Classification of severe asthma exacerbations: a proposal.
The intensity of asthma exacerbations may vary from mild to severe. Many studies have demonstrated that the speed at which severe asthma exacerbation (SAE) develops varies among patients. In some asthmatics, the exacerbation comes on very quickly, whereas in others there is a progressive deterioration of clinical, functional and blood gas parameters. Sudden SAE are characterised by their explosive presentation and quick recovery. This evolution contrasts with that of patients with a slow onset SAE, who often need prolonged hospitalization. Absence of secretions suctioned from the airways during mechanical ventilation has been reported in sudden SAE, whereas large amounts of viscid mucus are found in patients with the slow onset SAE. The lungs of patients who died during a sudden onset SAE often show empty airways and a predominant neutrophilic infiltration in the bronchial epithelium, in contrast to the presence of abundant eosinophils in patients who died during a slow onset SAE. Sudden onset SAE may occur as sporadic cases or in outbreaks. Sporadic cases may result from the ingestion of nonsteroidal anti-inflammatory drugs (NSAID) in patients with intolerance to these products, massive exposure to common allergens and ingestion of foods containing sulphites. Asthma outbreaks have been described in many cities. In contrast to sudden onset SAE, slow onset SAE is characterized by a progressive deterioration, accompanied by an increase in the use of bronchodilators. Lack of appropriate monitoring of function by peak expiratory flow (PEF) recording, failure of patients to recognize worsening symptoms and underusage of inhaled and oral steroid treatment have been repeatedly identified as factors which are likely to be associated with slow onset SAE. The contribution of psychosocial problems, depression, denial of asthma severity and nonadherence with the treatment should not be overlooked in patients with slow onset SAE. Classification of severe asthma exacerbations into two types (sudden onset and slow onset) could help to reveal the aetiology of the attack and may also be relevant to the management of the patient.


Comprehensive evaluation of polymer types and ratios in Spray-Dried Dispersions: Compaction, Dissolution, and physical stability.
Amorphous solid dispersion (ASD) is a well-established strategy for enhancing the solubility and bioavailability of poorly soluble drugs. A significant portion of ASD products are in tablet form. However, the influence of common polymers and drug loading on the manufacturability of ASD tablets remains underexplored. This study focuses on investigating spray-dried ASDs from a tableting perspective by evaluating their physiochemical and mechanical properties. Itraconazole (ITZ) and indomethacin (IND), at the drug loadings ranging from 10% to 50%, were prepared with two polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP), serving as representative systems. Our findings revealed that increasing the drug loading resulted in a decreased surface area in ITZ-HPMCAS, IND-HPMCAS, and IND-PVP ASDs. However, this trend was not observed in ITZ-PVP dispersions, possibly due to the morphological disparities. Compaction results demonstrated that tabletability improved with decreasing drug loadings, except for ITZ-PVP dispersions. A partial least square analysis underscored particle surface area as the key factor influencing the tensile strength of ASD tablets. Additionally, our study disclosed that ITZ-PVP ASDs exhibited the worst release profiles and stability performance. The comprehensive journey from characterizing ASD particles to analyzing their compaction behavior and investigating drug release and physical stability offered profound insights into the attributes crucial for the downstream processing of amorphous pharmaceuticals.


[Sleep disorders and dementia].
A clinically relevant sleep-wake disturbance is found in up to half the patients with dementia, and the sundowning agitation is a common cause of institutionalisation of demented geriatric patients. The circadian rhythm of demented patients is levelled off with increased daytime sleep and disrupted night sleep. Particularly in vascular dementia, Korsakow syndrome, Parkinson's disease, and depression the alteration of sleep architecture may be pronounced, whereas in Alzheimer's disease prominent hypersomnolence or insomnia is typically only found in later stages of the diseases. Greatly increased daytime sleepiness or striking insomnia at the very beginning of suspected dementia should thus prompt the search for other, possibly treatable causes of dementia. Neuropathological and neurophysiological studies support the hypothesis of a deteriorated hypothalamic suprachiasmatic nucleus (harbouring the biological clock) as a cause for the deranged circadian sleep-wake system in dementia. Management of sundowning behaviour includes restriction of daytime sleep, exposure to bright lights, and social interaction schedules during the day. The benzodiazepines and analogues usually not being sufficiently effectual, low doses of mild neuroleptics are often needed. Whether recent reports on efficacy of melatonin in elderly insomniacs also apply to demented patients is yet uncertain. The careful search and treatment of possible extracerebral physiologic factors causing reversible hypersomnia or insomnia is an important requisite. Polysomnographic studies are needed to recognise treatable sleep disturbance which could deteriorate or mimic dementia and sundowning. Particularly, a sleep-apnea-hypopnea syndrome must be searched for at the beginning of a suspected dementia, when successful treatment is still possible. Sleep studies should also identify periodic leg movements of sleep with restless legs and/or increased daytime sleepiness, and hyperkinetic parasomnias such as REM sleep behaviour disorder which may complicate or imitate sundowning.


Phenol antioxidant quantity and quality in foods: beers and the effect of two types of beer on an animal model of atherosclerosis.
The free phenols have been measured in 15 lagers, 6 porters and ales, and 11 light and nonalcoholic beers. Phenols were measured colorimetrically using an oxidation-reduction reaction with Folin-Ciocalteu reagent and catechin as the standard. The order of phenol concentration was ales > lagers > low calorie > nonalcoholic. The quality of antioxidants of the major phenols in beers and the quality of beer antioxidants were measured by (1) dose-response inhibition of lower density lipoprotein oxidation and (2) concentration of phenols in the beers at which 50% of the peroxide was destroyed in a luminescent assay for antioxidant activity. The beers' lipoprotein antioxidant quality was clearly superior to that of vitamin antioxidants and to that of the phenol ingredients, suggesting synergism among the antioxidants in the mixture. The average per capita consumption of beer in the United States in 2000 was 225 mL/day, equivalent to 42 mg/day of catechin equivalents. Beer provides more antioxidants per day than wine in the U.S. diet. A dark beer and a lager beer were given at two concentrations to cholesterol-fed hamsters, an animal model of atherosclerosis. At the high dose ((1)/(2)-diluted beer) both lager and dark beer significantly inhibited atherosclerosis compared to a control of 2% alcohol. At the high dose, lager significantly decreased cholesterol and triglycerides, and both beers acted as in vivo antioxidants by decreasing the oxidizability of lower density lipoproteins. At the low dose ((1)/(10)-diluted beer) only the lager beer significantly decreased atherosclerosis compared to the 0.4% alcohol control. The polyphenols in the beers appear to be responsible for the benefits of beer in this model. Lager beer inhibited atherosclerosis at a human equivalent dose in this hamster model of atherosclerosis.


Identification of domains participating in the substrate specificity and subcellular localization of the multidrug resistance proteins MRP1 and MRP2.
The human multidrug resistance protein MRP1 and its homolog, MRP2, are both thought to be involved in cancer drug resistance and the transport of a wide variety of organic anions, including the cysteinyl leukotriene C4 (LTC4) (Km = 0.1 and 1 microm). To determine which domain of these proteins is associated with substrate specificity and subcellular localization, we constructed various chimeric MRP1/MRP2 molecules and expressed them in polarized mammalian LLC-PK1 cells. We examined the kinetic properties of each chimeric protein by measuring LTC4 and methotrexate transport in inside-out membrane vesicles, sensitivity to an anticancer agent, etoposide, and subcellular localization by indirect immunofluorescence methods. The following results were determined in these studies: (i) when the NH2-proximal 108 amino acids of MRP2, including transmembrane (TM) helices 1-3, were exchanged with the corresponding region of MRP1, Km(LTC4) values of the chimera decreased approximately 4-fold and Km(methotrexate) values increased approximately 5-fold relative to those of wild-type MRP2 and MRP1, respectively, whereas resistance to etoposide increased approximately 3-fold; (ii) when the NH2-proximal region up to TM9 of MRP2 was exchanged with the corresponding region of MRP1, a further increase in etoposide resistance was observed, and subcellular localization moved from the apical to the lateral membrane; (iii) when two-thirds of MRP2 at the NH2 terminus were exchanged with the corresponding MRP1 region, the chimeric protein transported LTC4 with an efficiency comparable with that achieved by the wild-type MRP1; and (iv) exchange of the COOH-terminal 51 amino acids between MRP1 and MRP2 did not affect the localization of either of the proteins. These results provide a strong framework for further studies aimed at determining the precise domains of MRP1 and MRP2 with affinity for LTC4 and anticancer agents.


Alveolar rhabdomyosarcoma originating from the uterine cervix.
Cervical alveolar rhabdomyosarcoma is a rare condition associated with poor prognosis. An 18-year-old patient presented with vaginal bleeding and a protruding mass from the vagina. Biopsy of the mass revealed alveoler rhabdomyosarcoma (ARMS), and radiological evaluation demonstrated that it originated from the uterine cervix. First, Wertheim's operation was carried out followed by four cycles of vincristine, actinomycine-D, ifosfamide (VAI) chemotherapy. However, the disease relapsed within three months, and the patient died of disease progression. Despite combination treatment, we could not achieve a desirable survival advantage in ARMS. Future studies may unveil the genomic profile of this rare condition, leading to invention of targeted therapies, which is the emerging trend in the treatment of sarcomas.


Electronic mosquito repellers induce increased biting rates in Aedes aegypti mosquitoes (Diptera: Culicidae).
Studies have demonstrated that electronic mosquito repellers are useless and that some of them could even increase the attraction of mosquitoes. While testing some electronic repellers, we noted that they also promoted an increase in biting rates. The present work has evaluated three commercial devices and a computer program working on five different sound frequencies. In a test chamber, the number of Aedes aegypti L. bite attempts was computed during four cycles of 3 min each by alternately turning the devices off and on. The mosquito biting rates for five sound frequencies (ranging from 9.6 kHz to 18.2 kHz) initially demonstrated a significant increase (ranging from around 20% to 50%), which decreased from 8.3% to 25.1% when the repellers were turned off. The biting rate significantly increased at 11.8 kHz (33.7%) when the device was turned on again. The danger of using electronic repellers and the role of sound frequencies stimulating mosquito biting are discussed.


Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience.
Decitabine, a hypomethylating agent, is active and has been approved for the treatment of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia. Intensive chemotherapy is an accepted form of therapy for patients with higher risk MDS. The comparative efficacy of these 2 forms of treatment in MDS is unknown. The objective of the current study was to compare the efficacy and toxicity profiles of decitabine and intensive chemotherapy in MDS. The authors compared lower intensity decitabine therapy (n = 115 patients) with intensive chemotherapy (as it is used in acute myeloid leukemia [AML]) in patients with higher risk MDS. Two comparisons were made with a cohort of 376 historic patients (from 1995 to 2005): The first comparison included a subcohort of 115 patients (Group A) who matched the 115 decitabine study patients according to age, International Prognostic Scoring System, and cytogenetics; and the second comparison included the whole cohort of 376 patients without matching (Group B). A multivariate analysis was performed for outcome. The complete remission (CR) rate according to AML criteria was 43% with decitabine, 46% with intensive chemotherapy in Group A, and 52% with intensive chemotherapy in Group B. Compared with Group A, mortality at 6 weeks was 3% with decitabine versus 13% with intensive chemotherapy (P = .006) and, at 3 months, 7% with decitabine versus 23% with intensive chemotherapy (P = .001). Survival was better with decitabine versus intensive chemotherapy in Group A (median survival: 22 months vs 12 months; P < .001). A multivariate analysis of survival in all 491 patients who received decitabine or intensive chemotherapy (Group B) selected decitabine as an independent, favorable prognostic factor for survival (P = .006; hazard ratio, 0.74) after accounting for the independent prognostic effect of pretreatment factors. In this analysis, decitabine was associated with a survival advantage compared with intensive chemotherapy in patients with higher risk MDS. Future studies should evaluate prospectively the results of decitabine versus intensive chemotherapy in this setting.


Variable mutation rates as an adaptive strategy in replicator populations.
For evolving populations of replicators, there is much evidence that the effect of mutations on fitness depends on the degree of adaptation to the selective pressures at play. In optimized populations, most mutations have deleterious effects, such that low mutation rates are favoured. In contrast to this, in populations thriving in changing environments a larger fraction of mutations have beneficial effects, providing the diversity necessary to adapt to new conditions. What is more, non-adapted populations occasionally benefit from an increase in the mutation rate. Therefore, there is no optimal universal value of the mutation rate and species attempt to adjust it to their momentary adaptive needs. In this work we have used stationary populations of RNA molecules evolving in silico to investigate the relationship between the degree of adaptation of an optimized population and the value of the mutation rate promoting maximal adaptation in a short time to a new selective pressure. Our results show that this value can significantly differ from the optimal value at mutation-selection equilibrium, being strongly influenced by the structure of the population when the adaptive process begins. In the short-term, highly optimized populations containing little variability respond better to environmental changes upon an increase of the mutation rate, whereas populations with a lower degree of optimization but higher variability benefit from reducing the mutation rate to adapt rapidly. These findings show a good agreement with the behaviour exhibited by actual organisms that replicate their genomes under broadly different mutation rates.


Methods for Evaluating the Association Between Alcohol Outlet Density and Violent Crime.
The objective of this analysis was to compare measurement methods-counts, proximity, mean distance, and spatial access-of calculating alcohol outlet density and violent crime using data from Baltimore, Maryland. Violent crime data (n = 11,815) were obtained from the Baltimore City Police Department and included homicides, aggravated assaults, rapes, and robberies in 2016. We calculated alcohol outlet density and violent crime at the census block (CB) level (n = 13,016). We then weighted these CB-level measures to the census tract level (n = 197) and conducted a series of regressions. Negative binomial regression was used for count outcomes and linear regression for proximity and spatial access outcomes. Choropleth maps, partial R2 , Akaike's Information Criterion, and root mean squared error guided determination of which models yielded lower error and better fit. The inference depended on the measurement methods used. Eight models that used a count of alcohol outlets and/or violent crimes failed to detect an association between outlets and crime, and 3 other count-based models detected an association in the opposite direction. Proximity, mean distance, and spatial access methods consistently detected an association between outlets and crime and produced comparable model fits. Proximity, mean distance, and spatial access methods yielded the best model fits and had the lowest levels of error in this urban setting. Spatial access methods may offer conceptual strengths over proximity and mean distance. Conflicting findings in the field may be in part due to error in the way that researchers measure alcohol outlet density.


An Update on African Swine Fever Virology.
Animal diseases constitute a continuing threat to animal health, food safety, national economy, and the environment. Among those, African swine fever (ASF) is one of the most devastating viruses affecting pigs and wild suids due to the lack of vaccine or effective treatment. ASF is endemic in countries in sub-Saharan Africa, but since its introduction to the Caucasus region in 2007, a highly virulent strain of ASF virus (ASFV) has continued to circulate and spread into Eastern Europe and Russia, and most recently into Western Europe, China, and various countries of Southeast Asia. Given the importance of this disease, this review will highlight recent discoveries in basic virology with special focus on proteomic analysis, replication cycle, and some recent data on genes involved in cycle progression and viral-host interactions, such as I215L (E2 ubiquitin-conjugating enzyme), EP402R (CD2v), A104R (histone-like protein), QP509L, and Q706L (RNA helicases) or P1192R (Topoisomerase II). Taking into consideration the large DNA genome of ASFV and its complex interactions with the host, more studies and new approaches are to be taken to understand the basic virus-host interaction for ASFV. Proteomic studies are just paving the way for future research.


Comparative analysis of Oldenlandia diffusa and its substitutes by high performance liquid chromatographic fingerprint and mass spectrometric analysis.
Herba Oldenlandiae is the dried whole herb of Oldenlandia diffusa (Willd.) Roxb. (Family Rubiaceae) recorded in the Chinese pharmacopoeia. However, the herbs of O. corymbosa (L.) Lam and O. tenelliflora Bl. are also often available and used indiscriminately as Herba Oldenlandiae in the markets. In light of this, high-performance liquid chromatography (HPLC) combined with high resolution mass spectrometry (HR-MS) has been developed for a comparative analysis of chemical components in the three Oldenlandia species. The correlation coefficients of the entire chromatographic patterns of samples were calculated by software and used for appraising the similarity. The chemical information on the peaks in the chromatograms of O. diffusa was obtained by comparison of their exact mass data, UV spectra and literature values. The results indicated that the chemical profiling of O. diffusa is quite different in samples collected from different habitats. Furthermore, the variations in the abundance of asperuloside, E-6-O- P-coumaroylscandoside methyl ester and E-6-O- P-coumaroylscandoside methyl ester-10-methyl ether were significant in these related herbs. In conclusion, it is important to use the above three compounds as chemical markers for quality evaluation and chemical authentication of Herba Oldenlandiae and its substitutes.


Swelling of Random Copolymer Networks in Pure and Mixed Solvents: Multi-Component Flory-Rehner Theory.
A generalized extension of Flory-Rehner (FR) theory is derived to describe equilibrium swelling of polymer networks, including copolymers with two or more chemically distinct repeat units, in either pure or mixed solvents. The model is derived by equating the chemical potential of each solvent in the liquid and gel phases at equilibrium, while assuming the deformation of the network chains is affine. Simplifications of the model are derived for specific cases involving homopolymer networks, copolymer networks, pure solvents, and binary solvent mixtures. With reasonable assumptions, the number of polymer-solvent interaction parameters that must be determined by experiments can be reduced to two effective parameters (θ1 and θ2), which describe the net interactions between water/copolymer (θ1) and ethanol/copolymer (θ2), respectively. Experimental measurements of the swelling of random copolymer networks of n-butyl acrylate and 2-hydroxyethyl acrylate in water, ethanol, and a 100 g/L ethanol/water mixture are utilized to validate the model. For a random copolymer network, θ1 and θ2 can be obtained by fitting the three-component FR model to equilibrium swelling data obtained in the pure solvents. Predicted solvent volume fractions for swelling in water-ethanol mixtures obtained by inserting fitted values of θ1 and θ2 into the four-component FR model are in reasonable agreement with experimental measurements.


[Immortalization of erythroid progenitors for in vitro large-scale red cell production].
Population ageing and increase in cancer incidence may lead to a decreased availability of red blood cell units. Thus, finding an alternative source of red blood cells is a highly relevant challenge. The possibility to reproduce in vitro the human erythropoiesis opens a new era, particularly since the improvement in the culture systems allows to produce erythrocytes from induced-Pluripotent Stem Cells (iPSCs), or CD34+ Hematopoietic Stem Cells (HSCs). iPSCs have the advantage of in vitro self-renewal, but lead to poor amplification and maturation defects (high persistence of nucleated erythroid precursors). Erythroid differentiation from HSC allows a far better amplification and adult-like hemoglobin synthesis. But the inability of these progenitors to self-renew in vitro remains a limit in their use as a source of stem cells. A major improvement would consist in immortalizing these erythroid progenitors so that they could expand indefinitively. Inducible transgenesis is the first way to achieve this goal. To date, the best immortalized-cell models involve strong oncogenes induction, such as c-Myc, Bcl-xL, and mostly E6/E7 HPV16 viral oncoproteins. However, the quality of terminal differentiation of erythroid progenitors generated by these oncogenes is not optimal yet and the long-term stability of such systems is unknown. Moreover, viral transgenesis and inducible expression of oncogenes raise important problems in term of safety, since the enucleation rate is not 100% and no nucleated cells having replicative capacities should be present in the final product.


Relative contribution of THTR-1 and THTR-2 in thiamin uptake by pancreatic acinar cells: studies utilizing Slc19a2 and Slc19a3 knockout mouse models.
Thiamin is essential for normal function of pancreatic acinar cells, and its deficiency leads to a reduction in pancreatic digestive enzymes. We have recently shown that thiamin uptake by rat pancreatic acinar cells is carrier-mediated and that both thiamin transporter (THTR)-1 and THTR-2 are expressed in these cells; little, however, is known about the relative contribution of these transporters toward total carrier-mediated thiamin uptake by these cells. We addressed this issue using a gene-specific silencing approach (siRNA) in mouse-derived pancreatic acinar 266-6 cells and Slc19a2 and Slc19a3 knockout mouse models. First we established that thiamin uptake by mouse pancreatic acinar cells is via a carrier-mediated process. We also established that these cells as well as native human pancreas express THTR-1 and THTR-2, with expression of the former (and activity of its promoter) being significantly higher than that of the latter. Using gene-specific siRNA against mouse THTR-1 and THTR-2, we observed a significant inhibition in carrier-mediated thiamin uptake by 266-6 cells in both cases. Similarly, thiamin uptake by freshly isolated primary pancreatic acinar cells of the Slc19a2 and Slc19a3 knockout mice was significantly lower than uptake by acinar cells of the respective littermates; the degree of inhibition observed in the former knockout model was greater than that of the latter. These findings demonstrate, for the first time, that both mTHTR-1 and mTHTR-2 are involved in carrier-mediated thiamin uptake by pancreatic acinar cells.


Tunicate gonadotropin-releasing hormone (GnRH) peptides selectively activate Ciona intestinalis GnRH receptors and the green monkey type II GnRH receptor.
In vertebrates, GnRH binds to its receptor and stimulates predominantly G(q/11)-mediated signal transduction in gonadotropes. However, little is known about the GnRH receptor and its signaling pathway in tunicates, a group that arose before the vertebrates. Although tunicates have had duplications of a few genes in the last 600 million years, the early vertebrates had duplications of the full genome. Also unknown is the nature of GnRH signaling in the tunicate, which lacks both a pituitary gland and sex steroids. However, we know that tunicates have GnRH peptides because we previously reported six GnRH peptides encoded within the tunicate genome of Ciona intestinalis. Here we clone and sequence cDNAs for four putative GnRH receptors from C. intestinalis. These are the only invertebrate GnRH receptors found to date. Each Ciona GnRH receptor was expressed in COS-7 cells, incubated with each of the six C. intestinalis GnRHs and assayed for a signaling response. GnRH receptors 1, 2, and 3 responded to Ciona GnRH peptides to stimulate intracellular cAMP accumulation. In contrast, only GnRH receptor 1 activated inositol phosphate turnover in response to one of the Ciona GnRHs. The green monkey type II GnRH receptor cDNA was tested as a comparison and a positive control. In conclusion, the four GnRH receptors encoded within the C. intestinalis genome were all transcribed into messenger RNA, but only three of the Ciona GnRH receptors were biologically active in our assays. The Ciona GnRH receptors almost exclusively activated the cAMP pathway.


Expression of insulin-like growth factor binding proteins during mouse cochlear development.
Insulin-like growth factor (IGF) signaling plays important roles in growth and cellular differentiation in the cochlear sensory epithelium. However, the roles of IGF binding proteins (IGFBPs), a family of IGF modulators, remain to be elucidated in this system. To begin to examine the role of IGFBPs, we used reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization to determine the temporal and spatial patterns of expression for Igfbps within the developing mouse cochlea. RT-PCR analysis indicates that Igfpb2-5 are expressed in the cochlea between embryonic day (E) 13.5 and postnatal day (P) 0. In addition, the expression of each Igfbp significantly increased between E13.5 and P0. In situ hybridization indicates that Igfbp2, 3, 4, and 5 have distinct and complementary expression patterns in the developing cochlea. Moreover, expression patterns of Igfbp3 and 5 demonstrate contrasting gradients along the basal-to-apical axis of the cochlea. Igfbp2-5 are expressed in distinct and complementary patterns during cochlear development. These data suggest that IGFBPs may act to precisely regulate activation of IGF signaling in the developing cochlea in a cell type-specific manner, contributing to cellular patterning and differentiation in the cochlea.


Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses.
Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.96 (0.87-1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk.


Structure of complexes between a major protein of heterogeneous nuclear ribonucleoprotein particles and polyribonucleotides.
We have investigated the structure of complexes formed between a series of poly(A)n (n = 30 to 480) and HD40 (helix-destabilizing protein, molecular weight of 40,000), the major protein component of 30 S heterogeneous nuclear ribonucleoprotein particles (hnRNP) from the brine shrimp Artemia salina. Protein HD40 is similar to corresponding hnRNP proteins from higher eukaryotes and the complexes it forms with single-stranded nucleic acids are strikingly similar to the native "beads-on-a-string" structure of hnRNP. Using analytical ultracentrifugation and electron microscopy we find: (1) complexes formed between HD40 and long ribohomopolymers also have a beads-on-a-string structure, showing that the ability to form this structure is an inherent property of HD40, and is not dependent on any structural features of natural RNA; (2) complexes between HD40 and poly(A)160 form disks that are about 3 nm high by 18 nm in diameter and contain 20 HD40 molecules; (3) complexes of HD40 with poly(A)n with fewer than 160 nucleotides form sectors of a disk: 40 nucleotides give rise to a quarter of a disk, 80 nucleotides, half a disk, etc. The molecular weights increase with the size of poly(A)n at the rate of 5300 per nucleotide, a stoichiometry of eight nucleotides per HD40; (4) as the size of the poly(A)n increases beyond 160 nucleotides, the additional nucleoprotein elements may either initiate the formation of a second disk adjacent to the first or stack on top of the first disk to form a 6 nm high helix with a diameter of 18 nm. Based on these results, we propose that the existence of lateral protein-protein interactions that produce the basic 3 nm X 18 nm disk, combined with the marginal stability of the helix result in (a) interruptions of the helix that give rise to the beads-on-a-string appearance of the complexes, and (b) inherent heterogeneity of individual "beads" which may contain one or more turns of the helix. From measurements of HD40 complexes with coliphage MS2 RNA, phi X174 viral DNA as well as with the homopolymers, a bead is estimated to contain an average of approximately 300 nucleotides; approximately 1 X 8 turns of the helix.


Ongoing Cognitive Processing Influences Precise Eye-Movement Targets in Reading.
Reading is a highly complex learned skill in which humans move their eyes three to four times every second in response to visual and cognitive processing. The consensus view is that the details of these rapid eye-movement decisions-which part of a word to target with a saccade-are determined solely by low-level oculomotor heuristics. But maximally efficient saccade targeting would be sensitive to ongoing word identification, sending the eyes farther into a word the farther its identification has already progressed. Here, using a covert text-shifting paradigm, we showed just such a statistical relationship between saccade targeting in reading and trial-to-trial variability in cognitive processing. This result suggests that, rather than relying purely on heuristics, the human brain has learned to optimize eye movements in reading even at the fine-grained level of character-position targeting, reflecting efficiency-based sensitivity to ongoing cognitive processing.


Quantifying biopsychosocial aspects in everyday contexts: an integrative methodological approach from the behavioral sciences.
Contextual factors are crucial for evaluative research in psychology, as they provide insights into what works, for whom, in what circumstances, in what respects, and why. Studying behavior in context, however, poses numerous methodological challenges. Although a comprehensive framework for classifying methods seeking to quantify biopsychosocial aspects in everyday contexts was recently proposed, this framework does not contemplate contributions from observational methodology. The aim of this paper is to justify and propose a more general framework that includes observational methodology approaches. Our analysis is rooted in two general concepts: ecological validity and methodological complementarity. We performed a narrative review of the literature on research methods and techniques for studying daily life and describe their shared properties and requirements (collection of data in real time, on repeated occasions, and in natural settings) and classification criteria (eg, variables of interest and level of participant involvement in the data collection process). We provide several examples that illustrate why, despite their higher costs, studies of behavior and experience in everyday contexts offer insights that complement findings provided by other methodological approaches. We urge that observational methodology be included in classifications of research methods and techniques for studying everyday behavior and advocate a renewed commitment to prioritizing ecological validity in behavioral research seeking to quantify biopsychosocial aspects.


The JANUS of chronic inflammatory and autoimmune diseases onset during COVID-19 - A systematic review of the literature.
The diverse clinical manifestations of COVID-19 is emerging as a hallmark of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. While the initial target of SARS-CoV-2 is the respiratory tract, it is becoming increasingly clear that there is a complex interaction between the virus and the immune system ranging from mild to controlling responses to exuberant and dysfunctional multi-tissue directed autoimmune responses. The immune system plays a dual role in COVID-19, being implicated in both the anti-viral response and in the acute progression of the disease, with a dysregulated response represented by the marked cytokine release syndrome, macrophage activation, and systemic hyperinflammation. It has been speculated that these immunological changes may induce the loss of tolerance and/or trigger chronic inflammation. In particular, molecular mimicry, bystander activation and epitope spreading are well-established proposed mechanisms to explain this correlation with the likely contribution of HLA alleles. We performed a systematic literature review to evaluate the COVID-19-related autoimmune/rheumatic disorders reported between January and September 2020. In particular, we investigated the cases of incident hematological autoimmune manifestations, connective tissue diseases, antiphospholipid syndrome/antibodies, vasculitis, Kawasaki-like syndromes, acute arthritis, autoimmune-like skin lesions, and neurologic autoimmune conditions such as Guillain-Barré syndrome. We screened 6263 articles and report herein the findings of 382 select reports which allow us to conclude that there are 2 faces of the immune response against SARS-CoV-2, that include a benign virus controlling immune response and a many faceted range of dysregulated multi-tissue and organ directed autoimmune responses that provides a major challenge in the management of this viral disease. The number of cases for each disease varied significantly while there were no reported cases of adult onset Still disease, systemic sclerosis, or inflammatory myositis.


Promoting tobacco cessation via the workplace: opportunities for improvement.
Little research exists on the prevalence of evidence-based tobacco cessation practices in workplaces, employer promotion of state-sponsored quitlines and predictors of these practices. Cross-sectional analysis of the 2008 Healthy Worksite Survey, a telephone survey administered to Washington employers with 50 or more employees (n=693). The objectives were to describe workplaces' implementation of evidence-based tobacco cessation practices and identify key predictors of implementation in order to highlight opportunities for interventions. Among these employers, 38.6% promoted quitting tobacco, and 33.8% offered insurance coverage for cessation medications and counselling, 27.5% referred no-smoking violators to cessation services, and 5.7% included the state-sponsored quitline in health promotion messages. Larger workplaces and workplaces with a wellness staff, committee or coordinator had greater insurance coverage for tobacco cessation, communications promoting tobacco cessation, and promotion of the state-sponsored quitline (p<0.01). Workplaces with a wellness staff, committee or coordinator referred more violators of no-smoking policies to cessation services (p<0.01). In Washington State workplaces do little to promote tobacco cessation by their employees. The lack of tobacco cessation promoting practices at small businesses, restaurants and bars, and businesses without wellness personnel indicates an opportunity for finding and reaching current smokers at businesses with limited resources. By adopting inexpensive prevention efforts, such as promoting the state-sponsored tobacco cessation quitline, employers can help employees quit smoking and, thereby, assist in improving employee health and lower medical costs.


The theta-defensin, retrocyclin, inhibits HIV-1 entry.
Retrocyclin is a circular antimicrobial 18-residue peptide encoded in the human genome by a theta-defensin pseudogene. In the human genome, the gene for retrocyclin is inactivated by an in-frame stop codon in its signal sequence but its mature coding sequence is intact. The peptide corresponding to the processed human retrocyclin, generated by solid phase peptide synthesis, inhibited replication of R5 and X4 strains of HIV-1 in human cells. Luciferase reporter virus and Vpr-BLaM entry assays were used to demonstrate that retrocyclin specifically blocked R5 and X4 HIV-1 replication at entry. Surface plasmon resonance demonstrated that retrocyclin bound to soluble CD4 and gp120, but gp120 cell-binding assays revealed that retrocyclin did not fully inhibit the binding of soluble CD4 to gp120. A fluorescent retrocyclin congener localized in cell-surface patches either alone or colocalized with CD4, CXCR4, and CCR5. In the aggregate, these results suggest that retrocyclin blocks an entry step in HIV-1 replication. Retrocyclin represents a new class of small molecule HIV-1 entry inhibitors.


Resolving challenges in deep learning-based analyses of histopathological images using explanation methods.
Deep learning has recently gained popularity in digital pathology due to its high prediction quality. However, the medical domain requires explanation and insight for a better understanding beyond standard quantitative performance evaluation. Recently, many explanation methods have emerged. This work shows how heatmaps generated by these explanation methods allow to resolve common challenges encountered in deep learning-based digital histopathology analyses. We elaborate on biases which are typically inherent in histopathological image data. In the binary classification task of tumour tissue discrimination in publicly available haematoxylin-eosin-stained images of various tumour entities, we investigate three types of biases: (1) biases which affect the entire dataset, (2) biases which are by chance correlated with class labels and (3) sampling biases. While standard analyses focus on patch-level evaluation, we advocate pixel-wise heatmaps, which offer a more precise and versatile diagnostic instrument. This insight is shown to not only be helpful to detect but also to remove the effects of common hidden biases, which improves generalisation within and across datasets. For example, we could see a trend of improved area under the receiver operating characteristic (ROC) curve by 5% when reducing a labelling bias. Explanation techniques are thus demonstrated to be a helpful and highly relevant tool for the development and the deployment phases within the life cycle of real-world applications in digital pathology.


Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions.
TRH is a tripeptide amide that functions as a neurotransmitter but also serves as a neurohormone that has a critical role in the central regulation of the hypothalamic-pituitary-thyroid axis. Hypophysiotropic TRH neurons involved in this neuroendocrine process are located in the hypothalamic paraventricular nucleus and secrete TRH into the pericapillary space of the external zone of the median eminence for conveyance to anterior pituitary thyrotrophs. Under basal conditions, the activity of hypophysiotropic TRH neurons is regulated by the negative feedback effects of thyroid hormone to ensure stable, circulating, thyroid hormone concentrations, a mechanism that involves complex interactions between hypophysiotropic TRH neurons and the vascular system, cerebrospinal fluid, and specialized glial cells called tanycytes. Hypophysiotropic TRH neurons also integrate other humoral and neuronal inputs that can alter the setpoint for negative feedback regulation by thyroid hormone. This mechanism facilitates adaptation of the organism to changing environmental conditions, including the shortage of food and a cold environment. The thyroid axis is also affected by other adverse conditions such as infection, but the central mechanisms mediating suppression of hypophysiotropic TRH may be pathophysiological. In this review, we discuss current knowledge about the mechanisms that contribute to the regulation of hypophysiotropic TRH neurons under physiological and pathophysiological conditions.


[Structure of diseases of the peripheral nervous system].
The structure of peripheral nervous system diseases is reviewed by analyzing 941 in- and outpatient case histories. Of this number, 57.34% of the patients had radicular syndromes, 16.17%, acute injuries of nerves and plexuses, and 22.66%, tunnel and other compression syndromes. Cases of polyneuropathy and other disorders accounted for only 3.83%. A total of 21.46 cases with nontraumatic mechanical damage to nerves are analyzed in detail. In 87.88%, these syndromes involved upper and in 12.12% lower extremities. Syndromes of the carpal canal (43.01%), ulnar canal (14.72%), cervical neurovascular compression (12.95%), and tarsal canal (5.08%) occurred most frequently. A wide variety of other syndromes made up only 24.24% of all compression syndromes.


Decrease in knee joint pain and increase in function in patients with medial compartment arthrosis: a prospective analysis of valgus bracing.
We studied a brace designed to decrease loads on the medial tibiofemoral compartment in knees with chronic pain and arthrosis to determine if pain symptoms decreased, function improved, and dynamic gait characteristics altered during walking. Eighteen patients with symptomatic medial compartment arthrosis were fitted with a commercially available brace. All were evaluated after an average of 9 weeks of brace wear, and 13 patients were evaluated after 1 year of brace wear. The Cincinnati Knee Rating System and additional pain scales were used to analyze symptoms and functional limitations. Nine subjects underwent a dynamic gait analysis and were compared with a control group of 11 normal subjects matched for age and walking speed. The brace was worn an average of 7 hours a day, 5 days a week. Following 9 weeks of brace wear, statistically significant improvements were found for all pain parameters, and these improvements continued at the 1 year evaluation. Before brace wear, 78% had pain with activities of daily living, but after the first evaluation, only 39% continued to have such pain, and at the second evaluation, only 31% were so affected. Before brace wear, patients had a walking tolerance of 51 minutes prior to the onset of pain symptoms. At the first evaluation, patients could walk 138 minutes without pain, and after 1 year, they could walk 107 minutes without pain. Before brace wear, 78% rated their overall knee condition as fair or poor whereas at the first evaluation, only 33% continued to provide this rating. No differences were found in the dynamic gait parameters measured with and without the brace. While this brace did not provide the dramatic improvements in symptoms, function, and patient satisfaction obtainable after high tibial osteotomy, it did help the majority of patients. If the goal of brace use is to buy a short amount of time for patients who cannot undergo or wish to avoid osteotomy or knee arthroplasty, then bracing appears to offer a reasonable alternative for short-term pain relief and improved function.


Microchannels inside bulk PMMA generated by femtosecond laser using adaptive beam shaping.
In this contribution, we report on the generation of internal microchannels with basically unlimited channel length inside of PMMA bulk material by femtosecond laser. A precisely controllable and stable circular channel cross section is obtained by using a spatial light modulator to compensate the writing depth depending spherical aberration. Furthermore, the generation of a rotatable elliptical input beam by adaptive optics ensures a fitting of the beam shaping to the writing direction. In this study, we report on both, the effect of the ellipticity of the input beam and the effect of a correction of the spherical aberration on the circularity of the resulting internal microchannels. Moreover, we demonstrate the application of this writing technique by creating microfluidic testing structures inside of a transparent standard polymer.


The role of prison-based interventions for hepatitis C virus (HCV) micro-elimination among people who inject drugs in Montréal, Canada.
In Canada, hepatitis C virus (HCV) transmission primarily occurs among people who inject drugs (PWID) and people with experience in the prison system bare a disproportionate disease burden. These overlapping groups of individuals have been identified as priority populations for HCV micro-elimination in Canada, which is currently not on track to achieve its elimination targets. Considering the missed opportunities to intervene in provincial prisons, this study aims to estimate the population-level impact of prison-based interventions and post-release risk reduction strategies on HCV transmission among PWID in Montréal, a Canadian city with high HCV burden. A dynamic HCV transmission model among PWID was developed and calibrated to community and prison bio-behavioural surveys in Montréal. Then, the relative impact of prison-based testing and treatment or post-release linkage to care (both 90% testing and 75% treatment coverage), alone or in combination with strategies that reduce the heightened post-release transmission risk by 50%, was estimated from 2018 to 2030, and compared to counterfactual scenarios. Prison-based test-and-treat strategies could lead to the greatest declines in incidence (48%; 95%CrI: 38-57%) over 2018-2030 and prevent the most new first chronic infections (22%; 95%CrI: 16-28%) among people never exposed to HCV. Prison testing and post-release linkage to care lead to a slightly lower decrease in incidence and prevented fraction of new chronic infections. Combining test-and-treat with risk reduction measures could further its epidemiological impact, preventing 35% (95%CrI: 29-40%) of new first chronic infections. When implemented concomitantly with community-based treatment scale-up, prison-based interventions had synergistic effects, averting a higher fraction of new first chronic infections. Offering HCV testing and treatment in provincial prisons, where incarcerations are frequent and sentences short, could change the course of the HCV epidemic in Montréal. Prison-based interventions with potential integration of post-release risk reduction measures should be considered as an integral part of HCV micro-elimination strategies in this setting.


Age Differences in Age Perceptions and Developmental Transitions.
Is 50 considered "old"? When do we stop being considered "young"? If individuals could choose to be any age, what would it be? In a sample of 502,548 internet respondents ranging in age from 10 to 89, we examined age differences in aging perceptions (e.g., how old do you feel?) and estimates of the timing of developmental transitions (e.g., when does someone become an older adult?). We found that older adults reported older perceptions of aging (e.g., choosing to be older, feeling older, being perceived as older), but that these perceptions were increasingly younger than their current age. The age to which individuals hope to live dramatically increased after age 40. We also found that older adults placed the age at which developmental transitions occurred later in the life course. This latter effect was stronger for transitions involving middle-age and older adulthood compared to transitions involving young adulthood. The current study constitutes the largest study to date of age differences in age perceptions and developmental timing estimates and yielded novel insights into how the aging process may affect judgments about the self and others.


Simultaneous 31P-NMR spectroscopy and EMG in exercising and recovering human skeletal muscle: a correlation study.
A large number of studies have shown amplitude and spectral changes of the electromyogram during exercise, leading to several theories of how these changes might be related to the underlying metabolic changes. The amplitude and spectral changes are generally interpreted as changes in motor unit recruitment and a reduction of the muscle fiber conduction velocity due to proton or lactate accumulation. This study focuses on the causality of spectral changes of the surface electromyogram and proton or lactate accumulation and how the changes in motor unit recruitment are related to the metabolic status of the muscle. Simultaneous 31P-nuclear magnetic resonance spectroscopy and surface electromyography were performed during sustained static exercise and recovery in healthy volunteers and a patient with McArdle's disease. A clear dissociation between the median power frequency of the surface electromyogram and pH was seen in the healthy volunteers during recovery and during exercise in the patient with McArdle's disease. The results indicate that proton or lactate accumulation is not primarily responsible for the spectral changes of the surface electromyogram as previously suggested. The motor unit recruitment (as judged by the root mean square of the surface electromyogram) increased hyperbolically during the submaximal static exercise, with decreasing phosphocreatine-to-P(i) ratio reaching maximum at 0.6 (exhaustion), and seems to constitute a consistent metabolic limit to the exercise. The increased myoelectrical activity seen after exercise is not caused by an incomplete recovery of phosphorous metabolism, pH, or lactate but could probably be an impairment of the excitation-contraction coupling.


THNN - A Neural Network Model for Telehealth Data Incompleteness Prediction.
In modern-day medical practices, practitioners and physicians are adapting to new technologies and utilizing new methods of communication with patients. Telemedicine, or telehealth, is one of the newest innovations in medical technology, enabling practitioners to communicate with their patients over the phone, video conferencing, or chat. However, clinical data and sentiments/attitudes are often not reflected in the practitioner's analysis and diagnosis of the patients they serve. As a solution to the problem of data incompleteness in telehealth, THNN allows medical practices to accommodate for possible missing or incomplete data and provide a greater quality of care overall. Through an ensemble of Natural Language Processing (NLP) and AI-enabled systems, THNN produces sentiment and incompleteness mapping to provide seamless results.Clinical relevance- The method presented utilizes telehealth natural language data to process the sentiments of patients and the incompleteness found in the conversations, increasing the possibility of improved healthcare outcomes.


Weak signal propagation through noisy feedforward neuronal networks.
We determine under which conditions the propagation of weak periodic signals through a feedforward Hodgkin-Huxley neuronal network is optimal. We find that successive neuronal layers are able to amplify weak signals introduced to the neurons forming the first layer only above a certain intensity of intrinsic noise. Furthermore, we show that as low as 4% of all possible interlayer links are sufficient for an optimal propagation of weak signals to great depths of the feedforward neuronal network, provided the signal frequency and the intensity of intrinsic noise are appropriately adjusted.


Relationship between cigarette smoking and muscle strength in Japanese men.
To investigate the link between cigarette smoking and muscle strength in Japanese men. We used data on 4249 Japanese men, aged 43.3±13.9 years, in this cross-sectional investigation study. Grip strength and leg strength were measured as indicators of overall muscle strength. Meanwhile, subjects' cigarette smoking habits were recorded by trained medical staff. The effect of cigarette smoking on muscle strength was evaluated. A total of 1618 men (38.1%) were smokers and 1481 men (34.9%) exercised regularly. Significant differences in muscle strength were noted between men with and without a Brinkman index of 400 or greater, after adjusting for age. After adjusting for age, height, body weight and exercise habits, associations between the Brinkman index and leg strength and the ratio of leg strength to body weight were attenuated. Cigarette smoking might be negatively associated with muscle strength, especially grip strength in Japanese men.


Sublethal concentrations of chlorpyrifos induce changes in the thermal sensitivity and tolerance of anuran tadpoles in the toad Rhinella arenarum?
Amphibians are considered one of the groups most susceptible to chemical contamination, therefore are good bio-indicators of aquatic pollution. Synergistic effects of temperature and pesticides have been found in amphibians determining amplified toxicity effect on survival and malformations with increasing temperatures. We studied the sensitivity of sublethal concentrations of chlorpyrifos in Rhinella arenarum tadpoles over on two fitness related thermal traits: locomotor swimming performance and thermal tolerance limits (CTmax = critical thermal maximum and CTmin = critical thermal minimum). Our result shows a decrease in the locomotor performance of R. arenarum tadpoles with increasing sublethal chlorpyrifos concentrations. The experimental temperature increased locomotor performance but this being only significant for the control whereas tadpoles raised at any sublethal chlorpyrifos concentration did not increase their total swimming distance with temperature (Concentration × Temperature interaction, P < 0.019). Chlorpyrifos toxicity decreases maximum swimming distance but this reduction not compensated at high temperatures that do enhance swimming performance in the control treatment. On the other hand, higher chlorpyrifos sensitivity in CTmax than CTmin since tadpoles exposed to all polluted treatments exhibits a significant decline in CTmax but not in CTmin. Current global warming and the increase of atypical climatic events, such as heat waves may put at risk the larval chlorpyrifos polluted populations of R. arenarum. Our results show that the sublethal concentrations of the chlorpyrifos pesticide may affect the fitness and survival of the larvae of R. arenarum.


Fas- and interferon gamma-induced apoptosis in Chang conjunctival cells: further investigations.
Previously interferon (IFN)gamma-induced apoptosis and expression of inflammation-related proteins in a human conjunctival cell line were demonstrated. The aim of this study was to further investigate the mechanisms of IFNgamma-, Fas-, and cycloheximide (CHX)-induced programmed cell death, with special attention to the role of transcriptional factors NF-kappaB and STAT1. In a human conjunctival cell line (Chang conjunctival cells) apoptosis was induced with 500 ng/ml anti-Fas antibody (anti-Fas ab) alone (24 or 48 hours) or, as previously reported, with 300 U/ml of human recombinant IFNgamma alone (48 hours). To study the role of IFNgamma on Fas-induced apoptosis, cells were treated first with IFNgamma at 30 U/ml during 24 hours (nontoxic dose), and then anti-Fas ab was applied for 24 hours. Moreover, to study the influence of CHX on Fas- and IFNgamma-induced apoptosis, cells were treated for 24 hours with 300 U/ml IFNgamma together with a nontoxic concentration (1 microg/ml) of CHX, or with 500 ng/ml anti-Fas ab together with 1 microg/ml CHX (24 hours). After treatment, cell viability (neutral red assay), mitochondrial membrane potential (rhodamine 123 assay), chromatin condensation (Hoechst 33342 assay), and the index Hoechst/neutral red were studied by cold light microplate cytometry. The apoptotic process was sought for by contrast phase microscopy and DAPI staining and was confirmed by immunoblotting of PARP. Activation of caspase-3 (CPP32) and caspase-8 were investigated by Western blot analysis. NF-kappaB and STAT DNA-binding activities were studied by electrophoretic mobility shift assays (EMSA). After 24 and 48 hours of treatment with anti-Fas ab alone, 15% to 20% and 30%, respectively, of apoptotic cells were observed. When anti-Fas sera were applied after IFNgamma pretreatment or together with CHX, 50% to 80% of cells demonstrated morphologic characteristics of programmed cell death. Apoptosis was confirmed by a cleavage of PARP and CPP32, by caspase-8 activation, and by an index Hoechst/neutral red greater than one. All these modifications were preceded by a decrease in mitochondrial membrane potential. EMSA revealed that NF-kappaB was activated after IFNgamma and anti-Fas ab treatments and inhibited after CHX treatment. STAT1 was strongly activated after IFNgamma treatment and only in a minor degree after anti-Fas ab treatment. STAT1-binding activity persisted after CHX treatment. The relative resistance of Chang cells toward Fas-induced apoptosis could be related to the activation of NF-kappaB. IFNgamma-induced programmed cell death preferentially involves the activation of STAT1 that counterbalances NF-kappaB antiapoptotic effects. In fact, Fas-induced apoptosis was potentiated by IFNgamma or CHX treatments. These results suggest that NF-kappaB activation could maintain cell viability as well as participate in IFNgamma-induced inflammatory modifications, whereas STAT1 activation could provide, in this model, a proapoptotic signal.


Intuitive confidence: choosing between intuitive and nonintuitive alternatives.
People often choose intuitive rather than equally valid nonintuitive alternatives. The authors suggest that these intuitive biases arise because intuitions often spring to mind with subjective ease, and the subjective ease leads people to hold their intuitions with high confidence. An investigation of predictions against point spreads found that people predicted intuitive options (favorites) more often than equally valid (or even more valid) nonintuitive alternatives (underdogs). Critically, though, this effect was largely determined by people's confidence in their intuitions (intuitive confidence). Across naturalistic, expert, and laboratory samples (Studies 1-3), against personally determined point spreads (Studies 4-11), and even when intuitive confidence was manipulated by altering irrelevant aspects of the decision context (e.g., font; Studies 12 and 13), the authors found that decreasing intuitive confidence reduced or eliminated intuitive biases. These findings indicate that intuitive biases are not inevitable but rather predictably determined by contextual variables that affect intuitive confidence.


Diagnosis and prognosis in double-outlet right ventricle.
The aim of this study was to examine prenatal diagnosis of double-outlet right ventricle (DORV)-associated anomalies and prognosis of each case. Medical records were reviewed of fetuses with DORV who had fetal echocardiography at our institution from 2002 to 2006. Pre- and postnatal diagnosis and outcome were compared and evaluated. Twenty-one fetuses were diagnosed with DORV. The pregnancy was terminated in seven cases. Three cases had chromosomal abnormalities; three cases, hypoplastic left ventricle; and one case, encephalocele. Accurate prenatal diagnosis of the ventricular septal defect, outflow obstruction, and great artery relationship was achieved in 14 of 16 cases (87.5%). Only 2 of 13 live-born cases survived beyond 6 months. The overall prognosis for fetuses with DORV is poor. DORV is found in fetuses with a huge spectrum of associated cardiac and extracardiac anomalies. Careful assessment by fetal echocardiography can determine important anatomic details with adequate correctness for precise counseling.


Cyclooxygenase expression is not required for release of arachidonic acid from cells by some nonsteroidal anti-inflammatory drugs and cancer preventive agents.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective in inhibiting colorectal cancer. Cyclooxygenase activity is thought to mediate, in part, this cancer preventive effect. From observations made when cells that express cyclooxygenase activity were treated with NSAIDs and known cancer preventive agents, I have postulated that arachidonic acid (AA) release is associated with cancer prevention. In this study, the effects of NSAIDs on two cells that do not express cycloxygenase activity are detailed. NSAIDs and several cancer preventive agents release AA from human colon cancer cells (the HCT-15 cell line). The concentrations of NSAIDs required to release significant amounts of AA from the HCT-15 cells are greater than those required to inhibit the lactacystin plus 12-0-tetradecanoyl-13-acetate stimulated cyclooxygenase activity of rat liver cells. NSAIDs, tamoxifen and simvastatin were found to hemolyze erythrocyte cells which also do not express cyclooxygenase activity The data demonstrate that AA release is independent of cyclooxygenase activity and together with hemolysis suggest that intercalation of the plasma membrane by some NSAIDs and cancer preventive agents, e.g. tamoxifen, mediates this release. A mechanism by which many of these drugs affect several diverse biologic properties including deesterification of membrane phospholipids by phospholipases to release AA is presented.


Epidemiological study of people living in rural North Carolina for novel respiratory viruses.
During the last 10 years, scientists have grown increasingly aware that emerging respiratory viruses are often zoonotic in their origin. These infections can originate from or be amplified in livestock. Less commonly recognized are instances when humans have transmitted their respiratory pathogens to animals (reverse zoonoses). Even with this knowledge of viral exchange at the human-livestock interface, few studies have been conducted to understand this cross-over. In this pilot study, we examined persons with influenza-like illness at an outpatient clinic for evidence of infection with novel zoonotic respiratory pathogens in rural North Carolina where there are dense swine and poultry farming. Environmental air sampling was also conducted. From July 2016 to March 2017, a total of 14 human subjects were enrolled and sampled, and 192 bioaerosol samples were collected. Of the 14 human subject samples molecularly tested, three (21.4%) were positive for influenza A, one (7.1%) for influenza B and one (7.1%) for human enterovirus. Of the 192 bioaerosol samples collected and tested by real-time RT-PCR or PCR, three (1.6%) were positive for influenza A and two (1.0%) for adenovirus. No evidence was found for novel zoonotic respiratory viruses.


Dermatological publications in the Gulf Cooperation Council countries. An analysis of 1966-2004 Medline papers.
To investigate the publications in dermatology cited in the Medline from 6 countries of the Gulf Cooperation Council (GCC) from 1966 to 2004. Medline was searched with the aid of Internet provider Pubmed using the same strategy at a given time for all countries. At the time of search, the Medline listed biomedical research papers from the GCC countries totaled 12837. Of these, 140 were in Dermatology. The Kingdom of Saudi Arabia followed by Kuwait was by far the most prolific contributor, whereas almost none were noted from Bahrain. The publications were highest during the year 2002 (19) followed by 2003 (13), most of them being in the English language in the International Journal of Dermatology (60 citations) and Pediatric Dermatology (13 citations). Though the GCC countries have seen a relatively small period in the history of development of medical research, data show that they are trying to keep pace with the rest of the developed world. What remains to be exploited is their good economy that should be directed to provide better infrastructure and improve the quality of training programs. Professional societies within the region must play an active role in ensuring optimum and judicious use of funds.


Common Mutations of the Methylenetetrahydrofolate Reductase (MTHFR) Gene in Non-Syndromic Cleft Lips and Palates Children in North-West of Iran.
Cleft lips and cleft palates are common congenital abnormalities in children. Various chromosomal loci have been suggested to be responsible the development of these abnormalities. The present study was carried out to investigate the association between the suspected genes (methylenetetrahydrofolate reductase [MTHFR] A1298C and C677T) that might contribute into the etiology of these disorders through application of molecular methods. This cross-sectional and explanatory study was carried out on a study population of 65 affected children, 130 respective parents and 50 healthy individuals between 2009 and 2012 at Tabriz University of Medical Sciences, IR Iran. After DNA extraction, amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and restriction fragment length polymorphism (RFLP)-PCR were used respectively to investigate the C677T and A1298C mutations for the MTHFR gene. There was a significant difference in the rates of the C677T mutation when affected patients and their fathers were compared with the control group (odds ratio [OR]=0.44) (OR=0.64). However, there was no significant difference observed in the rate of this mutation between the patients' mothers and the control group (OR=1.35). In addition, the abnormality rate was higher in patients with the A1298C mutation and their parents, when compared with the control group. This abnormality rate was higher for the affected children and their fathers in comparison with their mothers (Fathers, OR=0.26; Mothers, OR=0.65; Children, OR=0.55). No significant difference was seen in the rate of the polymorphism C677T in its CC, when the affected children and their parents were compared with the control group. However, there was a significant difference in the A1298C mutation. An association was seen between the A1298C mutation and cleft lip and cleft palate abnormalities in Iran. However, there seems to be a stronger relationship between the C67TT mutation and these abnormalities in other countries, which could be explained by racial differences. Moreover, this association was more notable between the affected children and their fathers than their mothers. The findings in this study may be helpful in future studies and screening programs.


Two-stage treatment of an unusual haemobilia caused by intrahepatic pseudoaneurysm.
A 84-year-old man with a surgical history of subtotal gastrectomy for gastric cancer was transferred to our department because of a disorder of consciousness. Septic shock due to obstructive suppurative cholangitis secondary to choledocholithiasis was diagnosed. Anemia was also present, and upper gastrointestinal tract endoscopy revealed blood emerging from the Papilla of Vater. The cause of the anemia was identified as haemobilia. Angiography showed a small aneurysm over the artery on segment 3 (A3). The cause of the haemobilia was suspected to be the bleeding into the biliary tree from this aneurysm. Because the patient's general condition was poor, minimally invasive therapy was needed. Transcatheter arterial embolization (TAE) was selected initally. Later, lateral sectionectomy was performed in order to remove the aneurysm on A3. No surgical complication occurred and, after surgery, no haemobilia was identified. In conclusion, a two-stage treatment, namely, surgery following TAE, is recommended for patients in a physically poor condition who have haemobilia due to intrahepatic aneurysm.


Different effects of the antiprogesterone RU486 on progesterone secretion by the corpus luteum of rats with 4- and 5-day oestrous cycles.
Administration of the antiprogesterone RU486 (2 mg/day) for 14 days to rats with a 5-day reproductive cycle resulted in an increase in both ovarian and pituitary weight in contrast with rats with a 4-day oestrous cycle. Luteal progesterone production decreased earlier in 4-day than in 5-day cyclic rats. Treatment of 5-day cyclic rats with antiprogesterone from the day of metoestrus onwards resulted in the advancement of the preovulatory prolactin surge by 24 h. Progesterone production by the corpus luteum was, however, not affected, indicating that in 5-day cyclic rats the corpora lutea are still functionally active at the time of the preovulatory surge of prolactin. They become, therefore, stimulated both in size and progesterone production. In contrast, the corpora lutea in 4-day cyclic rats are functionally inactive at the time of the preovulatory surge of prolactin, and prolactin acts luteolytically. In conclusion, the advancement of the preovulatory surge of prolactin by 24 h accounts, at least in part, for the increase in ovarian weight in 5-day cyclic rats after treatment with antiprogesterone. The results of these experiments do not agree with a direct effect of the antiprogesterone RU486 on progesterone secretion by the corpus luteum.


Surface lesions of bone.
A surface lesion of bone may arise within the cortex, between the cortex and the periosteum, within the periosteum, or in the tissues immediately adjacent to the periosteum including tendinous and ligamentous attachments. While these lesions generally reflect the spectrum of more common intramedullary lesions and have an appearance similar to that of their intramedullary counterparts, their unusual surface origin often renders diagnosis difficult. Surface sarcomas are usually of a lower grade than that of the intramedullary tumor, and often they have a more favorable prognosis. Traumatic lesions of the bone surface are common and should be considered in the differential diagnosis of a surface lesion, especially in the young or athletic individual. An elevated peripheral white blood cell count and erythrocyte sedimentation rate may herald an infection of the bone surface.


Neighborhood social cohesion, religious participation and sexual risk behaviors among cisgender black sexual minority men in the southern United States.
Few studies have examined associations between neighborhood social cohesion and sexual risk behaviors among gay, bisexual, and other sexual minority men (SMM), and none have among Black SMM in the southern U.S. The purpose of the current study is to examine associations between neighborhood social cohesion and sexual risk behaviors among Black SMM in the southern U.S., a population heavily impacted by HIV. We also examined whether these relationships are modified by religious participation for Black SMM in the southern U.S. Data was obtained from the MARI Study, a sample of Black SMM ages 18-66 years, recruited from the Jackson, MS and Atlanta, GA metropolitan areas (n = 354). Neighborhood social cohesion was assessed with a validated 5-item scale. We conducted multivariable regression analyses to examine the association between neighborhood social cohesion with each of the sexual risk behaviors (e.g., condomless sex and drug use before or during sex), controlling for key confounders. We then performed moderation analysis by religious participation (religious attendance and private religiosity). Compared to Black SMM with higher perceived neighborhood social cohesion, Black SMM with lower neighborhood social cohesion had increased odds of alcohol use before or during sex (aPR = 1.56; 95% CI = 1.16-2.11) and condomless anal sex with casual partners (aPR = 1.55; 1.03-2.32). However, the magnitude of these associations varied by religious attendance and private religiosity. Black SMM with low religious service attendance had higher risk of alcohol use in the context of sex when perceived neighborhood social cohesion was low; those with high private religiosity had elevated alcohol use in the context of sex when perceived neighborhood social cohesion was low. Interventions that target connectedness among neighborhood members through community education or mobilization efforts, including the involvement of religious organizations, should be considered for HIV prevention focused on alcohol and condomless sex among Black SMM.


The effects of race and information variance on disagreement between psychiatric emergency service and research diagnoses in first-episode psychosis.
Previously, we reported that patient race was associated with disagreement between research and clinical diagnoses. To extend this work, we studied whether disagreement was specifically due to associations of patient race with information or criterion variance. Ninety-nine patients consecutively admitted through the University of Cincinnati Psychiatric Emergency Service (PES) for a first hospitalization for psychosis were evaluated using the Structured Clinical Interview for DSM-III-R. Diagnoses made in the PES were compared with those obtained from the structured interview. We examined the contributions of information variance and criterion variance to the association between race and diagnostic agreement of PES and research diagnoses. Agreement in PES and research diagnoses was present in only 42% of patients. Diagnostic agreement was less common in non-white patients than white patients, even after controlling for other sociodemographic and clinical variables. Information variance was the cause of diagnostic disagreement in 58% of cases and was associated with patient race. Criterion variance, occurring in 42% of cases, was not associated with race. Patient race may contribute to the diagnostic process in the psychiatric emergency service by influencing the information obtained from patients during clinical evaluations.


Cytological findings of microfilariae in different sites: A retrospective review of 22 cases from endemic region.
Filariasis is a major health problem in India. Despite the high prevalence, microfilariae are rarely found in cytology smears. Most of the cases are incidentally found, solely or in association with other pathologies. The study was undertaken to analyze the prevalence and cytology findings of cases of incidentally found microfilariae in cytology smears (fine-needle aspiration cytology [FNAC]/body fluids) from different body parts. This was a retrospective study over 5 years, where the cases of microfilariae in aspirates from swelling of different locations and body fluids were reviewed, and clinic-pathological data were analyzed. Out of 16,738 cases of FNAC and 882 cases of fluid cytology, 22 cases (0.124%) of incidental finding of microfilaria were documented in cytology smears. The cases were diagnosed from lymph nodes (5 cases), skin and soft tissue (4 cases), scrotal (4 cases), breast (3 cases), thyroid (2 cases), and pleural fluid (2 cases). We found eosinophilia in 15 cases (68.18%) of filarial lesions. We found two cases of incidental findings of microfilariae in association with malignant lesions. Filariasis should be considered as differential diagnosis of swelling of lymph nodes, skin, soft tissue, inguinoscrotal region, and other sites as well. Careful screening of cytology smears may help in detection of incidental cases in the association of other pathologies.


Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants.
Infants born to mothers with obesity have greater adiposity, ectopic fat storage, and are at increased risk for childhood obesity and metabolic disease compared with infants of normal weight mothers, though the cellular mechanisms mediating these effects are unclear. We tested the hypothesis that human, umbilical cord-derived mesenchymal stem cells (MSCs) from infants born to obese (Ob-MSC) versus normal weight (NW-MSC) mothers demonstrate altered fatty acid metabolism consistent with adult obesity. In infant MSCs undergoing myogenesis in vitro, we measured cellular lipid metabolism and AMPK activity, AMPK activation in response to cellular nutrient stress, and MSC DNA methylation and mRNA content of genes related to oxidative metabolism. We found that Ob-MSCs exhibit greater lipid accumulation, lower fatty acid oxidation (FAO), and dysregulation of AMPK activity when undergoing myogenesis in vitro. Further experiments revealed a clear phenotype distinction within the Ob-MSC group where more severe MSC metabolic perturbation corresponded to greater neonatal adiposity and umbilical cord blood insulin levels. Targeted analysis of DNA methylation array revealed Ob-MSC hypermethylation in genes regulating FAO (PRKAG2, ACC2, CPT1A, SDHC) and corresponding lower mRNA content of these genes. Moreover, MSC methylation was positively correlated with infant adiposity. These data suggest that greater infant adiposity is associated with suppressed AMPK activity and reduced lipid oxidation in MSCs from infants born to mothers with obesity and may be an important, early marker of underlying obesity risk.


Practical utility of general practice data capture and spatial analysis for understanding COPD and asthma.
General practice-based (GP) healthcare data have promise, when systematically collected, to support estimating local rates of chronic obstructive pulmonary disease (COPD) and asthma, variations in burden of disease, risk factors and comorbid conditions, and disease management and quality of care. The use of GP information systems for health improvement has been limited, however, in the scope and quality of data. This study assessed the practical utility of de-identified clinical databases for estimating local rates of COPD and asthma. We compared COPD and asthma rates to national benchmarks, examined health related risk factors and co-morbidities as correlates of COPD and asthma, and assessed spatial patterns in prevalence estimates at the small-area level. Data were extracted from five GP databases in western Adelaide, South Australia, for active patients residing in the region between 2012 and 2014. Prevalence estimates were computed at the statistical area 1 (SA1) spatial unit level using the empirical Bayes estimation approach. Descriptive analyses included summary statistics, spatial indices and mapping of geographic patterns. Bivariate associations were assessed, and disease profiles investigated to ascertain multi-morbidities. Multilevel logistic regression models were fitted, accounting for individual covariates including the number of comorbid conditions to assess the influence of area-level socio-economic status (SES). For 33,725 active patients, prevalence estimates were 3.4% for COPD and 10.3% for asthma, 0.8% higher and 0.5% lower for COPD and asthma, respectively, against 2014-15 National Health Survey (NHS) benchmarks. Age-specific comparisons showed discrepancies for COPD in the '64 years or less' and 'age 65 and up' age groups, and for asthma in the '15-25 years' and '75 years and up' age groups. Analyses confirmed associations with individual-level factors, co-morbid conditions, and area-level SES. Geographic aggregation was seen for COPD and asthma, with clustering around GP clinics and health care centres. Spatial patterns were inversely related to area-level SES. GP-based data capture and analysis has a clear potential to support research for improved patient outcomes for COPD and asthma via knowledge of geographic variability and its correlates, and how local prevalence estimates differ from NHS benchmarks for vulnerable age-groups.


[Do not resuscitate orders in the intensive care setting].
Even if Belgium (2002), The Netherlands (2002) and Luxemburg (2009) are the first three countries in the world to have legalized active euthanasia, there still is not a law on the do not resuscitate concept (NTBR or DNR). Nevertheless, numerous royal decrees and some consensus as well as advice given by the Belgian Medical Council, hold as jurisprudence. These rules remain amenable to change so as to suite the daily practice in intensive care units. This article describes the actual Belgian legal environment surrounding the intensive care specialist when he has to take such decisions.


Ethyl nitrite is produced in the human stomach from dietary nitrate and ethanol, releasing nitric oxide at physiological pH: potential impact on gastric motility.
Nitric oxide ((∙)NO), a ubiquitous molecule involved in a plethora of signaling pathways, is produced from dietary nitrate in the gut through the so-called nitrate-nitrite-NO pathway. In the stomach, nitrite derived from dietary nitrate triggers a network of chemical reactions targeting endogenous and exogenous biomolecules, thereby producing new compounds with physiological activity. The aim of this study was to ascertain whether compounds with physiological relevance are produced in the stomach upon consumption of nitrate- and ethanol-rich foods. Human volunteers consumed a serving of lettuce (source of nitrate) and alcoholic beverages (source of ethanol). After 15 min, samples of the gastric headspace were collected and ethyl nitrite was identified by GC-MS. Wistar rats were used to study the impact of ethyl nitrite on gastric smooth muscle relaxation at physiological pH. Nitrogen oxides, produced from nitrite in the stomach, induce nitrosation of ethanol from alcoholic beverages in the human stomach yielding ethyl nitrite. Ethyl nitrite, a potent vasodilator, is produced in vivo upon the consumption of lettuce with either red wine or whisky. Moreover, at physiological pH, ethyl nitrite induces gastric smooth muscle relaxation through a cGMP-dependent pathway. Overall, these results suggest that ethyl nitrite is produced in the gastric lumen and releases (∙)NO at physiological pH, which ultimately may have an impact on gastric motility. Systemic effects may also be expected if ethyl nitrite diffuses through the gastric mucosa reaching blood vessels, therefore operating as a (∙)NO carrier throughout the body. These data pinpoint posttranslational modifications as an underappreciated mechanism for the production of novel molecules with physiological impact locally in the gut and highlight the notion that diet may fuel compounds with the potential to modulate gastrointestinal welfare.


Contextual Sensing: Integrating Contextual Information with Human and Technical Geo-Sensor Information for Smart Cities.
In this article we critically discuss the challenge of integrating contextual information, in particular spatiotemporal contextual information, with human and technical sensor information, which we approach from a geospatial perspective. We start by highlighting the significance of context in general and spatiotemporal context in particular and introduce a smart city model of interactions between humans, the environment, and technology, with context at the common interface. We then focus on both the intentional and the unintentional sensing capabilities of today's technologies and discuss current technological trends that we consider have the ability to enrich human and technical geo-sensor information with contextual detail. The different types of sensors used to collect contextual information are analyzed and sorted into three groups on the basis of names considering frequently used related terms, and characteristic contextual parameters. These three groups, namely technical in situ sensors, technical remote sensors, and human sensors are analyzed and linked to three dimensions involved in sensing (data generation, geographic phenomena, and type of sensing). In contrast to other scientific publications, we found a large number of technologies and applications using in situ and mobile technical sensors within the context of smart cities, and surprisingly limited use of remote sensing approaches. In this article we further provide a critical discussion of possible impacts and influences of both technical and human sensing approaches on society, pointing out that a larger number of sensors, increased fusion of information, and the use of standardized data formats and interfaces will not necessarily result in any improvement in the quality of life of the citizens of a smart city. This article seeks to improve our understanding of technical and human geo-sensing capabilities, and to demonstrate that the use of such sensors can facilitate the integration of different types of contextual information, thus providing an additional, namely the geo-spatial perspective on the future development of smart cities.


Effect of hyaluronidase on the incidence of cystoid macular edema.
A prospective double-blind study of the effect of hyaluronidase on aphakic cystoid macular edema (CME) was performed. A 25% incidence of CME was encountered in patients receiving hyaluronidase admixed with the local anesthetic while no cases were diagnosed in the group not receiving hyaluronidase. The role of hyaluronidase in the pathogenesis of aphakic cystoid macular edema is discussed.


Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family.
Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+)/dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders.


Association of Interleukin-6 Levels and Futile Reperfusion After Mechanical Thrombectomy.
To assess whether interleukin-6 (IL-6) level is a marker of futile reperfusion in patients with acute ischemic stroke (AIS) with large vessel occlusion treated with mechanical thrombectomy (MT). The Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in Stroke (HIBISCUS-STROKE) includes patients with AIS treated with MT after MRI. We performed a sequential assessment of IL-6 (admission, 6 hours, 24 hours, 48 hours and 3 months from admission). Among patients with successful reperfusion (Thrombolysis in Cerebral Infarction scale 2b/3), reperfusion was considered effective if 3-month modified Rankin Scale (mRS) score was 0 to 2 and futile if 3-month mRS score was 3 to 6. Our model was adjusted for the main confounding variables. One hundred sixty-four patients represent the study population. One hundred thirty-three patients had successful reperfusion (81.1%), while in 46 (34.6%), reperfusion was classified as futile. In single-variable analyses, high IL-6 levels at 6, 24, and 48 hours in combination with a higher age, a prestroke mRS score >2, a history of hypertension or diabetes, lack of current smoking, a higher baseline NIH Stroke Scale score, the absence of associated intravenous thrombolysis, an intracranial internal carotid artery or a tandem occlusion, and an increased infarct growth were associated with futile reperfusion. After multivariable analyses, a high IL-6 level at 24 hours (odds ratio 6.15, 95% confidence interval 1.71-22.10) remained associated with futile reperfusion. IL-6 is a marker of futile reperfusion in the setting of MT.


Environmental determinants of the occurrence and distribution of Vibrio parahaemolyticus in the rias of Galicia, Spain.
Infections associated with Vibrio parahaemolyticus on the coast of Galicia (in northwestern Spain) were reported to be linked to large outbreaks of illness during 1999 and 2000. Little information is available about the ecological factors that influence the emergence of V. parahaemolyticus infections in this temperate region. We carried out a 3-year study to investigate the occurrence and distribution of V. parahaemolyticus at 26 sites located in the four main rias of Galicia in association with environmental and oceanographic variables. V. parahaemolyticus was detected in all the areas investigated and throughout the complete period of study with an overall incidence of 12.5%. Salinity was the primary factor governing the temporal and spatial distribution of V. parahaemolyticus, whereas seawater temperature had a secondary effect and only modulated the abundance in periods and areas of reduced salinities. Higher occurrence of V. parahaemolyticus was observed during periods of lower salinity in autumn, with a total of 61 positive samples (18%) and a mean density of 1,234 most probable number/100 g. V. parahaemolyticus was primarily detected in areas of reduced salinity close to freshwater discharge points, where it was found in up to 45% of the samples. Characterization of the isolates obtained from the study resulted in the first identification of two pathogenic tdh-positive strains of V. parahaemolyticus recovered from the marine environment in Galicia. These isolates showed serotypes identical to and DNA profiles indistinguishable from those of the clinical clone of V. parahaemolyticus dominant in infections in Spain in the last 10 years.


Movement through motherhood: Exploring mood, wellbeing, and prenatal emotional availability (EA) through EA-based dance intervention.
Emotional availability (EA) is a construct that describes the observed emotional connection in parent-child relationships. During pregnancy, EA is assessed only using caregiver sensitivity and nonhostility. We used the nonverbal aspects of these qualities to create a new dance/movement intervention ("EA-Based Dance Intervention"). Given the scarcity of pregnancy interventions, we provided training to participants on how to be emotionally engaged with their unborn babies through dance/movement. The EA-Based Dance Intervention alone comprised the first intervention arm (n = 12). A second intervention arm involved the combination of EA-Based Dance Intervention with brief psychoeducation (n = 10). The third arm was a control group, which received only the assessments (n = 7). Measures of self-reported symptoms of depression and anxiety, emotional expressivity, flourishing, and the (newly developed) self-reported prenatal EA were used at pre- and posttest. The measure of observed prenatal EA was used to compare intervention versus control at posttest only. In this pilot study, we found that participants receiving the EA-Based Dance Intervention alone or combined with psychoeducation, self-reported improved anxiety symptoms and self-reported higher prenatal EA. When compared with the control group, those experiencing EA-Based Dance Intervention reported fewer depressive symptoms from pre- to posttest.


Systematic tuning of heme redox potentials and its effects on O2 reduction rates in a designed oxidase in myoglobin.
Cytochrome c Oxidase (CcO) is known to catalyze the reduction of O2 to H2O efficiently with a much lower overpotential than most other O2 reduction catalysts. However, methods by which the enzyme fine-tunes the reduction potential (E°) of its active site and the corresponding influence on the O2 reduction activity are not well understood. In this work, we report systematic tuning of the heme E° in a functional model of CcO in myoglobin containing three histidines and one tyrosine in the distal pocket of heme. By removing hydrogen-bonding interactions between Ser92 and the proximal His ligand and a heme propionate, and increasing hydrophobicity of the heme pocket through Ser92Ala mutation, we have increased the heme E° from 95 ± 2 to 123 ± 3 mV. Additionally, replacing the native heme b in the CcO mimic with heme a analogs, diacetyl, monoformyl, and diformyl hemes, that posses electron-withdrawing groups, resulted in higher E° values of 175 ± 5, 210 ± 6, and 320 ± 10 mV, respectively. Furthermore, O2 consumption studies on these CcO mimics revealed a strong enhancement in O2 reduction rates with increasing heme E°. Such methods of tuning the heme E° through a combination of secondary sphere mutations and heme substitutions can be applied to tune E° of other heme proteins, allowing for comprehensive investigations of the relationship between E° and enzymatic activity.


[Building the meaning of disease recurrence: experience of women with breast cancer].
Regarding recurrence as a possibility in the lives of women with breast cancer, this work aimed at identifying how they construct the meaning of such possibility from their own existence. The study was based on the conceptions of symbolic interactionism and the content analysis of interviews with 12 mastectomized women was used. The possibility of recurrence was present in the lives of the women under study. It was configured by the uncertainty that they experienced and represented in the thematic units identified in their accounts when they stated to be "living with a stigmatizing disease", "experiencing a negative feeling" and "facing prejudice".


Evaluation of the Iconic Pain Assessment Tool by a heterogeneous group of people in pain.
The Iconic Pain Assessment Tool (IPAT) is a novel web-based instrument for the self-report of pain quality, intensity and location in the form of a permanent diary. Originally designed for people with central poststroke pain, the tool is being adapted for a larger, more diverse patient population. The present study aimed to collect evaluative feedback on the IPAT from a heterogeneous sample of individuals with chronic pain. The specific study aims were to evaluate participant comfort with the tool including enjoyment, ease of use and comfort with the electronic medium; to assess perceived value of the tool for communicating pain quality, intensity and location; to gauge participant intent to share their pain diaries with others and use the tool on a regular basis to track their pain over time; to assess the perceived descriptiveness of current IPAT icons and the numerical rating scale; and to identify strengths and weaknesses of the tool to refine the existing prototype. Written and verbal feedback from individuals with a variety of chronic pain conditions (n=23) were collected in the context of these objectives. Overall, the IPAT was positively endorsed by this heterogeneous sample of people in pain. The authors concluded that the IPAT is a user-friendly instrument that has the potential to help people express, document and share their personal experience with chronic pain.