Abnormal responses of myeloid progenitor cells to recombinant human colony-stimulating factors in congenital neutropenia.
The effects of recombinant human interleukin-3 (IL-3) and recombinant human granulocyte colony-stimulating factor (G-CSF) on the growth of myeloid progenitor cells (CFU-C) in semisolid agar culture were studied in two patients with Kostmann-type congenital neutropenia. CFU-C growth in bone marrow cells from patients was significantly reduced in response to various concentrations of either IL-3 or G-CSF alone, compared with that from normal subjects. There was no inhibitory effect of bone marrow cells from patients on normal CFU-C formation supported by IL-3 or G-CSF. However, the simultaneous stimulation with IL-3 and G-CSF induced the increase of CFU-C formation in patients with congenital neutropenia. Furthermore, CFU-C growth in both patients was supported when bone marrow cells were preincubated with IL-3 in liquid culture followed by the stimulation with G-CSF in semisolid agar culture. In contrast, that was not supported by the preincubation with G-CSF and the subsequent stimulation with IL-3. This evidence suggests that the hematopoietic progenitor cells in patients with congenital neutropenia have the potential for developing CFU-C in the combined stimulation with IL-3 and G-CSF, and that this growth may be dependent on the priming of IL-3 followed by the stimulation with G-CSF. The level of mature neutrophils in peripheral blood was not fully restored to normal levels by the daily administration of G-CSF in doses of 100 to 200 micrograms/m2 of body surface area for 20 to 25 days in both patients. These observations raise the possibility that the combination of IL-3 and G-CSF might have a potential role for the increase of neutrophil counts in patients with congenital neutropenia.


Critical land change information enhances the understanding of carbon balance in the United States.
Large-scale terrestrial carbon (C) estimating studies using methods such as atmospheric inversion, biogeochemical modeling, and field inventories have produced different results. The goal of this study was to integrate fine-scale processes including land use and land cover change into a large-scale ecosystem framework. We analyzed the terrestrial C budget of the conterminous United States from 1971 to 2015 at 1-km resolution using an enhanced dynamic global vegetation model and comprehensive land cover change data. Effects of atmospheric CO2 fertilization, nitrogen deposition, climate, wildland fire, harvest, and land use/land cover change (LUCC) were considered. We estimate annual C losses from cropland harvest, forest clearcut and thinning, fire, and LUCC were 436.8, 117.9, 10.5, and 10.4 TgC/year, respectively. C stored in ecosystems increased from 119,494 to 127,157 TgC between 1971 and 2015, indicating a mean annual net C sink of 170.3 TgC/year. Although ecosystem net primary production increased by approximately 12.3 TgC/year, most of it was offset by increased C loss from harvest and natural disturbance and increased ecosystem respiration related to forest aging. As a result, the strength of the overall ecosystem C sink did not increase over time. Our modeled results indicate the conterminous US C sink was about 30% smaller than previous modeling studies, but converged more closely with inventory data.


Atomic insights into the inhibition of R3 domain of tau protein by epigallocatechin gallate, quercetin and gallic acid.
Inhibiting tau protein aggregation has become a prospective avenue for the therapeutic development of tauopathies. The third microtubule-binding repeat (R3) domain of tau is confirmed as the most aggregation-favorable fragment of the whole protein. As dimerization is the first step of the aggregation of tau into amyloid fibrils, impeding the dimerization of the R3 domain is critical to prevent the full-length tau aggregation. Natural polyphenol small molecules epigallocatechin gallate (EGCG), quercetin (QE) and gallic acid (GA) are proven to inhibit the aggregation of the full-length recombinant tau (For EGCG and QE) or the R3 domain (For GA) of tau in vitro. However, the underlying molecular mechanisms of the inhibitive effects on the R3 domain of tau remain largely unknown. In this study, we conducted numerous all-atom molecular dynamics simulations on R3 dimers with and without EGCG, QE or GA, respectively. The results reveal that all three molecules can effectively decrease the β structure composition of the R3 dimer, induce the dimer to adopt loosely-packed conformations, and weaken interchain interactions, thus impeding the dimerization of the R3 peptide chains. The specific preferentially binding sites for the three molecules exhibit similarities and differences. Hydrophobic, π-π stacking and hydrogen-bonding interactions collectively drive EGCG, QE and GA respectively binding on the R3 dimer, while QE also binds with the dimer through cation-π interaction. Given the incurable nature of tauopathies hitherto, our research provides helpful knowledge for the development of drugs to treat tauopathies.


[Incidence of thyroid and cardiovascular diseases in menopausal females].
The purpose of the study was to estimate the incidence of thyroid dysfunction and cardiovascular diseases in perimenopausal females. The cross-sectional study covered 554 females (mean age 52.6±6.1 years). The levels of thyroid-stimulating hormone (TSH), total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL), and very low-density lipoproteins (VLDL), the incidence of arterial hypertension (AH), coronary heart disease, chronic heart failure, myocardial infarction, cerebral circulatory disorders, and the severity of menopausal syndrome (MS) were determined. The study detected euthyroldism in 381 (68.8%) patients, hypothyroidism in 168 (30.3%), out of them 35 (20.8%) patients having primary hypothyroidism, and hyperthyroidism in 5 (0.9%) females. Out of the 133 patients receiving L-thyroxine therapy, hypothyroidism was compensated. In 78(58.7%) cases, the dose of L-thyroxine was inadequate. The level of LDL was significantly higher in hypothyroidism; the median of TC was higher than the normal levels in both groups. There were no differences in the incidence of vascular disease between the groups. In both groups, AH was encountered In more than 60% of cases. The females with hypothyroidism had a more severe course of MS. With the adequate dose of L-thyroxine, the level of HDL was significantly higher and that of triglycerides and VLDL was lower than in hypothyroidism. It is expedient to include the measurement of TSH levels into the algorithm of examination of patients with severe MS.


Impact of Early Diabetic Ketoacidosis on the Developing Brain.
This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes. Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to <10 years, who participated in an observational study of the Diabetes Research in Children Network (DirecNet). Participants were grouped according to history of DKA severity (none/mild or moderate/severe). Each participant had unsedated MRI scans and cognitive testing at baseline and 18 months. In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry. The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group. When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants who had a history of moderate/severe DKA compared with none/mild DKA were observed to have significantly lower Full Scale Intelligence Quotient scores and cognitive performance on the Detectability and Commission subtests of the Conners' Continuous Performance Test II and the Dot Locations subtest of the Children's Memory Scale. A single episode of moderate/severe DKA in young children at diagnosis is associated with lower cognitive scores and altered brain growth. Further studies are needed to assess whether earlier diagnosis of type 1 diabetes and prevention of DKA may reduce the long-term effect of ketoacidosis on the developing brain.


Effect of electrical stunning frequency on meat quality, plasma parameters, and protein solubility of broilers.
This study was designed to compare the effects of different stunning frequencies of pulsed direct current on meat quality of broilers. This was achieved by investigating plasma parameters, blood loss, carcass damage, meat water-holding capacity, meat color, meat shear value, muscle pH, and protein solubility. A total of 400 broilers was divided into 5 treatment groups and stunned with 500, 600, 700, 800, and 900 Hz at 15 V for 10 seconds. Blood samples were collected immediately after cutting the neck. Pectoralis major muscles were removed from the carcass after chilling and placed in ice. Breast muscle pH and meat color were determined at both 2 and 24 h postmortem. Drip loss, cooking loss, pressing loss, and cooked breast meat-shear values were determined at 24 h postmortem. Treatment at 500 and 900 Hz significantly increased (P < 0.05) blood plasma corticosterone and lactate concentrations compared with the 700 Hz group. The wing damage of carcasses was significantly serious in the 500, 800, and 900 Hz groups. The Pectoralis minor damage of carcesses in the 700 Hz group was significantly lower (P < 0.05) compared to the other stunning groups. The pH at 2 h postmortem in the 500 and 900 Hz groups was significantly lower (P < 0.05) than in other groups. However, the final pH and meat color were not affected by stunning frequency. In the 500 and 900 Hz groups, the protein solubility and shear force values were significantly lower (P < 0.05) and drip loss was significantly higher (P < 0.05) than in the 700 Hz group. This study indicates that the waveform of the pulsed direct current is acceptable for stunning broilers at a stunning frequency of 700 Hz.


Communicative mind-reading in preverbal infants.
Pragmatic theories of communication assume that humans evolved a species-unique inferential capacity to express and recognize intentions via communicative actions. We show that 13-month-old non-verbal infants can interpret the turn-taking exchange of variable tone sequences between unfamiliar agents as indicative of communicative transfer of goal-relevant information from a knowledgeable to a naïve agent pursuing the goal. No such inference of information transfer was drawn by the infants, however, when a) the agents exchanged fully predictable identical signal sequences, which does not enable transmission of new information, or b) when no goal-relevant contextual change was observed that would motivate its communicative transmission. These results demonstrate that young infants can recognize communicative interactions between third-party agents and possess an evolved capacity for communicative mind-reading that enables them to infer what contextually relevant information has been transmitted between the agents even without language.


Mechanism of Aurora B activation by INCENP and inhibition by hesperadin.
Aurora family serine/threonine kinases control mitotic progression, and their deregulation is implicated in tumorigenesis. Aurora A and Aurora B, the best-characterized members of mammalian Aurora kinases, are approximately 60% identical but bind to unrelated activating subunits. The structure of the complex of Aurora A with the TPX2 activator has been reported previously. Here, we report the crystal structure of Aurora B in complex with the IN-box segment of the inner centromere protein (INCENP) activator and with the small molecule inhibitor Hesperadin. The Aurora B:INCENP complex is remarkably different from the Aurora A:TPX2 complex. INCENP forms a crown around the small lobe of Aurora B and induces the active conformation of the T loop allosterically. The structure represents an intermediate state of activation of Aurora B in which the Aurora B C-terminal segment stabilizes an open conformation of the catalytic cleft, and a critical ion pair in the kinase active site is impaired. Phosphorylation of two serines in the carboxyl terminus of INCENP generates the fully active kinase.


A 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2),Y Klinefelter variant with morbid obesity.
Klinefelter syndrome is the most common type of genetic cause of hypogonadism. This syndrome is characterized by the presence of 1 or more extra X chromosomes. Phenotype manifestations of this syndrome are small testes, fibrosis of the seminiferous tubules, inability to produce sperm, gynecomastia, tall stature, decrease of serum testosterone and increases of luteinizing hormone and follicle stimulating hormone. Most patients with Klinefelter syndrome are tall, with slender body compositions, and reports of obesity are rare. We report the case of a 35-yr-old man with hypogonadism and morbid obesity and diabetes mellitus. He had gynecomastia, small testes and penis, very sparse body hair and his body mass index was 44.85. He did not report experiencing broken voice and was able to have erections. We conducted a chromosome study. His genotype was 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2). In this case, the patient was diagnosed as Klinefelter syndrome. He showed rare phenotypes like morbid obesity and average height and the phenotype may be caused by the karyotype and the excess number of X chromosome. Further studies of the relationship between chromosomes and phenotype are warranted.


[Occupational differences in exposure to hazardous work conditions].
Few studies have been aimed at describing organizational and psychosocial conditions of the Italian workforce by occupational group, and they have been mainly conducted within specific occupations. The present study aimed at identifying specific groups of occupations which have unfavourable profiles from the point of view of exposure to specific organizational factors and psychosocial risks, and to physical, chemical and ergonomic risks, and analyzing their distribution by worker age. The analysis was conducted on a sample of 4,195 workers in the Piedmont Region who were members of the CGIL Trade Union (Italian General Confederation of Labour), who answered a self-administered questionnaire in 2000, aimed at assessing chemical, physical, and ergonomic risks, accidents, and psychosocial factors connected with work organization and work tasks. Psychosocial risks were assessed via three scales aimed at measuring the degree of control, psychophysical demands, and worker satisfaction. The proportion of workers exposed to the above mentioned risks was analysed according to occupational group. This group was then compared with all other groups taken together, according to prevalence of high strain condition (combination of high demand and low control) and HSUR condition (High Strain Unfairly Rewarded; combination of high strain and low satisfaction). Among males aged 25-44 years, restricted to the occupation groups with more than ten workers in high strain condition, significantly higher proportions of stress were observed in leather workers and shoemakers, paper factory workers, rubber workers, crane and bridge crane operators, plastic workers, painters, transport drivers and carpenters. For many of these groups, excesses were confirmed for the HSUR condition. Among subjects aged over 44 years, a higher risk for high strain was confirmed in rubber workers, transport drivers and carpenters. In addition, machine tool operators, assembly line and mechanical workers in this age group were exposed to higher risk of stress. In younger women there was a significantly higher risk of both high strain and HSUR conditions in workers employed in the rubber, plastic and the food industries, and in machine tool workers. Such excess risk was confirmed in the latter three categories also among older women. In general, the proportion of male workers classified as working in high strain conditions decreased as age increased, while in women it remained stable. The study allowed evaluation of the differential impact of exposure to physical, chemical, and psychosocial risk factors among occupational groups, thus contributing to the identification and classification of exhausting jobs. The results further showed, particularly among men, a smaller proportion of older workers, compared to younger ones, exposed to harmful physical, chemical, ergonomic and psychosocial conditions, indicating a possible propensity of companies to adapt workplace conditions, organization and internal mobility to worker age.


[The effectiveness of amantadine (midantan) in the treatment of the parkinsonian syndrome].
The author treated 83 patients with parkinsonism by analouges of amantadin--the Soviet preparation midantan and Swiss preparation simmetril. Twenty patients received only Amantadin and 63 Amantadin in combination with other antiparkinsonic drugs. Optimal doses of other antiparkinsonic drugs were determined prior to amantadin treatment. The preparation exerted a higher influence on such symptoms of parkinsonism as akinesis and rigidity and less on tremor. In 1/3 of the cases a positive effect of the treatment was temporary and disappeared altogether after 2--4 weeks despite the continuation of therapy. The preparation was well tolerated. Side effects observed in 32 of the 83 patients were usually expressed very midly and disappeared without special treatment. The author compares such preparations al 1-Dopa and Amantadin (Midantan).


Long-term care: a woman's world.
Long-term care is a world disproportionately comprised of women as consumers and as providers. Women comprise 75 percent of nursing home residents, 97 percent of professional caregivers, and the vast majority of family caregivers for elderly relatives at home. This article explores how and why long-term care, both in an institutional setting and home-based, is primarily utilized by women. The gender differences in the provision of care are also examined. The three key approaches to payment for long-term care (private payer, insurance, and Medicaid) are a focus with an emphasis on the role of Medicaid. Long-term care looms as an explosive issue and an accessible target for future program cutbacks. Since women are the predominant customers and providers of long-term care, this should be a priority issue for the feminist agenda.


Analysis of the creA gene, a regulator of carbon catabolite repression in Aspergillus nidulans.
The complete nucleotide sequence derived from a genomic clone and two cDNA clones of the creA gene of Aspergillus nidulans is presented. The gene contains no introns. The derived polypeptide of 415 amino acids contains two zinc fingers of the C2H2 class, frequent S(T)PXX motifs, and an alanine-rich region indicative of a DNA-binding repressor protein. The amino acid sequence of the zinc finger region has 84% similarity to the zinc finger region of Mig1, a protein involved in carbon catabolite repression in yeast cells, and it is related both to the mammalian Egr1 and Egr2 proteins and to the Wilms' tumor protein. A deletion removing the creA gene was obtained, by using in vitro techniques, in both a heterokaryon and a diploid strain but was unobtainable in a pure haploid condition. Evidence is presented suggesting that the phenotype of such a deletion, when not complemented by another creA allele, is leaky lethality allowing limited germination of the spore but not colony formation. This phenotype is far more extreme than that of any of the in vivo-generated mutations, and thus either the gene product may have an activator activity as well as a repressor function or some residual repressor function may be required for full viability.


Greater Proptosis Is Not Associated With Improved Compressive Optic Neuropathy in Thyroid Eye Disease.
Despite the paucity of supporting data, it has generally been held that proptosis in thyroid eye disease (TED) may provide relative protection from compressive optic neuropathy (CON) by producing spontaneous decompression. The objective of this study was to investigate this phenomenon in patients with bilateral TED-CON. We retrospectively reviewed the charts of 67 patients (134 orbits) with bilateral TED-CON at Columbia-Presbyterian Medical Center. Significant asymmetric proptosis (Hertel) was defined as ≥ 2 mm. Significant asymmetric CON was defined first, as the presence of an relative afferent pupillary defect. Those without an relative afferent pupillary defect were evaluated according to the TED-CON formula y = -0.69 - 0.31 × (motility) - 0.2 × (mean deviation) - 0.02 × (color vision) as previously established for the diagnosis of TED-CON. A difference in the formula result ≥ 1.0 between eyes was considered significant. Patients were then divided into 4 groups. Forty-one of 67 patients demonstrated asymmetric CON (29 by relative afferent pupillary defect, 12 by formula). Twenty-one of 67 patients demonstrated asymmetric proptosis. Only 5 of 12 (41.6%) of the patients who had both asymmetric proptosis and asymmetric CON (group 1) showed greater proptosis in the eye with less CON. Twenty-nine patients (group 2) showed that asymmetric CON occurred despite symmetrical proptosis. Seventeen patients (group 3), showed the inverse, that asymmetric differences in proptosis occurred with symmetrical CON. Despite commonly held assumptions, our results suggest that greater proptosis is not associated with improved TED-CON. Combining groups 1 to 3-all of which demonstrated asymmetry of either proptosis, CON, or both-91.4% of patients did not show a relationship between greater proptosis and improved CON.


Haematinic treatment of anaemia increases the risk of Plasmodium vivax malaria in pregnancy.
Nutritional deficiency and malaria are 2 major causes of anaemia during pregnancy in tropical areas. The relationship between anaemia, its treatment with iron and folate, and malaria was studied in a prospective cohort of 2112 pregnant Karen women on the north-western border of Thailand between 1993 and 1997. The development of Plasmodium vivax malaria was associated with a past mean haematocrit > 30% (hazard ratio = 1.5, 95% CI 1.2-2, P = 0.001) and recent (< or = 30 d) iron and folate supplementation (hazard ratio = 1.7, 95% CI 1.1-2.6, P = 0.01). There were no associations with P. falciparum infections. Plasmodium vivax has a predilection for young erythrocytes, and these results suggest that pregnant women with larger numbers of circulating young red cells are at greater risk of developing P. vivax malaria. In P. vivax-endemic areas, systematic iron and folate supplementation confers both benefit and risk in pregnancy.


Bending elasticity of vesicle membranes studied by Monte Carlo simulations of vesicle thermal shape fluctuations.
The membrane bending stiffness of nearly spherical lipid vesicles can be deduced from the analysis of their thermal shape fluctuations. The theoretical basis of this analysis [Milner and Safran, Phys. Rev. A: At., Mol., Opt. Phys., 1987, 36, 4371-4379] uses the mean field approximation. In this work we apply Monte Carlo simulations and estimate the error in the determination of the bending stiffness due to the approximations applied in the theory. It is less than 10%. The method presented in this work can also be used to determine the changes of the bending stiffness of biological membranes due to their chemical and/or structural modifications.


Outcome of osteoporosis evaluation, treatment, and follow-up in patients referred to a specialized outpatient clinic compared to patients in care of general practitioners.
In Denmark, osteoporosis treatment is either handled by general practitioners or at more resource demanding specialist clinics. We evaluated the treatment adherence and persistence in the two settings, which were overall similar. The type of medical support did, however, differ and was provided to two very different patient populations. The study aimed to investigate the effect of patient care by general practitioners (GPs) or specialists on treatment adherence among osteoporosis patients initiating treatment with oral bisphosphonates (OB). Dual-energy X-ray absorption (DXA)-scanning data from 2005 to 2013 were extracted. Treatment naïve patients with a T-score ≤ - 2.5 (spine or hip) were included. Information on medical treatment, comorbidities, and socio-economic status was extracted from Danish registries. Scanning results were evaluated by a specialist. Subsequent treatment initiation and follow-up was either handled by GPs or specialists: GP population (GPP) vs. specialist population (SP). Primary adherence was defined as treatment initiating within 12 months from diagnosis and secondary adherence as days with medicine possession rates (MPR) > 80%. Of 11,201 DXA-scanned patients, 3685 met the inclusion criteria (GPP = 2177, SP = 1508). The GPP consisted of relatively more men, was older, had shorter education, lower income, and more comorbidities. There was no difference in baseline T-score or prior incidence of major osteoporotic fractures (MOFs). The GPP was primarily treated with OB and had better primary adherence (adjusted ORGPP/SP = 1.52 [1.31-1.75], p < 0.0001) than the SP that to a higher degree received another treatment. Secondary adherence was similar (adjusted ORGPP/SP: OR12 months = 1.02 [0.83-1.26]; OR24 months = 0.90 [0.73-1.10]; OR4 years = 0.88 [0.71-1.07]; OR5 years = 0.91 [0.74-1.13]. Patients in care of specialists were most likely to receive a treatment other than OB. Primary adherence was highest in the GPP, whereas short- and long-term persistence was similar for up to 5 years whether treated by a specialist or a GP.


Corticostriatal Plasticity Established by Initial Learning Persists after Behavioral Reversal.
The neural mechanisms that allow animals to adapt their previously learned associations in response to changes in the environment remain poorly understood. To probe the synaptic mechanisms that mediate such adaptive behavior, we trained mice on an auditory-motor reversal task, and tracked changes in the strength of corticostriatal synapses associated with the formation of learned associations. Using a ChR2-based electrophysiological assay in acute striatal slices, we measured the strength of these synapses after animals learned to pair auditory stimuli with specific actions. Here, we report that the pattern of synaptic strength initially established by learning remains unchanged even when the task contingencies are reversed. Our findings reveal that synaptic changes associated with the initial acquisition of this task are not erased or overwritten, and that behavioral reversal of learned associations may recruit a separate neural circuit. These results suggest a more complex role of the striatum in regulating flexible behaviors where activity of striatal neurons may vary given the behavioral contexts of specific stimulus-action associations.


Use of ribonucleosides as protecting groups in synthesis of polynucleotides with phosphorylated terminals.
Two new protected 5'-ribonucleotides, 2'3'-O-bis(4,4'-dimethoxytrityl)uridine 5'-(4-chlorophenyl phosphate) and 2',3'-O-(methoxymethylene)uridine 5'-(4-chlorophenyl phosphate), form the basis of a chemical procedure for phosphorylating the 5'-ends of DNA fragments synthesized by the phosphotriester approach. Condensation of either of these mononucleotide units with the free 5'-hydroxyl of an otherwise fully protected oligomer results in high-yield formation of a 5'-5' triester linkage. Subsequently, the terminal ribonucleotide of the deprotected product rU5'-5'd(N-Nn-N) can be cleaved by periodate oxidation of its 2',3'-cis-hydroxyl system followed by beta-elimination, leaving its phosphate attached to the 5'-hydroxyl group of the oligodeoxyribonucleotide. This procedure together with a tactic employing a 2',3'-O-acylribonucleotide residue at the 3'-terminus of the chain allows the synthesis of oligomers possessing monophosphate groups at either end or both ends. Furthermore, oligonucleotide intermediates possessing a 5'-5'-linked uridine terminal are shown to have a special application as acceptors in RNA ligase reactions, where the presence of the ribonucleoside cap on the 5'-phosphate limits ligation specifically to the 3'-ends of the oligomers. Removal of the uridine residues to expose free 5'-phosphates would then enable the products to participate as donors in further elongation reactions.


Does N-terminal pro-brain natriuretic peptide correlate with measured shunt fraction in children with septal defects?
The aim of this study was to investigate the potential role of N-terminal pro-brain natriuretic peptide in the assessment of shunt severity and invasive haemodynamic parameters in children with atrial septal defects and ventricular septal defects. This is a prospective, controlled (n:62), observational study. Correlation analysis was performed between N-terminal pro-brain natriuretic peptide levels and various invasive haemodynamic measurements in 127 children (ventricular septal defect: 64; atrial septal defect: 63). A ratio of pulmonary to systemic blood flow (Qp/Qs⩾1.5) was considered to indicate a significant shunt. Statistically significant relationship was found between the mean N-terminal pro-brain natriuretic peptide values of the patients, with Qp/Qs⩾1.5 in both defect types and control group. For ventricular septal defect, N-terminal pro-brain natriuretic peptide level⩾113.5 pg/ml was associated with high specificity and sensitivity for determining the significant shunt. In addition, the cut-off point for determining the significant shunt for atrial septal defect was 57.9 pg/ml. Significant positive correlation was found between all invasive haemodynamic parameters and N-terminal pro-brain natriuretic peptide levels in patients with ventricular septal defects. Whereas significant positive correlation was found only between mean pulmonary artery pressure, right ventricular end-diastolic pressure, and systemic pressure to pulmonary pressure ratio and N-terminal pro-brain natriuretic peptide levels in patients with atrial septal defects. Our study demonstrated that the N-terminal pro-brain natriuretic peptide measurements could be used as a supporting parameter in determining significance of the shunt.


Linseed oil supplementation affects fatty acid desaturase 2, peroxisome proliferator activated receptor gamma, and insulin-like growth factor 1 gene expression in turkeys (Meleagris gallopavo).
Effects of linseed oil (LO) supplementation on the fat content and fatty acid profile of breast meat, and the expression of three genes in the liver, breast muscle and fat tissues of commercial 154-day-old hybrid male turkeys were investigated. The animals in the control group were fed a commercially available feed and received no LO supplementation (n = 70), whereas animals in the LO group (n = 70) were fed the same basic diet supplemented with LO (day 15 to 21, 0.5%; day 22 to 112, 1%). The effect of dietary LO supplementation on fatty acid composition of breast muscle was examined by gas chromatography, and the expression of fatty acid desaturase 2 (FADS2), peroxisome proliferator activated receptor gamma (PPARγ), and insulin-like growth factor 1 (IGF1) genes was analysed by means of quantitative reverse transcription polymerase chain reaction. The LO supplementation affected the fatty acid composition of breast muscle. Hepatic FADS2 levels were considerably lower (p<0.001), while adipose tissue expression was higher (p<0.05) in the control compared to the LO group. The PPARγ expression was lower (p<0.05), whereas IGF1 was higher (p<0.05) in the fat of control animals. There were no significant (p>0.05) differences in FADS2, PPARγ, and IGF1 gene expressions of breast muscle; however, omega-6/omega-3 ratio of breast muscle substantially decreased (p<0.001) in the LO group compared to control. Fatty acid composition of breast meat was positively influenced by LO supplementation without deterioration of fattening parameters. Remarkably, increased FADS2 expression in the liver of LO supplemented animals was associated with a significantly decreased omega-6/omega-3 ratio, providing a potentially healthier meat product for human consumption. Increased PPARγ expression in fat tissue of the LO group was not associated with fat content of muscle, whereas a decreased IGF1 expression in fat tissue was associated with a trend of decreasing fat content in muscle of the experimental LO group.


The incidence and prevalence of ankle sprain injury: a systematic review and meta-analysis of prospective epidemiological studies.
Ankle sprain is one of the most common musculoskeletal injuries, yet a contemporary review and meta-analysis of prospective epidemiological studies investigating ankle sprain does not exist. Our aim is to provide an up-to-date account of the incidence rate and prevalence period of ankle sprain injury unlimited by timeframe or context activity. We conducted a systematic review and meta-analyses of English articles using relevant computerised databases. Search terms included Medical Search Headings for the ankle joint, injury and epidemiology. The following inclusion criteria were used: the study must report epidemiology findings of injuries sustained in an observed sample; the study must report ankle sprain injury with either incidence rate or prevalence period among the surveyed sample, or provide sufficient data from which these figures could be calculated; the study design must be prospective. Independent extraction of articles was performed by two authors using pre-determined data fields. One-hundred and eighty-one prospective epidemiology studies from 144 separate papers were included. The average rating of all the included studies was 6.67/11, based on an adapted version of the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines for rating observational studies. 116 studies were considered high quality and 65 were considered low quality. The main findings of the meta-analysis demonstrated a higher incidence of ankle sprain in females compared with males (13.6 vs 6.94 per 1,000 exposures), in children compared with adolescents (2.85 vs 1.94 per 1,000 exposures) and adolescents compared with adults (1.94 vs 0.72 per 1,000 exposures). The sport category with the highest incidence of ankle sprain was indoor/court sports, with a cumulative incidence rate of 7 per 1,000 exposures or 1.37 per 1,000 athlete exposures and 4.9 per 1,000 h. Low-quality studies tended to underestimate the incidence of ankle sprain when compared with high-quality studies (0.54 vs 11.55 per 1,000 exposures). Ankle sprain prevalence period estimates were similar across sub-groups. Lateral ankle sprain was the most commonly observed type of ankle sprain. Females were at a higher risk of sustaining an ankle sprain compared with males and children compared with adolescents and adults, with indoor and court sports the highest risk activity. Studies at a greater risk of bias were more likely to underestimate the risk of ankle sprain. Participants were at a significantly higher risk of sustaining a lateral ankle sprain compared with syndesmotic and medial ankle sprains.


Development of calcium and secretory responses in the human promyelocytic leukemia cell line HL60.
We have begun to characterize the development of the excitation-response coupling sequence in the human promyelocytic leukemia cell line HL60. Using the recently developed fluorescent calcium probe quin-2, it was found that DMSO induced myeloid differentiation of the HL60 cells is accompanied by the development of a calcium response to the addition of the chemotactic factors fMet-Leu-Phe and leukotriene B4. The characteristics (time course, concentration dependence, stereospecificity, and metabolic dependence) of the calcium response are extremely similar to those previously described in human neutrophils. These results imply that functional receptors for leukotriene B4 appear in HL60 cells upon the induction of differentiation and also lend strong support to the use of these HL60 cells as a model of human myeloid differentiation. We have also characterized the emergence of a secretory response to fMet-Leu-Phe and leukotriene B4 in cytochalasin B treated HL60 cells. In addition, it is found that differentiation was required for the calcium ionophore A23187 to express its secretory activity toward the HL60 cells. This last set of results implies that differentiation is accompanied by the coordinated appearance of surface receptors and cytoplasmic factors required for the expression of cellular responsiveness.


Effects of temperature and salinity on Vibrio cholerae growth.
Laboratory microecosystems (microcosms) prepared with a chemically defined sea salt solution were used to study effects of selected environmental parameters on growth and activity of Vibrio cholerae. Growth responses under simulated estuarine conditions of 10 strains of V. cholerae, including clinical and environmental isolates as well as serovars O1 and non-O1, were compared, and all strains yielded populations of approximately the same final size. Effects of salinity and temperature on extended survival of V. cholerae demonstrated that, at an estuarine salinity (25%) and a temperature of 10 degrees C, V. cholerae survived (i.e., was culturable) for less than 4 days. Salinity was also found to influence activity, as measured by uptake of 14C-amino acids. Studies on the effect of selected ions on growth and activity of V. cholerae demonstrated that Na+ was required for growth. The results of this study further support the status of V. cholerae as an estuarine bacterium.


Racial differences in the relationship between number of cigarettes smoked and nicotine and carcinogen exposure.
Black smokers are reported to have higher lung cancer rates and greater tobacco dependence at lower levels of cigarette consumption compared to non-Hispanic White smokers. We studied the relationship between cigarettes per day (CPD) and biomarkers of nicotine and carcinogen exposure in Black and White smokers. In 128 Black and White smokers, we measured plasma nicotine and its main proximate metabolite cotinine, urine nicotine equivalents, 4-(methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites. The dose-response between CPD and nicotine equivalents, and NNAL and PAH was flat for Black but positive for White smokers (Race × CPD interaction, all ps < .05). Regression estimates for the Race × CPD interactions were 0.042 (95% CI 0.013-0.070), 0.054 (0.023-0.086), and 0.028 (0.004-0.052) for urine nicotine equivalents, NNAL, and PAHs, respectively. In contrast there was a strong correlation between nicotine equivalents and NNAL and PAH independent of race. Nicotine and carcinogen exposure per individual cigarette was inversely related to CPD. This inverse correlation was stronger in Black compared to White smokers and stronger in menthol compared to regular cigarette smokers (not mutually adjusted). Our data indicate that Blacks on average smoke cigarettes differently than White smokers such that CPD predicts smoke intake more poorly in Black than in White smokers.


Photocleavable peptide-DNA conjugates: synthesis and applications to DNA analysis using MALDI-MS.
The synthesis and characterization of photocleavable peptide-DNA conjugates is described along with their use as photocleavable mass marker (PCMM) hybridization probes for the detection of target DNA sequences by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. Three photocleavable peptide-DNA conjugates were synthesized, purified, and characterized using HPLC and denaturing gel electrophoresis, as well as IR-MALDI and UV-MALDI. The hybridization properties of the conjugates were also studied by monitoring their thermal denaturation with absorption spectroscopy. No significant difference in the melting temperature ( T (m)) of the duplexes was observed between the unmodified duplex and the duplex in which one strand was modified with the photocleavable peptide moiety. These conjugates were evaluated as hybridization probes for the detection of immobilized synthetic target DNAs using MALDI-MS. In these experiments, the DNA portion of the conjugate acts as a hybridization probe, whereas the peptide is photoreleased during the ionization/desorption step of UV-MALDI and can serve as a marker (mass tag) to identify a unique target DNA sequence. The method should be applicable to a wide variety of assays requiring highly multiplexed DNA/RNA analysis, including gene expression monitoring, genetic profiling and the detection of pathogens.


Prognostic value of the microRNA-214 in multiple human cancers: a meta-analysis of observational studies.
Previous studies showed that microRNA-214 (miR-214) may act as a prognostic biomarker of cancer. However, the available evidence is controversial. This study summarizes evidence and evaluates the prognostic role of miR-214 in various cancers. We carried out a systematic literature review and assessed the quality of included studies based on Oxford Centre for Evidence-based Medicine Criteria and Newcastle-Ottawa Scale (NOS). Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for overall survival (OS) and disease free survival/progressive free survival/recurrence free survival (DFS/PFS/RFS) were calculated to measure the effective value of miR-214 expression on prognosis. Thirteen studies were included in pooled analysis. We found that miR-214 was significantly correlated with OS (HR=2.21, 95%CI: 1.33-3.68, P=0.00), no significant difference was found with DFS/PFS/RFS (HR=1.73, 95%CI: 0.78-3.83, P=0.18) in various carcinomas. In subgroup analysis, higher expression of miR-214 was significantly associated with poor OS in Asians (HR=2.27, 95%CI: 1.09-4.73, P=0.00) and Caucasians (HR=2.04, 95%CI: 1.47-3.30, P=0.00). On the contrary, high miR-214 expression significantly predicted favorable DFS/PFS/RFS (HR=0.50, 95%CI: 0.31-0.82, P=0.00) in hepatocellular carcinoma (HCC) group. Our data indicates that high miR-214 could be a promising biomarker for prognosis prediction of cancer. However, further clinical studies are needed for the current insufficient relevant data.


Cross-linking of receptor-bound IgE to aggregates larger than dimers leads to rapid immobilization.
Controlled cross-linking of IgE-receptor complexes on the surface of rat basophilic leukemia cells and mast cells has allowed a comparison of the lateral mobility and cell triggering activity of monomers, dimers, and higher oligomers of receptors. Addition of a monoclonal anti-IgE(Fc) antibody to IgE-sensitized cells in stoichiometric amounts relative to IgE produces IgE-receptor dimers with high efficiency. These dimers are nearly as mobile as IgE-receptor monomers and trigger cellular degranulation poorly, but in the presence of 30% D2O, substantial immobilization of the dimers is seen and degranulation activity doubles. Addition of this monoclonal antibody in larger amounts results in the formation of larger oligomeric receptor clusters which are immobile and effectively trigger the cells. Thus, small receptor clusters that are active in stimulating degranulation are immobilized in a process that is not anticipated by simple hydrodynamic theories. Further experiments involving cross-linking of receptor-bound IgE by multivalent antigen demonstrate that immobilization of receptors occurs rapidly (less than 2 min) upon cross-linking and is fully and rapidly reversible by the addition of excess monovalent hapten. The rapidity and reversibility of the immobilization process are entirely consistent with the possibility that immobilization represents a recognition event between clustered receptors and cytoskeleton-associated components that plays an important role early in the cell triggering mechanism.


The effect of lithium on noradrenaline-induced cyclic AMP accumulation in rat brain: inhibition after chronic treatment and absence of supersensitivity.
Lithium (Li) has been reported to inhibit numerous adenylate cyclases, but often these reports used clinically toxic concentrations of Li and their relevance to a theory of Li action was questionable. The present report demonstrated Li inhibition beginning at 2 mM of the norepinephrine (NE)-induced cyclic AMP accumulation in a resuspended P2 pellet containing intact synaptosomes and in slices from rat cortex. The inhibition is demonstrable with isoproterenol as well and in the presence of a phosphodiesterase inhibitor. In cortical slices removed from rats treated for 21 days with therapeutically equivalent Li serum levels, NE-induced cyclic AMP accumulation is inhibited by over 70%. After cessation of 21 or 42 days of Li treatment, an enhancement of cyclic AMP accumulation to NE is not demonstrable. Rubidium and cesium do not inhibit NE-induced cyclic AMP accumulation. These ions cause an increase in basal cyclic AMP accumulation in the absence of NE, as does Li to a lesser degree. The effect of Li to inhibit NE-induced cyclic AMP accumulation is therefore specific to the Li ion, occurs at therapeutically equivalent concentrations, continues after chronic treatment and does not cause a compensatory supersensivity in the manner of the NE-receptor blocking drugs.


The Art and Science of Thyroid Surgery in the Age of Genomics: 100 years after Theodor Kocher.
Cancer is a disorder of the genome. The thyroid cancer genome is being decoded. Recent studies have identified a mutation or a genetic alteration in 95% of thyroid cancers. The National Cancer Institute initiated the Cancer Genome Atlas project in 2006 to catalogue genetic mutations associated with cancer, using genome sequencing and bioinformatics. The project has expanded to carry out genomic characterization and sequence analysis of thyroid cancer. The concept of risk stratification based on traditional parameters will soon vacate their role for clear molecular markers of non-invasive/focal, invasive/metastatic and systemic stages/phases of neoplastic disorder. A refined classification scheme based on genomics and its phenotypic expressions will accurately reflect the biologic differences between the different morphologic definitions we use today. Tumor differentiation/de-differentiation, and clinical behavior of an individual cancer will be defined by molecular markers, in addition to standard morpho-pathology. Empiricism in science of medicine and surgery has acquired a new method for testing the appropriate treatment for individual patients; that is molecular pathology, governed by genomics. The technology is present and rapidly evolving. The surgeons will determine the extent of interventions with molecular evidence and guidance.


The effects of heart rate on myocardial velocity and atrio-ventricular displacement during exercise with and without beta-blockade: a tissue Doppler echocardiographic study.
Colour tissue Doppler echocardiography (TDE) allows an objective assessment of regional myocardial function. Peak systolic velocity (PSV) and A-V plane displacement (AVPD) obtained from colour TDE correlate well with changes in cardiac wall motion and can discriminate ischemic areas during stress echocardiography. During exercise, the relationship between PSV and AVPD depends on several factors besides ischemia and should be considered when performing exercise stress echocardiography. To investigate the relation between PSV, AVPD and heart rate (HR) during semi-upright exercise with and without beta-blockade. Twelve healthy men underwent semi-upright exercise stress echocardiography with and without beta-blockade on two separate occasions. Standard echocardiographic projections were used for the stress echocardiography. Grey-scale echocardiographic pictures containing colour TDE information were obtained at rest and during a two-stage exercise test, and the images were analyzed off-line. The PSV and AVPD were measured at four points at the base of the left ventricle at the septum and lateral, inferior and anterior walls. PSV, AVPD and HR gradually increased during exercise. The increases in PSV and AVPD were linearly correlated with the increase in HR. The increases in PSV were significantly lower during exercise with beta-blockade than without beta-blockade (P<0.05). This was not observed in AVPD, as increments were not affected by beta-blockade. These data showing a relationship between HR and PSV, and a significantly lower PSV with beta-blockade at a given HR, suggest that PSV is influenced by HR and myocardial contractility, both of which are augmented by physical exercise-induced sympathetic stimulation.


Effects of intracoronary fentanyl on left ventricular mechanoenergetics in the excised cross-circulated canine heart.
It is still unclear whether fentanyl directly alters left ventricular (LV) contractility and oxygen consumption. This is because of the difficulty in defining and evaluating contractility and energy use independently of ventricular loading conditions and heart rate in beating whole hearts. This study was conducted to clarify the mechanoenergetic effects of intracoronary fentanyl in six excised cross-circulated canine hearts. The authors used the framework of the E(max) (a contractility index)-PVA (systolic pressure-volume area, a measure of total mechanical energy)-VO2 (myocardial oxygen consumption per beat) relationship practically independent of ventricular loading conditions. The authors measured LV pressure, volume, coronary flow, and arteriovenous oxygen content difference to calculate E(max), PVA, and VO2. They first obtained the VO2-PVA relationship for varied LV volumes at control E(max). The authors then obtained the VO2-PVA relationship at a constant LV volume, whereas coronary blood fentanyl concentration was increased in steps up to 240 ng/ml. Finally, they obtained the VO2-PVA relationship for varied LV volumes at the final dose of fentanyl. Fentanyl at any concentrations did not significantly change E(max), PVA, and VO2 from the control. The linear end-systolic pressure-volume relations and their slopes were virtually the same between the control and fentanyl volume loading in each heart. Further, either the slope (oxygen cost of PVA) or the VO2 intercept (unloaded VO2) of the linear VO2-PVA relationship remained unchanged by fentanyl. These results indicate that intracoronary fentanyl produces virtually no effects on LV mechanoenergetics for a wide range of its blood concentration.


Nano-in-Micro-Particles Consisting of PLGA Nanoparticles Embedded in Chitosan Microparticles via Spray-Drying Enhances Their Uptake in the Olfactory Mucosa.
Intranasal delivery has gained prominence since 1990, when the olfactory mucosa was recognized as the window to the brain and the central nervous system (CNS); this has enabled the direct site specific targeting of neurological diseases for the first time. Intranasal delivery is a promising route because general limitations, such as the blood-brain barrier (BBB) are circumvented. In the treatment of multiple sclerosis (MS) or Alzheimer's disease, for example, future treatment prospects include specialized particles as delivery vehicles. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are well known as promising delivery systems, especially in the area of nose-to-brain (N2B) delivery. Chitosan is also broadly known as a functional additive due to its ability to open tight junctions. In this study, we produced PLGA nanoparticles of different sizes and revealed for the first time their size-time-dependent uptake mechanism into the lamina propria of porcine olfactory mucosa. The intracellular uptake was observed for 80 and 175 nm within only 5 min after application to the epithelium. After 15 min, even 520 nm particles were detected, associated with nuclei. Especially the presence of only 520 nm particles in neuronal fibers is remarkable, implying transcellular and intracellular transport via the olfactory or the trigeminal nerve to the brain and the CNS. Additionally, we developed successfully specialized Nano-in-Micro particles (NiMPs) for the first time via spray drying, consisting of PLGA nanoparticles embedded into chitosan microparticles, characterized by high encapsulation efficiencies up to 51%, reproducible and uniform size distribution, as well as smooth surface. Application of NiMPs accelerated the uptake compared to purely applied PLGA nanoparticles. NiMPs were spread over the whole transverse section of the olfactory mucosa within 15 min. Faster uptake is attributed to additional paracellular transport, which was examined via tight-junction-opening. Furthermore, a separate chitosan penetration gradient of ∼150 µm caused by dissociation from PLGA nanoparticles was observed within 15 min in the lamina propria, which was demonstrated to be proportional to an immunoreactivity gradient of CD14. Due to the beneficial properties of the utilized chitosan-derivative, regarding molecular weight (150-300 kDa), degree of deacetylation (80%), and particle size (0.1-10 µm) we concluded that M2-macrophages herein initiated an anti-inflammatory reaction, which seems to already take place within 15 min following chitosan particle application. In conclusion, we demonstrated the possibility for PLGA nanoparticles, as well as for chitosan NiMPs, to take all three prominent intranasal delivery pathways to the brain and the CNS; namely transcellular, intracellular via neuronal cells, and paracellular transport.


Electrical tinnitus suppression (ETS) with a single channel cochlear implant.
Patients with intractable tinnitus in a dead ear were selected for electrical tinnitus suppression (ETS) first with a round window electrode inserted via the ear canal. Three patients have been selected for implantation with a UCH/RNID single channel extracochlear device to use with a sinusoidal tinnitus suppressor. We have also examined the effect of sinusoids on deafened implantees with tinnitus and conclude that tinnitus can be suppressed in some individuals with low frequency sine waves. Two patients are presented who have used cochlear implants to suppress their tinnitus for more than 18 months.


Early dialysis in acute kidney injury after cardiac surgery.
Acute kidney injury following cardiac surgery (AKICS) remains a frequent cause of major morbidity and mortality. The aim of this study was to examine the influence of timing of dialysis. A retrospective analysis of 3528 patients undergoing cardiac surgery between April 1995 and July 2006 was performed. In group 1 (April 1995-January 2000) intermittent haemodialysis was resorted to when other supportive measures failed. In group 2 (January 2000-July 2006) intermittent haemodialysis was commenced immediately when oliguria did not respond to fluid replacement or single-dose diuretics. In group 1, 49/1511 (3.2%) patients developed AKICS. Thirty-four patients did not receive dialysis and six patients died (18%). Of the remaining 15 patients who underwent dialysis, 13 died (87%). The overall mortality for group 1 AKICS patients was 19/49 (39%). In group 2, 87/2017 (4.3%) patients developed AKICS. Thirty-one patients did not require dialysis and none died. Of the 56 patients who were dialysed, 14 died (25%). During January 2005-July 2006, mortality following dialysis fell further to 17% (4/24). The overall mortality for group 2 patients developing AKICS was 14/87 (16%). Although the incidence of AKICS increased from 3.2% to 4.2%, earlier dialysis resulted in significantly improved survival (P=0.00001).


CD4 and CD8 T cells with high intracellular glutathione levels are selectively lost as the HIV infection progresses.
Maintenance of intracellular glutathione (GSH) levels has been implicated in blocking cytokine-stimulated HIV replication in vitro, in both acute and latent infection models. We demonstrate here that subsets of human peripheral blood mononuclear cells differ substantially in mean GSH levels, as measured on a cell-by-cell basis with the fluorescence-activated cell sorter (FACS): B cells have the lowest GSH levels; T cells are intermediate; and monocytes and macrophages have the highest levels. Furthermore, GSH levels subdivide the CD4 and CD8 T cell subsets into two classes each: high- and low-GSH cells, which cannot be distinguished by cell size or by currently known surface markers. Significantly, the high-GSH T cells are selectively depleted early during the HIV infection, and are effectively missing in all ARC and AIDS patients.


Survey of cancer incidence in Alaskan natives.
A survey of cancer incidence among Alaskan Natives for the 5-year period 1969--73 revealed fewer cases overall than expected in relation to rates in the United States. However, significantly increased risks were seen for certain sites: the nasopharynx in both sexes (with excesses over 15-fold), the liver in males, and the salivary glands, gallbladder, kidney, and thyroid in females. Compared with earlier reports, the observations suggested marked changes in cancer incidence among Alaskan Natives over the past two decades, with declines in esophageal and invasive cervical cancers, and increases in neoplasms of the lung, colon, and rectum.


Traumatic brain injury community case management: issues, impact and Hispanic orientation.
Community Case Management (or Case Management Services) is defined and distinguished from insurance, hospital, non-profit and independent case management. The areas of focus of Community Case Management - disseminating information, personal adjustment counseling and acting as a personal resource - are defined and explained. A Community Case Management services program is summarized and the results of community case management are documented. Case Management with the Hispanic population is discussed. Two case studies are presented, one for a young Hispanic man and the other for a young Anglo man. Suggestions for working with a Hispanic case load are discussed.


Correlates of deviance detection in auditory brainstem responses of bats.
Identifying unexpected acoustic inputs, which allows to react appropriately to new situations, is of major importance for animals. Neural deviance detection describes a change of neural response strength to a stimulus solely caused by the stimulus' probability of occurrence. In the present study, we searched for correlates of deviance detection in auditory brainstem responses obtained in anaesthetised bats (Carollia perspicillata). In an oddball paradigm, we used two pure tone stimuli that represented the main frequencies used by the animal during echolocation (60 kHz) and communication (20 kHz). For both stimuli, we could demonstrate significant differences of response strength between deviant and standard response in slow and fast components of the auditory brainstem response. The data suggest the presence of correlates of deviance detection in brain stations below the inferior colliculus (IC), at the level of the cochlea nucleus and lateral lemniscus. Additionally, our results suggest that deviance detection is mainly driven by repetition suppression in the echolocation frequency band, while in the communication band, a deviant-related enhancement of the response plays a more important role. This finding suggests a contextual dependence of the mechanisms underlying subcortical deviance detection. The present study demonstrates the value of auditory brainstem responses for studying deviance detection and suggests that auditory specialists, such as bats, use different frequency-specific strategies to ensure an appropriate sensation of unexpected sounds.


Astragaloside IV-induced BMSC exosomes promote neovascularization and protect cardiac function in myocardial infarction mice via the miR-411/HIF-1α axis.
This study focused on investigating the mechanism of the astragaloside IV-induced bone marrow mesenchymal stem cell exosome (AS-IV-MSC-exo)/microRNA(miR)-411/HIF-1α axis in affecting vascular neovascularization and protecting cardiac function in myocardial infarction (MI) mice. Exosomes (MSC-exo and AS-IV-MSC-exo) were separated by differential centrifugation and then characterized. MI mouse models were established by left anterior descending coronary artery ligation. Echocardiography was used to evaluate cardiac function. HE staining and Masson staining were performed to observe myocardial histopathology. Capillary density in the myocardium via immunohistochemistry and quantified the expression of vascular endothelial growth factor (VEGF) via RT-qPCR. The expression of miR-411 and HIF-1α was tested by RT-qPCR and western blot and the targeting relationship of miR-411 and HIF-1α was verified by bioinformatics website and dual luciferase reporter gene assay. Exosomes with lipid bi-layer membrane structure, expressing exosomal surface marker proteins, and being taken up by cardiomyocytes could be successfully isolated utilizing ultracentrifugation. Intramyocardial injection of MSC-exo could restore cardiac function, decrease myocardial pathological changes and collagen deposition, and promote neovascularization in MI mice; the effect of AS-IV-MSC-exo was more significant. The ability of AS-IV-MSC-exo to restore cardiac function, lower myocardial pathological changes and collagen deposition, and promote neovascularization in MI mice was diminished when miR-411 expression in AS-IV-MSC-exo was reduced. Mechanistically, miR-411 was found to target and inhibit HIF-1α expression. Overexpression of HIF-1α impaired the impact of AS-IV-MSC-exo on improving cardiac function and promoting neovascularization in MI mice. AS-IV-MSC-exo improves cardiac function and promoted neovascularization via the miR-411/HIF-1α axis, thereby ameliorating MI.


Impact of mono(2-ethylhexyl) phthalate (MEHP) on the development of mouse embryo in vitro.
Mono(2-ethylhexyl) phthalate (MEHP) is the most studied metabolite of di(2-ethylhexyl) phthalate (DEHP), a phthalate found in cosmetics, flooring, paints, and plastics products, including toys and medical tubing. Humans are frequently exposed to this compound due to its ubiquitous presence in our environment. DEHP and MEHP are known to be endocrine-disrupting chemicals and exposure levels have been associated to decreased reproductive success. However, few studies have focused on the direct effects of MEHP on embryos. The present study investigated effects of MEHP (0.1, 1, 10, 100 and 1000 µM) on mice preimplantation embryonic development, evaluating percentage of blastocyst formation, hatching from zona pellucida, methylation-related genes, cell lineage commitment, micronucleation, and adherens junction marker at different stages of development during in vitro culture for 6 days. We show MEHP negatively impacts embryo competence by reducing blastocyst formation and hatching at 100 and 1000 µM. In addition, 100 µM MEHP increases the expression of Tet3 gene in blastocysts, which is related to a reduction of DNA methylation, an important mechanism regulating gene expression. Exposed embryos that completed the hatching process in groups 0.1, 1 and 10 µM MEHP had similar number of inner cell mass and trophectoderm cells compared to the control, while micronucleation occurrence and E-cadherin expression was not affected in exposed morulae by MEHP at 10 or 100 µM. Our results showed that high concentrations of MEHP can negatively impact embryo development. New studies unveiling the mechanism of toxicity involved and encompassing further developmental stages are warranted for further understanding.


Radiodefluorination of 3-fluoro-5-(2-(2-[18F](fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile ([18F]SP203), a radioligand for imaging brain metabotropic glutamate subtype-5 receptors with positron emission tomography, occurs by glutathionylation in rat brain.
Metabotropic glutamate subtype-5 receptors (mGluR5) are implicated in several neuropsychiatric disorders. Positron emission tomography (PET) with a suitable radioligand may enable monitoring of regional brain mGluR5 density before and during treatments. We have developed a new radioligand, 3-fluoro-5-(2-(2-[(18)F](fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile ([(18)F]SP203), for imaging brain mGluR5 in monkey and human. In monkey, radioactivity was observed in bone, showing release of [(18)F]-fluoride ion from [(18)F]SP203. This defluorination was not inhibited by disulfiram, a potent inhibitor of CYP2E1. PET confirmed bone uptake of radioactivity and therefore defluorination of [(18)F]SP203 in rats. To understand the biochemical basis for defluorination, we administered [(18)F]SP203 plus SP203 in rats for ex vivo analysis of metabolites. Radio-high-performance liquid chromatography detected [(18)F]fluoride ion as a major radiometabolite in both brain extract and urine. Incubation of [(18)F]SP203 with brain homogenate also generated this radiometabolite, whereas no metabolism was detected in whole blood in vitro. Liquid chromatography-mass spectrometry analysis of the brain extract detected m/z 548 and 404 ions, assignable to the [M + H](+) of S-glutathione (SP203Glu) and N-acetyl-S-l-cysteine (SP203Nac) conjugates of SP203, respectively. In urine, only the [M + H](+) of SP203Nac was detected. Mass spectrometry/mass spectrometry and multi-stage mass spectrometry analyses of each metabolite yielded product ions consistent with its proposed structure, including the former fluoromethyl group as the site of conjugation. Metabolite structures were confirmed by similar analyses of SP203Glu and SP203Nac, prepared by glutathione S-transferase reaction and chemical synthesis, respectively. Thus, glutathionylation at the 2-fluoromethyl group is responsible for the radiodefluorination of [(18)F]SP203 in rat. This study provides the first demonstration of glutathione-promoted radiodefluorination of a PET radioligand.


[Contribution to the study of the cervical lymphatic system of the young and adult white rats (Rattus norvegicus). II (author's transl)].
This report is based upon microdissections of 30 young white rats and 21 adults, of both sexes, in which it was studied the morphology of cervical lymphatic system performed by injection of submandibular and deep cervical nodes with latex-neoprene colored. It was verified that: there are no differences between the lymph nodes of young and adult rats: the presence of a submandibular chain with variable number of lymph nodes; this chain give efferent lymphatic branches to the deep cervical lymph nodes; the presence of 2 groups of deep cervical lymph nodes, one caudal and other cranial; those lymph nodes give efferent branches which are going to form the deep jugular trunk, the join to the jugulo-subclavian angle; the jugular trunk may go to joing to branches coming from the thoracic limb, from the thorax cavity and branches which go along the external jugular vein and omocervical vein.


Melaleuca oil poisoning in a 17-month-old.
Ingestion of significant quantities of Melaleuca oil or Australian tea tree oil has been described only once in the medical literature. This report describes a 17-mo-old male who ingested less than 10 ml of the oil and developed ataxia and drowsiness. Emergency physicians, poison control personnel and pediatricians should be aware of potential toxicity from this product.


Expression of enzymes and key regulators of lipid synthesis is upregulated in adipose tissue during CLA-induced milk fat depression in dairy cows.
Milk fat depression (MFD) is a naturally occurring condition in dairy cows where milk fat synthesis is inhibited by intermediates of ruminal biohydrogenation. One of these bioactive fatty acids (FA), trans-10, cis-12 conjugated linoleic acid (CLA), decreases milk fat synthesis through transcriptional downregulation of genes involved in mammary lipid synthesis. Energy partitioning during MFD is not well characterized because of the complexity of observing energy metabolism in ruminant animals. To investigate energy partitioning during MFD, adipose tissue biopsies were taken from 4 cows arranged in a switchback design. Treatments were control and 4-d abomasal infusion of trans-10, cis-12 CLA (7.5 g/d). CLA decreased milk fat yield by 38% and milk fat content by 34%, but yields of milk and other milk components were unchanged. In contrast to reported changes in mammary tissue, adipose tissue expression of lipid synthesis enzymes, including lipoprotein lipase, FA synthase, stearoyl-CoA desaturase, and FA binding protein 4, was increased. Expression of regulators of lipid synthesis, including sterol-response element binding protein 1, thyroid hormone responsive spot 14, and PPARgamma, also increased in adipose tissue. Thus, a CLA dose resulting in near maximal inhibition of mammary lipid synthesis resulted in increased expression of lipid synthesis-related genes in adipose tissue. A meta-analysis of intake response during CLA infusion was conducted to extend the investigation of energy metabolism during MFD. Voluntary intake decreased (P < 0.001) by 1.5 kg/d during CLA-induced MFD in the 14 studies analyzed, but the reduction in intake only partially accounts for the energy spared from reduced milk fat synthesis. Results are consistent with energy spared from the reduction in milk fat synthesis being partitioned toward adipose tissue fat stores during short-term MFD.


Carbon-Dot/Silver-Nanoparticle Flexible SERS-Active Films.
Development of effective platforms for surface enhanced Raman scattering (SERS) sensing has mostly focused on fabrication of colloidal metal surfaces and tuning of their surface morphologies, designed to create "hot spots" in which plasmonic fields yield enhanced SERS signals. We fabricated distinctive SERS-active flexible films comprising polydimethylsiloxane (PDMS) embedding carbon dots (C-dots) and coated with silver nano-particles (Ag NPs). We show that the polymer-associated Ag NPs and C-dots intimately affected the physical properties of each other. In particular, the C-dot-Ag-NP-polymer films exhibited SERS properties upon deposition of versatile targets, both conventional SERS-active dyes as well as bacterial samples. We show that the SERS response was correlated to the formation C-dots within the polymer film and the physical proximity between the C-dots and Ag NPs, indicating that coupling between the plasmonic fields of the Ag NPs and C-dots' excitons constituted a prominent factor in the SERS properties.


Enhancing cognitive function in chronic TBI: The Role of α7 nicotinic acetylcholine receptor modulation.
Traumatic brain injury (TBI) results in several pathological changes within the hippocampus that result in adverse effects on learning and memory. Therapeutic strategies to enhance learning and memory after TBI are still in the early stages of clinical development. One strategy is to target the α7 nicotinic acetylcholine receptor (nAChR), which is highly expressed in the hippocampus and contributes to the formation of long-term memory. In our previous study, we found that AVL-3288, a positive allosteric modulator of the α7 nAChR, improved cognitive recovery in rats after moderate fluid-percussion injury (FPI). However, whether AVL-3288 improved cognitive recovery specifically through the α7 nAChR was not definitively determined. In this study we utilized Chrna7 knockout mice and compared their recovery to wild-type mice treated with AVL-3288 after TBI. We hypothesized that AVL-3288 treatment would improve learning and memory in wild-type mice, but not Chrna7-/- mice after TBI. Adult male C57BL/6 wild-type and Chrna7-/- mice received sham surgery or moderate controlled cortical impact (CCI) and recovered for 3 months. Mice were then treated with vehicle or AVL-3288 at 30 min prior to contextual fear conditioning. At 3 months after CCI, expression of α7 nAChR, choline acetyltransferase (ChAT), high-affinity choline transporter (ChT), and vesicular acetylcholine transporter (VAChT) were found to be significantly decreased in the hippocampus. Treatment of wild-type mice at 3 months after CCI with AVL-3288 significantly improved cue and contextual fear conditioning, whereas no beneficial effects were observed in Chrna7-/- mice. Parietal cortex and hippocampal atrophy were not improved with AVL-3288 treatment in either wild-type or Chrna7-/- mice. Our results indicate that AVL-3288 improves cognition during the chronic recovery phase of TBI through modulation of the α7 nAChR.


Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries.
Chronic hypoxia (CH) activates the Ca(2+)-dependent transcription factor nuclear factor of activated T cells isoform c3 (NFATc3) in mouse pulmonary arteries. However, the mechanism of this response has not been explored. Since we have demonstrated that NFATc3 is required for CH-induced pulmonary arterial remodeling, establishing how CH activates NFATc3 is physiologically significant. The goal of this study was to test the hypothesis that endothelin-1 (ET-1) contributes to CH-induced NFATc3 activation. We propose that this mechanism requires increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca(2+) concentration ([Ca(2+)](i)) and stimulation of RhoA/Rho kinase (ROK), leading to calcineurin activation and actin cytoskeleton polymerization, respectively. We found that: 1) CH increases pulmonary arterial pre-pro-ET-1 mRNA expression and lung RhoA activity; 2) inhibition of ET receptors, calcineurin, L-type Ca(2+) channels, and ROK blunts CH-induced NFATc3 activation in isolated intrapulmonary arteries from NFAT-luciferase reporter mice; and 3) both ET-1-induced NFATc3 activation in isolated mouse pulmonary arteries ex vivo and ET-1-induced NFATc3-green fluorescence protein nuclear import in human PASMC depend on ROK and actin polymerization. This study suggests that CH increases ET-1 expression, thereby elevating PASMC [Ca(2+)](i) and RhoA/ROK activity. As previously demonstrated, elevated [Ca(2+)](i) is required to activate calcineurin, which dephosphorylates NFATc3, allowing its nuclear import. Here, we demonstrate that ROK increases actin polymerization, thus providing structural support for NFATc3 nuclear transport.


Synergistically Boosting the Circularly Polarized Luminescence of Functionalized Pillar[5]arenes by Polymerization and Aggregation.
Supramolecular polymers based on chiral macrocycles have attracted increasing attention in the field of circularly polarized luminescence (CPL) owing to their unique properties. However, the construction of macrocyclic supramolecular polymers with highly efficient CPL properties in aggregate states still remains challenging. Herein, w e constructed a class of macrocycle-based coordination polymers by combining the planar chiral properties of pillar[5]arene with the excellent fluorescence properties of aggregation-induced emission luminogens. The formation of polymers enhances both the fluorescence and chiral properties, resulting in chiral supramolecular polymers with remarkable CPL properties. Increasing the aggregation degree of the polymers can further improve their CPL properties, as evidenced by a 21-fold increase in the dissymmetry factor and an over 25-fold increase in the fluorescence quantum yield in the aggregate state compared to the solution state. Such a synergistic effect of polymerization- and aggregation-enhanced CPL can be explained by the restriction of intramolecular motions and aggregation-induced conformation confinement. This work provides a promising method for developing highly efficient CPL supramolecular polymers.


Numerical analysis of cardiopulmonary blood volumes in 113In(m) radiocardiography.
A theory of streamline flow of a viscous liquid was applied to the calculation of cardiac and pulmonary parameters (minute volume, stroke volume, right heart, pulmonary and left heart blood volumes) in a radiocardiographic model based on the modified gamma function. The practical feasibility of the formulations was tested using a physical flow model. The cardiopulmonary blood volumes measured from 14 normal subjects were consistent with the results obtained by more complex techniques. The present method is manageable on a small computer and is well suited to clinical routine use in connection with standard single detector 113In(m) radiocardiography.


Catalytic cracking of Etek lignin with zirconia supported metal-oxides for alkyl and alkoxy phenols recovery.
Alkyl and alkoxy phenols are desirable products from the catalytic depolymerisation of lignin. In this work, ex-situ catalytic pyrolysis of Etek lignin in presence of Na, Ce, NiCe, MgCe, Fe and FePd on ZrO2 was studied. The largest combined yield of monomeric phenolics and alkylphenols was produced by Na/ZrO2 catalysts. A parametric study of the most promising Na/ZrO2 then resulted in using a catalyst:lignin ratio of 3:1 at 500 °C as the best option, enhancing at 17.5 wt% the recovery of total phenolics including 6 wt% alkyl phenols, which is equivalent to 27.8 wt% and 9.5 wt% of the starting lignin in Etek lignin waste. The study of the catalyst basicity indicates that the mild basicity of Na/ZrO2 was mostly responsible for the enhanced mono phenols recovery. Due to formation of thermally stable Na2CO3 during pyrolysis, successful Na/ZrO2 regeneration requires temperature of 900 °C or higher.


The same genotype of Sarcocystis neurona responsible for mass mortality in marine mammals induced a clinical outbreak in raccoons (Procyon lotor) 10 years later.
Here, we report the first known outbreak of clinical protozoal myeloencephalitis in naturally infected raccoons by the parasite Sarcocystis neurona. The North American opossum (Didelphis virginiana) and the South American opossum (Didelphis albiventris) are its known definitive hosts. Several other animal species are its intermediate or aberrant hosts. The raccoon (Procyon lotor) is considered the most important intermediate host for S. neurona in the USA. More than 50% of raccoons in the USA have sarcocysts in their muscles, however clinical sarcocystosis in raccoons is rare. In 2014, 38 free-living raccoons were found dead or moribund on the grounds of the Saint Louis Zoo, Missouri, USA. Moribund individuals were weak, lethargic, and mildly ataxic; several with oculo-nasal discharge. Seven raccoons were found dead and 31 were humanely euthanized. Postmortem examinations were conducted on nine raccoons. Neural lesions compatible with acute sarcocystosis were detected in eight raccoons. The predominant lesions were meningoencephalitis and perivascular mononuclear cells. Histologic evidence for the Canine Distemper Virus was found in one raccoon. Schizonts and merozoites were present in the encephalitic lesions of four raccoons. Mature sarcocysts were present within myocytes of five raccoons. In six raccoons, S. neurona schizonts and merozoites were confirmed by immunohistochemical staining with S. neurona-specific polyclonal antibodies. Viable S. neurona was isolated from the brains of two raccoons by bioassay in interferon gamma gene knockout mice and in cell cultures seeded directly with raccoon brain homogenate. Molecular characterization was based on raccoon no. 68. Molecular characterization based on multi-locus typing at five surface antigens (SnSAG1-5-6, SnSAG3 and SnSAG4) and the ITS-1 marker within the ssrRNA locus, using DNA isolated from bradyzoites released from sarcocysts in a naturally infected raccoon (no. 68), confirmed the presence of S. neurona antigen type I, the same genotype that caused a mass mortality event in which 40 southern sea otters stranded dead or dying within a 3 week period in April 2004 with S. neurona-associated disease. An expanded set of genotyping markers was next applied. This study reports the following new genotyping markers at 18S rRNA, 28S rRNA, COX1, ITS-1, RON1, RON2, GAPDH1, ROP20, SAG2, SnSRS21 and TUBA1 markers. The identity of Sarcocystis spp. infecting raccoons is discussed.


Autonomic function tests: some clinical applications.
Modern autonomic function tests can non-invasively evaluate the severity and distribution of autonomic failure. They have sufficient sensitivity to detect even subclinical dysautonomia. Standard laboratory testing evaluates cardiovagal, sudomotor and adrenergic autonomic functions. Cardiovagal function is typically evaluated by testing heart rate response to deep breathing at a defined rate and to the Valsalva maneuver. Sudomotor function can be evaluated with the quantitative sudomotor axon reflex test and the thermoregulatory sweat test. Adrenergic function is evaluated by the blood pressure and heart rate responses to the Valsalva maneuver and to head-up tilt. Tests are useful in defining the presence of autonomic failure, their natural history, and response to treatment. They can also define patterns of dysautonomia that are useful in helping the clinician diagnose certain autonomic conditions. For example, the tests are useful in the diagnosis of the autonomic neuropathies and distal small fiber neuropathy. The autonomic neuropathies (such as those due to diabetes or amyloidosis) are characterized by severe generalized autonomic failure. Distal small fiber neuropathy is characterized by an absence of autonomic failure except for distal sudomotor failure. Selective autonomic failure (which only one system is affected) can be diagnosed by autonomic testing. An example is chronic idiopathic anhidrosis, where only sudomotor function is affected. Among the synucleinopathies, autonomic function tests can distinguish Parkinson's disease (PD) from multiple system atrophy (MSA). There is a gradation of autonomic failure. PD is characterized by mild autonomic failure and a length-dependent pattern of sudomotor involvement. MSA and pure autonomic failure have severe generalized autonomic failure while DLB is intermediate.


Alterations and abnormal expression of A20 in peripheral monocyte subtypes in patients with rheumatoid arthritis.
As the precursors of macrophages and osteoclasts, monocytes play an important role in the pathogenesis of rheumatoid arthritis (RA). Since the deficiency of zinc-finger protein A20 in myeloid cells triggers erosive polyarthritis resembling RA, A20 in monocytes may play a protective role in RA. In the present study, we aimed to investigate the abnormality of monocyte subtypes and the expression of zinc-finger protein A20 in RA. Peripheral blood mononuclear cells and clinical data were collected from RA patients and healthy controls (HCs). Monocyte subtypes and A20 expression were determined through flow cytometry and compared between the two groups. Correlations between monocyte subtypes, A20 expression, and clinical data were analyzed. A total of 43 RA patients and 23 HCs were included in the present study. RA patients had higher absolute monocyte counts (p < 0.001) in the peripheral blood. The proportions and counts of intermediate monocytes (IMs) (both p < 0.001) and non-classical monocytes (NCMs) were higher (both p < 0.001) in RA patients. The expression of A20 in IMs (p < 0.001) was lower in RA patients compared with that in the HCs. Furthermore, the expression of A20 in IMs was negatively correlated with the anti-cyclic citrullinated peptide (CCP) antibody level in RA patients (r = - 0.409, p = 0.01). The expression of A20 in NCMs was positively correlated with modified total Sharp score (mTSS) in RA patients (r = 0.471, p = 0.02). Collectively, we proved that IMs and NCMs were increased in RA patients, suggesting that they played a suggestive role in the pathogenesis of RA. Furthermore, the downregulation of A20 in IMs might be correlated with anti-CCP antibody production. The A20 expression in NCMs might affect bone erosion in RA. Key Points • IMs and NCMs were increased in the peripheral blood of RA patients, suggesting their pathogenic role in RA. • The decreased expression of zinc-finger protein A20 in IMs of RA patients suggested the protective role of A20 in RA. • The negative correlation between the A20 expression in IMs and anti-CCP antibody revealed that A20 in IMs might be related to the formation of anti-CCP antibodies. • The positive correlation between the A20 expression in NCMs and mTSS revealed that A20 in NCMs might affect the bone erosion in RA.


Comparative analysis of gut bacteria of silkworm Bombyx mori L. on exposure to temperature through 16S rRNA high throughput metagenomic sequencing.
Global warming is one of the serious threats that adversely affects the development and reproduction of silkworms. The ideal temperature for silkworms to carryout normal life activities is 20-30 °C. Certain bivoltine silkworms that are raised in tropical regions are thermotolerant. But, prolonged exposure to high temperatures may be fatal. In the present study, fifth instar larvae of bivoltine silkworm were exposed to heat shock at 40 ± 2 °C for a short period of one hour per day to examine the changes in the gut microflora. The study used high throughput sequencing to evaluate the impact of intestinal microbes of silkworms in response to high temperature. The findings demonstrated that elevated temperature has a negative impact on the intestinal microbes of silkworm compared to the control which were reared under the optimum temperature (25 ± 3° C). Four hundred and fifty eight (458) species of microbes were reported in the control group whereas only 434 species were reported in the temperature exposed group. The digestive process of silkworms may also be impaired by heat shock due to their effect on digestive enzymes. So, the results indicated that heat shock has an impact on the intestinal microflora of silkworms that control the activity of associated digestive enzymes which affects the digestion and nutritional intake, eventually impacting the growth and development of silkworm larvae and cocoons produced. The morphometric parameters of silkworm larvae and cocoons also showed a considerable drop when exposed to heat shock.


Effect of cocoa extract supplementation on cognitive function: results from the clinic subcohort of the COSMOS trial.
Some prior randomized clinical trials (RCTs) that tested the effects of cocoa extract (CE), a source of flavanols, on late-life cognition have yielded promising findings. A long-term RCT using in-person neuropsychological tests covering multiple cognitive domains may clarify the cognitive effects of CE. To test whether daily supplementation with CE, compared with placebo, produces better cognitive change over 2 y. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a 2 × 2 factorial RCT of CE [500 mg flavanols/d, including 80 mg (-)-epicatechin] and/or a daily multivitamin-mineral supplement for cardiovascular disease and cancer prevention among 21,442 United States adults aged ≥60 y. There were 573 participants in the clinic subcohort of COSMOS (that is, COSMOS-Clinic) who completed all cognitive tests at baseline; of these, 492 completed 2-y follow-up assessments. The primary outcome was global cognition (averaging z-scores across 11 tests). Secondary outcomes were episodic memory and executive function/attention. Repeated measures models were used to compare randomized groups. Participants' mean age (standard deviation) was 69.6 (5.3); 49.2% were females. Daily supplementation with CE, compared with placebo, had no significant effect on 2-y change in global cognition {mean difference [95% confidence interval (CI)]: -0.01 (-0.08, 0.05) standard deviation units (SU)}. CE, compared with placebo, had no significant effects on 2-y change in episodic memory [mean difference (95% CI): -0.01 (-0.13, 0.10) SU] or executive function/attention [mean difference (95% CI): 0.003 (-0.07, 0.08) SU]. Subgroup analyses uncorrected for multiple-testing suggested cognitive benefits of CE supplementation, compared with placebo among those with poorer baseline diet quality. Among 573 older adults who underwent repeat in-person, detailed neuropsychological assessments over 2 y, daily CE supplementation, compared with placebo, showed no overall benefits for global or domain-specific cognitive function. Possible cognitive benefits of CE among those with poorer diet quality warrant further study. This trial was registered at clinicaltrials.gov with identifier - NCT02422745.


General practitioners' views on perceived and actual gains, benefits and barriers associated with the implementation of an Australian health assessment for people with intellectual disability.
Health assessments for people with intellectual disability have been implemented in the UK, New Zealand and Australia, and have led to improved health outcomes. The Comprehensive Health Assessment Program (CHAP) has been shown to improve the health of people with intellectual disability. Similar to other health assessments, it is designed to address healthcare needs, many of which are often overlooked in this population, through better communication between the general practitioner (GP), support worker and the person with intellectual disability. This study investigates GP views of the perceived and actual benefits, gains and barriers associated with its uptake and use in practice. As part of a larger randomised controlled trial of the CHAP, 46 GPs in Queensland, Australia, completed two telephone interviews that included open-ended questions about their perceptions of the health assessment. The GPs were enrolled in the intervention arm of the trial. Interviews took place at commencement and conclusion of the trial to gain the views of GPs as they experienced using the CHAP. Thematic analysis was used to identify key themes and patterns from the GP responses. Four themes were identified: better healthcare and uncertain benefits captured GP perceptions of the potential gains associated with use of the CHAP, while two further themes, organisational barriers in the general practice setting and engagement across the healthcare triad highlighted strengths and barriers related to implementation. Anticipated concerns about time raised by GPs at commencement of the trial were borne out in practice, but concerns about communication and cooperation of people with disabilities were not. Matters associated with support worker engagement emerged as an area of concern. GPs perceive the CHAP as a structured and comprehensive approach to the detection of medical problems as well as an aid in overcoming communication barriers between the doctor and the person with disability. Our findings suggest that some GPs may find it difficult to predict the benefits of using health assessments such as the CHAP. Achieving optimal uptake is likely to require attention at policy and systems levels to address: GP time constraints in providing healthcare to this population; enhancement of support worker training and organisational structures to encourage comprehensive health assessment and follow-up activities; and GP awareness of the improved health outcomes shown to derive from the use of comprehensive health assessments.


Ontological engineering for the definition of a COVID-19 pandemic ontology.
COVID-19 has generated a lot of information in different formats, and one of them is in the ontology format. Also, there are previous ontologies from other disciplines that can help to analyze the COVID-19 pandemic. Thus, due to the large quantity of COVID-19 information in the form of ontologies, approaches to ontology integration and interoperability could be beneficial. In this context, this research proposes a new ontology, called COVID-19 Pandemic ontology, which is the product of an ontological engineering process proposed in this research that allows the integration of several ontologies to cover all the aspects of this infectious disease. The ontological engineering process defines tasks of fusion, alignment, and linking for integrating the ontologies. The resulting pandemic ontology provides a simple repository for storing information about the COVID-19, reusing existing ontologies, to offer multiple views about the disease, including the social context. This ontology has been tested in different case studies to prove its capabilities to infer useful information about the COVID-19 pandemic.


Scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells.
Malignant gliomas are characterized by rapid growth, infiltration of normal brain tissue, and high levels of tumor-associated angiogenesis. The genetic and local environmental tissue factors responsible for the malignant progression from low to high grade gliomas and the highly malignant behavior of glioblastomas are not well understood. In a study of 77 human brain tissue extracts, high grade (III-IV) tumors had significantly greater scatter factor (SF) content than did low grade tumors or non-neoplastic tissue. To investigate the potential significance of SF accumulation in gliomas, we measured the effects of SF on DNA synthesis and motility of cultured human glioma cell lines. SF stimulated DNA synthesis in 7/10 glioma cell lines and in 3/3 neuromicrovascular endothelial cell (NMVEC) lines, consistent with our previous report that SF stimulated cell proliferation of a few human glioma cell lines. SF markedly stimulated the chemotactic migration of 10/10 glioma cell lines as well as 3/3 NMVEC lines. In addition, SF stimulated the 2-dimensional migration of glioma cells on culture surfaces coated with specific extracellular matrix molecules (collagen i.v., laminin, and fibronection). As expected based on these biologic responses to SF, 10/10 glioma lines and 4/4 NMVEC lines expressed mRNA for c-met, the SF receptor. To assess the possible in vivo significance of these migration assays, we compared the chemotactic response of a glioma cell line to human brain cyst fluids and tumor extracts that contained high or low SF concentrations. Fluids and extracts with high SF content tended to induce higher levels of chemotactic migration than did fluids and extracts with low SF content. Addition of anti-SF monoclonal antibody (MAb) inhibited migration induced by fluids and extracts with high SF content by about 30-50%.


Reconfiguration-based implementation of SVM classifier on FPGA for Classifying Microarray data.
Classifying Microarray data, which are of high dimensional nature, requires high computational power. Support Vector Machines-based classifier (SVM) is among the most common and successful classifiers used in the analysis of Microarray data but also requires high computational power due to its complex mathematical architecture. Implementing SVM on hardware exploits the parallelism available within the algorithm kernels to accelerate the classification of Microarray data. In this work, a flexible, dynamically and partially reconfigurable implementation of the SVM classifier on Field Programmable Gate Array (FPGA) is presented. The SVM architecture achieved up to 85× speed-up over equivalent general purpose processor (GPP) showing the capability of FPGAs in enhancing the performance of SVM-based analysis of Microarray data as well as future bioinformatics applications.


Generalized pseudopotentials for higher partial wave scattering.
We derive a generalized zero-range pseudopotential applicable to all partial wave solutions to the Schrödinger equation based on a delta-shell potential in the limit that the shell radius approaches zero. This properly models all higher order multipole moments not accounted for with a monopolar delta function at the origin, as used in the familiar Fermi pseudopotential for s-wave scattering. By making the strength of the potential energy dependent, we derive self-consistent solutions for the entire energy spectrum of the realistic potential. We apply this to study two particles in an isotropic harmonic trap, interacting through a central potential, and derive analytic expressions for the energy eigenstates and eigenvalues.


Direct evidence of surface exposed water ice in the lunar polar regions.
Water ice may be allowed to accumulate in permanently shaded regions on airless bodies in the inner solar system such as Mercury, the Moon, and Ceres [Watson K, et al. (1961) J Geophys Res 66:3033-3045]. Unlike Mercury and Ceres, direct evidence for water ice exposed at the lunar surface has remained elusive. We utilize indirect lighting in regions of permanent shadow to report the detection of diagnostic near-infrared absorption features of water ice in reflectance spectra acquired by the Moon Mineralogy Mapper [M (3)] instrument. Several thousand M (3) pixels (∼280 × 280 m) with signatures of water ice at the optical surface (depth of less than a few millimeters) are identified within 20° latitude of both poles, including locations where independent measurements have suggested that water ice may be present. Most ice locations detected in M (3) data also exhibit lunar orbiter laser altimeter reflectance values and Lyman Alpha Mapping Project instrument UV ratio values consistent with the presence of water ice and also exhibit annual maximum temperatures below 110 K. However, only ∼3.5% of cold traps exhibit ice exposures. Spectral modeling shows that some ice-bearing pixels may contain ∼30 wt % ice that is intimately mixed with dry regolith. The patchy distribution and low abundance of lunar surface-exposed water ice might be associated with the true polar wander and impact gardening. The observation of spectral features of H2O confirms that water ice is trapped and accumulates in permanently shadowed regions of the Moon, and in some locations, it is exposed at the modern optical surface.