-LS men there was a 20% nonsignificant increase in fracture risk for each 1 SD lower LS than FN T-score (HR 1.20; 95% CI, 0.10 to 1.67). Low-LS women had greater absolute fracture risks than the rest of the women. This increased risk was more apparent for lower levels of FN T-score and in older age groups. At an FN T-score of -2, low-LS women had a 3%, 10%, and 23% higher 5-year absolute fracture risk than non-low LS women in the 60 to 69 year, 70 to 79 year, and 80+ years age-groups, respectively. Furthermore, an osteoporotic LS T-score increased 5-year absolute fracture risk for women with normal or osteopenic FN T-score by 10% to 13%. Men in the low-LS group had very few fractures; therefore, a meaningful analyses of fracture risk could not be conducted. This study shows the significant contribution of lower LS BMD to fracture risk over and above FN BMD in women. A LS BMD lower than FN BMD should be incorporated into fracture risk calculators at least for women in older age-groups.


Motives for offending among violent and psychotic men.
Two hundred and three male remanded prisoners were interviewed with respect to their current offence, mental state, and social and psychiatric histories. All but nine of the sub-group of 121 psychotic men showed active symptoms at the time of committing a criminal offence; 20% of the actively ill psychotics were directly driven to offend by their psychotic symptoms, and a further 26% probably so. If some of the indirect consequences of the psychosis were taken into account, 82% of their offences were probably attributable to the illness. Among the normal and neurotic men, none claimed psychotic motives for offending, but motives suggesting high emotional arousal such as panic or retaliation triggered the greatest violence. Within the psychotic group, those driven to offend by their delusions were most likely to have been seriously violent, and psychotic symptoms probably accounted directly for most of the very violent behaviour.


Pathogen burden, co-infection and major histocompatibility complex variability in the European badger (Meles meles).
Pathogen-mediated selection is thought to maintain the extreme diversity in the major histocompatibility complex (MHC) genes, operating through the heterozygote advantage, rare-allele advantage and fluctuating selection mechanisms. Heterozygote advantage (i.e. recognizing and binding a wider range of antigens than homozygotes) is expected to be more detectable when multiple pathogens are considered simultaneously. Here, we test whether MHC diversity in a wild population of European badgers (Meles meles) is driven by pathogen-mediated selection. We examined individual prevalence (infected or not), infection intensity and co-infection of 13 pathogens from a range of taxa and examined their relationships with MHC class I and class II variability. This population has a variable, but relatively low, number of MHC alleles and is infected by a variety of naturally occurring pathogens, making it very suitable for the investigation of MHC-pathogen relationships. We found associations between pathogen infections and specific MHC haplotypes and alleles. Co-infection status was not correlated with MHC heterozygosity, but there was evidence of heterozygote advantage against individual pathogen infections. This suggests that rare-allele advantages and/or fluctuating selection, and heterozygote advantage are probably the selective forces shaping MHC diversity in this species. We show stronger evidence for MHC associations with infection intensity than for prevalence and conclude that examining both pathogen prevalence and infection intensity is important. Moreover, examination of a large number and diversity of pathogens, and both MHC class I and II genes (which have different functions), provide an improved understanding of the mechanisms driving MHC diversity.


Evidence for redundancy in cysteine biosynthesis in Rhizobium leguminosarum RL3841: analysis of a cysE gene encoding serine acetyltransferase.
A cysE gene encoding a serine acetyltransferase (SAT) potentially involved in the biosynthesis of cysteine was identified approximately 4 kb upstream of the previously described aapJQMP gene cluster that encodes an amino acid permease in Rhizobium leguminosarum strain 3841. The gene exhibits >40% identity to the family of SATs containing N-terminal extensions that have been described for other bacteria and plants. The ORF has three possible translation initiation sites which potentially encode polypeptides of 311, 277 and/or 259 amino acid residues, respectively. All three ORFs complemented the cysE mutation in an Escherichia coli cysteine auxotroph, strain JM39. Insertion of Tn5-lacZ into cysE in the genome of R. leguminosarum (strain RU632) lowered SAT activity in crude extracts by >95%. However, RU632 was not a cysteine auxotroph, which suggests that R. leguminosarum possesses some redundancy in cysteine biosynthesis. Additional copies of cysE could not be detected in the genome when the R. leguminosarum cysE gene was used as a hybridization probe. Therefore it is possible that R. leguminosarum possesses an alternative pathway for cysteine biosynthesis which avoids O-acetylserine. Strain RU632 was unaffected in its ability to nodulate Pisum sativum, and the nodules were effective for N(2) fixation (measured by C(2)H(2) reduction). Transcriptional activity of cysE was determined by measuring the beta-galactosidase arising from cysE::Tn5-lacZ fusions. Maximal levels of expression were observed during early exponential growth and were not influenced by the level of sulphur (supplied as sulphate). However, transcription was repressed by approximately twofold in ammonium-grown, as opposed to glutamate-grown, cultures. Repression by ammonium was not seen in a strain defective for ntrC.


Dietary intake of fish and PUFA, and clinical depressive and anxiety disorders in women.
Fish and PUFA consumption are thought to play a role in mental health; however, many studies do not take into account multiple sources of PUFA. The present study analysed data from a sample of 935 randomly selected, population-based women aged 20–93 years. A validated and comprehensive dietary questionnaire ascertained the consumption of n-3 and n-6 PUFA. Another assessed fish and energy intake and provided data for a dietary quality score. The General Health Questionnaire-12 (GHQ-12) measured psychological symptoms and a clinical interview (Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition) assessed depressive and anxiety disorders. Median dietary intakes of long-chain n-3 fatty acids (310 mg/d) were below suggested dietary target levels. The only PUFA related to categorical depressive and anxiety disorders was DHA. There was a non-linear relationship between DHA intake and depression; those in the second tertile of DHA intake were nearly 70% less likely to report a current depressive disorder compared to those in the first tertile. The relationship of DHA to anxiety disorders was linear; for those in the highest tertile of DHA intake, the odds for anxiety disorders were reduced by nearly 50% after adjustments, including adjustment for diet quality scores, compared to the lowest tertile. Those who ate fish less than once per week had higher GHQ-12 scores, and this relationship was particularly obvious in smokers. These are the first observational data to indicate a role for DHA in anxiety disorders, but suggest that the relationship between DHA and depressive disorders may be non-linear.


Design and Development of an Automated Feedback and Scoring System for Self-directed Learning of Flexible Nasal Endoscopy With an Airway Simulator.
The AirSim Multi (TruCorp) airway simulator is used to practice exploration of the upper respiratory tract with a flexible endoscope to assess the nasal cavities, their structures and spaces (inferior, middle, and superior turbinates and meati), and the nasopharynx. The passage of the flexible endoscope through the nose is usually the most annoying and painful maneuver to continue the exploration of the airway to the pharynx and larynx. For this reason, it is important to develop self-assessment training systems in safe environments that allow trainees to develop the necessary skills to carry out this type of assessment with the least inconvenience and the greatest security. Despite this simulator's accurate anatomical reproduction of the tract, its suitability as a tool for endoscope exploration learning is limited without a feedback system. Effective endoscopic exploration should not cause pain or lesions, not only for comfort and safety reasons, but also because only when discomfort is minimized is a complete and detailed exploration of the anatomical structures possible.The objective of the project was to provide a feedback system from the simulator to the trainee that would facilitate improvements in self-trained skills needed to perform an endoscopic exploration of the airways. A device based on the Hall-effect sensor was designed and placed outside the airway in the upper nasal turbinate. This device detects changes in the magnetic flux, indicating a displacement on the nasal turbinate due to endoscopic maneuvers that deform the inside of the simulator and would be expected to be harmful or painful in real life. The improved AirSim provides audible and visual feedback during exploration to indicate a change on the nasal turbinate due to endoscopic contact with the turbinate surface that would be expected to be harmful or painful in real life. We expect this feature to facilitate self-learning with minimal professional supervision and reduce the overall training time required to successfully perform a complete exploration of the airway. The inclusion of sensors on a passive simulator is a cost-effective measure that may allow for better training experiences using AirSim Multi simulator from the TruCorp company. Our improved simulator turns endoscopic exploration into a self-assessed exercise suitable for all disciplines and level of learners.


A one-time-only combination: Emergency medicine exports and the TRIPS agreement under Canada's access to medicines regime.
In 2008, a Canadian generic pharmaceutical firm, Apotex Inc. (Apotex), shipped 7 million doses of antiretroviral drugs to Rwanda for the treatment of HIV/AIDS. While this event may be seen as a positive outcome of international patent changes that facilitate the fulfillment of health as a human right, the fact that there has been only one shipment of medication in response to these changes highlights the difficulties with both the Canadian legislation and with the international decisions that it implements. The shipment was authorized under Canada's Access to Medicines Regime (CAMR), which implements the World Trade Organization (WTO) General Council Decision (the Decision), made in 2003, to permit someone other than the patent holder to manufacture a lower-cost version of a patented drug or medical device for export to developing countries that do not have the capacity to manufacture such products. The Decision requires that the developing country announce its intention to use this mechanism, to specify the expected quantity of drugs to be supplied, and to issue a compulsory license for the drugs. The requirement of notification in particular may render developing countries vulnerable to pressure from pharmaceutical firms. Neither the mechanism created by the Decision nor Canadian legislation implementing it have facilitated the export of generic medicines to developing countries. To date, the Canadian shipment is the only one to have occurred using the WTO mechanism.


Spatial and Temporal Variability of Visceral Leishmaniasis in Colombia, 2007 to 2018.
Visceral leishmaniasis (VL) is a neglected tropical disease associated with poverty and is endemic in 56 countries worldwide. Brazil, Venezuela, and Colombia are the most affected countries in South America. In Colombia, the National Public Health Surveillance System (SIVIGILA) consolidates epidemiological information and monitors all VL cases nationwide. However, to date, no studies have investigated the occurrence of VL in Colombia using metadata analysis. We studied the demographic data, the spatial and temporal distribution of VL cases, and the association with vector distribution of Leishmania species in Colombia from 2007 to 2018. We found 306 VL cases reported to SIVIGILA for this period, with a coverage of 25.5 cases/year, and a mortality of 2.28% (seven deaths). The highest number of confirmed cases (N = 52) occurred in 2007; the lowest (N = 9) occurred in 2012. The cases were reported mainly in children (< 7 years) affiliated with the subsidized health regimen. Regarding the geographic distribution, the cases were reported by 42 municipalities distributed in 10 departments. The occurrence of VL cases toward the northeast of Colombia, and the distribution of vectors, such as Lutzomyia longipalpis and Lu. evansi, may be changing the panorama of VL in the country. We conclude that VL, mainly in recent years, shows a temporal and spatial variability associated with the occurrence of cases in new settings. Our findings increase our understanding and knowledge of this disease, and suggest the need to monitor and prioritize areas with changes in geographic expansion to improve prevention and control actions in the country.


Interaction between neonatal vitamin A supplementation and timing of measles vaccination: a retrospective analysis of three randomized trials from Guinea-Bissau.
In Guinea-Bissau we conducted three trials of neonatal vitamin A supplementation (NVAS) from 2002 to 2008. None of the trials found a beneficial effect on mortality. From 2003 to 2007, an early measles vaccine (MV) trial was ongoing, randomizing children 1:2 to early MV at 4.5 months or no early MV, in addition to the usual MV at 9 months. We have previously found interactions between vitamin A and vaccines. We investigated whether there were interactions between NVAS and early MV. We compared the mortality of NVAS and placebo recipients: first, from 4.5 to 8 months for children randomized to early MV or no early MV; and second, from 9 to 17 months in children who had received two MV or one MV. Mortality rates (MR) were compared in Cox models producing mortality rate ratios (MRR). A total of 5141 children were randomized to NVAS (N=3015) or placebo (N=2126) and were later randomized to early MV (N=1700) or no early MV (N=3441). Between 4.5 and 8 months, NVAS compared with placebo was associated with higher mortality in early MV recipients (MR=30 versus MR=0, p=0.01), but not in children who did not receive early MV (p for interaction between NVAS and early MV=0.03). From 9 to 17 months NVAS was not associated with mortality. Overall, from 4.5 to 17 months NVAS was associated with increased mortality in early MV recipients (Mortality rate ratio=5.39 (95% confidence interval: 1.62, 17.99)). These observations indicate that NVAS may interact with vaccines given several months later. This may have implications for the planning of future child intervention programs.


Evaluation of hospital factors associated with hospital postoperative venous thromboembolism imaging utilisation practices.
Recent research suggests that hospital rates of postoperative venous thromboembolism (VTE) are subject to surveillance bias: the more hospitals 'look for' VTE, the more VTE they find. However, little is known about what drives variation in hospital VTE imaging rates. We conducted an observational study to examine hospital and market characteristics that were associated with hospital-level rates of postoperative VTE imaging, focusing on hospitals with particularly high rates. For Medicare beneficiaries undergoing 11 major operations (2009-2010) at 2820 hospitals, hospital-level postoperative VTE imaging use rates were calculated. Hospital characteristics associated with hospital VTE imaging use rates were examined including case severity, size, ownership, VTE process measure adherence, accreditations, staffing, malpractice environment, and county market factors. Associations between explanatory variables and VTE imaging rates were assessed using quantile regressions at the 25th, median, 75th and 90th quantiles. Mean postoperative VTE imaging rates ranged from 85.26 (SD=67.38) per 1000 discharges in the lowest quartile of hospitals ranked by VTE imaging rates to 168.86 (SD=76.70) in the highest quartile. Drivers of high imaging rates at the 90th quantile were high resident-to-bed ratio (coefficient=51.35, p<0.01), Joint Commission accreditation (coefficient=19.05, p<0.01), presence of other hospitals in the same market with high imaging rates (coefficient=15.29, p<0.01), average case severity (coefficient=11.97, p<0.01), local malpractice costs (coefficient=11.29, p<0.01), and market competition (coefficient=11.03, p<0.01). Hospital teaching status, resident-to-bed ratio, malpractice environment and local market factors drive hospital postoperative VTE imaging use, suggesting that non-clinical forces predominantly drive hospital VTE imaging practices.


Five-year results of the peer assessment program of the College of Physicians and Surgeons of Ontario.
The office practices of 918 physicians selected through stratified random sampling from the College of Physicians and Surgeons of Ontario (CPSO) registry were assessed by peers and the Peer Assessment Committee of the CPSO from 1981 to 1985. The sample comprised 662 general practitioners (GPs) and family physicians (FPs) and 256 specialists in 11 fields. Of the physicians 749 (82%) had neither deficient records nor an unsatisfactory level of patient care. Of the GPs and FPs 97 (15%) had serious deficiencies in one or both areas, as compared with 4 (2%) of the specialists (p2 less than 0.00001). The proportions of certificants of the Royal College of Physicians and Surgeons of Canada and of the College of Family Physicians of Canada (CFPC) with serious deficiencies were low (2% and 3% respectively). Three statistically significant predictors of physician performance were found among the GPs and FPs: age, CFPC membership status and type of practice. Of the 56 physicians who were reassessed 6 to 12 months later 29 (52%) had made the improvements recommended by the committee. Our findings demonstrate the need, feasibility and acceptance of a peer assessment program of office practices in Ontario.


Neuroprotective effects of SMADs in a rat model of cerebral ischemia/reperfusion.
Previous studies have shown that up-regulation of transforming growth factor β1 results in neuroprotective effects. However, the role of the transforming growth factor β1 downstream molecule, SMAD2/3, following ischemia/reperfusion remains unclear. Here, we investigated the neuroprotective effects of SMAD2/3 by analyzing the relationships between SMAD2/3 expression and cell apoptosis and inflammation in the brain of a rat model of cerebral ischemia/reperfusion. Levels of SMAD2/3 mRNA were up-regulated in the ischemic penumbra 6 hours after cerebral ischemia/reperfusion, reached a peak after 72 hours and were then decreased at 7 days. Phosphorylated SMAD2/3 protein levels at the aforementioned time points were consistent with the mRNA levels. Over-expression of SMAD3 in the brains of the ischemia/reperfusion model rats via delivery of an adeno-associated virus containing the SMAD3 gene could reduce tumor necrosis factor-α and interleukin-1β mRNA levels, down-regulate expression of the pro-apoptotic gene, capase-3, and up-regulate expression of the anti-apoptotic protein, Bcl-2. The SMAD3 protein level was negatively correlated with cell apoptosis. These findings indicate that SMAD3 exhibits neuroprotective effects on the brain after ischemia/reperfusion through anti-inflammatory and anti-apoptotic pathways.


A randomized study on eversion versus standard carotid endarterectomy: study design and preliminary results: the Everest Trial.
The EVEREST Trial was designed to determine whether the surgical technique influences the durability and complications of carotid endarterectomy (CEA). The current report focuses on the study design and preliminary results. EVEREST is a randomized multicenter trial. A total of 1353 patients with carotid stenosis requiring surgical treatment were randomly assigned to received standard (n = 675) or eversion (n = 678) CEA. Primary end points included carotid occlusion, major stroke, death, and restenosis rate. The rate of perioperative major stroke and death (1.3 for each study group) and the incidence of early carotid occlusion (0.6% for eversion vs 0.4% for standard) were similar. No significant differences were found between eversion and standard CEA with respect to incidence of perioperative transient ischemic accident, minor stroke, cranial nerve injuries, neck hematoma, myocardial infarction, or surgical defects as detected with intraoperative quality controls. Clamping time was significantly shorter for eversion CEA compared with patch standard procedures (31.7 +/- 15.9 vs 34.5 +/- 14.4 minutes, p = 0.02). A shunt was inserted in 11% of patients undergoing eversion CEAs and in 16% of patients undergoing standard procedures. Overall 30-day events occurred in 13.3% of the eversion group and in 11.4% of the standard group (p = 0.3). At a mean follow-up of 14.9 months (range, 1 to 38 months), 16 (2.4%) restenoses occurred in the eversion group and 28 (4.1%) occurred in the standard group (odds ratio, 0.56; 95% confidence interval, 0.3 to 1.1; p = 0.08). The preliminary results of the EVEREST Trial suggest that eversion CEA is a safe and rapid procedure with low major complication rates. No significant differences in restenosis rates were observed between eversion and standard CEA at the available follow-up. Longer-term results are necessary to assess whether the eversion technique influences the durability of CEA.


A 3D Bioprinted Pseudo-Bone Drug Delivery Scaffold for Bone Tissue Engineering.
A 3D bioprinted pseudo-bone drug delivery scaffold was fabricated to display matrix strength, matrix resilience, as well as porous morphology of healthy human bone. Computer-aided design (CAD) software was employed for developing the 3D bioprinted scaffold. Further optimization of the scaffold was undertaken using MATLAB® software and artificial neural networks (ANN). Polymers employed for formulating the 3D scaffold comprised of polypropylene fumarate (PPF), free radical polymerized polyethylene glycol- polycaprolactone (PEG-PCL-PEG), and pluronic (PF127). Simvastatin was incorporated into the 3D bioprinted scaffolds to further promote bone healing and repair properties. The 3D bioprinted scaffold was characterized for its chemical, morphological, mechanical, and in vitro release kinetics for evaluation of its behavior for application as an implantable scaffold at the site of bone fracture. The ANN-optimized 3D bioprinted scaffold displayed significant properties as a controlled release platform, demonstrating drug release over 20 days. The 3D bioprinted scaffold further displayed formation as a pseudo-bone matrix, using a human clavicle bone model, induced with a butterfly fracture. The strength of the pseudo-bone matrix, evaluated for its matrix hardness (MH) and matrix resilience (MR), was evaluated to be as strong as original bone, having a 99% MH and 98% MR property, to healthy human clavicle bones.


Parental perceptions of participation of preschool children with and without mobility limitations: validity and reliability of the PART.
This study provides information on the psychometric properties of a newly developed Dutch-language instrument for measuring parental perceptions of participation of preschool children (aged 2+ to 5+ years): the PART. The PART was administered to parents of preschool children with (n = 51) and without (n = 285) physical developmental disabilities. In the group with disabilities, children with no or relatively minor mobility limitations (capability scores in mobility domain higher than one standard deviation below population mean) were excluded from all analyses. A subgroup of parents of children without disabilities (n = 56) filled out the PART a second time, after a five-week interval. Hypotheses regarding group differences in PART scores and correlations of PART scores with different, but related ICF-constructs were tested. Test-retest reliability of the PART scales was examined. Expectations about group differences were confirmed. PART scores were associated in predicted ways with related constructs. PART scales showed good test-retest reliability (ICCs from 0.76 to 0.87). These findings indicate that the Dutch-language PART is a reliable and valid instrument for measuring parental perceptions of participation of preschool children with and without mobility limitations. The PART can prove useful for both clinical and research purposes.


Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation.
A hallmark of apoptosis is the fragmentation of nuclear DNA. Although this activity involves the caspase-3-dependent DNAse CAD (caspase-activated DNAse), evidence exists that DNA fragmentation can occur independently of caspase activity. Here we report on the ability of truncated Bid (tBid) to induce the release of a DNAse activity from mitochondria. This DNAse activity was identified by mass spectrometry as endonuclease G, an abundant 30 kDa protein released from mitochondria under apoptotic conditions. No tBid-induced endonuclease G release could be observed in mitochondria from Bcl-2-transgenic mice. The in vivo occurrence of endonuclease G release from mitochondria during apoptosis was confirmed in the liver from mice injected with agonistic anti-Fas antibody and is completely prevented in Bcl-2 transgenic mice. These data indicate that endonuclease G may be involved in CAD-independent DNA fragmentation during cell death pathways in which truncated Bid is generated.


Intellectual disability is associated with increased runs of homozygosity in simplex autism.
Intellectual disability (ID), often attributed to autosomal-recessive mutations, occurs in 40% of autism spectrum disorders (ASDs). For this reason, we conducted a genome-wide analysis of runs of homozygosity (ROH) in simplex ASD-affected families consisting of a proband diagnosed with ASD and at least one unaffected sibling. In these families, probands with an IQ ≤ 70 show more ROH than their unaffected siblings, whereas probands with an IQ > 70 do not show this excess. Although ASD is far more common in males than in females, the proportion of females increases with decreasing IQ. Our data do support an association between ROH burden and autism diagnosis in girls; however, we are not able to show that this effect is independent of low IQ. We have also discovered several autism candidate genes on the basis of finding (1) a single gene that is within an ROH interval and that is recurrent in autism or (2) a gene that is within an autism ROH block and that harbors a homozygous, rare deleterious variant upon analysis of exome-sequencing data. In summary, our data suggest a distinct genetic architecture for participants with autism and co-occurring intellectual disability and that this architecture could involve a role for recessively inherited loci for this autism subgroup.


σ Aromaticity Dominates in the Unsaturated Three-Membered Ring of Cyclopropametallapentalenes from Groups 7-9: A DFT Study.
Aromaticity, an old but still fantastic topic, has long attracted considerable interest of chemists. Generally, π aromaticity is described by π-electron delocalization in closed circuits of unsaturated compounds whereas σ-electron delocalization in saturated rings leads to σ aromaticity. Interestingly, our recent study shows that σ aromaticity can be dominating in an unsaturated three-membered ring (3MR) of cyclopropaosmapentalene. An interesting question is raised: Can the σ aromaticity, which is dominant in the unsaturated 3MR, be extended to other cyclopropametallapentalenes? If so, how could the metal centers, ligands, and substituents affect the σ aromaticity? Here, we report a thorough theoretical study on these issues. The nucleus-independent chemical shift calculations and the anisotropy of the current-induced density plots reveal the dominant σ aromaticity in these unsaturated 3MRs. In addition, our calculations show that substituents on the 3MRs have significant effects on the σ aromaticity, whereas the ligand effect is particularly small.


The anti-inflammatory and analgesic effects of formulated full-spectrum cannabis extract in the treatment of neuropathic pain associated with multiple sclerosis.
Cannabis has been used for thousands of years in many cultures for the treatment of several ailments including pain. The benefits of cannabis are mediated largely by cannabinoids, the most prominent of which are tetrahydrocannabinol (THC) and cannabidiol (CBD). As such, THC and/or CBD have been investigated in clinical studies for the treatment of many conditions including neuropathic pain and acute or chronic inflammation. While a plethora of studies have examined the biochemical effects of purified THC and/or CBD, only a few have focused on the effects of full-spectrum cannabis plant extract. Accordingly, studies using purified THC or CBD may not accurately reflect the potential health benefits of full-spectrum cannabis extracts. Indeed, the cannabis plant produces a wide range of cannabinoids, terpenes, flavonoids, and other bioactive molecules which are likely to contribute to the different biological effects. The presence of all these bioactive molecules in cannabis extracts has garnered much attention of late especially with regard to their potential role in the treatment of neuropathic pain associated with multiple sclerosis. Literature review was performed to further understand the effect of clinically used full-spectrum cannabis extract in patients with multiple sclerosis. Herein, the current knowledge about the potential beneficial effects of existing products of full-spectrum cannabis extract in clinical studies involving patients with multiple sclerosis is extensively reviewed. In addition, the possible adverse effects associated with cannabis use is discussed along with how the method of extraction and the delivery mechanisms of different cannabis extracts contribute to the pharmacokinetic and biological effects of full-spectrum cannabis extracts.Herein, the current knowledge about the potential beneficial effects of existing products of full-spectrum cannabis extract in clinical studies involving patients with multiple sclerosis is extensively reviewed. In addition, the possible adverse effects associated with cannabis use is discussed along with how the method of extraction and the delivery mechanisms of different cannabis extracts contribute to the pharmacokinetic and biological effects of full-spectrum cannabis extracts.


Aggregating factor from Torpedo electric organ induces patches containing acetylcholine receptors, acetylcholinesterase, and butyrylcholinesterase on cultured myotubes.
A factor in extracts of the electric organ of Torpedo californica causes the formation of clusters of acetylcholine receptors (AChRs) and aggregates of acetylcholinesterase (AChE) on myotubes in culture. In vivo, AChRs and AChE accumulate at the same locations on myofibers, as components of the postsynaptic apparatus at neuromuscular junctions. The aim of this study was to compare the distribution of AChRs, AChE, and butyrylcholinesterase (BuChE), a third component of the postsynaptic apparatus, on control and extract-treated myotubes. Electric organ extracts induced the formation of patches that contained high concentrations of all three molecules. The extract-induced aggregation of AChRs, AChE, and BuChE occurred in defined medium, and these components accumulated in patches simultaneously. Three lines of evidence indicate that a single factor in the extracts induced the aggregation of all three components: the dose dependence for the formation of patches of AChRs was the same as that for patches of AChE and BuChE; the AChE- and BuChE-aggregating activities co-purified with the AChR-aggregating activity; and all three aggregating activities were immunoprecipitated at the same titer by a monoclonal antibody against the AChR-aggregating factor. We have shown previously that this monoclonal antibody binds to molecules concentrated in the synaptic cleft at neuromuscular junctions. Taken together, these results suggest that during development and regeneration of myofibers in vivo, the accumulation at synaptic sites of at least three components of the postsynaptic apparatus, AChRs, AChE, and BuChE, are all triggered by the same molecule, a molecule similar if not identical to the electric organ aggregating factor.


The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study.
In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both. Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%-56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%-88%) for two doses and 44% (95% CI -27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%-88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943-86,205) cases in Zimbabwe, 78,317 (95% PI 57,435-100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490-3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture uncertainty due to imperfect surveillance data and uncertainty about the transmission dynamics of cholera in each setting. Reactive vaccination campaigns using a single dose of OCV may avert more cases and deaths than a standard two-dose campaign when vaccine supplies are limited, while at the same time reducing logistical complexity. These findings should motivate consideration of the trade-offs between one- and two-dose campaigns in resource-constrained settings, though further field efficacy data are needed and should be a priority in any one-dose campaign.


Laminin alpha5 is required for dental epithelium growth and polarity and the development of tooth bud and shape.
In tooth development, the oral ectoderm and mesenchyme coordinately and reciprocally interact through the basement membrane for their growth and differentiation to form the proper shape and size of the tooth. Laminin alpha5 subunit-containing laminin-10/11 (LM-511/521) is the major laminin in the tooth germ basement membrane. Here, we have examined the role of laminin alpha5 (Lama5) in tooth development using laminin alpha5-null mouse primary dental epithelium and tooth germ organ cultures. Lama5-null mice develop a small tooth germ with defective cusp formation and have reduced proliferation of dental epithelium. Also, cell polarity and formation of the monolayer of the inner dental epithelium are disturbed. The enamel knot, a signaling center for tooth germ development, is defective, and there is a significant reduction of Shh and Fgf4 expression in the dental epithelium. In the absence of laminin alpha5, the basement membrane in the inner dental epithelium becomes discontinuous. In normal mice, integrin alpha6beta4, a receptor for laminin alpha5, is strongly localized at the basal layer of the epithelium, whereas in mutant mice, integrin alpha6beta4 is expressed around the cell surface. In primary dental epithelium culture, laminin-10/11 promotes cell growth, spreading, and filopodia-like microspike formation. This promotion is inhibited by anti-integrin alpha6 and beta4 antibodies and by phosphatidylinositol 3-kinase inhibitors and dominant negative Rho-GTPase family proteins Cdc42 and Rac. In organ culture, anti-integrin alpha6 antibody and wortmannin reduce tooth germ size and shape. Our studies demonstrate that laminin alpha5 is required for the proliferation and polarity of basal epithelial cells and suggest that the interaction between laminin-10/11-integrin alpha6beta4 and the phosphatidylinositol 3-kinase-Cdc42/Rac pathways play an important role in determining the size and shape of tooth germ.


Enzyme-free synthesis of cyclic single-stranded DNA constructs containing a single triazole, amide or phosphoramidate backbone linkage and their use as templates for rolling circle amplification and nanoflower formation.
Cyclic oligonucleotides are valuable targets with a broad range of potential applications spanning molecular biology and nanotechnology. Of particular importance is their role as templates in the rolling circle amplification (RCA) reaction. We describe three different chemical cyclisation methods for the preparation of single-stranded cyclic DNA constructs. These chemical cyclisation reactions are cheaper to carry out than the enzymatic reaction, and more amenable to preparative scale purification and characterisation of the cyclic product. They can also be performed under denaturing conditions and are therefore particularly valuable for cyclic DNA templates that contain secondary structures. The resulting single-stranded cyclic DNA constructs contain a single non-canonical backbone linkage at the ligation point (triazole, amide or phosphoramidate). They were compared to unmodified cyclic DNA in rolling circle amplification reactions using φ-29 and Bst 2.0 DNA polymerase enzymes. The cyclic templates containing a phosphoramidate linkage were particularly well tolerated by φ-29 polymerase, consistently performing as well in RCA as the unmodified DNA controls. Moreover, these phosphoramidate-modified cyclic constructs can be readily produced in oligonucleotide synthesis facilities from commercially available precursors. Phosphoramidate ligation therefore holds promise as a practical, scalable method for the synthesis of fully biocompatible cyclic RCA templates. The triazole-modified cyclic templates generally gave lower and more variable yields of RCA products, a significant proportion of which were double-stranded, while the performances of the templates containing an amide linkage lie in between those of the phosphoramidate- and triazole-containing templates.


OrthoFinder: solving fundamental biases in whole genome comparisons dramatically improves orthogroup inference accuracy.
Identifying homology relationships between sequences is fundamental to biological research. Here we provide a novel orthogroup inference algorithm called OrthoFinder that solves a previously undetected gene length bias in orthogroup inference, resulting in significant improvements in accuracy. Using real benchmark datasets we demonstrate that OrthoFinder is more accurate than other orthogroup inference methods by between 8 % and 33 %. Furthermore, we demonstrate the utility of OrthoFinder by providing a complete classification of transcription factor gene families in plants revealing 6.9 million previously unobserved relationships.


Terrorist attacks in the largest metropolitan city of Pakistan: Profile of soft tissue and skeletal injuries from a single trauma center.
Pakistan has been hugely struck with massive bomb explosions (car and suicide bombs) resulting in multiple casualties in the past few years. The aim of this study is to present the patterns of skeletal and soft tissue injuries and to review the outcome of the victims who presented to our hospital. This is a retrospective chart review from January 2008 to December 2012. The medical record numbers of patients were obtained from the hospital Health Information and Management Sciences (HIMS) as per the ICD-9 coding. During the study period, more than 100 suicide and implanted bomb blast attacks took place in the public proceedings, government offices, residential areas and other places of the city. Altogether 262 patients were enrolled in the study. The mean age of the patients was 31±14 years. The shrapnel inflicted wounds were present on to the upper limb in 24 patients and the lower limb in 50. Long bone fractures were the most common skeletal injuries. The fractures were complicated by penetrating fragments and nails which result in post operative infections and prolonged hospital stay.


Interstitial lung disease and neuropathy as predominant extra-articular manifestations in patients with rheumatoid arthritis: a prospective study.
Rheumatoid arthritis (RA) patients with extra-articular manifestations (ExRA) have a severe course of the disease and higher mortality. Indian patients are considered to have a low prevalence of ExRA. We prospectively assessed ExRA in patients with rheumatoid arthritis from southern India. 140 RA patients were qualified for the study. Patients with confounding factors were excluded. A detailed history and clinical examination was performed. Two independent investigators made a thorough search with relevant investigations for ExRA, according to well-defined criteria. At least one ExRA was present in 36 patients (25.7%). The predominant ExRA (9.29%) was Interstitial Lung Disease (ILD). 12 patients had neuropathy (8.57%). 5 patients had eye involvement, while 3 had cutaneous vasculitis. 4 patients had rheumatoid nodules, and 1 had amyloidosis. The median age at diagnosis and duration of disease were significantly higher in patients with ExRAs than in those without. Deformities and the use of steroids were more common in the ExRA cohort. The present study shows a high prevalence of ILD and neuropathy as ExRAs in our population. A more extensive investigative protocol is warranted for picking up milder presentations of these serious manifestations.


The pathogen-host interactions database (PHI-base) provides insights into generic and novel themes of pathogenicity.
Fungal and oomycete pathogens of plants and animals are a major global problem. In the last 15 years, many genes required for pathogenesis have been determined for over 50 different species. Other studies have characterized effector genes (previously termed avirulence genes) required to activate host responses. By studying these types of pathogen genes, novel targets for control can be revealed. In this report, we describe the Pathogen-Host Interactions database (PHI-base), which systematically compiles such pathogenicity genes involved in pathogen-host interactions. Here, we focus on the biology that underlies this computational resource: the nature of pathogen-host interactions, the experimental methods that exist for the characterization of such pathogen-host interactions as well as the available computational resources. Based on the data, we review and analyze the specific functions of pathogenicity genes, the host-specific nature of pathogenicity and virulence genes, and the generic mechanisms of effectors that trigger plant responses. We further discuss the utilization of PHI-base for the computational identification of pathogenicity genes through comparative genomics. In this context, the importance of standardizing pathogenicity assays as well as integrating databases to aid comparative genomics is discussed.


Analysis of Self-Inflicted Lacerations to the Wrist: A Multi-Disciplinary Approach to Treating.
Background: Self-inflicted wrist lacerations have the potential to lead to crippling sequelae and repeated suicidal attempt. To obtain good results, we have treated self-inflicted wrist lacerations using a multidisciplinary team - emergency, hand surgery, psychiatry, and rehabilitation. This study aims to review features of this type of injuries and suggest multidisciplinary team approach as an optimal treatment. Methods: Our multidisciplinary approach can be summarized as follows: initial evaluation, psychological interview, surgery, and rehabilitation. The medical records including wound features, injured structures and psychological data were reviewed retrospectively. Assessment of functional outcomes, and comparative analysis of various psychological parameters were conducted. Results: Most patients resulted in excellent or good functional outcomes. Five patients reattempted wrist cutting with suicidal intent during follow-up. Only 21.3% patients had a suicidal intent and it was not associated with injury severity and functional recovery. Alcohol ingestion and presence of associated injuries was significant different between severity groups. Presence of suicidal intent was irrelevant to injury severity and functional recovery, but relevant to alcohol ingestion, presence of associated injuries and presence of psychiatric diagnosis. Conclusions: In order to minimize catastrophic disability and repeated suicide attempts, a balanced multidisciplinary approach is one of the best methods to obtain excellent functional outcomes and prevent repeated injuries in patients with self-inflicted wrist lacerations.


Connecting neurosis and psychosis: the direct influence of emotion on delusions and hallucinations.
Diagnostic classification systems contain a core divide between neurosis and psychosis, leading to their separate study and treatment. The basis for the separation of the disorders is outlined and reassessed. It is argued that the empirical evidence does not support such a sharp distinction between neurosis and psychosis. The frequent occurrence of emotional disorder prior to and accompanying psychosis indicates that neurosis contributes to the development of the positive symptoms of psychosis. Psychological theories and experimental evidence concerning the influence of emotion on the content and form of delusions and hallucinations are therefore reviewed. It is argued that in many cases delusions are a direct representation of emotional concerns, and that emotion contributes to delusion formation and maintenance. The content of hallucinations less often directly expresses the emotional concerns of the individual, but emotion can trigger and contribute to the maintenance of hallucinatory phenomena, although how this occurs is not well understood. It is concluded that study needs to be made of the interaction between psychotic and neurotic processes in the development of delusions and hallucinations, and that neurotic and psychotic disorders may have common maintenance processes.


Distribution of anopheline mosquitoes in Eritrea.
The spatial distribution of anopheline mosquito species was studied throughout Eritrea during the 1999-2001 malaria transmission seasons from October to December for the highlands and western lowlands and February to April for the coastal region. Of the 302 villages sampled, 59 were visited in both the first and second year. Overall, 13 anopheline species were identified, with the Anopheles gambiae complex predominating during the first year (75.6%, n = 861) and the second year (91.9%, n = 1,262). Intrazonal variation accounted for 90% of the total variation in mosquito distribution. Polymerase chain reaction results indicated that 99% (n = 1,309) of the An. gambiae s.l. specimens were An. arabiensis, indicating that this was the only member of the gambiae complex present. There was a high degree of aggregation of anophelines within zones and villages, with more than 80% of the total anophelines being collected from less than 20% of the villages and from only 10% of the houses sampled. At least 80% of the anopheline mosquitoes were collected from grass-thatched Agudo-type housing. Vector abundance showed an inverse relationship with elevation, with highest densities in the low-lying western lowlands. Multiple regression analysis of log-transformed mean density of An. arabiensis with rainfall and the normalized difference vegetation index (NDVI) (average NDVI, minimum NDVI, and maximum NDVI) showed that these independent variables were not significantly associated with mosquito densities (R2 = 0.058). Our study contributes to the basic understanding of the ecology and distribution of malaria vectors with respect to species composition and spatial heterogeneities both that could be used to guide vector control operations in Eritrea.


First Report of Magnaporthe poae, Cause of Summer Patch Disease on Annual Bluegrass, in Canada.
The ectotrophic, root-infecting fungus Magnaporthe poae Landschoot & Jackson, the causal agent of summer patch disease in the U.S. (2), is implicated in the damage and loss of annual bluegrass (Poa annua L.) on golf course greens. This pathogenic fungus, one of the important root pathogens of turfgrass, attacks and colonizes susceptible turfgrass roots suffering from environmental or cultural stresses. Over 100 turf samples that exhibited symptoms (chlorotic circular or irregular patches of ≥15 cm in diameter with necrotic crowns and discolored roots) reminiscent of summer patch were collected from 77 southwestern Ontario golf courses from July to August of 2009 and 2010. Roots and crowns were often covered with dark, ectotrophic runner hyphae, lobed hyphopodia, and growth cessation structures, characteristic of M. poae. Sections of root tissue were surface sterilized in 0.6% sodium hypochlorite (NaOCl) for 5 min. Sterilized root tissue was plated on potato dextrose agar (PDA) containing 50 mg L-1 streptomycin sulfate and incubated at 28°C for 7 to 10 days. A fungus with morphological characteristics (hyaline mycelium that appears gray or olive-brown when mature) similar to those of M. poae (1) was consistently isolated (≥100 isolates were obtained) and used to identify M. poae through molecular techniques and Koch's postulates. DNA was extracted from the fungal mycelium of the collected isolates using the PowerPlant DNA isolation kit (MO BIO Laboratories, Inc., Carlsbad, CA). The rDNA internal transcribed spacer (ITS) regions of the isolates (≥100 isolates) were amplified by PCR using universal fungal rDNA primers ITS 4 (5'-TCCTCCGCTTATTGATATGC-3') and ITS 5 (5'- GGAAGTAAAAGTCGTAACAAGG-3') (3). The purified PCR products were sequenced (GenBank Accession No. JX134588 through JX134601) and a BLAST search exhibited seven isolates with 99% (MAG3, MAG6, MAG13, MAG16, and MAG17) and 100% (MAG1 and MAG14) similarity to M. poae in the GenBank database. Pathogenicity of four isolates (MAG1, MAG3, MAG6, and MAG14) was confirmed with Koch's postulates. Sixteen healthy P. annua core samples (four replicates of each treatment/isolate) collected from an Ontario golf course were inoculated with 25 mg M. poae-infested Kentucky bluegrass seed (Poa pratensis L.; 12.5 mg inoculum applied at the surface of the potting medium and 12.5 mg inoculum applied on the foliar surface) and were placed in a growth chamber with 12-h day/night cycles at 30/25°C and approximate relative humidity. After 2 to 3 weeks, inoculated plants exhibited chlorotic foliage and necrotic roots covered with dark ectotrophic runner hyphae and lobed hyphopodia. Infected root sections from each replication were surface sterilized and placed on PDA containing 50 mg L-1 streptomycin sulfate. The fungal cultures exhibited morphological characteristics consistent with M. poae (1). To our knowledge, this is the first report of summer patch caused by M. poae in Canada. References: (1) B. B. Clarke and A. B. Gould, eds. Turfgrass Patch Diseases Caused by Ectotrophic Root-Infecting Fungi. The American Phytopathological Society, St. Paul, MN, 1993. (2) P. J. Landschoot and N. Jackson. Mycol. Res. 93:59, 1989. (3) T. J. White et al. Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. Pages 315-322 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al. eds. Academic Press, San Diego, CA, 1990.


Perceptions of shared care among survivors of colorectal cancer from non-English-speaking and English-speaking backgrounds: a qualitative study.
Colorectal cancer (CRC) survivors experience difficulty navigating complex care pathways. Sharing care between GPs and specialist services has been proposed to improve health outcomes in cancer survivors following hospital discharge. Culturally and Linguistically Diverse (CALD) groups are known to have poorer outcomes following cancer treatment but little is known about their perceptions of shared care following surgery for CRC. This study aimed to explore how non-English-speaking and English-speaking patients perceive care to be coordinated amongst various health practitioners. This was a qualitative study using data from face to face semi-structured interviews and one focus group in a culturally diverse area of Sydney with non-English-speaking and English-speaking CRC survivors. Participants were recruited in community settings and were interviewed in English, Spanish or Vietnamese. Interviews were recorded, transcribed, and analysed by researchers fluent in those languages. Data were coded and analysed thematically. Twenty-two CRC survivors participated in the study. Participants from non-English-speaking and English-speaking groups described similar barriers to care, but non-English-speaking participants described additional communication difficulties and perceived discrimination. Non-English-speaking participants relied on family members and bilingual GPs for assistance with communication and care coordination. Factors that influenced the care pathways used by participants and how care was shared between the specialist and GP included patient and practitioner preference, accessibility, complexity of care needs, and requirements for assistance with understanding information and navigating the health system, that were particularly difficult for non-English-speaking CRC survivors. Both non-English-speaking and English-speaking CRC survivors described a blend of specialist-led or GP-led care depending on the complexity of care required, informational needs, and how engaged and accessible they perceived the specialist or GP to be. Findings from this study highlight the role of the bilingual GP in assisting CALD participants to understand information and to navigate their care pathways following CRC surgery.


Sibship effects on dispersal behaviour in a pre-industrial human population.
Understanding dispersal behaviour and its determinants is critical for studies on life-history maximizing strategies. Although many studies have investigated the causes of dispersal, few have focused on the importance of sibship, despite that sibling interactions are predicted to lead to intrafamilial differences in dispersal patterns. Using a large demographic data set from pre-industrial Finland (n = 9000), we tested whether the sex-specific probability of dispersal depended on the presence of same-sex or opposite-sex elder siblings who can both compete and cooperate in the family. Overall, following our predictions, the presence of same-sex elder siblings increased the probability of dispersal from natal population for both sexes, whereas the number of opposite-sex siblings had less influence. Among males, dispersal was strongly linked to access to land resources. Female dispersal was mainly associated with competition over availability of mates but likely mediated by competition over access to wealthy mates rather mate availability per se. Besides ecological constraints, sibling interactions are strongly linked with dispersal decisions and need to be better considered in the studies on the evolution of family dynamics and fitness maximizing strategies in humans and other species.